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After almost twenty years of intense work on the celebrated LaAlO3/SrTiO3system, the recent discovery of a superconducting two-dimensional electron gas (2-DEG) in (111)-oriented KTaO3-based heterostructures injects new momentum to the field of oxides interface. However, while both interfaces share common properties, experiments also suggest important differences between the two systems. Here, we report gate tunable superconductivity in 2-DEGs generated at the surface of a (111)-oriented KTaO3 crystal by the simple sputtering of a thin Al layer. We extract the superfluid stiffness of the 2-DEGs and show that its temperature dependence is consistent with a node-less superconducting order parameter having a gap value larger than expected within a simple BCS weak-coupling limit model. The superconducting transition follows the Berezinskii-Kosterlitz-Thouless scenario, which was not reported on SrTiO3-based interfaces. Our finding offers innovative perspectives for fundamental science but also for device applications in a variety of fields such as spin-orbitronics and topological electronics. Heterostructures based on (111)-oriented KTaO3crystals are a new platform for studying oxide interfaces. Gate-tunable superconductivity in 2D electron gases at the surface of (111)-oriented KTaO3is now reported, with the superconducting transition being of the Berezinskii-Kosterlitz-Thouless type. [ABSTRACT FROM AUTHOR]

During mitosis in eukaryotic cells, mechanical forces generated by the mitotic spindle pull the sister chromatids into the nascent daughter cells. How do mitotic chromosomes achieve the necessary mechanical stiffness and stability to maintain their integrity under these forces? Here we use optical tweezers to show that ions involved in physiological chromosome condensation are crucial for chromosomal stability, stiffness and viscous dissipation. We combine these experiments with high-salt histone depletion and theory to show that chromosomal elasticity originates from the chromatin fibre behaving as a flexible polymer, whereas energy dissipation can be explained by modelling chromatin loops as an entangled polymer solution. Taken together, we show how collective properties of mitotic chromosomes, a biomaterial of incredible complexity, emerge from molecular properties, and how they are controlled by the physico-chemical environment., (© 2024. The Author(s).)

A quantitative description of nuclear mechanics is crucial for understanding its role in force sensing within eukaryotic cells. Recent studies indicate that the chromatin within the nucleus cannot be treated as a homogeneous material. To elucidate its material properties, we combine optical tweezers manipulation of isolated nuclei with multi-color fluorescence imaging of lamin and chromatin to map the response of nuclei to local deformations. Force spectroscopy reveals nuclear strain stiffening and an exponential force dependence, well described by a hierarchical chain model. Simultaneously, fluorescence data show a higher compliance of chromatin compared to the nuclear envelope at strains <30%. Micrococcal nuclease (MNase) digestion of chromatin results in nuclear softening and can be captured by our model. Additionally, we observe stretching responses showing a lipid tether signature, suggesting that these tethers originate from the nuclear membrane. Our combined approach allows us to elucidate the nuclear force response while mapping the deformation of lamin, (eu)chromatin, and membrane., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Abstract: Background: The recruitment of neutrophils to sites of localized injury or infection is initiated by changes on the surface of endothelial cells located in proximity to tissue damage. Inflammatory mediators, such as TNF-α, increase surface expression of adhesive ligands and receptors on the endothelial surface to which neutrophils tether and adhere. Neutrophils then transit through the activated endothelium to reach sites of tissue injury with little lasting vascular injury. However, in cases of sepsis, the interaction of endothelial cells with highly activated neutrophils can cause damage vascular damage. The identification of molecules that are essential for neutrophil diapedesis may reveal targets of therapeutic opportunity for preservation of endothelial function in the presence of critical illness. We tested the hypothesis that inhibition of neutrophil β1 integrin very late antigen-3 (VLA-3; α3β1) and/or inhibition of the tetraspanin (TM4) family member CD151 would protect against neutrophil-mediated loss of endothelial function. Methods: Blood was obtained from septic patients or healthy donors. Neutrophils were purified, and aliquots were treated with/without proinflammatory molecules. Confluent human umbilical vascular endothelial cells were activated with TNF-α. Electric cell impedance sensing was used to determine monolayer resistance over time after the addition of neutrophils that were treated with blocking antibodies against VLA-3 and/or CD151 or isotype controls. Groups (depending on relevancy) were analyzed by Mann-Whitney U test, Wilcoxon test, or repeated-measures one-way ANOVA. Results: Neutrophils from septic patients and neutrophils activated ex vivo reduced endothelial monolayer resistance to a greater extent than neutrophils from healthy donors. Antibody blockade of VLA-3 and/or CD151 significantly reduced activation-associated endothelial damage. Similar findings were demonstrated on fibronectin, collagen I, collagen IV, and laminin, suggesting that neutrophil surface VLA-3 and CD151 are responsible for endothelial damage regardless of substrata and are likely to be operative in all bodily tissues. Conclusion: This report identifies VLA-3 and CD151 on the activated human neutrophil, which are responsible for damage to endothelial function. Targeting these molecules in vivo may demonstrate preservation of organ function during critical illness., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

In the context of soft matter and cellular mechanics, microrheology - the use of micron-sized particles to probe the frequency-dependent viscoelastic response of materials - is widely used to shed light onto the mechanics and dynamics of molecular structures. Here we present the implementation of active microrheology in an Acoustic Force Spectroscopy setup (AFMR), which combines multiplexing with the possibility of probing a wide range of forces ( ~ pN to ~nN) and frequencies (0.01-100 Hz). To demonstrate the potential of this approach, we perform active microrheology on biological samples of increasing complexity and stiffness: collagen gels, red blood cells (RBCs), and human fibroblasts, spanning a viscoelastic modulus range of five orders of magnitude. We show that AFMR can successfully quantify viscoelastic properties by probing many beads with high single-particle precision and reproducibility. Finally, we demonstrate that AFMR to map local sample heterogeneities as well as detect cellular responses to drugs., (© 2024. The Author(s).)

Aims: Recent trial data demonstrate beneficial effects of active rhythm management in patients with atrial fibrillation (AF) and support the concept that a low arrhythmia burden is associated with a low risk of AF-related complications. The aim of this document is to summarize the key outcomes of the 9th AFNET/EHRA Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA)., Methods and Results: Eighty-three international experts met in Münster for 2 days in September 2023. Key findings are as follows: (i) Active rhythm management should be part of the default initial treatment for all suitable patients with AF. (ii) Patients with device-detected AF have a low burden of AF and a low risk of stroke. Anticoagulation prevents some strokes and also increases major but non-lethal bleeding. (iii) More research is needed to improve stroke risk prediction in patients with AF, especially in those with a low AF burden. Biomolecules, genetics, and imaging can support this. (iv) The presence of AF should trigger systematic workup and comprehensive treatment of concomitant cardiovascular conditions. (v) Machine learning algorithms have been used to improve detection or likely development of AF. Cooperation between clinicians and data scientists is needed to leverage the potential of data science applications for patients with AF., Conclusions: Patients with AF and a low arrhythmia burden have a lower risk of stroke and other cardiovascular events than those with a high arrhythmia burden. Combining active rhythm control, anticoagulation, rate control, and therapy of concomitant cardiovascular conditions can improve the lives of patients with AF., Competing Interests: Conflict of interest The 9th AFNET/EHRA consensus conference was partially supported by the European Union MAESTRIA project (grant agreement 965286) to AFNET. The following participants and authors are employees of companies active in cardiovascular health as indicated in their affiliations: M.D.M., E.D., C.E., G.H., L.H.H., T.H., R.H.v.L., M.W., and H.W. P.K. was partially supported by the European Union AFFECT-AF (grant agreement 847770) and MAESTRIA (grant agreement 965286), German Center for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK, grant numbers DZHK FKZ 81X2800182, 81Z0710116, and 81Z0710110), German Research Foundation (Ki 509167694), and Leducq Foundation. He