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Spinocerebellar ataxia 27B (SCA27B) is a common autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. Neuropathological studies have shown that neuronal loss is largely restricted to the cerebellum. Although the repeat locus is highly unstable during intergenerational transmission, it remains unknown whether it exhibits cerebral mosaicism and progressive instability throughout life. We conducted an analysis of the FGF14 GAA•TTC repeat somatic instability across 156 serial blood samples from 69 individuals, fibroblasts, induced pluripotent stem cells, and post-mortem brain tissues from six controls and six patients with SCA27B, alongside methylation profiling using targeted long-read sequencing. Peripheral tissues exhibited minimal somatic instability, which did not significantly change over periods of more than 20 years. In post-mortem brains, the GAA•TTC repeat was remarkably stable across all regions, except in the cerebellar hemispheres and vermis. The levels of somatic expansion in the cerebellar hemispheres and vermis were, on average, 3.15 and 2.72 times greater relative to other examined brain regions, respectively. Additionally, levels of somatic expansion in the brain increased with repeat length and tissue expression of FGF14. We found no significant difference in methylation of wild-type and expanded FGF14 alleles in post-mortem cerebellar hemispheres between patients and controls. In conclusion, our study revealed that the FGF14 GAA•TTC repeat exhibits a cerebellar-specific expansion bias, which may explain the pure cerebellar involvement in SCA27B., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. 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.)

Objectives: We report our single-center experience of mid-term to long-term retrieval and reimplantation of a tines-based leadless pacemaker (Micra transcatheter pacing system; TPS)., Backgrounds: The TPS is a clinically effective alternative to transvenous single-chamber ventricular pacemakers. Whereas it is currently recommended to abandon the TPS at the end of device life, catheter-based retrieval may be favorable in specific scenarios., Methods: We report on nine consecutive patients with the implanted TPS who subsequently underwent transcatheter retrieval attempts. The retrieval system consists of the original TPS delivery catheter and an off-the-shelf single-loop 7 mm snare. The procedure was guided by fluoroscopy and intracardiac echocardiography., Results: After an implantation duration of 3.1 ± 2.8 years (range 0.4-9.0), the overall retrieval success rate was 88.9% (8 of 9 patients). The mean procedure time was 89 ± 16 minutes, and fluoroscopy time was 18.0 ± 6.6 min. No procedure-related adverse device events occurred. In the one unsuccessful retrieval, intracardiac echocardiography revealed that the TPS was partially embedded in the ventricular tissue surrounding the leadless pacemaker body in the right ventricle. After retrieval, three patients were reimplanted with a new TPS device. All implantations were successful without complications., Conclusions: A series of transvenous late retrievals of implanted TPS devices demonstrated safety and feasibility, followed by elective replacement with a new leadless pacing device or conventional transvenous pacing system. This provides a viable end-of-life management alternative to simple abandonment of this leadless pacemaker., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Paralysis of the muscles controlling the hand dramatically limits the quality of life for individuals living with spinal cord injury (SCI). Here, with a non-invasive neural interface, we demonstrate that eight motor complete SCI individuals (C5-C6) are still able to task-modulate in real-time the activity of populations of spinal motor neurons with residual neural pathways. In all SCI participants tested, we identified groups of motor units under voluntary control that encoded various hand movements. The motor unit discharges were mapped into more than 10 degrees of freedom, ranging from grasping to individual hand-digit flexion and extension. We then mapped the neural dynamics into a real-time controlled virtual hand. The SCI participants were able to match the cue hand posture by proportionally controlling four degrees of freedom (opening and closing the hand and index flexion/extension). These results demonstrate that wearable muscle sensors provide access to spared motor neurons that are fully under voluntary control in complete cervical SCI individuals. This non-invasive neural interface allows the investigation of motor neuron changes after the injury and has the potential to promote movement restoration when integrated with assistive devices., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The aim of this study was to develop and validate methods for the determination of vitamins B2, B9, E and A in serum using liquid chromatography with mass spectrometry (MS) detection. Vitamin analysis was performed using an ultra performance liquid chromatography combined with tandem MS. The compounds were separated on a BEH C18 RP column (2.1 × 100 mm, 1.7 μm) using a gradient elution with an analysis time of 10 min. Sample preparation included protein precipitation with ethanol. The concentration range in human serum was as follows: riboflavin 5-1000 nmol/L, folic acid 2.5-250 nmol/L, α-tocopherol 0.5-100 μmol/L and all-trans-retinol 25-2500 nmol/L. Accuracy and precision were validated according to Food and Drug Administration guidelines, with coefficients of variation ranging from 3.1-11.7% and recoveries from 94.4-107.5%. Routine monitoring of the complex range of vitamins in bariatric medicine is still not common. This is despite the fact that patients are at risk for glitch deficits, especially of a neurological nature. An analytical method that allows for the complex measurement of both water-soluble and fat-soluble vitamins is important and necessary for the clinical monitoring of bariatric patients. The method we have described could benefit both clinical practice and nutritional research., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Advanced ablation strategies are needed to treat ventricular tachycardia (VT) and premature ventricular contractions (PVC) refractory to standard unipolar radiofrequency ablation (Uni-RFA). Bipolar radiofrequency catheter ablation (Bi-RFA) has emerged as a treatment option for refractory VT, PVC. Multicenter registry data on the use of Bi-RFA in the setting of refractory VT and PVC are lacking., Purpose: The aim of this Bi-RFA registry is to determine its real-world safety, feasibility, and efficacy in patients with refractory VT/PVC., Methods: Consecutive patients undergoing Bi-RFA at sixteen European centers for recurring VT/PVC after at least one standard Uni-RFA were included. Second ablation catheter was used instead of a dispersive patch and was positioned at the opposite site of the ablation target., Results: Between March 2021 and August 2024, ninety-one patients underwent 94 Bi-RFA procedures (74 males, age 62±13, prior Uni-RFA range 1-8). Indications were recurrence of PVC (n=56), VT (n=20), electrical storm (n=13), or PVC-triggered ventricular fibrillation (n=2). Procedural time was 160±73min, Bi-RFA time 426±286s, mean Uni-RFA time 819±697s. Elimination of clinical VT/PVC was achieved in 67 (74%) patients, suppression of VT/PVC in a further 10 (11%) patients. In the remaining 14 patients (15%) no effect on VT/PVC was observed. Three major complications occurred: coronary artery occlusion, AV block and arteriovenous fistula. Follow-up lasted 7±8 months. Nineteen (61%) remained VT-free. ≥80% PVC burden reduction was achieved in 45 (78%)., Conclusions: This real-world registry data indicates that Bi-RFA appears safe, is feasible, and effective in the majority of patients with VT/PVC., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Diurnal gene expression is a pervasive phenomenon occurring across all kingdoms of life, orchestrating adaptive responses to daily environmental fluctuations and thus enhancing organismal fitness. Our understanding of the plant circadian clock is primarily derived from studies in Arabidopsis and direct comparisons are difficult due to differences in gene family sizes. To this end, the identification of functional orthologs based on diurnal and tissue expression is necessary. The diurnal.plant.tools database constitutes a repository of gene expression profiles from 17 members of the Archaeplastida lineage, with built-in tools facilitating cross-species comparisons. In this database update, we expand the dataset with diurnal gene expression from 4 agriculturally significant crop species and Marchantia, a plant of evolutionary significance. Notably, the inclusion of diurnal gene expression data for Marchantia enables researchers to glean insights into the evolutionary trajectories of the circadian clock and other biological processes spanning from algae to angiosperms. Moreover, integrating diurnal gene expression data with datasets from related gene co-expression databases, such as CoNekt-Plants and CoNekt-Stress, which contain gene expression data for tissue and perturbation experiments, provides a comprehensive overview of gene functions across diverse biological contexts. This expanded database serves as a valuable resource for elucidating the intricacies of diurnal gene regulation and its evolutionary underpinnings in plant biology., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. 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.)

