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Background: Steroidal mineralocorticoid receptor antagonists reduce morbidity and mortality among patients with heart failure and reduced ejection fraction, but their efficacy in those with heart failure and mildly reduced or preserved ejection fraction has not been established. Data regarding the efficacy and safety of the nonsteroidal mineralocorticoid receptor antagonist finerenone in patients with heart failure and mildly reduced or preserved ejection fraction are needed., Methods: In this international, double-blind trial, we randomly assigned patients with heart failure and a left ventricular ejection fraction of 40% or greater, in a 1:1 ratio, to receive finerenone (at a maximum dose of 20 mg or 40 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of total worsening heart failure events (with an event defined as a first or recurrent unplanned hospitalization or urgent visit for heart failure) and death from cardiovascular causes. The components of the primary outcome and safety were also assessed., Results: Over a median follow-up of 32 months, 1083 primary-outcome events occurred in 624 of 3003 patients in the finerenone group, and 1283 primary-outcome events occurred in 719 of 2998 patients in the placebo group (rate ratio, 0.84; 95% confidence interval [CI], 0.74 to 0.95; P = 0.007). The total number of worsening heart failure events was 842 in the finerenone group and 1024 in the placebo group (rate ratio, 0.82; 95% CI, 0.71 to 0.94; P = 0.006). The percentage of patients who died from cardiovascular causes was 8.1% and 8.7%, respectively (hazard ratio, 0.93; 95% CI, 0.78 to 1.11). Finerenone was associated with an increased risk of hyperkalemia and a reduced risk of hypokalemia., Conclusions: In patients with heart failure and mildly reduced or preserved ejection fraction, finerenone resulted in a significantly lower rate of a composite of total worsening heart failure events and death from cardiovascular causes than placebo. (Funded by Bayer; FINEARTS-HF ClinicalTrials.gov number, NCT04435626.)., (Copyright © 2024 Massachusetts Medical Society.)

Aims: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used to treat type 2 diabetes and obesity. Albeit cardiovascular outcomes generally improve, treatment with GLP-1 RAs is associated with increased heart rate, the mechanism of which is unclear., Methods and Results: We employed a large animal model, the female landrace pig, and used multiple in vivo and ex vivo approaches including pharmacological challenges, electrophysiology, and high-resolution mass spectrometry to explore how GLP-1 elicits an increase in heart rate. In anaesthetized pigs, neither cervical vagotomy, adrenergic blockers (alpha, beta, or combined alpha-beta blockade), ganglionic blockade (hexamethonium), nor inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (ivabradine) abolished the marked chronotropic effect of GLP-1. GLP-1 administration to isolated perfused pig hearts also increased heart rate, which was abolished by GLP-1 receptor blockade. Electrophysiological characterization of GLP-1 effects in vivo and in isolated perfused hearts localized electrical modulation to the atria and conduction system. In isolated sinus nodes, GLP-1 administration shortened the action potential cycle length of pacemaker cells and shifted the site of earliest activation. The effect was independent of HCN blockade. Collectively, these data support a direct effect of GLP-1 on GLP-1 receptors within the heart. Consistently, single nucleus RNA sequencing showed GLP-1 receptor expression in porcine pacemaker cells. Quantitative phosphoproteomics analyses of sinus node samples revealed that GLP-1 administration leads to phosphorylation changes of calcium cycling proteins of the sarcoplasmic reticulum, known to regulate heart rate., Conclusion: GLP-1 has direct chronotropic effects on the heart mediated by GLP-1 receptors in pacemaker cells of the sinus node, inducing changes in action potential morphology and the leading pacemaker site through a calcium signalling response characterized by PKA-dependent phosphorylation of Ca2+ cycling proteins involved in pacemaking. Targeting the pacemaker calcium clock may be a strategy to lower heart rate in people treated with GLP-1 RAs., Competing Interests: Conflict of interest: J.J.H. has been on advisory boards for Novo Nordisk. The other authors report no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Global longitudinal strain (GLS) is recognized as a powerful predictor of heart failure (HF). However, the entire strain curve may entail important prognostic information regarding HF risk that might be undiscovered by only focusing on the peak strain value., Objective: The hypothesis of the present study was, that analysis of the entire strain curve using unsupervised machine learning (uML) would reveal novel ventricular deformation patterns capable of predicting incident HF independently of GLS., Methods: Longitudinal strain curves from 3710 subjects from the general population without prevalent HF were analyzed using uML., Results: Mean age was 56 years and 43 % were male. During a median follow-up of 5.3 years, 92 subjects (2.5 %) developed HF. The uML algorithm generated a hierarchical clustering tree (HCT) resulting in 10 different clusters. Generally, the strain curves displayed reduced early diastolic strain to peak-strain ratio with an increasing incidence rate of HF. In multivariable Cox regressions, cluster 9 was significantly associated with increased risk of HF when compared to cluster 2-5, and 7-8 [For cluster 3: HR 8.95, 95 %CI: 2.08;38.48, P = 0.003] even though the subjects of cluster 9 were younger, displayed healthier clinical baseline characteristics, and only had slightly reduced GLS. The mean strain curve of cluster 9 displayed an early systolic lengthening followed by a late and reduced contraction specifically related to the basal lateral segment., Conclusion: The unsupervised machine learning algorithm identified unknown strain patterns beyond GLS presumably related to increased risk of HF., Competing Interests: Declaration of competing interest Nothing to Disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims/hypothesis: Type 2 diabetes is a chronic condition that is caused by hyperglycaemia. Our aim was to characterise the metabolomics to find their association with the glycaemic spectrum and find a causal relationship between metabolites and type 2 diabetes., Methods: As part of the Innovative Medicines Initiative - Diabetes Research on Patient Stratification (IMI-DIRECT) consortium, 3000 plasma samples were measured with the Biocrates AbsoluteIDQ p150 Kit and Metabolon analytics. A total of 911 metabolites (132 targeted metabolomics, 779 untargeted metabolomics) passed the quality control. Multivariable linear and logistic regression analysis estimates were calculated from the concentration/peak areas of each metabolite as an explanatory variable and the glycaemic status as a dependent variable. This analysis was adjusted for age, sex, BMI, study centre in the basic model, and additionally for alcohol, smoking, BP, fasting HDL-cholesterol and fasting triacylglycerol in the full model. Statistical significance was Bonferroni corrected throughout. Beyond associations, we investigated the mediation effect and causal effects for which causal mediation test and two-sample Mendelian randomisation (2SMR) methods were used, respectively., Results: In the targeted metabolomics, we observed four (15), 34 (99) and 50 (108) metabolites (number of metabolites observed in untargeted metabolomics appear in parentheses) that were significantly different when comparing normal glucose regulation vs impaired glucose regulation/prediabetes, normal glucose regulation vs type 2 diabetes, and impaired glucose regulation vs type 2 diabetes, respectively. Significant metabolites were mainly branched-chain amino acids (BCAAs), with some derivatised BCAAs, lipids, xenobiotics and a few unknowns. Metabolites such as lysophosphatidylcholine a C17:0, sum of hexoses, amino acids from BCAA metabolism (including leucine, isoleucine, valine, N-lactoylvaline, N-lactoylleucine and formiminoglutamate) and lactate, as well as an unknown metabolite (X-24295), were associated with HbA 1c progression rate and were significant mediators of type 2 diabetes from baseline to 18 and 48 months of follow-up. 2SMR was used to estimate the causal effect of an exposure on an outcome using summary statistics from UK Biobank genome-wide association studies. We found that type 2 diabetes had a causal effect on the levels of three metabolites (hexose, glutamate and caproate [fatty acid (FA) 6:0]), whereas lipids such as specific phosphatidylcholines (PCs) (namely PC aa C36:2, PC aa C36:5, PC ae C36:3 and PC ae C34:3) as well as the two n-3 fatty acids stearidonate (18:4n3) and docosapentaenoate (22:5n3) potentially had a causal role in the development of type 2 diabetes., Conclusions/interpretation: Our findings identify known BCAAs and lipids, along with novel N-lactoyl-amino acid metabolites, significantly associated with prediabetes and diabetes, that mediate the effect of diabetes from baseline to follow-up (18 and 48 months). Causal inference using genetic variants shows the role of lipid metabolism and n-3 fatty acids as being causal for metabolite-to-type 2 diabetes whereas the sum of hexoses is causal for type 2 diabetes-to-metabolite. Identified metabolite markers are useful for stratifying individuals based on their risk progression and should enable targeted interventions., (© 2024. The Author(s).)