receives research support for basic, translational, and clinical research projects from several drug and device companies active in AF and has received honoraria from several such companies in the past, but not in the last 3 years. He is listed as an inventor on two issued patents held by the University of Hamburg (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). J.G.A. was partially supported by the Canadian Arrhythmia Network and the Michael Smith Foundation for Health Research, Baylis Medical. He receives consulting fees/honoraria from Bayer, BMS/Pfizer Alliance, Servier, and Medtronic Inc. E.A. receives consulting fees/honoraria from Biosense Webster and Bayer. G.B. receives consulting fees/honoraria from Bayer, BMS, Boston Scientific, Daiichi Sankyo, Sanofi, and Janssen. A.J.C. receives consulting fees/honoraria from Bayer, Pfizer/BMS, Daiichi Sankyo, Menarini, Sanofi, Boston Scientific, Biosense Webster, Abbott, Acesion Pharma, Huya Bio, and Milestone. V.C. receives consulting fees/honoraria from Bayer, Boehringer Ingelheim, and Ever Pharma (paid to the institution of employment). W.D. receives consulting fees/honoraria from Reata and research grants from MicroPort, Boston Scientific, and Abbott. S.Z.D. receives consulting fees from BMS/Pfizer, Cortrium, and Acesion Pharma and speaker fees from MS/Pfizer and Bayer. He is listed as a medical advisor for Vital Beats. Dobromir D. receives consulting fees/honoraria from Elsevier, Springer Healthcare Ltd, and Daiichi Sankyo and research grants as follows: four NIH grants (partially) from Baylor College of Medicine, Houston; one NIH grant from UC Davis, one NIH grant from the University of Minnesota, and one EU-Project H2020. David D. receives consulting fees/honoraria from Abbott, Astra Zeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, BMS/Pfizer, CVRx, Medtronic, MicroPort, and Zoll and research grants from Roche, CVRx, and Zoll. L.E. has received lecture fees from various companies in AF in the past but none related to the present work. L.F. receives consulting fees/honoraria from Roche (paid to the institution of employment). She is currently employed at the UKE and previously at the University of Birmingham. She was partially supported by the European Union AFFECT-EU (grant agreement 847770), MAESTRIA (grant agreement 965286), CATCH ME (grant agreement 633196), and the British Heart Foundation (AA/18/2/3218). D.F.-R. receives research grants from Abbott. He is listed as an inventor on two issued patents: EP3636147A1 (method for the identification of cardiac fibrillation drivers and/or the footprint of rotational activations) and PCT/EP2022/071364 (system and method of assessment of electromechanical remodelling). A.G. receives consulting fees/honoraria from Daiichi Sankyo, Bayer, BMS/Pfizer, Medtronic, Abbott, and Boston Scientific and was partially supported by the European Union MAESTRIA (grant agreement 965286). K.G.H. receives consulting fees/honoraria from Abbott, Alexion, Amarin, Astra Zeneca, Bayer Healthcare, Biotronik, Boehringer Ingelheim, Boston Scientific, BMS/Pfizer, Daiichi Sankyo, Edwards Lifesciences, Medtronic, Novaris, Portola, Premier Research, Sanofi, SUN Pharma, and W. L. Gore and Associates. J.S.H. receives speaking fees from BMS/Pfizer, Bayer, Servier, and Boston Scientific and consulting fees from Bayer and Boston Scientific. He receives research grants from BMS/Pfizer, Servier, Novartis, Boston Scientific, and Medtronic. H.H. receives lecture and consulting fees from Bayer, Biotronik, BMS/Pfizer, Daiichi Sankyo, Milestone Pharmaceuticals, Centrix India, C.T.I. Germany, ESC, Medscape, and Springer Healthcare Ltd. He receives research grants (paid to the institution of employment, University of Antwerp and/or University of Hasselt) from Abbott, Bayer, Biosense Webster, Boston Scientific, Daiichi Sankyo, Fibricheck/Qompium, Medtronic, and BMS/Pfizer. Z.H. receives consulting fees/honoraria from Boehringer Ingelheim, BMS/Pfizer, and Roche Diagnostics. He was partially supported by The Swedish Society for Medical Research (S17-0133), Hjärt-Lungfonden (The Swedish Heart-Lung Foundation, 20200722), and the institution he is currently employed at (Uppsala University Hospital). L.H.-M. receives research grants from the Spanish Ministry of Science and Innovation (PID2020-116927RB-C21) and Fondo Europeo de Desarrollo Regional (FEDER). D.K. receives consulting fees/honoraria from Bayer, Amomed, and Protherics Medicines Development. He receives research grants from the National Institute for Health Research (NIHR CDF-2015-08-074 RAE-AF; NIHR130280 DaRe2THINK; NIHR13274 D2T-NeuroVascular; and NIHR203326 Biomedical Research Centre), the British Heart Foundation (PG/17/55/33087, AA/182/3218, and FS/CDRF/21/21032), the EU/EFPIA Innovative Medicines Initiative (BigData@Heart 116074), EU Horizon and UKRI (HYPERMARKER 101095480) UK National Health Service—Data for R&D-Subnational Secure Data Environment programme, UK Department for Business, Energy Industrial Strategy Regulators Pioneer Fund, the Cook & Wolstenholme Charitable Trust, and the European Society of Cardiology supported by educational grants from Boehringer Ingelheim, BMS/Pfizer, Alliance, Bayer, Daiichi Sankyo, Boston Scientific, the NIHR/University of Oxford Biomedical Research Centre, and the British Hear Foundation, the University of Birmingham Accelerator Award (STEEER-AF). J.L.M. receives consulting fees/honoraria from Biotronik, Medtronic, MicroPort, and Milestone Pharmaceuticals. A.M. receives consulting fees/honoraria from Medtronic, Biosense Webster, and Boston Scientific and lecture fees from Medtronic, Boston Scientific, Biosense Webster, BMS, and Bayer. L.M. receives consulting fees/honoraria from Abbott, Medtronic, Boston Scientific, and Johnson & Johnson. G.A.N. receives lecture fees from AliveCor, consultant fees from Biosense Webster, and research grants from Abbott and Biosense Webster. H.P. receives consulting fees/honoraria from Abbott, Boston Scientific, Biosense Webster, Medtronic, Daiichi Sankyo, Bayer, and Pfizer. P.S. receives consulting fees/honoraria from Medtronic, Boston Scientific, Abbott, CathRx, and PaceMate (paid to the institution of employment). He is currently employed at the University of Adelaide, which receives research grants from Medtronic, Boston Scientific, and Becton-Dickenson. R.B.S. receives consulting fees/honoraria from BMS/Pfizer. She was partially supported by the European Union Horizon 2020 research and innovation programme (grant agreement 648131 and 847770), German Center for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK, grant numbers 81Z1710103 and 81Z0710114), German Ministry of Research and Education (BMBF 01ZX1408A), ERACoSysMed3 (031L0239), Wolfgang Seefried project funding German Heart Foundation. U.S. receives consulting fees/honoraria from University Svizzerra Italiana, Stanford, and Johnson & Johnson and research grants from the European Union, Dutch Heart Foundation, Roche, and EP Solution. He is a shareholder of YourRhythmics B.V. T.T. receives consulting fees/honoraria from Boston Scientific and Medtronic. I.C.v.G. receives consulting fees/honoraria from Bayer (paid to the institution of employment). She is currently employed at the University of Groningen. K.V. receives consulting fees/honoraria from Abbott, Philips, Medtronic, Biosense Webster, and Boston Scientific and research grants from Medtronic and Biosense Webster. R.W. receives consulting fees/honoraria from Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo, Boston Scientific, Biotronik, Abiomed, and Zoll and a research grant from Boston Scientific, BMS/Pfizer, and Abiomed. S.W. receives consulting fees/honoraria from Boehringer Ingelheim, Boston Scientific, Abbott, and Bayer Vital and a research grant from Boston Scientific. All remaining authors (G.B., J.C.N., T.D.P., N.D., M.F., E.G., S.H., S.K., D.L., K.M.-R., M.O., A.S.P., U.R., M.R., D.S., C.S., G.S., D.S., S.T., R.H.v.L., and S.Z.) have declared no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Genetic predisposition is crucial in the pathogenesis of early-onset chronic pancreatitis (CP). So far, several genetic alterations have been identified as risk factors, predominantly in genes encoding digestive enzymes. However, many early-onset CP cases have no identified underlying cause. Chymotrypsins are a family of serine proteases that can cleave trypsinogen and lead to its degradation. Because genetic alterations in the chymotrypsins CTRC, CTRB1, and CTRB2 are associated with CP, we genetically and functionally investigated chymotrypsin-like protease (CTRL) as a potential risk factor., Methods: We screened 1005 non-alcoholic CP patients and 1594 controls for CTRL variants by exome sequencing. We performed Western blots and activity assays to analyse secretion and proteolytic activity. We measured BiP mRNA expression to investigate the potential impact of identified alterations on endoplasmic reticulum (ER) stress., Results: We identified 13 heterozygous non-synonymous CTRL variants: five exclusively in patients and three only in controls. Functionality was unchanged in 6/13 variants. Four alterations showed normal secretion but reduced (p.G20S, p.G56S, p.G61S) or abolished (p.S208F) activity. Another three variants (p.C201Y, p.G215R and p.C220G) were not secreted and already showed reduced or no activity intracellularly. However, intracellular retention did not lead to ER stress., Conclusion: We identified several CTRL variants, some showing potent effects on protease function and secretion. We observed these effects in variants found in patients and controls, and CTRL loss-of-function variants were not significantly more common in patients than controls. Therefore, CTRL is unlikely to play a relevant role in the development of CP., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Accurate identification of brain tumor molecular subgroups is increasingly important. We aimed to establish the most accurate and reproducible ependymoma subgroup biomarker detection techniques, across 147 cases from International Society of Pediatric Oncology (SIOP) Ependymoma II trial participants, enrolled in the pan-European "Biomarkers of Ependymoma in Children and Adolescents (BIOMECA)" study., Methods: Across 6 European BIOMECA laboratories, we evaluated epigenetic profiling (DNA methylation array); immunohistochemistry (IHC) for nuclear p65-RELA, H3K27me3, and Tenascin-C; copy number analysis via fluorescent in situ hybridization (FISH) and MLPA (1q, CDKN2A), and MIP and DNA methylation array (genome-wide copy number evaluation); analysis of ZFTA- and YAP1-fusions by RT-PCR and sequencing, Nanostring and break-apart FISH., Results: DNA Methylation profiling classified 65.3% (n = 96/147) of cases as EPN-PFA and 15% (n = 22/147) as ST-ZFTA fusion-positive. Immunohistochemical loss of H3K27me3 was a reproducible and accurate surrogate marker for EPN-PFA (sensitivity 99%-100% across 3 centers). IHC for p65-RELA, FISH, and RNA-based analyses effectively identified ZFTA- and YAP-fused supratentorial ependymomas. Detection of 1q gain using FISH exhibited only 57% inter-center concordance and low sensitivity and specificity while MIP, MLPA, and DNA methylation-based approaches demonstrated greater accuracy., Conclusions: We confirm, in a prospective trial cohort, that H3K27me3 immunohistochemistry is a robust EPN-PFA biomarker. Tenascin-C should be abandoned as a PFA marker. DNA methylation and MIP arrays are effective tools for copy number analysis of 1q gain, 6q, and CDKN2A loss while FISH is inadequate. Fusion detection was successful, but rare novel fusions need more extensive technologies. Finally, we propose test sets to guide future diagnostic approaches., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

The generation of traction forces by neutrophils regulates many crucial effector functions responsible for host defense, such as attachment, spreading, migration, phagocytosis, and NETosis. The activation state of the cell is a strong determinant of the functional efficacy of the neutrophil; however, the effect of activation on traction force production has not yet been determined experimentally. Previously, the mapping of cellular-generated forces produced by human neutrophils via a Traction Force Microscopy (TFM) method has required a three-dimensional imaging modality to capture out-of-plane forces, such as confocal or multiphoton techniques. A method newly developed in our laboratories can capture out-of-plane forces using only a two-dimensional imaging modality. This novel technique-combined with a topology-based single particle tracking algorithm and finite element method calculations-can construct high spatial frequency three-dimensional traction fields, allowing for traction forces in-plane and out-of-plane to the substrate to now be differentially visualized and quantified with a standard epifluorescence microscope. Here we apply this technology to determine the effect of neutrophil activation on force generation. Sepsis is a systemic inflammatory response that causes dysregulated neutrophil activation in vivo. We found that neutrophils from septic patients produced greater total forces than neutrophils from healthy donors and that the majority of this dysregulation occurred in-plane to the substrate. Ex vivo activation of neutrophils from healthy donors showed differential consequences depending on activation stimuli with mechanosensitive force decreases observed in some cases. These findings demonstrate the feasibility of epifluorescence-based microscopy in mapping traction forces to ask biologically significant questions regarding neutrophil function., (© 2023. The Author(s).)

Background: ZFTA-RELA (formerly known as c11orf-RELA) fused supratentorial ependymoma ( ZFTA fus ST-EPN) has been recognized as a novel entity in the 2016 WHO classification of CNS tumors and further defined in the recent 2021 edition. ZFTA fus ST-EPN was reported to portend poorer prognosis when compared to its counterpart, YAP1 ST-EPN in some previously published series. The aim of this study was to determine the treatment outcome of molecularly confirmed and conventionally treated ZFTA fus ST-EPN patients treated in multiple institutions., Methods: We conducted a retrospective analysis of all pediatric patients with molecularly confirmed ZFTA fus ST-EPN patients treated in multiple institutions in 5 different countries (Australia, Canada, Germany, Switzerland, and Czechia). Survival outcomes were analyzed and correlated with clinical characteristics and treatment approaches., Results: A total of 108 patients were collated from multiple institutions in 5 different countries across three continents. We found across the entire cohort that the 5- and 10-year PFS were 65% and 63%, respectively. The 5- and 10-year OS of this cohort of patients were 87% and 73%. The rates of gross total resection (GTR) were high with 84 out of 108 (77.8%) patients achieving GTR. The vast majority of patients also received post-operative radiotherapy, 98 out of 108 (90.7%). Chemotherapy did not appear to provide any survival benefit in our patient cohort., Conclusion: This is the largest study to date of contemporaneously treated molecularly confirmed ZFTA fus ST-EPN patients which identified markedly improved survival outcomes compared to previously published series. This study also re-emphasizes the importance of maximal surgical resection in achieving optimal outcomes in pediatric patients with supratentorial ependymoma., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: There is no clear guidance on how to implement opportunistic atrial fibrillation (AF) screening in daily clinical practice., Objectives: This study evaluated the perception of general practitioners (GPs) about value and practicalities of implementing screening for AF, focusing on opportunistic single-time point screening with a single-lead electrocardiogram (ECG) device., Methods: A descriptive cross-sectional study was conducted with a survey developed to assess overall perception concerning AF screening, feasibility of opportunistic single-lead ECG screening and implementation requirements and barriers., Results: A total of 659 responses were collected (36.1% Eastern, 33.4% Western, 12.1% Southern, 10.0% Northern Europe, 8.3% United Kingdom & Ireland). The perceived need for standardized AF screening was rated as 82.7 on a scale from 0 to 100. The vast majority (88.0%) indicated no AF screening program is established in their region. Three out of four GPs (72.1%, lowest in Eastern and Southern Europe) were equipped with a 12-lead ECG, while a single-lead ECG was less common (10.8%, highest in United Kingdom & Ireland). Three in five GPs (59.3%) feel confident ruling out AF on a single-lead ECG strip. Assistance through more education (28.7%) and a tele-healthcare service offering advice on ambiguous tracings (25.2%) would be helpful. Preferred strategies to overcome barriers like insufficient (qualified) staff, included integrating AF screening with other healthcare programs (24.9%) and algorithms to identify patients most suitable for AF screening (24.3%)., Conclusion: GPs perceive a strong need for a standardized AF screening approach. Additional resources may be required to have it widely adopted into clinical practice., Competing Interests: BF has received grants to the institution for investigator-initiated studies from the BMS-Pfizer Alliance, personal fees and nonfinancial support from BMS-Pfizer Alliance and Pfizer, and loan devices from AliveCor. HH did receive personal lecture and consultancy fees from Abbott, Biotronik, Daiichi-Sankyo, Pfizer-BMS, Medscape, and Springer Healthcare Ltd. He received unconditional research grants through the University of Antwerp and/or the University of Hasselt from Abbott, Bayer, Biotronik, Biosense-Webster, Boston-Scientific, Boehringer-Ingelheim, Daicchi-Sankyo, Fibricheck/Qompium, Medtronic, and Pfizer-BMS. HP received speaker fees from Bayer, Pfizer, Boehringer Ingelheim and Daiichi-Sankyo. LN and CH hold an investigator initiated grant from Daiichi Sankyo (£75,000). MF received speaker fees from Pfizer Poland and Boehringer Ingelheim Poland. RS has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program under the grant agreement No 648131, from the European Union’s Horizon 2020 research and innovation program 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). RS has received lecture fees and advisory board fees from BMS/Pfizer outside this work. HW was employed by Pfizer Pharma GmbH, Berlin, Germany. MH was employed by StopAfib.org, Dallas, TX, United States. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Vermunicht, Grecu, Deharo, Buckley, Palà, Mairesse, Farkowski, Bergonti, Pürerfellner, Hanson, Neubeck, Freedman, Witt, Hills, Lund, Giskes, Engler, Schnabel, Heidbuchel, Desteghe and for the AFFECT-EU investigators.)