Stem CO2 efflux is an important component of the carbon balance in forests. The efflux is considered to principally reflect the net result of two dominating and opposing processes: stem respiration and stem photosynthesis. In addition, transport of CO2 in xylem sap is thought to play an appreciable role in affecting the net flux. This work presents an approach to partition stem CO2 efflux among these processes using sap-flux data and CO2-exchange measurements from dark and transparent chambers placed on mature Scots pine (Pinus sylvestris) trees. Seasonal changes and monthly parameters describing the studied processes were determined. Respiration contributed most to stem net CO2 flux, reaching up to 79% (considering the sum of the absolute values of stem respiration, stem photosynthesis, and flux from CO2 transported in xylem sap to be 100%) in June, when stem growth was greatest. The contribution of photosynthesis accounted for up to 13% of the stem net CO2 flux, increasing over the monitoring period. CO2 transported axially with sap flow decreased towards the end of the growing season. At a reference temperature, respiration decreased starting around midsummer, while its temperature sensitivity increased during the summer. A decline was observed for photosynthetic quantum yield around midsummer together with a decrease in light-saturation point. The proposed approach facilitates modeling net stem CO2 flux at a range of time scales., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

DNA methyltransferases are drug targets for myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), acute myelogenous leukemia (AML) and possibly β-hemoglobinopathies. We characterize the interaction of nucleoside analogues in DNA with a prokaryotic CpG-specific DNA methyltransferase (M.MpeI) as a model for mammalian DNMT1 methyltransferases. We tested DNA containing 5-hydroxymethylcytosine (5hmC), 5-hydroxycytosine (5OHC), 5-methyl-2-pyrimidinone (in the ribosylated form known as 5-methylzebularine, 5mZ), 5,6-dihydro-5-azacytosine (dhaC), 5-fluorocytosine (5FC), 5-chlorocytosine (5ClC), 5-bromocytosine (5BrC) and 5-iodocytosine (5IC). Covalent complex formation was by far most efficient for 5FC. Non-covalent complexes were most abundant for dhaC and 5mZ. Surprisingly, we observed methylation of 5IC and 5BrC, and to a lesser extent 5ClC and 5FC, in the presence, but not the absence of small molecule thiol nucleophiles. For 5IC and 5BrC, we demonstrated by mass spectrometry that the reactions were due to methyltransferase driven dehalogenation, followed by methylation. Crystal structures of M.MpeI-DNA complexes capture the 'in' conformation of the active site loop for analogues with small or rotatable (5mZ) 5-substituents and its 'out' form for bulky 5-substituents. Since very similar 'in' and 'out' loop conformations were also observed for DNMT1, it is likely that our conclusions generalize to other DNA methyltransferases., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The BisI family of restriction endonucleases is unique in requiring multiple methylated or hydroxymethylated cytosine residues within a short recognition sequence (GCNGC), and in cleaving directly within this sequence, rather than at a distance. Here, we report that the number of modified cytosines that are required for cleavage can be tuned by the salt concentration. We present crystal structures of two members of the BisI family, NhoI and Eco15I_Ntd (N-terminal domain of Eco15I), in the absence of DNA and in specific complexes with tetra-methylated GCNGC target DNA. The structures show that NhoI and Eco15I_Ntd sense modified cytosine bases in the context of double-stranded DNA (dsDNA) without base flipping. In the co-crystal structures of NhoI and Eco15I_Ntd with DNA, the internal methyl groups (G5mCNGC) interact with the side chains of an (H/R)(V/I/T/M) di-amino acid motif near the C-terminus of the distal enzyme subunit and arginine residue from the proximal subunit. The external methyl groups (GCNG5mC) interact with the proximal enzyme subunit, mostly through main chain contacts. Surface plasmon resonance analysis for Eco15I_Ntd shows that the internal and external methyl binding pockets contribute about equally to sensing of cytosine methyl groups., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Stereotactic arrythmia radioablation (STAR) is a novel, non-invasive and promising treatment option for ventricular arrythmias (VA). It has been applied in highly selected patients mainly as bail-out procedure, when (multiple) catheter-ablations, together with anti-arrhythmic drugs, were unable to control the VAs. Despite the increasing clinical use there is still limited knowledge of the acute and long-term response of normal and diseased myocardium to STAR. Acute toxicity appeared to be reasonably low but potential late adverse effects may be underreported. Among published studies, the provided methodological information is often limited, and patient selection, target volume definition, methods for determination and transfer of target volume, and techniques for treatment planning and execution differ across studies, hampering pooling of data and comparison across studies. In addition, STAR requires close and new collaboration between clinical electrophysiologists and radiation oncologists, which is facilitated by shared knowledge in each collaborator's area of expertise and a common language. This clinical consensus statement provides uniform definition of cardiac target volumes. It aims to provide advice in patient selection for STAR including etiology specific aspects, and advice in optimal cardiac target volume identification based on available evidence. Safety concerns and the advice for acute and long-term monitoring including the importance of standardized reporting and follow-up are covered by this document. Areas of uncertainty are listed, which require high-quality, reliable pre-clinical and clinical evidence before expansion of STAR beyond clinical scenarios in which proven therapies are ineffective or unavailable., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: We aimed to analyse serious cardiac adverse drug reactions to COVID-19 vaccines from the Europe-wide EudraVigilance database., Methods and Results: In this retrospective, cross-sectional study, the EudraVigilance database was searched to identify suspected serious cardiac postvaccination adverse drug reactions to COVID-19 vaccines. This data was coupled with the number of total vaccine doses administered in the European Economic Area for Comirnaty (Pfizer BioNTech), Spikevax (Moderna), Vaxzevria (AstraZeneca), Jcovden (Janssen), Nuvaxovid (Novavax), products, available from the European Centre for Disease Prevention and Control "Vaccine Tracker" database. The analysis included 772,228,309 administered doses of eligible vaccines from the "Vaccine Tracker" database and 86,051 eligible records of cardiac adverse drug reactions from the EudraVigilance database.The frequency of most of the investigated adverse drug reactions was very rare (<1/10,000 i.e. <100/1,000,000 doses). The lowest risk of any serious cardiac adverse drug reactions was noticed for vaccination with Comirnaty (135.5 per million doses), while Spikevax, Jcovden, Vaxzevria and Nuvaxovid were characterised by higher risk (respectively, 140.9, 194.8, 313.6 and 1065.2 per million doses). The most common complications of vaccinations included syncope, arrhythmia, tachycardia, palpitations, angina pectoris, hypertension, myocarditis, thrombosis and pulmonary embolism., Conclusions: The risk of serious cardiac adverse drug reactions to COVID-19 vaccines is low and the benefit of active immunisation against that disease seems to outweigh the potential risk of serious postvaccination cardiac adverse drug reactions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Chironomids of the genus Diamesa (Meigen, 1835, Diptera: Chironomidae) inhabit cold, oxygen-rich running waters. We have investigated the presence of Diamesa and other freshwater macroinvertebrates at 22 stream sampling sites in 3 European high mountain regions (the Central Pyrenees, the Ötztal Alps, and the Tatra Mountains) to establish suitable temperature conditions for Diamesa dominance. It has been generally accepted that their high abundance was linked to the presence of glaciers; however, we have shown that in the Tatra Mountains, where there are no glaciers, the conditions for the dominance of Diamesa species are created due to permanent snowfields, the geographical orientation of the valley and shading by the surrounding high peaks. The historical connection of Diamesa to glaciers was investigated from the paleolimnological records of subfossil chironomid assemblages from the Bohemian Forest, where glaciers disappeared before or during the Late Glacial period. As expected, water temperature seems to be the main driver of Diamesa distribution, and we determined that the relative abundance of Diamesa species was significantly higher at the sites with a mean July water temperature below 6.5 °C. The Diamesa-dominated stream communities seems to be endangered due to ongoing climate warming and this assumption is supported by our paleolimnological results from the Bohemian Forest lakes, where Diamesa has disappeared due to warming of lake inflows at the beginning of the Holocene. These findings strengthen the former suggestions that some Diamesa species could be used as an indicator for tracking recent environmental changes in vulnerable ecosystems of cold mountain streams., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America. 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.)

Background and Aims: The G protein coupled receptor GPR15 is expressed on and functionally important for T cells homing to the large intestine. However, the precise mechanisms by which GPR15 controls gut homing have been unclear. Thus, we aimed to elucidate these mechanisms as well as to explore the potential of targeting GPR15 for interfering with T cell recruitment to the colon in inflammatory bowel disease [IBD]., Methods: We used dynamic adhesion and transmigration assays, as well as a humanised in vivo model of intestinal cell trafficking, to study GPR15-dependent effects on gut homing. Moreover, we analysed GPR15 and integrin expression in patients with and without IBD, cross-sectionally and longitudinally., Results: GPR15 controlled T cell adhesion to MAdCAM-1 and VCAM-1 upstream of α4β7 and α4β1 integrin, respectively. Consistently, high co-expression of these integrins with GPR15 was found on T cells from patients with IBD, and GPR15 also promoted T cell recruitment to the colon in humanised mice. Anti-GPR15 antibodies effectively blocked T cell gut homing in vitro and in vivo. In vitro data, as well as observations in a cohort of patients treated with vedolizumab, suggest that this might be more effective than inhibiting α4β7., Conclusions: GPR15 seems to have a broad, but organ-selective, impact on T cell trafficking and is therefore a promising target for future therapy of IBD. Further studies are needed., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. 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.)