Background: Finerenone improves outcomes in patients with HF and mildly reduced or preserved ejection fraction (HFmrHF/HFpEF). It is important to understand the efficacy and safety of finerenone in these patients according to age. Methods: The aim of this analysis was to evaluate the interaction between age and the efficacy and safety of finerenone in the FINEARTS-HF trial (Finerenone trial to investigate efficacy and safety compared to placebo in patients with heart failure). A total of 6,001 patients aged 40-97 years were stratified by quartile (Q 1-4) of baseline age: Q1 40-66 years (n=1,581), Q2 67-73 years (n=1,587), Q 3 74-79 years (n=1,421), and Q4 ≧ 80 years (n=1,412). FINEARTS-HF evaluated the impact of age on the efficacy of finerenone with respect to the primary composite outcome of cardiovascular death and total (first and recurrent) HF events, including HF hospitalization or urgent HF event, along with secondary efficacy and safety outcomes. Results: The incidence of primary outcome increased with age. Finerenone reduced the risk of the primary outcome consistently across all age categories: RR (95% CI) Q1 0.70 (0.53- 0.92), Q2 0.83 (0.64-1.07), Q3 0.98 (0.76-1.26), and Q4 0.85 (0.67-1.07); p for interaction =0.27. Similarly, a consistent effect was observed for the components of the primary outcome. The mean increase in Kansas City Cardiomyopathy Questionnaire-total symptom score from baseline to 12 months was greater with finerenone than placebo, with a consistent effect across all age categories: mean placebo-corrected change (95% CI) Q1 2.87 (1.09-4.66), Q2 1.24 (-0.59-3.07), Q3 0.94 (-0.98-2.86), and Q4 1.24 (-0.90-3.38); P-interaction=0.50. Adverse events were similar across all age categories. The odds of experiencing hypotension, elevated creatinine, or hyperkalemia (increased) or hypokalemia (decreased) related to finerenone did not differ by age. Conclusions: In the FINEARTS-HF trial, finerenone reduced the primary outcome and components of the primary outcome, and improved symptoms across a wide age spectrum. In addition, finerenone was safe and well-tolerated, irrespective of age. Trial Registration: URL: https://clinicaltrials.gov Unique Identifiers: NCT04435626 and EudraCT 2020-000306-29.

Aims: Real-world data show that guidelines are insufficiently implemented, and particularly guideline-directed medical therapies (GDMT) are underused in patients with heart failure and reduced ejection fraction (HFrEF) in clinical practice. The Council for Cardiology Practice and the Heart Failure Association of the European Society of Cardiology (ESC) developed a survey aiming to (i) evaluate the perspectives of the cardiology community on the 2021 ESC heart failure (HF) guidelines, (ii) pinpoint disparities in disease management, and (iii) propose strategies to enhance adherence to HF guidelines., Methods and Results: A 22-question survey regarding the diagnosis and treatment of HFrEF was delivered between March and June 2022. Of 457 physicians, 54% were general cardiologists, 19.4% were HF specialists, 18.9% other cardiac specialists, and 7.7% non-cardiac specialists. For diagnosis, 52.1% employed echocardiography and natriuretic peptides (NPs), 33.2% primarily used echocardiography, and 14.7% predominantly relied on NPs. The first drug class initiated in HFrEF was angiotensin-converting enzyme inhibitors/angiotensin receptor-neprilysin inhibitor (ACEi/ARNi) (91.2%), beta-blockers (BB) (73.8%), mineralocorticoid receptor antagonists (MRAs) (53.4%), and sodium-glucose cotransporter 2 (SGLT2) inhibitors (48.1%). The combination ACEi/ARNi + MRA+ BB was preferred by 39.3% of physicians, ACEi/ARNi + SGLT2 inhibitors + BB by 33.3%, and ACEi/ARNi + BB by 22.2%. The time required to initiate and optimize GDMT was estimated to be <1 month by 8.3%, 1-3 months by 52%, 3-6 months by 31.8%, and >6 months by 7.9%. Compared to general cardiologists, HF specialists/academic cardiologists reported lower estimated time-to-initiation, and more commonly preferred a parallel initiation of GDMT rather than a sequential approach., Conclusion: Participants generally followed diagnostic and treatment guidelines, but variations in HFrEF management across care settings or HF specialties were noted. The survey may raise awareness and promote standardized HF care., (© 2024 European Society of Cardiology.)

Background: During the COVID-19 pandemic, disturbing images of ambulances unable to respond to the demands for prehospital assistance appeared from several parts of the world. In Denmark, however, a notion occurred that the demands for emergency medical assistance declined. The purpose of this study was to compare the patients' use of the Danish Emergency Medical Services (EMS) before and during the COVID-19 pandemic. Furthermore, we investigated the overall mortality of the ambulance population, the main reason for calling the emergency medical dispatch centre, and the diagnosis assigned to the admitted patients., Methods: The study was a nationwide registry-based cohort study based on the national prehospital medical records and the Danish National Patient Registry. The primary outcome was the requested number of ambulances. Secondary outcomes included the primary reason for contact with the dispatch centre (reflected by the dispatch criteria), patient mortality, and the diagnoses assigned to the patients transported to the hospital by ambulance during the COVID-19 pandemic in Denmark in March-December 2020. Comparisons were made using a similar period in 2019 before the pandemic., Results: In comparison with the baseline values before the pandemic, the total number of patients treated by the EMS was reduced by 4.5% during the COVID-19 pandemic. The number of patients transported to the hospital during the pandemic was similarly reduced by 3.5%. Compared with baseline values, fewer were patients hospitalised with respiratory diseases during the pandemic (a reduction of 53.3% from April 2019 to April 2020). Compared to the baseline period, there were significant increases in both the 48-h mortality (from 1.4% to 1.5%) and the 30-day mortality (from 4.9% to 5.4%) (p < 0.03 and p < 0.001, respectively), in patients hospitalised during the pandemic., Conclusion: During the first wave of the COVID-19 pandemic, the Danish EMS experienced an overall reduction in the requests for and the use of ambulances and, especially, in the number of patients admitted to hospitals for respiratory diseases. Despite the overall reduction in EMS requests, the mortality of the ambulance population increased, indicating that despite the reduced ambulance use, the prehospital population was more severely ill during the pandemic., (© 2024. The Author(s).)

Background: Team reflexivity and peer feedback in daily clinical work can improve patient safety. However, teams do not always engage in reflection after patient care. A reason could be that team members may lack skills in engaging in team reflection. This study explores the use of interprofessional team-based simulations to encourage and equip teams for reflective conversations in the real-world clinical practice., Methods: This was a prospective, explorative study of team members' perceptions of the use of in situ simulation-based scenarios with critically ill patient cases to train team-based reflections and peer feedback. The study took place in two neurological wards. Prior to the intervention, a 1-day observation in each ward and semi-structured short interviews with physicians and nurses were conducted., Results: A total of 94 staff members, 57 nurses, 8 nurse assistants and 29 physicians participated in the in situ simulation scenarios. All team members showed appreciation of the safe learning environment. The authors found that the simulations and the debriefing structure provided an opportunity for training of team reflexivity and feedback. The team members evaluated the simulation-based training very positively, and their initial reaction indicated that they found peer feedback useful for the individual and the team. This approach allowed them to reflect on their own clinical practice., Conclusion: The simulation-based training scenarios and the debriefing structure promoted team members' team reflexivity and peer feedback skills. The method is feasible and could be used in other specialties and situations. The team members' reactions to feedback were positive, and based on their reflections, there is a potential to increase both individual and team skills as well as improve patient treatment., (© 2024. The Author(s).)