Despite marked progress in the management of atrial fibrillation (AF), detecting AF remains difficult and AF-related complications cause unacceptable morbidity and mortality even on optimal current therapy. This document summarizes the key outcomes of the 8th AFNET/EHRA Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA). Eighty-three international experts met in Hamburg for 2 days in October 2021. Results of the interdisciplinary, hybrid discussions in breakout groups and the plenary based on recently published and unpublished observations are summarized in this consensus paper to support improved care for patients with AF by guiding prevention, individualized management, and research strategies. The main outcomes are (i) new evidence supports a simple, scalable, and pragmatic population-based AF screening pathway; (ii) rhythm management is evolving from therapy aimed at improving symptoms to an integrated domain in the prevention of AF-related outcomes, especially in patients with recently diagnosed AF; (iii) improved characterization of atrial cardiomyopathy may help to identify patients in need for therapy; (iv) standardized assessment of cognitive function in patients with AF could lead to improvement in patient outcomes; and (v) artificial intelligence (AI) can support all of the above aims, but requires advanced interdisciplinary knowledge and collaboration as well as a better medico-legal framework. Implementation of new evidence-based approaches to AF screening and rhythm management can improve outcomes in patients with AF. Additional benefits are possible with further efforts to identify and target atrial cardiomyopathy and cognitive impairment, which can be facilitated by AI., Competing Interests: Conflict of interest: RBS has received lecture fees and advisory board fees from BMS/Pfizer outside this work and 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.) (8121710103); German Ministry of Research and Education (BMBF 01ZX1408A) and ERACoSysMed3 (031L0239).EAM is employee of Daiichi Sankyo Europe GmbH producing and marketing an oral anticoagulant (edoxaban). EA has received consulting / speaker fees for Biosense Webster. GB has received speaker's fees of small amount from Boston, Bayer, Daiichi, Boehringer. SB is consultant for Medtronic, Boston Scientific, Microport, and Zoll. JC has received consulting fees / honoraria fees from Acesion, Allergan, Alta Thera, Arca, lncarda, Menarini, Milestone, Sanofi, Bayer, Daiichi Sankyo, Pfizer, Abbott, Biosense Webster, Biotronik, Boston Scientific, Lilly, Medtronic, Johnson and Johnson. BC has received in kind contribution for research Support from iRhythm. WC has received advisory board fees for Roche Diagnostics AG. MDM is employee of Medtronic. SZB has received fees as member of Advisory Board in Bristol Myers Squibb-Pfizer. DD has received fees from Abbott, Astra Zenica, Bayer, Bosten Scientific, Bristol Myers Squibb-Pfizer, Medtonic, Zoll. LE has received lecture Honoria from Medtronic, Biotronik, Boston Scientific, Boehringer Ingelheim, Daiichy Sankyo, Bayer, MMS, Pfizer, Sanofi and received research grants from DFG and DGK. CE is employee of Preventicus GmbH. LF has received institutional research grants and non-financial support from European Union, DFG, British Heart Foundation, Medical Research Council (UK), NIHR, and several biomedical companies. The Institute of Cardiovascular Research, University of Birmingham, has received an Accelerator Award by the British Heart Foundation M/18/2/34218. LF is listed as inventor of two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). BF receiving fees from Bristol-Myers Squibb and Pfizer Alliance, Bayer, Daiichi Sankyo, Omron. (largely speaker fees and travel support for speaking at session or official satellites of large international/continental society meetings) and investigator-initiated research grants to the institution from Bristol-Myers and Squibb and Pfizer Alliance and Ownership / Employee of Nil. LG and AZ are employees of Roche Diagnostics International Ltd. AG has received funding from Daiichi Sankyo, Astra Zenica, Bayer, Bristol Myers Squibb-Pfizer, Viola, Medtonic, Berlin Charitè. JHS has received Advisory board fees in Medtronic and Speaker fee from Medtronic. KGH has received fees from Abbott, Alexion, AMARIN, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Bristol-Myers-Squibb, Daiichi Sankyo, Edwards Lifesciences, Medtronic, Pfizer, Premier Research, SUN Pharma and W. L. Gare & Associates and Research Grants from Bayer Vital, Sanofi-Aventis. JSH received fees from Boston Scientific, Servier, Bayer, Myokardia, Bristol-Myers-Squibb, Pfizer, and research grants from Medtronic, Boston Scientific, Bristol-Myers-Squibb, Abbott. HH has received lecture and consultancy fees from Abbott, Biotronik, Bristol-Myers-Squibb- Pfizer, Medscape, Daiichi Sankyo, Springer Healthcare Ltd and receive un conditional research grants through the Univerity of Antwerp and/or University of Hasselt from Abbott, Bayer, Biotronik, Biosense-Webster, Fibrickeck/Qompium, Medtronic, Bristol-Myers-Squibb- Pfizer, Boston Scientific, Daiichi Sankyo and Boehringer Ingelheim. RH has received speacker fees from BI, Bayer and Bristol-Myers-Squibb- Pfizer and AZ. TH is CEO of Preventicus GmbH. DK has received funding from Bayer, AtriCure, Protherics Medicines Development and Myokardia and Research grant from rants from the National Institute for Health Research (NIHR CDF-2015-08-074 RATE-AF; NIHR HTA-130280 DaRe2THINK; NIHR EME- 132974 D2T-NV), the British Heart Foundation (PG/17/55/33087 and AA/18/2/34218), EU/EFPIA IMI (BigData@Heart 116074),the European Society of Cardiology supported by educationalgrants from Boehringer Ingelheim/BMS-Pfizer Alliance/Bayer/Daiichi Sankyo/Boston Scientific, the NIHR/the University of Ox- ford Biomedical Research Centre, and British Heart Foundation/ the University of Birmingham Accelerator Award (STEEER-AF NCT04396418), Amomed Pharma, and IRCCS San Raffaele/Menarini (beta-blockers in Heart Failure Collaborative Group NCT0083244). MK is employee of Bristol-Myers and Squibb. CL has received fees from medtonic, Boston Scientific, Biotronik and Bristol-Myers and Squibb- Pfizer and research grants from Rennes Univerity, Metronik, Biotonik and Boston Scientific. DL has received research grant for EHRA-PATHS, NovoNordisk Young Investigator Award. MLL has received lecture fees from Bristol-Myers and Squibb and research grant from H2020 AFFECT-EU (grant No. 847770). SM has received research grant from Daiichi Sankyo (EPDAURUS IIT) and Bristol-Myers and Squibb (APPROACH ACS AF IIT). JLM has received Abbott, Boston Scientific, Biotronik, Boehringer Ingelheim, Sanofi, Microport and received research grants from Medtronic, Abbott, Microport, Biosense. RM is employee of Medtronic. LM is Stockholder for Galgomedical and Corify and receiving consuting fees from Abbott, Biosense-Webster, Bosten Scientific, Medtronik and receiving research grants from Abbott, Biosense-Webster, Bosten Scientific, Medtronik. LN has received consulting fees from Bristol-Myers and Squibb- Pfizer. GP is employee of Bayer AG. HP has received consulting fees from Abbott, Biosense-Webster, Bosten Scientific, Medtronik and receiving research grants from Abbott, Bayer, Biosense-Webster, Bosten Scientific, Medtronik, Bristol-Myers and Squibb- Pfizer. MR has received consulting fees for Medtonic, Arca BiopharmaInc, Roche and received research grants from Dutch Heart Foundation: RACE V, RED-CVD, CVON-AI, DECISION studies; grant from SJM/Abbott to institution: VIP-HF study; Grant for Medtronic to institution: Cryoballoon AF registry/biobank study. The other authors declare that there is no conflict of interest.LR has received research grants from Canadian Insititute of Health research and Byer Inc. U.S. received consultancy fees or honoraria from Università della Svizzera Italiana (USI, Switzerland), Roche Diagnostics (Switzerland), EP Solutions Inc. (Switzerland), Johnson & Johnson Medical Limited, (United Kingdom), Bayer Healthcare (Germany). U.S. is co-founder and shareholder of YourRhythmics BV, a spin-off company of the University Maastricht and Research grant from the Dutch Heart Foundation (CVON RACE V, CVON2014–09) European Union's Horizon 2020 Research and Innovation Program granted to MS under the Marie Sklodowska-Curie grant agreement #813716 (TRAIN-HEART Innovative Training Network), and various other programs of the European Union granted to US (ITN Network Personalize AF: Personalized Therapies for Atrial Fibrillation: a translational network – grant #860974; CATCH ME: Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly – grant #633196; MAESTRIA: Machine Learning Artificial Intelligence Early Detection Stroke Atrial Fibrillation – grant #965286; REPAIR: Restoring cardiac mechanical function by polymeric artificial muscular tissue – grant #952166). DS has received consultation fees from Biosense Webster, Abbott, Boston Scientific, Consultant with stock option: SentiAR, Arga Medtech. RS is employee of Daiichi Sankyo Europe GmbH. DS has received consultation fees from Boston Scientific, Abbott and Research grant from Biosense Webster. ES has received lecture fees from Bayer, Bristol-Myers and Squibb- Pfizer, Boehringer Ingelheim, Johnson & Johnson, Merck Sharp & Dohme and Sanofi. DT has received lecture fees from Bayer Vital, Bristol-Myers and Squibb- Pfizer, Daiichi Sankyo, Medtonic, Zoll CMS, Sanofi, St. Jude Medical and research grant from Daiichi Sankyo. MTH is employee/owner of American Foundation of women's Health /StopAfib.org and employee/owner