Background: The adjuvanted respiratory syncytial virus (RSV) prefusion F protein-based vaccine (RSVPreF3 OA) is approved in adults aged ≥60 years. We evaluated RSVPreF3 OA immunogenicity and safety in adults aged 50-59 years without or with increased risk for RSV disease due to specific chronic medical conditions., Methods: This observer-blind, phase 3, noninferiority trial included adults aged 50-59 years, stratified into 2 subcohorts: those with and those without predefined, stable, chronic medical conditions leading to an increased risk for RSV disease. Participants in both subcohorts were randomized 2:1 to receive RSVPreF3 OA or placebo. A control group of adults aged ≥60 years received RSVPreF3 OA. Primary outcomes were RSV-A and RSV-B neutralization titers (geometric mean titer ratios and sero-response rate differences) 1 month post-vaccination in 50-59-year-olds versus ≥60-year-olds. Cell-mediated immunity and safety were also assessed., Results: The exposed population included 1152 participants aged 50-59 years and 381 participants aged ≥60 years. RSVPreF3 OA was immunologically noninferior in 50-59-year-olds versus ≥60-year-olds; noninferiority criteria were met for RSV-A and RSV-B neutralization titers in those with and those without increased risk for RSV disease. Frequencies of RSVPreF3-specific polyfunctional CD4+ T cells increased substantially from pre- to 1 month post-vaccination. Most solicited adverse events had mild-to-moderate intensity and were transient. Unsolicited and serious adverse event rates were similar in all groups., Conclusions: RSVPreF3 OA was immunologically noninferior in 50-59-year-olds compared to ≥60-year-olds, in whom efficacy was previously demonstrated. The safety profile in 50-59-year-olds was consistent with that in ≥60-year-olds., Clinical Trial Registration: ClinicalTrials.gov: NCT05590403., Competing Interests: Potential conflicts of interest . H. A. H., M. d. H., B. S., S. D., M.-P. D., D. D., J. H., C. V., and V. H. are/were GSK employees at the time when the study was designed and/or conducted. H. A. H., M. d. H., B. S., S. D., M.-P. D., D. D., J. H., and V. H. hold shares in GSK as part of their employee remuneration. M.-P. D. is a co-applicant on a pending patent filed by GSK. M. F. received study-related payments for training and study conduct from GSK. T. F. S. received honoraria for lectures from AstraZeneca, Bavarian Nordic, Biogen, CSL-Seqirus, GSK, Janssen-Cilag, Merck-Serono, Moderna, Novavax, MSD, Pfizer, Roche, Sanofi-Aventis, and Takeda; he participated on advisory boards for Bavarian Nordic, CSL-Seqirus, BioNTech, GSK, Moderna, Novavax, and Takeda. S. A. N. declares study-related payments to his institution from GSK and support from GSK to attend investigators meetings. J. R.-G. declares study-related payments from GSK and honoraria and support for attending meetings and/or travel from GSK, Pfizer, and Sanofi-MSD; he also participated on data and safety monitoring boards or advisory boards from GSK and Pfizer. C. Z. received grants from GSK for the conduct of this study and support from GSK for attending meetings. J. G. declares study-related payments from GSK; grants from Novartis, Pharmalog, New Amsterdam Pharma, Syneos, Winecker Pharma, and Lilly; and consulting fees, honoraria, payment for expert testimony, and support for attending meetings and/or travel from GSK. C. V.-P. is a former employee of QPS Netherlands B.V. The other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: Mechanical composite valve grafts (MCVGs) are the first-line therapy for aortic root replacement in young adults. Decellularized aortic homografts (DAH) present a promising novel alternative due to their lower thrombogenicity. We aimed to compare both treatment options regarding survival and valve-related adverse events., Methods: This study was designed as a single-centre retrospective cohort study including patients who underwent root replacement with MCVG or DAH between 2000 and 2022. Urgent or emergent procedures were excluded., Results: The study cohort included 289 patients (MCVG n = 216, DAH n = 73) with a mean age of 48.5 ± 12 years (MCVG 49 ± 12 years vs DAH 47 ± 11 years; P = 0.23) and a median EuroScore II of 1.7% (1.2, 2.6). The 30-day mortality was 1% (n = 3). Cumulative survival at 3 years was 99% for DAH and 94% for MCVG, respectively (P = 0.15). Mean follow-up was 98.9 ± 72.7 months. Bleeding events (n = 14, 6.5%) and thromboembolism (n = 14, 6.5%) were only observed in the MCVG group (P = 0.19 and 0.09, respectively). Four cases (5%) of moderate structural valve deterioration occurred, all in the DAH group (P ≤ 0.001). The cumulative incidence of a composite end point of valve-related adverse events was significantly higher in the MCVG group (P = 0.0295)., Conclusions: Aortic root replacement with MCVGs and decellularized aortic homografts showed low mortality in an elective setting. Patients in the homograft cohort demonstrated significantly higher freedom from valve-related adverse events. DAH present a promising treatment option for young patients requiring root replacement; however, data on long-term durability are needed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: Management of hypertrophic obstructive cardiomyopathy (HOCM) is often challenging, depending on clinical manifestation. This case report illustrates the complex treatment of HOCM with associated recurrent ventricular arrhythmias., Case Summary: A 54-year-old female with HOCM diagnosed in 2012 underwent a failed attempt for alcohol septal ablation, implantation of an implantable cardioverter-defibrillator, and repeated radiofrequency ablations (including ablation of the septal bulge to reduce LV obstruction). For ventricular tachycardia (VT) recurrences, she had stereotactic arrhythmia radioablation with subsequent epicardial cryoablation from mini-thoracotomy, and endocardial ablation with pulsed field energy. The situation was finally solved by mechanical support and heart transplantation., Discussion: A few important lessons can be learned from the case. First, radiofrequency ablation was used successfully to decrease left outflow tract obstruction. Second, stereotactic radiotherapy has been used after four previous endo/epicardial catheter ablations to decrease the recurrences of VT. Third, mini-thoracotomy was used after previous epicardial ablation with subsequent adhesions to modify the epicardial substrate with cryoenergy. Fourth, pulsed field ablation of atrial fibrillation resulted in an excellent therapeutic effect. Fifth, pulsed field ablation was also used to modify the substrate for VT, and was complicated by transient AV block with haemodynamic deterioration requiring mechanical support. Finally, a heart transplant was the ultimate solution in the management of recurrent VT., Competing Interests: Conflict of interest: J.K. reports personal fees from Biosense Webster, Boston Scientific, GE Healthcare, Medtronic, and St. Jude Medical (Abbott) for participation in scientific advisory boards and has received speaker honoraria from Biosense Webster, Biotronik, Boston Scientific, Medtronic, ProMed CS, St. Jude Medical (Abbott), and Viatris. J.H. received speaker honoraria from Boehringer Ingelheim, ProMed CS, and Viatris. J.C. reports personal fees from Accuray and Roche for lectures. P.P. has received speaker honoraria from St. Jude Medical (Abbott) and has served as a consultant for Biotronik and Boston Scientific. The remaining author has no disclosures., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Randomized trials conducted in low- and middle-income settings demonstrated efficacy of influenza vaccination during pregnancy against influenza infection among infants <6 months of age. However, vaccine effectiveness (VE) estimates from settings with different population characteristics and influenza seasonality remain limited., Methods: We conducted a test-negative study in Ontario, Canada. All influenza virus tests among infants <6 months from 2010 to 2019 were identified and linked with health databases to ascertain information on maternal-infant dyads. VE was estimated from the odds ratio for influenza vaccination during pregnancy among cases versus controls, computed using logistic regression with adjustment for potential confounders., Results: Among 23 806 infants tested for influenza, 1783 (7.5%) were positive and 1708 (7.2%) were born to mothers vaccinated against influenza during pregnancy. VE against laboratory-confirmed infant influenza infection was 64% (95% confidence interval [CI], 50%-74%). VE was similar by trimester of vaccination (first/second, 66% [95% CI, 40%-80%]; third, 63% [95% CI, 46%-74%]), infant age at testing (0 to <2 months, 63% [95% CI, 46%-75%]; 2 to <6 months, 64% [95% CI, 36%-79%]), and gestational age at birth (≥37 weeks, 64% [95% CI, 50%-75%]; < 37 weeks, 61% [95% CI, 4%-86%]). VE against influenza hospitalization was 67% (95% CI, 50%-78%)., Conclusions: Influenza vaccination during pregnancy offers effective protection to infants <6 months, for whom vaccines are not currently available., Competing Interests: Potential conflicts of interest . During the conduct of this work, D. B. F. worked for the University of Ottawa and had academic appointments at the Children's Hospital of Eastern Ontario Research Institute and ICES; she is currently employed by Pfizer. K. W. is a cofounder and Chief Scientific Officer of CANImmunize, Inc; he served on the Independent Data Monitoring Committee for Medicago; and is a member of the Moderna Global Advisory Core Consultancy Group. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