Background: Atrial fibrillation (AF), the most prevalent cardiac arrhythmia, disrupts the heart's rhythm through numerous small re-entry circuits in the atrial tissue, leading to irregular atrial contractions. The condition poses significant health risks, including increased stroke risk, heart failure, and reduced quality of life. Given the complexity of AF and its growing incidence globally, exercise-based cardiac rehabilitation (ExCR) may provide additional benefits for people with AF or those undergoing routine treatment for the condition., Objectives: To assess the benefits and harms of ExCR compared with non-exercise controls for people who currently have AF or who have been treated for AF., Search Methods: We searched the following electronic databases: CENTRAL in the Cochrane Library, MEDLINE Ovid, Embase Ovid, PsycINFO Ovid, Web of Science Core Collection Thomson Reuters, CINAHL EBSCO, LILACS BIREME, and two clinical trial registers on 24 March 2024. We imposed no language restrictions., Selection Criteria: We included randomised clinical trials (RCTs) that investigated ExCR interventions compared with any type of non-exercise control. We included adults 18 years of age or older with any subtype of AF or those who had received treatment for AF., Data Collection and Analysis: Five review authors independently screened and extracted data in duplicate. We assessed risk of bias using Cochrane's RoB 1 tool as outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We assessed clinical and statistical heterogeneity by visual inspection of the forest plots and by using standard Chi² and I² statistics. We performed meta-analyses using random-effects models for continuous and dichotomised outcomes. We calculated standardised mean differences where different scales were used for the same outcome. We used the GRADE approach to assess the certainty of the evidence., Main Results: We included 20 RCTs involving a total of 2039 participants with AF. All trials were conducted between 2006 and 2024, with a follow-up period ranging from eight weeks to five years. We assessed the certainty of evidence as moderate to very low. Five trials assessed comprehensive ExCR programmes, which included educational or psychological interventions, or both; the remaining 15 trials compared exercise-only cardiac rehabilitation with controls. The overall risk of bias in the included studies was mixed. Details on random sequence generation, allocation concealment, and use of intention-to-treat analysis were typically poorly reported. Evidence from nine trials (n = 1173) suggested little to no difference in mortality between ExCR and non-exercise controls (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.76 to 1.49; I² = 0%; 101 deaths; low-certainty evidence). Based on evidence from 10 trials (n = 825), ExCR may have little to no effect on SAEs (RR 1.30, 95% CI 0.63 to 2.67; I² = 0%; 28 events; low-certainty evidence). Evidence from four trials (n = 378) showed that ExCR likely reduced AF recurrence (measured via Holter monitoring) compared to controls (RR 0.70, 95% CI 0.56 to 0.88; I² = 2%; moderate-certainty evidence). ExCR may reduce AF symptom severity (mean difference (MD) -1.59, 95% CI -2.98 to -0.20; I² = 61%; n = 600; low-certainty evidence); likely reduces AF symptom burden (MD -1.61, 95% CI -2.76 to -0.45; I² = 0%; n = 317; moderate-certainty evidence); may reduce AF episode frequency (MD -1.29, 95% CI -2.50 to -0.07; I² = 75%; n = 368; low-certainty evidence); and likely reduces AF episode duration (MD -0.58, 95% CI -1.14 to -0.03; I² = 0%; n = 317; moderate-certainty evidence), measured via the AF Severity Scale (AFSS) questionnaire. Moderate-certainty evidence from six trials (n = 504) showed that ExCR likely improved the mental component summary measure in health-related quality of life (HRQoL) of the 36-item Short Form Health Survey (SF-36) (MD 2.66, 95% CI 1.22 to 4.11; I² = 2%), but the effect of ExCR on the physical component summary measure was very uncertain (MD 1.75, 95% CI -0.31 to 3.81; I² = 52%; very low-certainty evidence). ExCR also may improve individual components of HRQoL (general health, vitality, emotional role functioning, and mental health) and exercise capacity (peak oxygen uptake (VO 2peak ) and 6-minute walk test) following ExCR. The effects of ExCR on serious adverse events and exercise capacity were consistent across different models of ExCR delivery: centre compared to home-based, exercise dose, exercise only compared to comprehensive programmes, and aerobic training alone compared to aerobic plus resistance programmes. Using univariate meta-regression, there was evidence of significant association between location of trial and length of longest follow-up on exercise capacity., Authors' Conclusions: Due to few randomised participants and typically short-term follow-up, the impact of ExCR on all-cause mortality or serious adverse events for people with AF is uncertain. ExCR likely improves AF-specific measures including reduced AF recurrence, symptom burden, and episode duration, as well as the mental components of HRQoL. ExCR may improve AF symptom severity, episode frequency, and VO 2peak . Future high-quality RCTs are needed to assess the benefits of ExCR for people with AF on patient-relevant outcomes including AF symptom severity and burden, AF recurrence, AF-specific quality of life, and clinical events such as mortality, readmissions, and serious adverse events. High-quality trials are needed to investigate how AF subtype and clinical setting (i.e. primary and secondary care) may influence ExCR effectiveness., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Staphylococcus aureus bacteremia (SAB) is a high-risk condition associated with high morbidity and mortality. In the presence of cardiac implantable electronic devices (CIEDs), SAB may cause or clinically indicate device infection. We aimed to estimate the 10-year absolute risk of SAB in adult Danish first-time CIED carriers. Secondary aims included identification of risk factors associated with SAB., Methods: A registry-based study utilizing Danish nationwide registers and including consecutive Danish patients undergoing first CIED implantation between 2000 and 2020 was conducted. The primary outcome was first-time SAB after CIED implantation., Results: A total of 87 257 patients with first CIED implantation in the study period were identified (median age, 75 years; 62.6% were male; median follow-up, 3.8 years). Patients with pacemakers (PMs) were older and with more noncardiovascular comorbidities compared to patients with implantable cardioverter defibrillators (ICDs) and cardiac resynchronization therapy devices with or without defibrillator capacity (CRTs). In total, 1366 patients (1.6%) developed SAB. The 10-year absolute risk (95% confidence interval) of SAB was 2.0% (1.9%-2.1%) for PM, 2.6% (2.2%-3.1%) for ICD, and 3.7% (3.0%-4.5%) for CRT. A multivariable Cox analysis identified hemodialysis (hazard ratio [HR], 8.51), SAB before CIED (HR, 2.76), liver disease (HR, 2.35), and carrying a CRT device (HR, 1.68) among the covariates associated with increased risk of SAB., Conclusions: The absolute risk of SAB in Danish CIED carriers increased with more advanced CIED systems. The risk was highest within the first 3 months after CIED implantation and increased with the presence of certain covariates including renal dialysis, SAB before CIED, male sex, and advancing age., Competing Interests: Potential conflicts of interest. N. E. B. reports grants/contracts not related to this study from the Novo Nordisk Foundation and Health Insurance Denmark, and participation on a data and safety monitoring board or advisory board in the Heart Runner Project. E. F. reports grants/contracts not related to this study from the Novo Nordisk Foundation. J. B. J. reports payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events not related to this project from Medtonic and Merit Medical. J. C. N. reports a role as executive editor for Europace. S. R. reports grants/contracts not related to this study from the Novo Nordisk Foundation. A. C. R. reports payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events nor related to this project from Novartis, Bristol-Myers Squibb, and AstraZeneca. L. Ø. reports grants/contracts not related to this study from the Novo Nordisk Foundation. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: Cosmetic paraffin oil injections can lead to granuloma formation causing hypercalcemia and kidney failure. This study explores whether debulking surgery is an effective treatment for improving calcium homeostasis, inflammation and clinical symptoms., Materials and Methods: In a retrospective study, we reviewed 33 patients undergoing debulking surgery. Changes in calcium, inflammatory markers, and renal function from baseline up to twelve months post-surgery were assessed. Patients were interviewed post-surgery., Results: The patients were 34.6 years (SD 6.9) and had 1,104 grams (SD 591) of granuloma tissue removed following injection of 1,329 mL (SD 803) paraffin oil 7.9 years (SD 3.2) earlier. Seventeen patients had hypercalcemia and experienced a significant decline in ionized calcium from 1.48 mmol/L (SD 0.16) at baseline to 1.33 mmol/L (SD 0.03) at twelve months (p<0.002), although only four men (23.5%) became normocalcemic. Serum ferritin was reduced by 50% after twelve months (p=0.048). Sixteen patients were normocalcemic and had no change in calcium homeostasis but experienced a 20% drop in serum ferritin levels (p=0.025) after surgery. Fifteen patients completed all their planned surgeries within the study period and experienced a decline in serum ionized calcium (p=0.031), ferritin (p=0.011), and interleukin 2-receptor (p=0.037). A patient satisfaction survey showed that 55% of patients reported post-operative satisfaction scores of 10/10, and 59% of the patients reported reduced pain., Conclusion: Surgery improved calcium homeostasis in a fraction of patients, reduced inflammation and subjective symptoms such as pain and mental well-being in a patient group left with few treatment options except high-dose prednisolone., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Introduction: Sodium glucose co-transporter-2 inhibitors (SGLT-2i) are increasingly being used among hospitalized patients. Our objective was to assess the risk of diabetic ketoacidosis (DKA) among hospitalized patients receiving an SGLT-2i., Research Design and Methods: We conducted a multicentre cohort study of patients hospitalized at 19 hospitals. We included patients over 18 years of age who received an SGLT-2i or a dipeptidyl peptidase-4 inhibitor (DPP-4i) in hospital. The primary outcome was the risk of DKA during their hospitalization., Results: 61,517 patients received a DPP-4i and 11,061 received an SGLT-2i. The risk of inpatient DKA was 0.07 % (N = 41 events) among adults who received a DPP-4i and 0.18 % (N = 20 events) among adults who received an SGLT-2i; adjusted odds ratio of 3.30 (95 % CI: 1.85-5.72)., Conclusions: In hospitalized patients, the absolute risk of DKA was 0.2 %, which corresponded to a three-fold higher relative risk., Competing Interests: Declaration of competing interest MF was a consultant for ProofDx, a start-up company creating point of care diagnostic tests for COVID-19 using CRISPR. MF is an advisor for SIGNAL1, a start-up company deploying machine learned models to improve inpatient care. MF has been paid for medicolegal cases unrelated to the content of this study. FR is a provincial clinical lead for quality improvement at Ontario Health (as a part-time salaried employee). This research was undertaken, in part, with funding from the Canada Research Chairs Program. AV is a part-time employee of Ontario Health and is supported by the Temerty Professorship of AI Research and Education in Medicine at the University of Toronto., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Fibrosis, driven by fibroblast activities, is an important contributor to morbidity and mortality in most chronic diseases. Endotrophin, a signaling molecule derived from processing of type VI collagen by highly activated fibroblasts, is involved in fibrotic tissue remodeling. Circulating levels of endotrophin have been associated with an increased risk of mortality in multiple chronic diseases. We conducted a systematic literature review collecting evidence from original papers published between 2012 and January 2023 that reported associations between circulating endotrophin (PROC6) and mortality. Cohorts with data available to the study authors were included in an Individual Patient Data (IPD) meta-analysis that evaluated the association of PROC6 with mortality (PROSPERO registration number: CRD42023340215) after adjustment for age, sex and BMI, where available. In the IPD meta-analysis including sixteen cohorts of patients with different non-communicable chronic diseases (NCCDs) (N = 15,205) the estimated summary hazard ratio for 3-years all-cause mortality was 2.10 (95 % CI 1.75-2.52) for a 2-fold increase in PROC6, with some heterogeneity observed between the studies (I 2 =70 %). This meta-analysis is the first study documenting that fibroblast activities, as quantified by circulating endotrophin, are independently associated with mortality across a broad range of NCCDs. This indicates that, irrespective of disease, interstitial tissue remodeling, and consequently fibroblast activities, has a central role in adverse clinical outcomes, and should be considered with urgency from drug developers as a target to treat., Competing Interests: Declaration of competing interest Federica Genovese, Cecilie Bager, Peder Frederiksen, Dario Vazquez, Jannie Marie Bülow Sand, Diana Julie Leeming, Daniel Guldager Kring Rasmussen, Alexander Lynge Reese-Petersen, Neel I Nissen and Morten Karsdal are or have been at the time of writing, full-time employees at Nordic Bioscience. Federica Genovese, Cecilie Bager, Jannie Maria Bülow Sand, Diana Julie Leeming, Daniel Guldager Kring Rasmussen, Alexander Lynge Reese-Petersen and Morten Karsdal hold Nordic Bioscience stocks. Nordic Bioscience holds the patent for the PROC6 assays and commercializes the assay. Peter Rossing has received research support from Astra Zeneca, Novo Nordisk and Bayer, and has received honoraria (to Steno Diabetes Center Copenhagen) from Astra Zeneca, Boehringer Ingelheim, Bayer, Novo Nordisk, Gilead, Sanofi, Abbott for consultancy or education. Louise V. Wain has received research funding or collaborative support from Orion Pharma, GSK, Genentech, AstraZeneca and Sysmex, outside of the submitted work and provided consultancy for GSK and Galapagos., (Copyright © 2024. Published by Elsevier B.V.)

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibrosis in the lungs. Activated fibroblasts play a central role in fibrogenesis and express fibroblast activation protein α. A truncated, soluble form (sFAP) can be measured in blood and is a potential novel biomarker of disease activity. The aim was to study the association between sFAP and clinical, radiological, and histopathological measures of disease severity, progression, and survival in a prospective, multicentre, real-world cohort of patients with IPF. Patients with IPF were recruited from the tertiary interstitial lung disease centres in Denmark and followed for up to 3 years. Baseline serum levels of sFAP were measured by ELISA in patients with IPF and compared to healthy controls. Pulmonary function tests, 6-minute walk test and quality of life measures were performed at baseline and during follow-up. The study included 149 patients with IPF. Median sFAP in IPF was 49.6 ng/mL (IQR: 43.1-61.6 ng/mL) and in healthy controls 73.8 ng/mL (IQR: 62.1-92.0 ng/mL). Continuous sFAP was not associated with disease severity, progression or survival (p > 0.05). After dichotomization of sFAP below or above mean sFAP + 2 SD for healthy controls, higher levels of sFAP were associated with lower FVC % predicted during follow-up (p < 0.01). Higher than normal serum levels of sFAP were associated with longitudinal changes in FVC % predicted, but sFAP did not show clear associations with other baseline or longitudinal parameters. As such, sFAP has limited use as a biomarker of disease progression or survival in patients with IPF., (© 2024 The Author(s). Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.)