of True Hills Inc.. BV is employee of Bayer AG. RW has received consultation fees from Boston Scientific, Biotronic, Pfizer, Daiichi Sankyo, Bayer, Adagio Medical and Research grant from Bristol-Myers and Squibb- Pfizer, Boston Scientific. CW has received consulation fees from Biotronik, Boston Scientific, Novartis and research grant from BMBF, AFNET, DZHK, Biotronik. MW is employee and shareholder of Sanofi. SW has received Consulting fees from Boston Scientific, Abbott, Bayer, Bristol-Myers and Squibb- Pfizer, Boehringer Ingelheim and research grant from Boston Scientific. HW is employee and stockholder of Pfizer Germany. MDZ has received advisory and speaker fee from Bristol-Myers and Squibb- Pfizer. PK reports grants and non-financial support from BMBF (German Ministry of Education and Research), grants from Sanofi and Abbott, grants and non-financial support from EHRA (European Heart Rhythm Association), and grants from German Heart Foundation and DZHK (German Center for Cardiovascular Research), during the conduct of the study, and grants from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and non-financial support from German Centre for Heart Research, outside the submitted work; in addition, P.K. has a patent Atrial Fibrillation Therapy WO 2015140571 issued to University of Birmingham and a patent Markers for Atrial Fibrillation WO 2016012783 issued to University of Birmingham., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Rationale: Although type II alveolar epithelial cells (AEC2s) are chronically injured in idiopathic pulmonary fibrosis (IPF), they contribute to epithelial regeneration in IPF. Objectives: We hypothesized that Notch signaling may contribute to AEC2 proliferation, dedifferentiation characterized by loss of surfactant processing machinery, and lung fibrosis in IPF. Methods: We applied microarray analysis, kinome profiling, flow cytometry, immunofluorescence analysis, western blotting, quantitative PCR, and proliferation and surface activity analysis to study epithelial differentiation, proliferation, and matrix deposition in vitro (AEC2 lines, primary murine/human AEC2s), ex vivo (human IPF-derived precision-cut lung slices), and in vivo (bleomycin and pepstatin application, Notch1 [Notch receptor 1] intracellular domain overexpression). Measurements and Main Results: We document here extensive SP-B and -C (surfactant protein-B and -C) processing defects in IPF AEC2s, due to loss of Napsin A, resulting in increased intra-alveolar surface tension and alveolar collapse and induction of endoplasmic reticulum stress in AEC2s. In vivo pharmacological inhibition of Napsin A results in the development of AEC2 injury and overt lung fibrosis. We also demonstrate that Notch1 signaling is already activated early in IPF and determines AEC2 fate by inhibiting differentiation (reduced lamellar body compartment, reduced capacity to process hydrophobic SP) and by causing increased epithelial proliferation and development of lung fibrosis, putatively via altered JAK (Janus kinase)/Stat (signal transducer and activator of transcription) signaling in AEC2s. Conversely, inhibition of Notch signaling in IPF-derived precision-cut lung slices improved the surfactant processing capacity of AEC2s and reversed fibrosis. Conclusions: Notch1 is a central regulator of AEC2 fate in IPF. It induces alveolar epithelial proliferation and loss of Napsin A and of surfactant proprotein processing, and it contributes to fibroproliferation.

Background: PRSS1 and PRSS2 constitute the only functional copies of a tandemly-arranged five-trypsinogen-gene cluster (i.e., PRSS1, PRSS3P1, PRSS3P2, TRY7 and PRSS2) on chromosome 7q35. Variants in PRSS1 and PRSS2, including missense and copy number variants (CNVs), have been reported to predispose to or protect against chronic pancreatitis (CP). We wondered whether a common trypsinogen pseudogene deletion CNV (that removes two of the three trypsinogen pseudogenes, PRSS3P2 and TRY7) might be associated with CP causation/predisposition., Methods: We analyzed the common PRSS3P2 and TRY7 deletion CNV in a total of 1536 CP patients and 3506 controls from France, Germany, India and Japan by means of quantitative fluorescent multiplex polymerase chain reaction., Results: We demonstrated that the deletion CNV variant was associated with a protective effect against CP in the French, German and Japanese cohorts whilst a trend toward the same association was noted in the Indian cohort. Meta-analysis under a dominant model yielded a pooled odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52-0.89; p = 0.005) whereas an allele-based meta-analysis yielded a pooled OR of 0.84 (95% CI 0.77-0.92; p = 0.0001). This protective effect is explicable by reference to the recent finding that the still functional PRSS3P2/TRY7 pseudogene enhancers upregulate pancreatic PRSS2 expression., Conclusions: The common PRSS3P2 and TRY7 deletion CNV was associated with a reduced risk for CP. This finding provides additional support for the emerging view that dysregulated PRSS2 expression represents a discrete mechanism underlying CP predisposition or protection., Competing Interests: Declaration of competing interest The authors are unaware of any conflict of interest., (Copyright © 2022 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Aims: Atrial fibrillation (AF) carries a substantial risk of ischemic stroke and other complications, and estimates suggest that over a third of cases remain undiagnosed. AF detection is particularly pressing in stroke survivors. To tailor AF screening efforts, we explored German health claims data for routinely available predictors of incident AF in primary care and post-stroke using machine learning methods., Methods and Results: We combined AF predictors in patients over 45 years of age using claims data in the InGef database (n = 1 476 391) for (i) incident AF and (ii) AF post-stroke, using machine learning techniques. Between 2013-2016, new-onset AF was diagnosed in 98 958 patients (6.7%). Published risk factors for AF including male sex, hypertension, heart failure, valvular heart disease, and chronic kidney disease were confirmed. Component-wise gradient boosting identified additional predictors for AF from ICD-codes available in ambulatory care. The area under the curve (AUC) of the final, condensed model consisting of 13 predictors, was 0.829 (95% confidence interval (CI) 0.826-0.833) in the internal validation, and 0.755 (95% CI 0.603-0.890) in a prospective validation cohort (n = 661). The AUC for post-stroke AF was of 0.67 (95% CI 0.651-0.689) in the internal validation data set, and 0.766 (95% CI 0.731-0.800) in the prospective clinical cohort., Conclusion: ICD-coded clinical variables selected by machine learning can improve the identification of patients at risk of newly diagnosed AF. Using this readily available, automatically coded information can target AF screening efforts to identify high-risk populations in primary care and stroke survivors., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Alterations in genes specifically expressed in the pancreas have been associated with chronic pancreatitis (CP). A significant percentage of patients with non-alcoholic CP, however, do not have mutations in known risk genes, suggesting the existence of further susceptibility genes. Four aquaporins are expressed in the exocrine pancreas: AQP1, AQP5, AQP8 and AQP12, the latter being found exclusively in this organ. Therefore, we investigated the two AQP12 genes, AQP12A and AQP12B, in CP patients., Methods: We analyzed all exons and adjacent intronic regions of AQP12A and AQP12B in 292 German patients with non-alcoholic CP and 143 control subjects by direct DNA sequencing., Results: In total, we discovered 41 non-synonymous changes, three of which were nonsense variants. Genotype and allele frequencies of these variants did not differ significantly between patients and controls (all p-values >0.05). Remarkably, we found a common nonsense variant in AQP12B, p.S152Tfs∗24, with an allele frequency of 15.7% in controls, including 2.8% homozygous subjects. This finding suggests that AQP12B is physiologically dispensable for normal pancreatic function., Conclusions: Our results suggest that genetic alterations in AQP12A and AQP12B do not predispose to the development of non-alcoholic CP., Competing Interests: Declaration of compacting interest All authors approved the final manuscript and contributed critical revisions to its intellectual content., (Copyright © 2022 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Digital technology is now an integral part of medicine. Tools for detecting, screening, diagnosis, and monitoring health-related parameters have improved patient care and enabled individuals to identify issues leading to better management of their own health. Wearable technologies have integrated sensors and can measure physical activity, heart rate and rhythm, and glucose and electrolytes. For individuals at risk, wearables or other devices may be useful for early detection of atrial fibrillation or sub-clinical states of cardiovascular disease, disease management of cardiovascular diseases such as hypertension and heart failure, and lifestyle modification. Health data are available from a multitude of sources, namely clinical, laboratory and imaging data, genetic profiles, wearables, implantable devices, patient-generated measurements, and social and environmental data. Artificial intelligence is needed to efficiently extract value from this constantly increasing volume and variety of