May Measurement Month 2021 (MMM21) is the fourth edition of the global initiative in Poland initiated by the International Society of Hypertension (ISH) and aimed at raising awareness of hypertension and the need for blood pressure (BP) screening. An opportunistic cross-sectional survey of volunteers aged ≥18 was carried out in 132 sites - between May and September 2021. Blood pressure was measured in 1699 subjects (mean age: 40.8 ± 17.0 years; 68.8% females). After multiple imputation, the age and sex standardized systolic and diastolic BP was 126.6/78.7 mmHg for the entire group, 133.8/81.9 mmHg in individuals on antihypertensive medication, and 125.4/78.6 mmHg in those not taking antihypertensive drugs. The proportion of subjects with high BP (≥140/90 mmHg) were: 30.9% for the entire group, 40.4% in subjects taking antihypertensive drugs, and 17.9% in those not taking antihypertensive drugs. Of all participants, 33.9% were in the age range of 18-29 years and we observed higher BP levels and more frequent BP elevation in males in this age group. These data provide unique insights into the hypertension rates during the COVID-19 pandemic. Due to the associated restrictions, only limited data could be obtained for older adults. Interestingly, among young Polish participants, the rate of hypertension and the level of BP were higher in males compared to females, suggestive perhaps of a higher susceptibility of males to experience a rise in BP during specific circumstances associated with a pandemic., Competing Interests: Conflict of interest: All co-authors none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Root hairs have become an important model system for studying plant growth, and in particular how plants modulate their growth in response to cell-intrinsic and environmental stimuli. In this review, we discuss recent advances in our understanding of the molecular mechanisms underlying the growth of Arabidopsis root hairs in the interface between responses to environmental cues (e.g. nutrients such as nitrates and phosphate, and microorganisms) and hormonal stimuli (e.g. auxin). Growth of root hairs is under the control of several transcription factors that are also under strong regulation at different levels. We highlight recent new discoveries along these transcriptional pathways that might have the potential to increase our capacity to enhance nutrient uptake by the roots in the context of abiotic stresses. We use the text-mining capacities of the PlantConnectome database to generate an up-to-date view of root hairs growth within these complex biological contexts., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Experimental Biology. 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.)

Background: The time following a recent onset of psychosis is a critical period during which intervention may be maximally effective. Studying individuals in this period also offers an opportunity to investigate putative brain biomarkers of illness prior to the long-term effects of chronicity and medication. The Human Connectome Project for Early Psychosis (HCP-EP) was funded by the National Institutes of Mental Health (NIMH) as an extension of the original Human Connectome Project's approach to understanding the human brain and its structural and functional connections., Design: The HCP-EP data were collected at 3 sites in Massachusetts (Beth Israel Deaconess Medical Center, McLean Hospital, and Massachusetts General Hospital), and one site in Indiana (Indiana University). Brigham and Women's Hospital served as the data coordination center and as an imaging site., Results: The HCP-EP dataset includes high-quality clinical, cognitive, functional, neuroimaging, and blood specimen data acquired from 303 individuals between the ages of 16-35 years old with affective psychosis (n = 75), non-affective psychosis (n = 148), and healthy controls (n = 80). Participants with early psychosis were within 5 years of illness onset (mean duration = 1.9 years, standard deviation = 1.4 years). All data and novel or modified analytic tools developed as part of the study are publicly available to the research community through the NIMH Data Archive (NDA) or GitHub (https://github.com/pnlbwh)., Conclusions: This paper provides an overview of the specific HCP-EP procedures, assessments, and protocols, as well as a brief characterization of the study participants to make it easier for researchers to use this rich dataset. Although we focus here on discussing and comparing affective and non-affective psychosis groups, the HCP-EP dataset also provides sufficient information for investigators to group participants differently., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. 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.)

Homologous recombination involves the formation of branched DNA molecules that may interfere with chromosome segregation. To resolve these persistent joint molecules, cells rely on the activation of structure-selective endonucleases (SSEs) during the late stages of the cell cycle. However, the premature activation of SSEs compromises genome integrity, due to untimely processing of replication and/or recombination intermediates. Here, we used a biochemical approach to show that the budding yeast SSEs Mus81 and Yen1 possess the ability to cleave the central recombination intermediate known as the displacement loop or D-loop. Moreover, we demonstrate that, consistently with previous genetic data, the simultaneous action of Mus81 and Yen1, followed by ligation, is sufficient to recreate the formation of a half-crossover precursor in vitro. Our results provide not only mechanistic explanation for the formation of a half-crossover, but also highlight the critical importance for precise regulation of these SSEs to prevent chromosomal rearrangements., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Aims: Sufficient survival time following left atrial appendage occlusion (LAAO) is essential for ensuring the efficacy and cost-effectiveness of this strategy for stroke prevention. Understanding prognostic factors for early mortality after LAAO could optimize patient selection. In the current study, we perform an in-depth analysis of 2-year mortality after LAAO, focusing particularly on potential predictors., Methods and Results: The EWOLUTION registry is a real-world cohort comprising 1020 patients that underwent LAAO. Endpoint definitions were pre-specified, and death was categorized as cardiovascular, non-cardiovascular, or unknown origin. Mortality rates were calculated from Kaplan-Meier estimates. Baseline characteristics significantly associated with death in univariate Cox regression analysis were incorporated into the multivariate analysis. All multivariate predictors were included in a risk model. Two-year mortality rate was 16.4% [confidence interval (CI): 14.0-18.7%], with 50% of patients dying from a non-cardiovascular cause. Multivariate baseline predictors of 2-year mortality included age [hazard ratio (HR) 1.05, CI: 1.03-1.08, per year increase], heart failure (HR 1.73, CI: 1.24-2.41), vascular disease (HR 1.47, CI: 1.05-2.05), valvular disease (HR 1.63, CI: 1.15-2.33), abnormal liver function (HR 1.80, CI: 1.02-3.17), and abnormal renal function (HR 1.58, CI: 1.10-2.27). Mortality rate exhibited a gradual rise as the number of risk factors increased, reaching 46.1% in patients presenting with five or six risk factors., Conclusion: One in six patients died within 2 years after LAAO. We identified six independent predictors of mortality. When combined, this model showed a gradual increase in mortality rate with a growing number of risk factors, which may guide appropriate patient selection for LAAO., Clinical Trial Registration: The original EWOLUTION registry was registered at clinicaltrials.gov under identifier NCT01972282., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: Gender difference in the outcome after type A aortic dissection (TAAD) surgery remains an issue of ongoing debate. In this study, we aimed to evaluate the impact of gender on the short- and long-term outcome after surgery for TAAD., Methods: A multicentre European registry retrospectively included all consecutive TAAD surgery patients between 2005 and 2021 from 18 hospitals across 8 European countries. Early and late mortality, and cumulative incidence of aortic reoperation were compared between genders., Results: A total of 3902 patients underwent TAAD surgery, with 1185 (30.4%) being females. After propensity score matching, 766 pairs of males and females were compared. No statistical differences were detected in the early postoperative outcome between genders. Ten-year survival was comparable between genders (47.8% vs 47.1%; log-rank test, P = 0.679), as well as cumulative incidences of distal or proximal aortic reoperations. Ten-year relative survival compared to country-, year-, age- and sex-matched general population was higher among males (0.65) compared to females (0.58). The time-period subanalysis revealed advancements in surgical techniques in both genders over the years. However, an increase in stroke was observed over time for both populations, particularly among females., Conclusions: The past 16 years have witnessed marked advancements in surgical techniques for TAAD in both males and females, achieving comparable early and late mortality rates. Despite these findings, late relative survival was still in favour of males., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Gluteal augmentation with autologous fat grafting, colloquially referred to as Brazilian butt lift (BBL), is an increasingly common procedure with a highly reported complication profile., Objectives: In this study we aimed to analyze the prevalence and characteristics of complications that accompanied these surgeries at ambulatory surgery facilities., Methods: Adults patients who experienced fat grafting complications from 2019 to 2021 were identified in QUAD A, formerly known as the American Association for Accreditation of Ambulatory Surgery Facilities (AAAASF, Highland Park, IL, USA), database. Patients and complications were analyzed based on sociodemographic, surgery-, and facility-specific variables with descriptive statistics and logistic regression., Results: Overall, 436 fat grafting procedures with complications were reported to QUAD A, with an overall complication rate of 0.94%. Of these complications, 164 (37.6%) were confirmed to be from gluteal augmentation procedures. Notably, the number of gluteal augmentation with fat grafting complications decreased from the year 2019 (48) to 2020 (36), then nearly doubled from 2020 to 2021 (69). The majority of patients were female (96.7%), with a mean age of 42.0 years and a mean BMI of 28.3 kg/m2. Wound infection was the most commonly documented complication (22.3%). Of the patients who experienced complications, 35.9% presented to a hospital for their complications and 12.6% required reoperation. Four deaths were described. There was no association between sociodemographic or surgical variables and increased odds of readmission or reoperation (P > .05), except for increasing surgeon number and reoperation (P = .02)., Conclusions: Gluteal augmentation accounts for a large proportion of complications from fat grafting procedures. Increased reporting requirements may aid in future determination of incidences of complications and improve patient safety., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Aesthetic Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