Aims: Atrial fibrillation (AF) is a common arrhythmia associated with reduced quality of life that can lead to serious complications such as stroke and heart failure. Ablation is a safe and effective treatment for AF but is not offered equally to all patients. The aim of this study is to identify demographic groups more or less likely to undergo AF ablation., Methods and Results: All patients with newly diagnosed AF between 2010 and 2018 were identified in the Danish nationwide registries. The association between gender, age, level of education and attachment to the job market, and the likelihood of receiving AF ablation was investigated using multivariable Cox proportional hazard analysis. Cumulative incidence was calculated using the Aalen-Johansen estimator. A total of 176 248 patients were included. Men were more likely to receive ablation than women (7% vs. 3%). Patients aged 25-44 and 45-64 were most likely to receive ablation, while only 0.7% of patients aged 80 or above received ablation. The rate of ablation significantly decreased with decreasing level of education. Full-time employed patients were most likely to receive ablation, followed by self-employed, unemployed, on sick leave, undergoing education, and early retired patients. Retired patients were the least likely to receive ablation (3%)., Conclusion: This study found that women, older patients, patients with lower levels of education, and patients on social benefits are less likely to receive AF ablation. These findings suggest that there are significant social and economic disparities in AF ablation treatment in Denmark., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Despite improved survival, hospitalization is still common among patients with heart failure (HF)., Objective: This study aimed to examine temporal trends in infection-related hospitalization among HF patients and compare it to temporal trends in the risk of HF hospitalization and death., Methods: Using Danish nationwide registers, we included all patients aged 18 to 100 years, with HF diagnosed between January 1, 1997 and December 31, 2017, resulting in a total population of 147.737 patients. The outcomes of interest were primarily infection-related hospitalization and HF hospitalization and secondarily all-cause mortality. The Aalen Johansen's estimator was used to estimate 5-year absolute risks for the primary outcomes. Additionally, cox analysis was used for adjusted analyses., Results: The population had a median age of 74 [64, 82] years and 57.6 % were males. Patients with HF had a higher risk of infection over time 16.4 % (95% CI 16.0-16.8) in 1997 to 2001 vs 24.5% (95% CI 24.0-24.9) in 2012 to 2017. In contrast, they had a lower risk of HF hospitalization 26.5% (95% CI 26.1-27.0) in 1997 to 2001 vs 23.2% (95% CI 22.8-23.7) in 2012 to 2017. The risk of infection stratified by infection type showed similar trends for all infection types and marked the risk of pneumonia infection as the most significant in all subintervals., Conclusion: In the period from 1997 to 2017, we observed patients with HF had an increased risk of infection-related hospitalization, driven by pneumonia infections. In contrast, the risk of HF hospitalization decreased over time., Competing Interests: Conflict of interest None reported., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: Atrial fibrillation (AF) and coronary artery disease (CAD) have several common risk factors, and 10-15% of patients with AF undergo percutaneous coronary intervention (PCI). Little is known about changes over time in modifiable risk factors and self-reported health in patients with and without a history of AF after PCI. Therefore, the aims were to determine and compare changes in modifiable risk factors and self-reported health in patients with and without a history of AF after PCI., Methods and Results: CONCARDPCI, a prospective multicentre cohort study including patients after PCI, was conducted at seven high-volume PCI centres in Norway and Denmark (N=3417). Of these, 408 had a history of AF. Data collection was conducted at the index admission and at 2-, 6- and 12 months after discharge. Self-reported health was assessed with RAND-12 and the Myocardial Infarction Dimensional Assessment Scale (MIDAS). Patients with a history of AF reported a poorer health at baseline. However, the physical (p=0.012) and mental (p<0.001) health improved over time in both groups. The patients with a history of AF reported more emotional reactions (p=0.029) and insecurities (p=0.015). The proportion of smokers increased from 2- to 12 months in patients with a history of AF (p=0.041), however, decreased in patients without AF from baseline to 6 months (p<0.001)., Conclusion: An intensified focus on lifestyle interventions is needed to improve modifiable risk factors and self-reported health in patients with and without a history of AF after PCI., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Anti-interleukin (IL)-5 biologics effectively reduce exacerbations and the need for maintenance oral corticosteroids (mOCS) in severe eosinophilic asthma. However, it is unknown how long anti-IL-5 treatment should be continued. Data from clinical trials indicate a gradual but variable loss of control after treatment cessation. In this pilot study of titration, we evaluated a dose-titration algorithm in patients who had achieved clinical control on an anti-IL-5 biologic., Methods: In this open-label randomised controlled trial conducted over 52 weeks, patients with clinical control (no exacerbations or mOCS) on anti-IL-5 treatment were randomised to continue with unchanged intervals or have dosing intervals adjusted according to a titration algorithm that gradually extended dosing intervals and reduced them again at signs of loss of disease control. The OPTIMAL algorithm was designed to down-titrate dosing until signs of loss of control, to enable assessment of the longest dosing interval possible., Results: Among 73 patients enrolled, 37 patients were randomised to the OPTIMAL titration arm; 78% of patients tolerated down-titration of treatment. Compared to the control arm, the OPTIMAL arm tended to have more exacerbations during the study (32% versus 17%; p=0.13). There were no severe adverse events related to titration, and lung function and symptoms scores remained stable and comparable in both study arms throughout., Conclusion: This study serves as a proof of concept for titration of anti-IL-5 biologics in patients with severe asthma with clinical control on treatment, and the OPTIMAL algorithm provides a potential framework for individualising dosing intervals in the future., Competing Interests: Conflict of interest: M.B. Soendergaard reports payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK and AstraZeneca, and participation on a data safety monitoring board or advisory board with AstraZeneca. A-S. Bjerrum reports payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK and AstraZeneca. L.M. Rasmussen reports payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, GSK, Teva and ALK, support for attending meetings from AstraZeneca and Chiesi, and participation on a data safety monitoring board or advisory board with AstraZeneca, GSK, Teva and Sanofi. A. von Bulow reports consultancy fees from Novartis, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Novartis and GSK, and participation on a data safety monitoring board or advisory board with AstraZeneca and Novartis. C. Porsbjerg reports grants paid to their institution from AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi and ALK, consultancy fees (paid both to institution and as personal honoraria) from AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi and ALK, payment or honoraria for lectures, presentations, manuscript writing or educational events (paid both to institution and as personal honoraria) from AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi and ALK, and participation on a data safety monitoring board or advisory board (fees paid both to institution and as personal honoraria) with AstraZeneca, Novartis, Teva, Sanofi and ALK. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Background: Ischemic Heart Disease (IHD) can lead to prolonged sick leave and loss of ability to work. This study aimed to describe non-return to work (non-RTW) across three IHD subgroups at 3 and at 12 months post discharge, and explore whether baseline characteristics, and patient-reported mental and physical health were associated with work detachment., Methods: Data from the national cohort study DenHeart were used, including the patient-reported outcomes (PROs) Short-Form 12, Hospital Anxiety and Depression Scale, Edmonton Symptom Assessment Scale and HeartQoL measured at discharge and register-based follow-up at 3 and at 12 months. A total of 3873 patients with IHD ≤ 63 years old and part of the workforce prior to hospitalisation, were included in the analyses and divided into three groups: chronic IHD/stable angina, non-STEMI (non-ST-Elevation Myocardial Infarction)/unstable angina and STEMI (ST-Elevation Myocardial Infarction). A composite outcome of 'prolonged sick leave' and/or 'left the workforce' was defined as non-return to work (non-RTW). Adjusted logistic regression models were performed., Results: Overall, the frequency of non-RTW was 37.7% and 38.0% at 3 and 12 months, respectively, thus not improving with time. The largest proportion of non-RTW was found in STEMI patients, followed by non-STEMI/unstable angina and IHD/stable angina patients. Several clinical and socio-demographic factors, as well as patient-reported mental and physical health were associated with non-RTW among the subgroups., Conclusion: The findings demonstrate a need for identifying IHD patients at risk of non-RTW after discharge based on their mental and physical health and a need for initiatives to minimize unwanted non-RTW., Competing Interests: Declaration of competing interest The Author(s) declare(s) that there is no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

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., Competing Interests: Conflict of interest: L.D.R.-V., J.T., C.R.Z., C.M., R.H., A.J., R.H.W., G.G.: none. M.H.R.: Speaker honoraria from Boston Scientific and CardioFocus. J.H.: Speaker fees and consultant honoraria from Boston Scientific and Biosense Webster. M.L.H.: Received research grants from Biosense Webster and Medtronic., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Nitrate and nitrite are naturally occurring in both plant- and animal-sourced foods, are used as additives in the processing of meat, and are found in water. There is growing evidence that they exhibit a spectrum of health effects, depending on the dietary source. The aim of the study was to examine source-dependent associations between dietary intakes of nitrate/nitrite and both all-cause and cause-specific mortality., Methods: In 52,247 participants of the Danish Diet, Cancer and Health Study, associations between source-dependent nitrate and nitrite intakes--calculated using comprehensive food composition and national drinking water quality monitoring databases--and all-cause, cardiovascular disease (CVD)-related, and cancer-related mortality over 27 years were examined using restricted cubic splines within Cox proportional hazards models adjusting for demographic, lifestyle, and dietary confounders. Analyses were stratified by factors hypothesised to influence the formation of carcinogenic N-nitroso compounds (namely, smoking and dietary intakes of vitamin C, vitamin E, folate, and polyphenols)., Results: Plant-sourced nitrate intake was inversely associated with all-cause mortality [HR Q5vsQ1 : 0.83 (0.80, 0.87)] while higher risks of all-cause mortality were seen for higher intakes of naturally occurring animal-sourced nitrate [1.09 (1.04, 1.14)], additive permitted meat-sourced nitrate [1.19 (1.14, 1.25)], and tap water-sourced nitrate [1.19 (1.14, 1.25)]. Similar source-dependent associations were seen for nitrite and for CVD-related and cancer-related mortality except that naturally occurring animal-sourced nitrate and tap water-sourced nitrate were not associated with cancer-related mortality and additive permitted meat-sourced nitrate was not associated with CVD-related mortality. No clear patterns emerged in stratified analyses., Conclusion: Nitrate/nitrite from plant sources are inversely associated while those from naturally occurring animal-sources, additive-permitted meat sources, and tap water-sources are positively associated with mortality., (© 2024. The Author(s).)