data and to help in its interpretation. Indeed, it is not the acquisition of digital information, but rather the smart handling and analysis that is challenging. There are multiple stakeholder groups involved in the development and effective implementation of digital tools. While the needs of these groups may vary, they also have many commonalities, including the following: a desire for data privacy and security; the need for understandable, trustworthy, and transparent systems; standardized processes for regulatory and reimbursement assessments; and better ways of rapidly assessing value., Competing Interests: Conflict of interest: C.L. receives consulting fees from Medtronic, Boston Scientific, Abbott, and Biotronik; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Medtronic, Boston Scientific, Abbott, and Biotronik. H.W. has stock or stock options from Pfizer. R.P.K. has stock or stock options from Medtronic; and employment by Medtronic. D.A. has multiple patents including those for AliveCor, and GE assignments; stock or stock options from AliveCor, Inc.; and salary/officer position with AliveCor, Inc. M.R.C. receives consulting fees from AstraZeneca, Servier, Medtronic, and Abbott; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Servier, Medtronic, Abbott, and Bayer; served as Chair for ESC-Digital Health Committee (unpaid), Chair for Clinical Advisory Board of Pumping Marvellous Foundation (unpaid), Trustee of the Atrial Fibrillation Association (unpaid), and Non-executive Director of NICE from 2016-2020 (paid). T.D. receives consulting fees from Farapulse; payment or honoraria for lectures from Biotronik and Abbott; participation on a clinical events committee for Boston Scientific; served as a board member for the German Cardiology Society. P.F. participated on advisory board for Abbot, Medtronic, and Boston Scientific; IP, licensing fees, and equity stake via Mayo Clinic (employer) in AliveCor, EkoHealth, and Anuman. I.L. has stock or stock options from Amgen; and employment by Amgen. M.V.M. served as Co-Chair for the Consumer Technology Association (CTA)-American College of Cardiology (ACC) CV Technology Working Group; stock or stock options from Google; and employment by Google. L.R. supports for the present manuscript from Medtronic; employment by Medtronic. E.S. has stock or stock options from GE Healthcare; and employment by GE Vingmed Ultrasound AS. M.P.T. receives consulting fees from Medtronic, Abbott, Biotronik, Sanofi, Pfizer, Bayer, Myokardia, Johnson & Johnson, Milestone Pharmaceuticals, InCarda Pharmaceuticals, 100Plus, AliveCor, Actus Medical, and BrightInsight; grants from Bristol-Myers Squibb, American Heart Association, Apple, Bayer, and the US Food and Drug Administration; and editorship with JAMA Cardiology. J.P.S. receives consulting fees from Abbott, Biotronik, Boston Scientific, Cardiologs, CVRx, Cardiac Rhythm Group, EBR, Impulse Dynamics, Implicity, Medtronic, Medscape, Microport, New Century Health, Nopras, Orchestra BioMed, Octagos Health, and Sanofi. E.S. receives institutional research grants from the Stockholm County Council, the Åke Wiberg Foundation, and the Swedish Heart Foundation; consulting fees from Bayer, Bristol-Myers Squibb-Pfizer, Boehringer-Ingelheim, Johnson & Johnson, Merck Sharp & Dohme; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer, Johnson & Johnson, Merck Sharp & Dohme, Bristol-Myers Squibb-Pfizer, Boehringer-Ingelheim; participation on a data safety monitoring board or advisory board for Bristol-Myers Squibb-Pfizer; board membership for the European Heart Rhythm Association (EHRA), served as Chair of the Digital Committee for EHRA, and membership on the Digital Committee of the Heart Rhythm Society. M.W. supports for the present manuscript from Biotelemetry; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Biotelemetry; support for meeting attendance and/or travel from Biotelemetry; patents for Biotelemetry; stock or stock options from Biotelemetry. Other authors have none to declare., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Human and animal studies suggest an important role of autophagy in the pathogenesis of pancreatitis. ATG16L1 (autophagy-related 16 like 1) is part of a protein complex that is involved in the formation of autophagosomes. The c.898A > G (p.T300A) variant of ATG16L1 is associated with Crohn disease. In this study, we analyzed ATG16L1 c.898A > G (p.T300A) for an association with pancreatitis., Methods: We genotyped 777 patients and 551 control subjects of German origin by melting curve analysis using fluorescence resonance energy transfer probes. The patient group included 429 patients with nonalcoholic chronic pancreatitis (CP), 141 patients with alcoholic CP, and 207 patients with acute pancreatitis (AP). We classified AP by severity according to the Atlanta symposium 1992., Results: Allele and genotype frequencies of ATG16L1 c.898A > G (p.T300A) did not differ significantly between patients and controls (G allele frequencies: nonalcoholic CP, 49.9%; alcoholic CP, 48.2%; AP, 49.5%; controls, 52.7%). We found no significant association with the severity of AP either., Conclusions: Our data do not support a role of ATG16L1 c.898A > G (p.T300A) in the pathogenesis of AP or CP or an influence on the severity of AP., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Genetic alterations in digestive enzymes have been associated with chronic pancreatitis (CP). Recently, chymotrypsin like elastase 3B (CELA3B) emerged as a novel risk gene. Thus, we evaluated CELA3B in two European cohorts with CP., Methods: We analyzed all 8 CELA3B exons in 550 German non-alcoholic CP (NACP) patients and in 241 German controls by targeted DNA sequencing. In addition, we analyzed exons 6 and 7 by Sanger sequencing and the c.129+1G>A variant by melting curve analysis in 1078 further German controls. As replication cohort, we investigated up to 243 non-German European NACP patients and up to 1665 controls originating from Poland, Hungary, and Sweden. We assessed the cellular secretion and the elastase activity of recombinant CELA3B variants., Results: In the German discovery cohort, we detected a splice-site variant in intron 2, c.129+1G>A, in 9/550 (1.64%) CP patients and in 5/1319 (0.38%) controls (P=0.007, OR=4.4, 95% CI=1.5-13.0). In the European replication cohort, this variant was also enriched in patients (9/178 [5.06%]) versus controls (13/1247 [1.04%]) (P=0.001, OR=5.1, 95% CI=2.1-12.0). We did not find the two previously reported codon 90 variants, p.R90C and p.R90L., Conclusions: Our data indicate that CELA3B is a susceptibility gene for CP. In contrast to previous reports suggesting that increased CELA3B activity is associated with CP risk, the splice-site variant identified here is predicted to cause diminished CELA3B expression. How reduced CELA3B function predisposes to pancreatitis remains to be elucidated., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Atrial fibrillation (AF) burden on patients and healthcare systems warrants innovative strategies for screening asymptomatic individuals., Objective: We sought to externally validate a predictive model originally developed in a German population to detect unidentified incident AF utilising real-world primary healthcare databases from countries in Europe and Australia., Methods: This retrospective cohort study used anonymized, longitudinal patient data from 5 country-level primary care databases, including Australia, Belgium, France, Germany, and the UK. The study eligibility included adult patients (≥45 years) with either an AF diagnosis (cases) or no diagnosis (controls) who had continuous enrolment in the respective database prior to the study period. Logistic regression was fitted to a binary response (yes/no) for AF diagnosis using pre-determined risk factors., Results: AF patients were from Germany (n = 63,562), the UK (n = 42,652), France (n = 7,213), Australia (n = 2,753), and Belgium (n = 1,371). Cases were more likely to have hypertension or other cardiac conditions than controls in all validation datasets compared to the model development data. The area under the receiver operating characteristic (ROC) curve in the validation datasets ranged from 0.79 (Belgium) to 0.84 (Germany), comparable to the German study model, which had an area under the curve of 0.83. Most validation sets reported similar specificity at approximately 80% sensitivity, ranging from 67% (France) to 71% (United Kingdom). The positive predictive value (PPV) ranged from 2% (Belgium) to 16% (Germany), and the number needed to be screened was 50 in Belgium and 6 in Germany. The prevalence of AF varied widely between these datasets, which may be related to different coding practices. Low prevalence affected PPV, but not sensitivity, specificity, and ROC curves., Conclusions: AF risk prediction algorithms offer targeted ways to identify patients using electronic health records, which could improve screening number and the cost-effectiveness of AF screening if implemented in clinical practice., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RBS has received lecture fees and advisory board fees from BMS/Pfizer outside this work. RM, HW, RM, and TL are employees and shareholders of Pfizer. RBS 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 Researh (DZHK e.V.) (81Z1710103); German Ministry of Research and Education (BMBF 01ZX1408A) and ERACoSysMed3 (031L0239). RBS has received lecture fees and advisory board fees from BMS/Pfizer outside this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: Atrial fibrillation (AF) screening may increase early detection and reduce complications of AF. European, Australian and World Heart Federation guidelines recommend opportunistic screening, despite a current lack of clear evidence supporting a net benefit for systematic screening. Where screening is implemented, the most appropriate approaches are unknown. We explored the views of European stakeholders about opportunities and challenges of implementing four AF screening scenarios., Design: Telephone-based semi-structured interviews with results reported using Consolidated criteria for Reporting Qualitative research guidelines. Data were thematically analysed using the framework approach., Setting: AF screening stakeholders in 11 European countries., Participants: Healthcare professionals and regulators (n=24) potentially involved in AF screening implementation., Intervention: Four AF screening scenarios: single time point opportunistic, opportunistic prolonged, systematic single time point/prolonged and patient-led screening., Primary Outcome Measures: Stakeholder views about the challenges and feasibility of implementing the screening scenarios in the respective national/regional healthcare system., Results: Three themes developed. (1) Current screening approaches: there are no national AF screening programmes, with most AF detected in symptomatic patients. Patient-led screening exists via personal devices, creating screening inequity. (2) Feasibility of screening: single time point opportunistic screening in primary care using single-lead ECG devices was considered the most feasible. Software algorithms may aid identification of suitable patients and telehealth services have potential to support diagnosis. (3) Implementation requirements: sufficient evidence of benefit is required. National screening processes are required due to different payment mechanisms and health service regulations. Concerns about data security, and inclusivity for those without primary care access or personal devices must be addressed., Conclusions: There is an overall awareness of AF screening. Opportunistic screening appears the most feasible across Europe. Challenges are health inequalities, identification of best target groups for screening, streamlined processes, the need for evidence of benefit and a tailored approach adapted to national realities., Competing Interests: Competing interests: RS has received speaker and advisory board honoraria by BMS/Pfizer outside this work. BF reports research grants to institution for investigator initiated studies from BMS/Pfizer alliance, and speaker fees and non-financial support from BMS/Pfizer, Daiichi Sankyo and OMRON. GB reported speaker’s fees of small amount from Bayer, Boehringer, Boston, Biotronik and Medtronic. HH did receive personal fees from Biotronik and BMS/Pfizer. He received unconditional research grants through the University of Antwerp and/or the University of Hasselt from Bayer, Boehringer-Ingelheim, Bracco Imaging Europe, Abbott, Medtronic, Biotronik, Daiichi Sankyo, BMS/Pfizer and Boston Scientific, all outside the scope of this work. SZD is a part-time employee of Vital Beats without relation to the current work. TSP: consultancy (no fee) and small speaker fee from Bayer and BMS/Pfizer outside this work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In Germany, there is little real-world evidence on physicians' choice of oral anticoagulants (OACs). Our study aimed at assessing preferences for and prescribing patterns of treatment options for stroke prevention in atrial fibrillation in clinical practice in Germany. We conducted a nationwide quantitative online survey among office-based physicians in Germany. Physicians were asked about their preference for and use of treatment options as well as factors influencing their choice of a specific OAC. A total of n = 953 physicians was surveyed in September and October 2020 (general physicians: 36.0%; internists: 37.3%; cardiologists: 23.7%; neurologists: 10.5%; multiple specialties possible). Preference and use were highest for non-vitamin K oral anticoagulants (NOACs); followed by vitamin K antagonists (VKAs). Most preferred OACs were apixaban (39.3%), rivaroxaban (28.5%) and edoxaban (14.7%). Most used OACs were apixaban (24.3%), rivaroxaban (21.2%) and phenprocoumon (21.4%). NOACs were preferred more often than used (85.6% > 68.6%). VKAs were preferred less often than used (9.6% < 23.5%). OAC attributes and patient characteristics related to efficacy and safety, as well as patients' kidney function were most important when selecting a specific OAC. Federal and regional governance instruments likely influenced treatment decision-making. We found a high divergence between preferences for and use of available treatment options in clinical practice. Further exploration of the importance of OAC attributes, patient characteristics as well as federal and regional governance instruments for physicians' choice of a specific OAC may help to further optimize the healthcare of patients with atrial fibrillation in the long-term., Competing Interests: The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Anja Mocek, Valeria Weber and Holger Gothe are employees of the vendor IGES Institut GmbH, which is a paid consultant to Bristol-Myers Squibb GmbH & Co. KGaA and Pfizer Pharma GmbH for designing the survey, carrying out the statistical analyses, interpreting the results and writing the manuscript. The vendor Schlesinger Group Germany GmbH was subcontracted and reimbursed by the vendor IGES Institut GmbH for recruiting participants and conducting the online survey. Johanna Schmölders is an employee of Bristol-Myers Squibb GmbH & Co. KGaA. Henning Witt is an employee of Pfizer Pharma GmbH. Fees for data provision as well as publication fees are paid by IGES Institut GmbH as incurred costs and reimbursed by Bristol-Myers Squibb GmbH & Co. KGaA and Pfizer Pharma GmbH. The funding for designing the survey, carrying out the statistical analyses, interpreting the results and writing the manuscript as well as reimbursement of fees was shared between Bristol-Myers Squibb GmbH & Co. KGaA and Pfizer Pharma GmbH. All authors had complete autonomy for the process of designing the survey, carrying out the statistical analyses, interpreting the results and writing the manuscript. This also includes the full right to publish the results without limitation., (© 2022 The Authors. Published by Elsevier Inc.)

Objective: Non-alcoholic chronic pancreatitis (NACP) frequently develops in the setting of genetic susceptibility associated with alterations in genes that are highly expressed in the pancreas. However, the genetic basis of NACP remains unresolved in a significant number of patients warranting a search for further risk genes., Design: We analyzed CUZD1, which encodes the CUB and zona pellucida-like domains 1 protein that is found in high levels in pancreatic acinar cells. We sequenced the coding region in 1163 European patients and 2018 European controls. In addition, we analyzed 297 patients and 1070 controls from Japan. We analyzed secretion of wild-type and mutant CUZD1 from transfected cells using Western blotting., Results: In the European cohort, we detected 30 non-synonymous variants. Using different prediction tools (SIFT, CADD, PROVEAN, PredictSNP) or the combination of these tools, we found accumulation of predicted deleterious variants in patients (p-value range 0.002-0.013; OR range 3.1-5.2). No association was found in the Japanese cohort, in which 13 non-synonymous variants were detected. Functional studies revealed >50% reduced secretion of 7 variants, however, these variants were not significantly enriched in European CP patients., Conclusion: Our data indicate that CUZD1 might be a novel susceptibility gene for NACP. How these variants predispose to pancreatitis remains to be elucidated., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2022 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

The digestive protease chymotrypsin C (CTRC) protects the pancreas against pancreatitis by degrading potentially harmful trypsinogen. Loss-of-function genetic variants in CTRC increase risk for chronic pancreatitis (CP) with variable effect size, as judged by the reported odds ratio (OR) values. Here, we performed a meta-analysis of published studies on four variants that alter the CTRC amino-acid sequence, are clinically relatively common (global carrier frequency in CP >1%), reproducibly showed association with CP and their loss of function phenotype was verified experimentally. We found strong enrichment of CTRC variants p.A73T, p.V235I, p.K247&#95;R254del, and p.R245W in CP cases versus controls, yielding OR values of 6.5 (95% confidence interval (CI) 2.4-17.8), 4.5 (CI 2.2-9.1), 5.4 (CI 2.6-11.0), and 2.6 (CI 1.6-4.2), respectively. Subgroup analysis demonstrated disease association of variants p.K247&#95;R254del and p.R245W in alcoholic CP with similar effect sizes as seen in the overall CP group. Homozygosity or compound heterozygosity were rare and seemed to be associated with higher risk. We also identified a so far unreported linkage disequilibrium between variant p.K247&#95;R254del and the common c.180C>T (p.G60 =) haplotype. Taken together, the results indicate that heterozygous loss-of-function CTRC variants increase the risk for CP approximately 3-7-fold. This meta-analysis confirms the clinical significance of CTRC variants and provides further justification for the genetic screening of CP patients., Competing Interests: The authors have declared that no competing interests exist.