MicroRNAs (miRNAs) that share identical or near-identical sequences constitute miRNA families and are predicted to act redundantly. Yet recent evidence suggests that members of the same miRNA family with high sequence similarity might have different roles and that this functional divergence might be rooted in their precursors' sequence. Current knock-down strategies such as antisense oligonucleotides (ASOs) or miRNA sponges cannot distinguish between identical or near identical miRNAs originating from different precursors to allow exploring unique functions of these miRNAs. We here develop a novel strategy based on short 2'-OMe/LNA-modified oligonucleotides to selectively target specific precursor molecules and ablate the production of individual members of miRNA families in vitro and in vivo. Leveraging the highly conserved Xenopus miR-181a family as proof-of-concept, we demonstrate that 2'-OMe/LNA-ASOs targeting the apical region of pre-miRNAs achieve precursor-selective inhibition of mature miRNA-5p production. Furthermore, we extend the applicability of our approach to the human miR-16 family, illustrating its universality in targeting precursors generating identical miRNAs. Overall, our strategy enables efficient manipulation of miRNA expression, offering a powerful tool to dissect the functions of identical or highly similar miRNAs derived from different precursors within miRNA families., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Objectives: Evidence on long-term clinical outcomes considering suture-securing techniques used for surgical aortic valve replacement is still uncertain., Methods: A total of 1405 patients who underwent surgical aortic valve replacement between January 2016 and December 2022 were included and grouped according to the suture-securing technique used (automated titanium fastener versus hand-tied knots). The occurrence of infective endocarditis during follow-up was set as the primary study end-point. As secondary study end-points, stroke, all-cause mortality and a composite outcome of either infective endocarditis, stroke, or all-cause mortality were assessed., Results: The automated titanium fastener was used in 829 (59%) patients, whereas the hand-knot tying technique was used in 576 (41%) patients. The multivariable proportional competing risk regression analysis showed a significantly lower risk of infective endocarditis during follow-up in the automated titanium fastener group (adjusted sub-hazard ratio 0.44, 95% confidence interval 0.20-0.94, P = 0.035). The automated titanium fastener group was not associated with an increased risk of mortality or attaining the composite outcome, respectively (adjusted hazard ratio 0.81, 95% confidence interval 0.60-1.09, P = 0.169; adjusted hazard ratio 0.82, 95% confidence interval 0.63-1.07, P = 0.152). This group was not associated with an increased risk of stroke (adjusted sub-hazard ratio 0.82, 95% confidence interval 0.47-1.45, P = 0.504). Also, a significantly lower rate of early-onset infective endocarditis was observed in the automated titanium fastener group, (0.4% vs 1.4%, P = 0.032)., Conclusions: Suture-securing with an automated titanium fastener device appears to be superior compared to the hand-knot tying technique in terms of lower risk of infective endocarditis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

MicroRNAs act via targeted suppression of messenger RNA translation in the DNA-RNA-protein axis. The dysregulation of microRNA(s) reflects the epigenetic changes affecting the cellular processes in multiple disorders. To understand the complex effect of dysregulated microRNAs linked to neurodegeneration, we performed a cross-sectional microRNA expression analysis in idiopathic Parkinson's disease ( n = 367), progressive supranuclear palsy ( n = 35) and healthy controls ( n = 416) from the Luxembourg Parkinson's Study, followed by prediction modelling, enriched pathway analysis and target simulation of dysregulated microRNAs using probabilistic Boolean modelling. Forty-six microRNAs were identified to be dysregulated in Parkinson's disease versus controls and 16 in progressive supranuclear palsy versus controls with 4 overlapping significantly dysregulated microRNAs between the comparisons. Predictive power of microRNA subsets (including up to 100 microRNAs) was modest for differentiating Parkinson's disease or progressive supranuclear palsy from controls (maximal cross-validated area under the receiver operating characteristic curve 0.76 and 0.86, respectively) and low for progressive supranuclear palsy versus Parkinson's disease (maximal cross-validated area under the receiver operating characteristic curve 0.63). The enriched pathway analysis revealed natural killer cell pathway to be dysregulated in both, Parkinson's disease and progressive supranuclear palsy versus controls, indicating that the immune system might play an important role in both diseases. Probabilistic Boolean modelling of pathway dynamics affected by dysregulated microRNAs in Parkinson's disease and progressive supranuclear palsy revealed partially overlapping dysregulation in activity of the transcription factor EB, endoplasmic reticulum stress signalling, calcium signalling pathway, dopaminergic transcription and peroxisome proliferator-activated receptor gamma coactivator-1α activity, though involving different mechanisms. These findings indicated a partially convergent (sub)cellular end-point dysfunction at multiple levels in Parkinson's disease and progressive supranuclear palsy, but with distinctive underlying molecular mechanisms., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Transcription factor RBPJ is the central component in Notch signal transduction and directly forms a coactivator complex together with the Notch intracellular domain (NICD). While RBPJ protein levels remain constant in most tissues, dynamic expression of Notch target genes varies depending on the given cell-type and the Notch activity state. To elucidate dynamic RBPJ binding genome-wide, we investigated RBPJ occupancy by ChIP-Seq. Surprisingly, only a small set of the total RBPJ sites show a dynamic binding behavior in response to Notch signaling. Compared to static RBPJ sites, dynamic sites differ in regard to their chromatin state, binding strength and enhancer positioning. Dynamic RBPJ sites are predominantly located distal to transcriptional start sites (TSSs), while most static sites are found in promoter-proximal regions. Importantly, gene responsiveness is preferentially associated with dynamic RBPJ binding sites and this static and dynamic binding behavior is repeatedly observed across different cell types and species. Based on the above findings we used a machine-learning algorithm to predict Notch responsiveness with high confidence in different cellular contexts. Our results strongly support the notion that the combination of binding strength and enhancer positioning are indicative of Notch responsiveness., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Extended aortic repair is considered a key issue for the long-term durability of surgery for DeBakey type 1 aortic dissection. The risk of aortic degeneration may be higher in young patients due to their long life expectancy. The early outcome and durability of aortic surgery in these patients were investigated in the present study., Methods: The subjects of the present analysis were patients under 60 years old who underwent surgical repair for acute DeBakey type 1 aortic dissection at 18 cardiac surgery centres across Europe between 2005 and 2021. Patients underwent ascending aortic repair or total aortic arch repair using the conventional technique or the frozen elephant trunk technique. The primary outcome was 5-year cumulative incidence of reoperation on the distal aorta., Results: Overall, 915 patients underwent surgical ascending aortic repair and 284 patients underwent surgical total aortic arch repair. The frozen elephant trunk procedure was performed in 128 patients. Among 245 propensity score-matched pairs, total aortic arch repair did not decrease the rate of distal aortic reoperation compared to ascending aortic repair (5-year cumulative incidence, 6.7% versus 6.7%, subdistributional hazard ratio 1.127, 95% c.i. 0.523 to 2.427). Total aortic arch repair increased the incidence of postoperative stroke/global brain ischaemia (25.7% versus 18.4%, P = 0.050) and dialysis (19.6% versus 12.7%, P = 0.003). Five-year mortality was comparable after ascending aortic repair and total aortic arch repair (22.8% versus 27.3%, P = 0.172)., Conclusions: In patients under 60 years old with DeBakey type 1 aortic dissection, total aortic arch replacement compared with ascending aortic repair did not reduce the incidence of distal aortic operations at 5 years. When feasible, ascending aortic repair for DeBakey type 1 aortic dissection is associated with satisfactory early and mid-term outcomes., Trial Registration: ClinicalTrials.gov Identifier: NCT04831073., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Bacteria have evolved structured RNAs that can associate with RNA polymerase (RNAP). Two of them have been known so far-6S RNA and Ms1 RNA but it is unclear if any other types of RNAs binding to RNAP exist in bacteria. To identify all RNAs interacting with RNAP and the primary σ factors, we have established and performed native RIP-seq in Bacillus subtilis, Corynebacterium glutamicum, Streptomyces coelicolor, Mycobacterium smegmatis and the pathogenic Mycobacterium tuberculosis. Besides known 6S RNAs in B. subtilis and Ms1 in M. smegmatis, we detected MTS2823, a homologue of Ms1, on RNAP in M. tuberculosis. In C. glutamicum, we discovered novel types of structured RNAs that associate with RNAP. Furthermore, we identified other species-specific RNAs including full-length mRNAs, revealing a previously unknown landscape of RNAs interacting with the bacterial transcription machinery., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Motivation: ITree is an intuitive web tool for the manual, semi-automatic, and automatic induction of decision trees. It enables interactive modifications of tree structures and incorporates Relative Expression Analysis for detecting complex patterns in high-throughput molecular data. This makes ITree a versatile tool for both research and education in biomedical data analysis., Results: The tool allows users to instantly see the effects of modifications on decision trees, with updates to predictions and statistics displayed in real time, facilitating a deeper understanding of data classification processes., Availability and Implementation: Available online at https://itree.wi.pb.edu.pl. Source code and documentation are hosted on GitHub at https://github.com/hsokolowski/iTree and in supplement., (© The Author(s) 2024. Published by Oxford University Press.)