Pathogenic variants in CACNA1E are associated with early-onset epileptic and developmental encephalopathy (DEE). Severe to profound global developmental delay, early-onset refractory seizures, severe hypotonia, and macrocephaly are the main clinical features. Patients harboring the recurrent CACNA1E variant p.(Gly352Arg) typically present with the combination of early-onset DEE, dystonia/dyskinesia, and contractures. We describe a 2-year-and-11-month-old girl carrying the p.(Gly352Arg) CACNA1E variant. She has a severe DEE with very frequent drug-resistant seizures, profound hypotonia, and episodes of dystonia and dyskinesia. Long-term video-EEG-monitoring documented subsequent tonic asymmetric seizures during wakefulness and mild paroxysmal dyskinesias of the trunk out of sleep which were thought to be a movement disorder and instead turned out to be focal hyperkinetic seizures. This is the first documented description of the EEG findings in this disorder. Our report highlights a possible overlap between cortical and subcortical phenomena in CACNA1E-DEE. We also underline how a careful electro-clinical evaluation might be necessary for a correct discernment between the two disorders, playing a fundamental role in the clinical assessment and proper management of children with CACNA1E-DEE., (© 2024 The Author(s). Epileptic Disorders published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: First-time detected atrial fibrillation (AF) is associated with aggravated prognosis in patients admitted with acute coronary syndrome (ACS). Yet, among patients surviving beyond one year after ACS, it remains unclear how the recurrence of AF within the initial year after ACS affects the risk of stroke., Methods: With Danish nationwide data from 2000 to 2021, we identified all patients with first-time ACS who were alive one year after discharge (index date). Patients were categorized into: i) no AF; ii) first-time detected AF during ACS admission without a recurrent hospital contact with AF (transient AF); and iii) first-time detected AF during ACS admission with a subsequent recurrent hospital contact with AF (recurrent AF). From index date, two-year rates of ischemic stroke were compared using multivariable adjusted Cox regression analysis. Treatment with antithrombotic therapy was assessed as filled prescriptions between 12 and 15 months following ACS discharge., Results: We included 139,137 patients surviving one year post ACS discharge: 132,944 (95.6%) without AF, 3920 (2.8%) with transient AF, and 2273 (1.6%) with recurrent AF. Compared to those without AF, the adjusted two-year hazard ratios of ischemic stroke were 1.45 (95% CI, 1.22-1.71) for patients with transient AF and 1.47 (95% CI: 1.17-1.85) for patients with recurrent AF. Prescription rates of oral anticoagulation increased over calendar time, reaching 68.3% and 78.7% for transient and recurrent AF, respectively, from 2019 to 2021., Conclusion: In patients surviving one year after ACS with first-time detected AF, recurrent and transient AF were associated with a similarly increased long-term rate of ischemic stroke., Competing Interests: Declaration of competing interest Jeppe Kofoed Petersen: None. Jawad Haider Butt: Advisory board honoraria from Bayer. Adelina Yafasova: None. Christian Torp-Pedersen: Grants for studies from Bayer and Novo Nordisk. Rikke Sørensen: None. Christina Kruuse: Independent research grant from Novo Nordisk Foundation. Local PI in trials from Bayer and Bristol-Myers Squibb. Naja Emborg Vinding: None. Anna Gundlund: None. Lars Køber: Speakers honorarium from Novo, Novartis, AstraZeneca and Boehringer. Emil Loldrup Fosbøl: Independent research grant from Novo Nordisk foundation. Lauge Østergaard: Independent research grant from Novo Nordisk foundation., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Pulmonary embolism (PE) is described as a prognostic factor in patients with cancer however, the prognostic impact of PE remains unknown. This study investigated, the 1-year prognosis following PE in patients with breast-, gastrointestinal-, or lung cancer stratified by cancer status., Methods: All Danish patients with first-time PE from 2008 to 2018 were included. Cancer status was categorized as no cancer, history of cancer, non-active cancer and active cancer. Unadjusted and age-stratified 1-year risk of death was estimated using the Kaplan-Meier estimator. Cause of death was reported using the Aalen-Johansen method., Results: Of 35,679 patients with PE, 18% had a breast-, gastrointestinal-, or lung cancer. Patients with cancer were older compared with no cancer (69.8 years [IQR: 56.2-79.8]). One-year risk of death (95% confidence interval) for active breast-, gastrointestinal-, and lung cancer was 49.5% (44.0%-54.9%), 75.0% (72.5%-77.4%) and 80.1% (78.0%-82.3%) respectively, compared with 18.9% (18.4%-19.3%) for no cancer. Age-stratified analysis revealed no association with increasing age in non-active lung cancer and all active cancers. Further, non-cardiovascular death accounted for an increasing proportion by cancer status (no cancer < history of cancer < non-active cancer < active cancer)., Conclusions: One-year risk of death was dependent on both cancer type and status; no association with age was found for patients with active cancers. Non-cardiovascular death was leading in non-active and active cancers. Thus, the occurrence of first-time PE could be regarded as a marker of cancer severity for patients with breast-, gastrointestinal-, and lung cancer., Competing Interests: Declaration of competing interest The authors report the following relationships unrelated to this study. NN reports speaker fees from Bayer and AstraZeneca. CFA reports research grants from The Danish Heart Foundation, Toyota Foundation, Aase & Ejnar Danielsen's Foundation, Arvid Nilsson's Foundation, The Research and Innovation Foundation of the Department of Cardiology, Herlev and Gentofte University Hospital, Fru Asta Florida Bolding's Memorial Grant and the KV Foundation; support for attending meetings from AstraZeneca and European Heart Foundation Association. ML reports research grants from Karen Elise Jensen Fonden, Danish Heart Foundation, Bayer, and BMS; speaker fees from BMS, Pfizer, Bayer and Astra Zeneca; and advisory board positions with Pfizer and Astra Zeneca. MS reports speaker fees from Novartis, Boehringer Ingelheim, Bayer, Novo, and Astra Zeneca. ELG research grants from Boehringer Ingelheim; speaker fees from Pfizer, Bayer, AstraZeneca and Bristol Myers-Squibb; consulting fees from Bayer, Bristol Myers-Squibb, MSD and Boehringer Ingelheim. AH, JES, SKN, CS, DN and JT report no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Chronic inflammation is increasingly recognized as a risk factor for VTE, but unlike other inflammatory diseases including systemic lupus erythematosus and rheumatoid arthritis, data on the risk of VTE in patients with sarcoidosis are sparse., Research Question: Do patients with sarcoidosis have a higher long-term risk of VTE (pulmonary embolism or DVT, and each of these individually) compared with the background population?, Study Design and Methods: Using Danish nationwide registries, patients aged ≥ 18 years with newly diagnosed sarcoidosis (two or more inpatient/outpatient visits, 1996-2020) without prior VTE were matched 1:4 by age, sex, and comorbidities with individuals from the background population. The primary outcome was VTE., Results: We included 14,742 patients with sarcoidosis and 58,968 matched individuals (median age, 44.7 years; 57.2% male). The median follow-up was 8.8 years. Absolute 