Chromosome inheritance depends on centromeres, epigenetically specified regions of chromosomes. While conventional human centromeres are known to be built of long tandem DNA repeats, much of their architecture remains unknown. Using single-molecule techniques such as AFM, nanopores, and optical tweezers, we find that human centromeric DNA exhibits complex DNA folds such as local hairpins. Upon binding to a specific sequence within centromeric regions, the DNA-binding protein CENP-B compacts centromeres by forming pronounced DNA loops between the repeats, which favor inter-chromosomal centromere compaction and clustering. This DNA-loop-mediated organization of centromeric chromatin participates in maintaining centromere position and integrity upon microtubule pulling during mitosis. Our findings emphasize the importance of DNA topology in centromeric regulation and stability., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In preparation for mitotic cell division, the nuclear DNA of human cells is compacted into individualized, X-shaped chromosomes 1 . This metamorphosis is driven mainly by the combined action of condensins and topoisomerase IIα (TOP2A) 2,3 , and has been observed using microscopy for over a century. Nevertheless, very little is known about the structural organization of a mitotic chromosome. Here we introduce a workflow to interrogate the organization of human chromosomes based on optical trapping and manipulation. This allows high-resolution force measurements and fluorescence visualization of native metaphase chromosomes to be conducted under tightly controlled experimental conditions. We have used this method to extensively characterize chromosome mechanics and structure. Notably, we find that under increasing mechanical load, chromosomes exhibit nonlinear stiffening behaviour, distinct from that predicted by classical polymer models 4 . To explain this anomalous stiffening, we introduce a hierarchical worm-like chain model that describes the chromosome as a heterogeneous assembly of nonlinear worm-like chains. Moreover, through inducible degradation of TOP2A 5 specifically in mitosis, we provide evidence that TOP2A has a role in the preservation of chromosome compaction. The methods described here open the door to a wide array of investigations into the structure and dynamics of both normal and disease-associated chromosomes., (© 2022. The Author(s).)

Background: Previous genome-wide association studies (GWAS) identified genome-wide significant risk loci in chronic pancreatitis and investigated underlying disease causing mechanisms by simple overlaps with expression quantitative trait loci (eQTLs), a procedure which may often result in false positive conclusions., Methods: We conducted a GWAS in 584 non-alcoholic chronic pancreatitis (NACP) patients and 6040 healthy controls. Next, we applied Bayesian colocalization analysis of identified genome-wide significant risk loci from both, our recently published alcoholic chronic pancreatitis (ACP) and the novel NACP dataset, with pancreas eQTLs from the GTEx V8 European cohort to prioritize candidate causal genes and extracted credible sets of shared causal variants., Results: Variants at the CTRC (p = 1.22 × 10 -21 ) and SPINK1 (p = 6.59 × 10 -47 ) risk loci reached genome-wide significance in NACP. CTRC risk variants colocalized with CTRC eQTLs in ACP (PP4 = 0.99, PP4/PP3 = 95.51) and NACP (PP4 = 0.99, PP4/PP3 = 95.46). For both diseases, the 95% credible set of shared causal variants consisted of rs497078 and rs545634. CLDN2-MORC4 risk variants colocalized with CLDN2 eQTLs in ACP (PP4 = 0.98, PP4/PP3 = 42.20) and NACP (PP4 = 0.67, PP4/PP3 = 7.18), probably driven by the shared causal variant rs12688220., Conclusions: A shared causal CTRC risk variant might unfold its pathogenic effect in ACP and NACP by reducing CTRC expression, while the CLDN2-MORC4 shared causal variant rs12688220 may modify ACP and NACP risk by increasing CLDN2 expression., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2022 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Genetic mutations in various pancreatic enzymes or their counteracting proteins have been linked to chronic pancreatitis. In particular, variants in the genes encoding pancreatic lipase (PNLIP) and carboxyl ester lipase (CEL) have been associated with pancreatitis. Therefore, we investigated pancreatic phospholipase A2 (PLA2G1B) as a promising candidate gene in patients with chronic pancreatitis., Methods: We analyzed all coding exons and adjacent intronic regions of PLA2G1B in 416 German patients with non-alcoholic chronic pancreatitis (NACP) and 186 control subjects by direct DNA sequencing., Results: We detected 2 frequent synonymous variants in exon 3: c.222T>C (p.Y74 = ) and c.294G>A (p.S98 = ). The genotype and allele frequencies of these variants were similar between patients and controls (c.222 TC: 9.6% in NACP vs. 9.7% in controls; c.222CC: 0.2% in NACP vs. 0% in controls; c.294 GA: 31.3% in NACP vs. 28.0% in controls; c.294AA: 2.4% in NACP vs. 1.1% in controls). All p-values were non-significant. In addition, we found one synonymous variant, c.138C>T (p.N46 = ) and one non-synonymous variant, c.244A>G (p.S82G), in a single case each., Conclusions: Our results suggest that genetic alterations in PLA2G1B do not predispose to the development of non-alcoholic chronic pancreatitis., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2022 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

The human rights of transgender and gender non-conforming individuals are under attack at unprecedented levels all over the United States. This article begins by defining and describing human rights and explaining in detail the threats to the human rights and safety of transgender and gender non-conforming individuals. Finally, the article urges ongoing social work engagement in advocating for the protection of those rights by utilizing the policy window created by the Bostock v. Clayton County ruling and recent executive orders issued by the Biden Administration to promote safety for transgender and gender non-conforming community members. The article concludes with suggestions for social workers practitioners and educators.

Purpose: Loss of function variants of the transient receptor potential cation channel, subfamily V, member 6 (TRPV6) have been recently associated with chronic pancreatitis (CP) in Japanese, German and French patients. Here, we investigated the association of TRPV6 variants with CP in independent European cohorts of early-onset CP patients from Poland and Germany., Patients and Methods: We enrolled 152 pediatric CP patients (median age 8.6 yrs) with no history of alcohol/smoking abuse and 472 controls from Poland as well as 157 nonalcoholic young CP patients (median age 20 yrs) and 750 controls from Germany. Coding regions of TRPV6 were screened by Sanger and next generation sequencing. Selected, potentially pathogenic TRPV6 variants were expressed in HEK293T cells and TRPV6 activity was analyzed using ratiometric Ca 2+ measurements., Results: Overall, we identified 10 novel (3 nonsense and 7 missenses) TRPV6 variants in CP patients. TRPV6 p.V239SfsX53 nonsense variant and the variants showing significant decrease in intracellular Ca 2+ concentration in HEK293T cells (p.R174X, p.L576R, p.R342Q), were significantly overrepresented in Polish patients as compared to controls (6/152, 3.9% vs. 0/358, 0%; P = 0,0007). Nonsense TRPV6 variants predicted as loss of function (p.V239SfsX53 and p.R624X) were also significantly overrepresented in German patients (3/157; 2.0% vs 0/750; 0%, P = 0.005)., Conclusions: We showed that TRPV6 loss of function variants are associated with elevated CP risk in early-onset Polish and German patients confirming that TRPV6 is a novel CP susceptibility gene., Competing Interests: Declaration of competing interest The authors are unaware of any conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)