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

This study compared computational approaches to parallelization of an SNP calling workflow. The data comprised DNA from five Holstein-Friesian cows sequenced with the Illumina platform. The pipeline consisted of quality control, alignment to the reference genome, post-alignment, and SNP calling. Three approaches to parallelization were compared: (i) a plain Bash script in which a pipeline for each cow was executed as separate processes invoked at the same time, (ii) a Bash script wrapped in a single Nextflow process and (iii) a Nextflow script with each component of the pipeline defined as a separate process. The results demonstrated that on average, the multi-process Nextflow script performed 15-27% faster depending on the number of assigned threads, with the biggest execution time advantage over the plain Bash approach observed with 10 threads. In terms of RAM usage, the most substantial variation was observed for the multi-process Nextflow, for which it increased with the number of assigned threads, while RAM consumption of the other setups did not depend much on the number of threads assigned for computations. Due to intermediate and log files generated, disk usage was markedly higher for the multi-process Nextflow than for the plain Bash and for the single-process Nextflow., (© The Author(s) 2024. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Objective: To introduce 2 R-packages that facilitate conducting health economics research on OMOP-based data networks, aiming to standardize and improve the reproducibility, transparency, and transferability of health economic models., Materials and Methods: We developed the software tools and demonstrated their utility by replicating a UK-based heart failure data analysis across 5 different international databases from Estonia, Spain, Serbia, and the United States., Results: We examined treatment trajectories of 47 163 patients. The overall incremental cost-effectiveness ratio (ICER) for telemonitoring relative to standard of care was 57 472 €/QALY. Country-specific ICERs were 60 312 €/QALY in Estonia, 58 096 €/QALY in Spain, 40 372 €/QALY in Serbia, and 90 893 €/QALY in the US, which surpassed the established willingness-to-pay thresholds., Discussion: Currently, the cost-effectiveness analysis lacks standard tools, is performed in ad-hoc manner, and relies heavily on published information that might not be specific for local circumstances. Published results often exhibit a narrow focus, central to a single site, and provide only partial decision criteria, limiting their generalizability and comprehensive utility., Conclusion: We created 2 R-packages to pioneer cost-effectiveness analysis in OMOP CDM data networks. The first manages state definitions and database interaction, while the second focuses on Markov model learning and profile synthesis. We demonstrated their utility in a multisite heart failure study, comparing telemonitoring and standard care, finding telemonitoring not cost-effective., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Background: Most longitudinal studies found heightened feelings of loneliness in older people in spring 2020 compared to times before the pandemic. However, longer-term effects are more disputed. We, therefore, investigated changes in loneliness in older people throughout the first 21 months of the COVID-19 pandemic in Switzerland and examined the association between the stringency of COVID-19 measures and feelings of loneliness., Methods: We assessed loneliness (3-item University of California Los Angeles (UCLA) loneliness scale) in a nationally representative longitudinal observational online survey. Older people (65-79 years) were surveyed between March 2020 and December 2021. Proportions of people feeling lonely (UCLA loneliness scale >6) were compared in two stringent phases ('lockdown', Oxford University stringency index ≥55) and two less restricted phases. Additionally, we explored the situation of potentially more susceptible subgroups (living alone, women, chronic and mental diseases, low educational level and low income)., Results: Phases with stringent measures were associated with higher levels of loneliness in older people. People living alone, women, people with noncommunicable or mental disease diagnoses and lower income show consistently higher levels of loneliness. However, the differences are not accentuated in phases with more stringent measures. We found little differences between subgroups with varying educational levels., Conclusions: Even in a country with relatively less stringent COVID-19 measures like Switzerland, an increase in the proportion of older people that feel lonely could be found during phases with more stringent COVID-19 measures. Lockdown phases should, therefore, be accompanied by evidence-based interventions to relieve loneliness to avoid adverse short- and long-term consequences., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