10-year risks of outcomes for patients with sarcoidosis vs the background population were the following: VTE, 2.9% vs 1.6% (P < .0001), pulmonary embolism, 1.5% vs 0.7% (P < .0001), and DVT, 1.6% vs 1.0% (P < .0001), respectively. In multivariable Cox regression, sarcoidosis was associated with an increased rate of all outcomes in the first year after diagnosis (VTE: hazard ratio [HR], 4.94; 95% CI, 3.61-6.75) and after the first year (VTE: HR, 1.65; 95% CI, 1.45-1.87) compared with the background population. These associations persisted when excluding patients with a history of cancer and censoring patients with incident cancer during follow-up. Three-month mortality was not significantly different between patients with VTE with and without sarcoidosis (adjusted HR, 0.84; 95% CI, 0.61-1.15)., Interpretation: In this nationwide cohort study, sarcoidosis was associated with a higher long-term risk of VTE compared with a matched background population., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: A. Y. reports a grant from the Foundation of Rigshospitalet. E. L. F. reports independent and unrelated research funding from the Danish Heart Association and the Novo Nordisk Foundation. F. G. reports being an advisor for Abbott, Fineheart, AdjuCor, Bayer, Ionis, Alnylam, AstraZeneca, and Pfizer; and a speaker for Novartis, all outside the submitted work. S. L. K. reports being on the advisory board for Bayer, outside the submitted work. M. S. reports lecture fees from Novo Nordisk, Bohringer, Astra Zeneca, and Novartis, outside the submitted work. K. R. reports being an advisory board member for Abbott, Novo Nordisk, and Boehringer-Ingelheim; and speaking fees from AstraZeneca, Boehringer-Ingelheim, Abbott, and MSD, all outside the submitted work. L. K. reports compensation from Novartis, Novo Nordisk, and AstraZeneca for other services, outside the submitted work. J. H. B. reports advisory board honoraria from AstraZeneca and Bayer, consultant honoraria from Novartis and AstraZeneca, and travel grants from AstraZeneca, all outside the submitted work. None declared (S. B. K., J. K. P., G. S., S. N. D.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Birth weight (BW) is associated with risk of cardiometabolic disease (CMD) in adulthood, which may depend on the state of obesity, in particular if developed at a young age. We hypothesised that BW and a polygenic score (PGS) for BW were associated with cardiometabolic risk and related plasma protein levels in children and adolescents. We aimed to determine the modifying effect of childhood obesity on these associations., Methods: We used data from The cross-sectional HOLBAEK Study with 4263 participants (median [IQR] age, 11.7 [9.2, 14.3] years; 57.1% girls and 42.9% boys; 48.6% from an obesity clinic and 51.4% from a population-based group). We gathered information on BW and gestational age, anthropometrics, cardiometabolic risk factors, calculated a PGS for BW, and measured plasma proteins using Olink Inflammation and Cardiovascular II panels. We employed multiple linear regression to examine the associations with BW as a continuous variable and performed interaction analyses to assess the effect of childhood obesity on cardiometabolic risk and plasma protein levels., Findings: BW and a PGS for BW associated with cardiometabolic risk and plasma protein levels in childhood and adolescence. Childhood obesity modified the associations between BW and measures of insulin resistance, including HOMA-IR (βadj [95% CI per SD] for obesity: -0.12 [-0.15, -0.08]; normal weight: -0.04 [-0.08, 0.00]; Pinteraction = 0.004), c-peptide (obesity: -0.11 [-0.14, -0.08]; normal weight: -0.02 [-0.06, 0.02]; Pinteraction = 5.05E-04), and SBP SDS (obesity: -0.12 [-0.16, -0.08]; normal weight: -0.06 [-0.11, -0.01]; Pinteraction = 0.0479). Childhood obesity also modified the associations between BW and plasma levels of 14 proteins (e.g., IL15RA, MCP1, and XCL1; Pinteraction < 0.05)., Interpretation: We identified associations between lower BW and adverse metabolic phenotypes, particularly insulin resistance, blood pressure, and altered plasma protein levels, which were more pronounced in children with obesity. Developing effective prevention and treatment strategies for this group is needed to reduce the risk of future CMD., Funding: Novo Nordisk Foundation (NNF15OC0016544, NNF0064142 to T.H., NNF15OC0016692 to T.H. and A.K., NNF18CC0033668 to S.E.S, NNF18SA0034956 to C.E.F., NNF20SA0067242 to DCA, NNF18CC0034900 to NNF CBMR), The Innovation Fund Denmark (0603-00484B to T.H.), The Danish Cardiovascular Academy (DCA) and the Danish Heart Foundation (HF) (PhD2021007-DCA to P.K.R, 18-R125-A8447-22088 (HF) and 21-R149-A10071-22193 (HF) to M.A.V.L., PhD2023009-HF to L.A.H), EU Horizon (668031, 847989, 825694, 964590 to A.K.), Innovative Health Initiative (101132901 for A.K.), A.P. Møller Foundation (19-L-0366 to T.H.), The Danish National Research Foundation, Steno Diabetes Center Sjælland, and The Region Zealand and Southern Denmark Health Scientific Research Foundation., Competing Interests: Declaration of interests C.E.F. has received speaker honoria from The Danish Society for General Practice, Novo Nordisk, Nestlé and payment for manuscript writing from The Danish Health Authority. C.B. and T.H. have stocks in Novo Nordisk. A.K. receives royalties from Gyldendal, payment for lectures from Norgine, Siemens, Nordic Bioscience, Novo Nordisk. A.K. has two patents planned/pending, participates on an advisory board for Norgine, Siemens, Novo Nordisk, B&I. A.K. has a leadership role as the Secretary General European Association for the Study of The Liver (EASL) 2023–2025. A.K. has received equipment, materials, and drugs from Norgine (Rifaximin), Siemens (ELF Test), Echosence (FibroScan), and Nordic Bioscience (ECM markers). A.K. has finical interest as the Board member and co-founder Evido. J-C.H. has received payment for expert testimony from Novo Nordisk and support for meetings and travel from Rhytm, provides training and treatment of obesity. We declare no other competing interests from remaining coauthors., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The microbial communities of the oral cavity are important elements of oral and systemic health. With emerging evidence highlighting the heritability of oral bacterial microbiota, this study aimed to identify host genome variants that influence oral microbial traits. Using data from 16S rRNA gene amplicon sequencing, we performed genome-wide association studies with univariate and multivariate traits of the salivary microbiota from 610 unrelated adults from the Danish ADDITION-PRO cohort. We identified six single nucleotide polymorphisms (SNPs) in human genomes that showed associations with abundance of bacterial taxa at different taxonomical tiers (P < 5 × 10 -8 ). Notably, SNP rs17793860 surpassed our study-wide significance threshold (P < 1.19 × 10 -9 ). Additionally, rs4530093 was linked to bacterial beta diversity (P < 5 × 10 -8 ). Out of these seven SNPs identified, six exerted effects on metabolic traits, including glycated hemoglobin A1c, triglyceride and high-density lipoprotein cholesterol levels, the risk of type 2 diabetes and stroke. Our findings highlight the impact of specific host SNPs on the composition and diversity of the oral bacterial community. Importantly, our results indicate an intricate interplay between host genetics, the oral microbiota, and metabolic health. We emphasize the need for integrative approaches considering genetic, microbial, and metabolic factors., (© 2024. The Author(s).)