A significant proportion of patients who suffer from atrial fibrillation (AF) and are in need of thromboembolic protection are not treated with oral anticoagulation or discontinue this treatment shortly after its initiation. This undertreatment has not improved sufficiently despite the availability of direct oral anticoagulants which are associated with less major bleeding than vitamin K antagonists. Multiple reasons account for this, including bleeding events or ischaemic strokes whilst on anticoagulation, a serious risk of bleeding events, poor treatment compliance despite best educational attempts, or aversion to drug therapy. An alternative interventional therapy, which is not associated with long-term bleeding and is as effective as vitamin K anticoagulation, was introduced over 20 years ago. Because of significant improvements in procedural safety over the years, left atrial appendage closure, predominantly achieved using a catheter-based, device implantation approach, is increasingly favoured for the prevention of thromboembolic events in patients who cannot achieve effective anticoagulation. This management strategy is well known to the interventional cardiologist/electrophysiologist but is not more widely appreciated within cardiology or internal medicine. This article introduces the devices and briefly explains the implantation technique. The indications and device follow-up are more comprehensively described. Almost all physicians who care for adult patients will have many with AF. This practical guide, written within guideline/guidance boundaries, is aimed at those non-implanting physicians who may need to refer patients for consideration of this new therapy, which is becoming increasingly popular., Competing Interests: Conflict of interest: C.B.: none declared. R.B.: personal fees from Bayer, Bristol-Myers Squibb, LEO-Pharma, Pfizer, VIATRIS, and research support by the Bavarian State Ministry of Health; CPC University of Colorado; FADOI, Italy. S.Be.: proctor and speaker fees from Boston Scientific, Edwards, Abbott, fees go to the department. S.Bi.: none declared. L.V.A.B.: consultant for Medtronic, Boston Scientific, Adagio, and ACUTUS, fees go to the department. G.B.: speaker fees from Bayer, Boehringer Ingelheim, Boston Scientific, Daiichi-Sankyo, Janssen, and Sanofi. S.Bo.: Consultant for Medtronic, Boston Scientific, Microport, and Zoll. A.J.C.: personal fees from Abbott, Boston Scientific, Medtronic, Pfizer/BMS, Daiichi Sankyo, Bayer and Sanofi. T.D.P.: no personal disclosures to report. Consultancy activity for Boston Scientific, invoiced through institutional research fund. W.D.: consulting and speaker fees from Ai Mediq, Bayer, Boehringer Ingelheim, Medtronic, Boston Scientific, Vifor Pharma; travel support from Pharmacosmos; research support from EU (Horizon2020), German Ministry of Education and Research, German Center for Cardiovascular Research, Vifor Pharma. S.G.: consulting and speaker fees from Boston Scientific. M.G.: Advisory Board Member for Boston Scientific; proctor for Boston Scientific, Abbott; fees for lectures and travel grants: from Boston Scientific, Abbott, Occlutech, Pfizer. K.G.H.: speaker’s honoraria, consulting fees, lecture honoraria and/or study grants from Abbott, Amarin; Alexion, AstraZeneca, Bayer Healthcare, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi-Sankyo, Edwards Lifesciences, Medtronic, Novartis, Pfizer, Portola, Premier Research, Sanofi, SUN Pharma, and W.L. Gore and Associates. J.E.N.-K.: consultant to Boston Scientific, Medtronic, Edwards Lifesciences, Picardia, Venus Medtech, speaker for Abbott. U.L.: research grant to institution from Abbott, Bayer, speaker or consulting honorary from Abbott, Boston Scientific, Bayer; Pfizer, Daiichi-Sankyo. G.Y.H.L.: consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Anthos. No fees are received personally. National Institute for Health and Care Research (NIHR) Senior Investigator and co-principal investigator of the AFFIRMO project on multi-morbidity in AF, funded from the European Union's Horizon 2020 research and innovation programme under grant agreement no. 899871. J.E.N.-K.: research grants from Abbott, Boston Scientific, Novo Nordic Foundation. J.E.N.-K.: research grants from Abbott, Boston Scientific, Novo Nordic Foundation. E.M.: research grants from Abbott, Biotronik, Boston Scientific, Medtronic, MicroPort, and Zoll. Consultant and speaker fees from Abbott, Abbott, Medtronic, and Zoll. J.E.N.-K.: research grants from Abbott, Boston Scientific, Novo Nordic Foundation. P.O.: speaking honoraria from Bayer, Abbott, Boston Scientific. T.P.: none declared. B.S.: consultant and speaker for Bostin Scientific, Abbott, Medtronic, Biosense Webster. M.S.: none declared. R.B.S. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme under the grant agreement no. 648131, from the European Union's Horizon 2020 research and innovation programme under the grant agreement no. 847770 (AFFECT-EU) and German Center for Cardiovascular Research (DZHK e.V.) (81Z1710103 and 81Z0710114); German Ministry of Research and Education (BMBF 01ZX1408A) and ERACoSysMed3 (031L0239); Wolfgang Seefried project funding German Heart Foundation; lecture fees and advisory board fees from BMS/Pfizer and Novartis outside this work. C.T.: advisory board member of Boston Scientific; proctor for Boston Scientific and Abbott; fees for lectures and travel grants from Boston Scientific and Abbott. A portion of the fees goes to the institute. A.T.: consultant and proctor for Abbott, consultant for Boston Scientific and Pie Medical., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Changes in the hippocampus after brain metastases radiotherapy can significantly impact neurocognitive functions. Numerous studies document hippocampal atrophy correlating with the radiation dose. This study aims to elucidate volumetric changes in patients undergoing whole-brain radiotherapy (WBRT) or targeted stereotactic radiotherapy (SRT) and to explore volumetric changes in the individual subregions of the hippocampus., Method: Ten patients indicated to WBRT and 18 to SRT underwent brain magnetic resonance before radiotherapy and after 4 months. A structural T1-weighted sequence was used for volumetric analysis, and the software FreeSurfer was employed as the tool for the volumetry evaluation of 19 individual hippocampal subregions., Results: The volume of the whole hippocampus, segmented by the software, was larger than the volume outlined by the radiation oncologist. No significant differences in volume changes were observed in the right hippocampus. In the left hippocampus, the only subregion with a smaller volume after WBRT was the granular cells and molecular layers of the dentate gyrus (GC-ML-DG) region (median change -5 mm 3 , median volume 137 vs. 135 mm 3 ; P  = .027), the region of the presumed location of neuronal progenitors., Conclusions: Our study enriches the theory that the loss of neural stem cells is involved in cognitive decline after radiotherapy, contributes to the understanding of cognitive impairment, and advocates for the need for SRT whenever possible to preserve cognitive functions in patients undergoing brain radiotherapy., Competing Interests: The authors declare no conflict of interest. The funders had no role in the writing of the manuscript and in the decision to publish this article., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Aims: While heart failure (HF) symptoms are associated with adverse prognosis after myocardial infarction (MI), they are not routinely used for patients' stratification. The primary objective of this study was to develop and validate a score to predict mortality risk after MI, combining remotely recorded HF symptoms and clinical risk factors, and to compare it against the guideline-recommended GRACE score., Methods: A cohort study design using prospectively collected data from consecutive patients hospitalized for MI at a large tertiary heart centre between June 2017 and September 2022 was used., Results: Data from 1,135 patients (aged 64±12 years, 26.7% women), were split into derivation (70%) and validation cohort (30%). Components of the 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ) questionnaire and clinical variables were used as possible predictors. The best model included the following variables - age, heart failure history, admission creatinine and heart rate, ejection fraction at hospital discharge, and HF symptoms 1 month after discharge including walking impairment, leg swelling, and change in HF symptoms. Based on these variables, the PragueMi score was developed. In the validation cohort, the PragueMi score showed superior discrimination to the GRACE score for 6 months (AUC 90.1, 95% CI 81.8-98.4 vs. 77.4, 95% CI 62.2-92.5, p=0.04) and 1-year risk prediction (AUC 89.7, 95% CI 83.5-96.0 vs. 76.2, 95% CI 64.7-87.7, p=0.004)., Conclusion: The PragueMi score combining heart failure symptoms and clinical variables performs better than the currently recommended GRACE score., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Hypolimnas misippus is a Batesian mimic of the toxic African Queen butterfly (Danaus chrysippus). Female H. misippus butterflies use two major wing patterning loci (M and A) to imitate three color morphs of D. chrysippus found in different regions of Africa. In this study, we examine the evolution of the M locus and identify it as an example of adaptive atavism. This phenomenon involves a morphological reversion to an ancestral character that results in an adaptive phenotype. We show that H. misippus has re-evolved an ancestral wing pattern present in other Hypolimnas species, repurposing it for Batesian mimicry of a D. chrysippus morph. Using haplotagging, a linked-read sequencing technology, and our new analytical tool, Wrath, we discover two large transposable element insertions located at the M locus and establish that these insertions are present in the dominant allele responsible for producing mimetic phenotype. By conducting a comparative analysis involving additional Hypolimnas species, we demonstrate that the dominant allele is derived. This suggests that, in the derived allele, the transposable elements disrupt a cis-regulatory element, leading to the reversion to an ancestral phenotype that is then utilized for Batesian mimicry of a distinct model, a different morph of D. chrysippus. Our findings present a compelling instance of convergent evolution and adaptive atavism, in which the same pattern element has independently evolved multiple times in Hypolimnas butterflies, repeatedly playing a role in Batesian mimicry of diverse model species., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Objectives: The aim of this study was to evaluate in-hospital outcomes and long-term survival of patients undergoing cardiac surgery with preoperative atrial fibrillation (AF). We compared different strategies, including no-AF treatment, left atrial appendage occlusion (LAAO) alone, concomitant surgical ablation (SA) alone or both., Methods: A retrospective analysis using the KROK registry included all patients with preoperative diagnosis of AF who underwent cardiac surgery in Poland between between January 2012 and December 2022. Risk adjustment was performed using regression analysis with inverse probability weighting of propensity scores. We assessed 6-year survival with Cox proportional hazards models. Sensitivity analysis was performed based on index cardiac procedure., Results: Initially, 42 510 patients with preoperative AF were identified, and, after exclusion, 33 949 included in the final analysis. A total of 1107 (3.26%) received both SA and LAAO, 1484 (4.37%) received LAAO alone, 3921 (11.55%) SA alone and the remaining 27 437 (80.82%) had no AF-directed treatment. As compared to no treatment, all strategies were associated with survival benefit over 6-year follow-up. A gradient of treatment was observed with the highest benefit associated with SA + LAAO followed by SA alone and LAAO alone (log-rank P < 0.001). Mortality benefits were reflected when stratified by surgery type with the exception of aortic valve surgery where LAAO alone fare worse than no treatment., Conclusions: Among patients with preoperative AF undergoing cardiac surgery, surgical management of AF, particularly SA + LAAO, was associated with lower 6-year mortality. These findings support the benefits of incorporating SA and LAAO in the management of AF during cardiac surgery., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

More than a decade after the Consolidated Standards of Reporting Trials group released a reporting items checklist for non-inferiority randomized controlled trials, the infectious diseases literature continues to underreport these items. Trialists, journals, and peer reviewers should redouble their efforts to ensure infectious diseases studies meet these minimum reporting standards., Competing Interests: Potential conflicts of interest . A. K. K. reports receipt of an honorarium from Gilead for a regional review lecture on the Conference on Retroviruses and Opportunistic Infections; M. S. reports grant funding unrelated to this publication from the Canadian Institutes of Health Research and Air Canada (COVID-19 in International Travelers Study: staff and reagent costs), and the Ontario Research Fund for COVID research (COVID Automation: equipment costs); and M. L. reports a contract with the WHO to help update antibiotics in the Essential Medicines List. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

DNA polymerases synthesize DNA from deoxyribonucleotides in a semiconservative manner and serve as the core of DNA replication and repair machinery. In eukaryotic cells, there are 2 genome-containing organelles, mitochondria, and plastids, which were derived from an alphaproteobacterium and a cyanobacterium, respectively. Except for rare cases of genome-lacking mitochondria and plastids, both organelles must be served by nucleus-encoded DNA polymerases that localize and work in them to maintain their genomes. The evolution of organellar DNA polymerases has yet to be fully understood because of 2 unsettled issues. First, the diversity of organellar DNA polymerases has not been elucidated in the full spectrum of eukaryotes. Second, it is unclear when the DNA polymerases that were used originally in the endosymbiotic bacteria giving rise to mitochondria and plastids were discarded, as the organellar DNA polymerases known to date show no phylogenetic affinity to those of the extant alphaproteobacteria or cyanobacteria. In this study, we identified from diverse eukaryotes 134 family A DNA polymerase sequences, which were classified into 10 novel types, and explored their evolutionary origins. The subcellular localizations of selected DNA polymerases were further examined experimentally. The results presented here suggest that the diversity of organellar DNA polymerases has been shaped by multiple transfers of the PolI gene from phylogenetically broad bacteria, and their occurrence in eukaryotes was additionally impacted by secondary plastid endosymbioses. Finally, we propose that the last eukaryotic common ancestor may have possessed 2 mitochondrial DNA polymerases, POP, and a candidate of the direct descendant of the proto-mitochondrial DNA polymerase I, rdxPolA, identified in this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

BloodSpot is a specialised database integrating gene expression data from acute myeloid leukaemia (AML) patients related to blood cell development and maturation. The database and interface has helped numerous researchers and clinicians to quickly get an overview of gene expression patterns in healthy and malignant haematopoiesis. Here, we present an update to our framework that includes protein expression data of sorted single cells. With this update we also introduce datasets broadly spanning age groups, which many users have requested, with particular interest for researchers studying paediatric leukaemias. The backend of the database has been rewritten and migrated to a cloud-based environment to accommodate the growth, and provide a better user-experience for our many international users. Users can now enjoy faster transfer speeds and a more responsive interface. In conclusion, the continuing popularity of the database and emergence of new data modalities has prompted us to rewrite and futureproof the back-end, including paediatric centric views, as well as single cell protein data, allowing us to keep the database updated and relevant for the years to come. The database is freely available at www.bloodspot.eu., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Amikacin monotherapy is recommended for urinary tract infection (UTI) treatment with multi-resistant pathogens. Even though amikacin efficacy in the treatment of UTIs is dependent on its urinary concentration, there are no robust data proving that sufficiently high urinary concentration is reached in patients with reduced glomerular filtration rate (GFR)., Methods: A prospective study to monitor amikacin penetration into urine of 70 patients [40 males, median (interquartile range) age 70 (65-79) years] with different levels of glomerular filtration decline, including patients treated by dialysis, was conducted. The bactericidal efficacy of amikacin in urine samples has been evaluated., Results: Patients with estimated GFR (eGFR) <30 mL/min had significantly lower median amikacin urinary concentration than patients with eGFR >30 mL/min (89.75 vs 186.0 mg/L, P  < .0001; 200.5 vs 830.0 mg/L, P  < .0001; and 126.0 vs 408.0 mg/L, P  < .0001 for minimal, maximal and minimal together with maximal concentrations, respectively). The amount of amikacin eliminated in the first 10-13 h after dose administration was dependent on eGFR (r 2  = 0.6144, P  < .0001). The urinary concentration of amikacin in patients treated by dialysis was indirectly proportional to pH of urine. The plasma concentrations of amikacin did not correlate with urinary levels in patients in either of the GFR categories. Microbiological evaluation showed that the critical urinary concentration for efficacy of amikacin during UTI monotherapy in patients treated by dialysis is 100 mg/L. We found that 4 out of 11 patients treated by dialysis did not reach this level during the treatment., Conclusion: Systemic administration of amikacin monotherapy in patients treated by dialysis is questionable as the concentrations of amikacin in their urine are often below the threshold of effectivity. Amikacin plasma concentrations are not a major determinant of amikacin concentration in urine, therefore pulse dosing is neither necessary nor safe in patients treated by dialysis, and may cause undesirable toxicity., Competing Interests: The authors declare they do not have any conflict of interest regarding this article., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

The escape of DNA from mitochondria into the nuclear genome (nuclear mitochondrial DNA, NUMT) is an ongoing process. Although pervasively observed in eukaryotic genomes, their evolutionary trajectories in a mammal-wide context are poorly understood. The main challenge lies in the orthology assignment of NUMTs across species due to their fast evolution and chromosomal rearrangements over the past 200 million years. To address this issue, we systematically investigated the characteristics of NUMT insertions in 45 mammalian genomes and established a novel, synteny-based method to accurately predict orthologous NUMTs and ascertain their evolution across mammals. With a series of comparative analyses across taxa, we revealed that NUMTs may originate from nonrandom regions in mtDNA, are likely found in transposon-rich and intergenic regions, and unlikely code for functional proteins. Using our synteny-based approach, we leveraged 630 pairwise comparisons of genome-wide microsynteny and predicted the NUMT orthology relationships across 36 mammals. With the phylogenetic patterns of NUMT presence-and-absence across taxa, we constructed the ancestral state of NUMTs given the mammal tree using a coalescent method. We found support on the ancestral node of Fereuungulata within Laurasiatheria, whose subordinal relationships are still controversial. This study broadens our knowledge on NUMT insertion and evolution in mammalian genomes and highlights the merit of NUMTs as alternative genetic markers in phylogenetic inference., Competing Interests: Conflict of Interest The authors declare no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Aims: Transoesophageal echocardiography (TOE) is often performed before catheter ablation or cardioversion to rule out the presence of left atrial appendage thrombus (LAT) in patients on chronic oral anticoagulation (OAC), despite associated discomfort. A machine learning model [LAT-artificial intelligence (AI)] was developed to predict the presence of LAT based on clinical and transthoracic echocardiography (TTE) features., Methods and Results: Data from a 13-site prospective registry of patients who underwent TOE before cardioversion or catheter ablation were used. LAT-AI was trained to predict LAT using data from 12 sites (n = 2827) and tested externally in patients on chronic OAC from two sites (n = 1284). Areas under the receiver operating characteristic curve (AUC) of LAT-AI were compared with that of left ventricular ejection fraction (LVEF) and CHA2DS2-VASc score. A decision threshold allowing for a 99% negative predictive value was defined in the development cohort. A protocol where TOE in patients on chronic OAC is performed depending on the LAT-AI score was validated in the external cohort. In the external testing cohort, LAT was found in 5.5% of patients. LAT-AI achieved an AUC of 0.85 [95% confidence interval (CI): 0.82-0.89], outperforming LVEF (0.81, 95% CI 0.76-0.86, P < .0001) and CHA2DS2-VASc score (0.69, 95% CI: 0.63-0.7, P < .0001) in the entire external cohort. Based on the proposed protocol, 40% of patients on chronic OAC from the external cohort would safely avoid TOE., Conclusion: LAT-AI allows accurate prediction of LAT. A LAT-AI-based protocol could be used to guide the decision to perform TOE despite chronic OAC., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

It is well established that right ventricular pacing is detrimental in patients with reduced cardiac function who require ventricular pacing (VP), and alternatives nowadays are comprised of biventricular pacing (BiVP) and conduction system pacing (CSP). The latter modality is of particular interest in patients with a narrow baseline QRS as it completely avoids, or minimizes, ventricular desynchronization associated with VP. In this article, experts debate whether BiVP or CSP should be used to treat these patients., Competing Interests: Conflict of interest: H.B. has received institutional research and fellowship support and/or speaker fees from Abbott, Biotronik, Boston Scientific, Medtronic, Microport. M.G. is on an advisory board of Medtronic and received speaker fees from Abbott. M.R.G. has received institutional research support from Abbott and Boston Scientific, Medtronic and consulting fees from Boston Scientific and Medtronic. M.J. has received speaker/consultant fees from Medtronic, Abbott and Biotronik. K.E. has not reported any disclosures., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)