Background: Danish women-who were HPV-vaccinated as girls-are now reaching an age where they are invited to cervical cancer screening. Because of their expected lower cervical cancer risk, we must reassess our screening strategies. We analyzed Danish HPV-vaccinated women's outcomes after the first screening test at age 23., Methods and Findings: Our study was embedded in Danish routine cytology-based screening. We conducted an observational study and included women born in 1994, offered the 4-valent HPV vaccine at age 14, and subsequently invited to screening at age 23. Cervical cytology was used for diagnostics and clinical management. Residual material was HPV tested with Cobas® 4800/6800. The most severe histology diagnosis within 795 days of screening was found through linkage with the Danish National Pathology Register. We calculated the number of women undergoing follow-up (repeated testing and/or colposcopy) per detected cervical intraepithelial neoplasia (CIN2+). A total of 6021 women were screened; 92% were HPV-vaccinated; 12% had abnormal cytology; 35% were high-risk HPV-positive, including 0.9% HPV16/18 positive, and 20% had follow-up. In women that were cytology-abnormal and HPV-positive (Cyt+/HPV+), 610 (98.5%) had been followed up, and 138 CIN2+ cases were diagnosed, resulting in 4.4 (95% CI 3.9-5.2) women undergoing follow-up per detected CIN2+. In contrast to recommendations, 182 (12.2%) cytology-normal and HPV-positive (Cyt-/HPV+) women were followed up within 795 days, and 8 CIN2+ cases were found, resulting in 22.8 (95% CI 13.3-59.3) women undergoing follow-up per detected CIN2+., Conclusion: Overall, HPV prevalence was high in HPV-vaccinated women, but HPV16/18 had largely disappeared. In the large group of cytology-normal and HPV-positive women, 23 had been followed up per detected CIN2+ case. Our data indicated that primary HPV screening of young HPV-vaccinated women would require very effective triage methods to avoid an excessive follow-up burden., Trial Registration: Trial registration number: NCT0304955., Competing Interests: EL and MHN received HPV-DNA test kits for Trial23 from Roche Diagnostics, Switzerland. BA received HPV-DNA test kits from Roche Diagnostics, Switzerland for other studies. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have nothing to declare., (Copyright: © 2024 Nonboe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Paroxysmal atrial fibrillation (pAF) occurs sporadically and can impair athletic performance. Gold standard for diagnosis is surface electrocardiography (ECG), however, this requires AF to be sustained. Implantable loop recorders (ILRs) are routinely used for AF detection in human medicine. While ILR placement has been studied in horses, its AF detection performance is unknown., Objectives: (I) Validation of ILRs for AF detection in horses. (II) Determining pAF incidence using ILRs and estimate the positive predictive value (PPV)., Study Design: (I) Experimental study; (II) Longitudinal observational study., Methods: (I) Implantation of ILRs in 15 horses with AF and 13 horses in sinus rhythm. Holter ECGs were recorded at: 1, 4, 8, 12 and 16 weeks of AF. The ILR ECGs were compared with surface ECGs to assess diagnostic sensitivity and specificity. (II) Eighty horses (43 Warmbloods, 37 Standardbreds) with ILRs were monitored for 367 days [IQR 208-621]., Results: (I) ILRs detected AF on all recording days, in horses with AF, with a sensitivity of 66.1% (95% CI: 65.8-66.5) and a specificity of 99.99% (95% CI: 99.97-99.99). The sensitivity remained consistent across all time points. (II) The incidence of pAF was 6.3% (5/80). In horses with pAF, the PPV ranged from 8% to 87%. Increased body condition score (BCS > 6/9) was associated with an increased number of false positive episodes (p = 0.005)., Main Limitations: (I) Horses were stabled during the ECG recordings, and AF was induced, rather than naturally occurring pAF. (II) Integrated algorithm in this ILR is optimised for AF detection in humans using remote monitors. Additionally, sensing is affected by motion artefacts., Conclusion: The ILR reliably detected AF in resting horses, particularly in horses with normal BCS (6/9). The ILR proved useful to detect pAF and is recommended alongside Holter monitoring for diagnostic workup of horses with suspected pAF., (© 2024 The Author(s). Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.)

Aims: Ferric carboxymaltose (FCM) is guideline-recommended for iron deficiency (ID) in heart failure with reduced ejection fraction (HFrEF). Despite a well-established safety profile, the magnitude and clinical significance of FCM-induced hypophosphataemia in HFrEF remains unclear. This pre-specified substudy of HEART-FID evaluated serum phosphate, 1,25-dihydroxyvitamin D, and plasma parathyroid hormone (PTH) subsequent to FCM., Methods and Results: HEART-FID was a randomized, double-blind, placebo-controlled trial of ambulatory patients with HFrEF and ID randomized to FCM versus placebo. This substudy assessed mean change from baseline across eight visits over 6 months for the following endpoints: serum phosphate, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and PTH, in addition to the clinical severity of potential hypophosphataemia. Overall, 133 patients (n = 62 FCM, n = 71 placebo) were prospectively enrolled. Mean age was 68 ± 11 years, 55 (41.4%) were women, and 29 (21.8%) had chronic kidney disease. Phosphate levels decreased in 34 (57.6%) patients in the FCM group compared with 7 (10.3%) in the placebo group. Mean change in phosphate levels reached a nadir at day 21 (-0.36 ± 0.27 mmol/L) subsequent to FCM infusion with 28 (51%) having moderate-to-severe hypophosphataemia. Reductions in 1,25-dihydroxyvitamin D were also observed, whilst PTH increased. These biochemical changes returned to baseline levels by day 91. Serum levels of 25-hydroxyvitamin D remained stable throughout the study. No serious adverse events associated with hypophosphataemia were reported., Conclusions: Transient moderate-to-severe hypophosphataemia was frequent subsequent to FCM infusion, accompanied by 1,25-dihydroxyvitamin D decrease and PTH increase. Serum levels of 25-hydroxyvitamin D remained stable. No evidence of symptomatic hypophosphataemia was reported, collectively indicating FCM-related hypophosphataemia to be clinically benign and transient in HFrEF., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Purpose: Autonomic nervous system dysfunction (ANSD), for which presently no treatment exists, has a negative impact on prognosis in people with type 2 diabetes (T2D). Periosteal pressure sensitivity (PPS) on sternum may be a measure of autonomic nervous system dysfunction (ANSD). We tested if a non-pharmacological PPS-feedback-guided treatment program based on non-noxious sensory nerve stimulation, known to reduce PPS, changed empowerment, treatment satisfaction, and quality of life in people with T2D, compared to usual treatment., Patients and Methods: Analysis of secondary endpoints in a single center, two-armed, parallel-group, observer-blinded, randomized controlled trial of individuals with T2D. Participants were randomized to non-pharmacological intervention as an add-on to treatment as usual. Endpoints were evaluated by five validated questionnaires: Diabetes specific Empowerment (DES-SF), Diabetes Treatment Satisfaction (DTSQ), quality of life (QOL) (WHO-5), clinical stress signs (CSS), and self-reported health (SF-36). Sample size calculation was based on the primary endpoint HbA1c., Results: We included 144 participants, 71 allocated to active intervention and 73 to the control group. Active intervention compared to control revealed improved diabetes-specific empowerment (p = 0.004), DTSQ (p = 0.001), and SF-36 self-reported health (p=0.003) and tended to improve quality of life (WHO-5) (p = 0.056). The findings were clinically relevant with a Cohen's effect size of 0.5 to 0.7., Conclusion: This non-pharmacological intervention, aiming to reduce PPS, and thus ANSD, improved diabetes-specific empowerment, treatment satisfaction, and self-reported health when compared to usual treatment. The proposed intervention may be a supplement to conventional treatment for T2D., Competing Interests: Søren Ballegaard developed the PPS measurement device and holds shares in the company that owns the associated patents. To mitigate bias, he was not involved in patient interactions, data collection, or statistical analysis. Consequently, he did not have access to the study site (Herlev University Hospital) throughout the entire study period. In addition, Dr Søren Ballegaard has a patent 8,206,313 and a patent 8,706,213. Dr Peter Rossing reports grants and honoraria to institutions from Astra Zeneca; grants from Bayer and Novo Nordisk; honoraria to institutions from Sanofi, Abbott, Gilead, Novartis, and Boehringer Ingelheim, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2024 Hecquet et al.)