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Background: Anomalies of the origin and course of the circumflex artery are amongst the most common seen at coronary angiography. There is limited information regarding patient and procedural characteristics, technical feasibility and outcomes associated with percutaneous intervention (PCI) to these vessels. The aim of this study is to examine our experience with PCI to anomalous circumflex vessels and compare this to some aspects of percutaneous intervention on non-anomalous circumflex vessels. Methods: Over a 41 month period, 20 PCI procedures on anomalous circumflex vessels were identified and 1550 PCI procedures on non-anomalous circumflex arteries. Results: In 9 anomalous cases, the circumflex arose from the left coronary cusp, in 7 cases from the right coronary cusp, and in the remaining 4 cases from the proximal right coronary artery. There were no differences in demographics or pattern or severity of coronary disease between the 2 groups. A higher proportion of patients with anomalous vessels presented acutely. Screening times were longer in the anomalous group. All 20 procedures were associated with immediate procedural success. There was one peri-procedural myocardial infarction unrelated to anomalous circumflex intervention. After a median follow-up period of 7.3 months, the only major adverse cardiac event recorded in the anomalous group was an ischaemia-driven revascularisation to a non-target vessel branch. We describe techniques which can be used to improve support and facilitate successful PCI to anomalous circumflex vessels. Conclusion: PCI to anomalous circumflex vessels may be technically challenging, but is feasible and carries favourable short and long-term clinical outcomes. Summary: This single centre observational study demonstrates that percutaneous coronary intervention to anomalous circumflex coronary arteries although technically challenging can be performed with satisfactory procedural success rates and favourable short and longer-term clinical outcomes. It describes various techniques that can be employed to optimise successful intervention. [ABSTRACT FROM AUTHOR]

The article presents an ethics roundtable regarding the issue of using U.S. Medicare quality measures as a means of determining the level of care administered to a 76-year-old terminally ill patient. Several ethicists, physicians and nurses discuss the different ethical issues raised by the patient's situation including the role of the nurse in advocating for the rights of the patient and family and the role of the medical staff in providing quality care irrespective of financial concerns.

The sinoatrial node is the primary pacemaker of the heart. Nodal dysfunction with aging, heart failure, atrial fibrillation, and even endurance athletic training can lead to a wide variety of pathological clinical syndromes. Recent work utilizing molecular markers to map the extent of the node, along with the delineation of a novel paranodal area intermediate in characteristics between the node and the surrounding atrial muscle, has shown that pacemaker tissue is more widely spread in the right atrium than previously appreciated. This can explain the phenomenon of a 'wandering pacemaker' and concomitant changes in the P-wave morphology. Extensive knowledge now exists regarding the molecular architecture of the node (in particular, the expression of ion channels) and how this relates to pacemaking. This review is an up-to-date summary of the current state of our appreciation of the above topics. (PACE 2010; 1392-1406) [ABSTRACT FROM AUTHOR]

Deals with the different perspectives on a case study relating to dementia, quality of life and appropriate treatment for a woman with Alzheimer's disease. Facts presented in the case study; Principles surrounding the withdrawal of a patient from dialysis; Legal and ethical perspectives on the case study.

Discusses a case study of a patient with terminal metastatic carcinoma of the lung. Perceptions of a physician regarding the case study; Opinion of a legal practitioner on hospice care; Views from a medical ethicist in relation to informed consent for sedation for palliation of terminal symptoms; Perceptions of a nurse regarding the question of ethical obligation based on the case study.

Background: Sinoatrial node (SAN) activation and sinoatrial conduction pathways (SACPs) have been assessed in animals but not in humans., Objectives: We used ultrahigh-density mapping and simulated models to characterize the SAN and to investigate whether slowed SAN conduction may contribute to the atrial flutter (AFL) substrate., Methods: Twenty-seven patients undergoing electrophysiologic procedures had right atrial mapping. SAN activation patterns and conduction block were analyzed. The interaction between the SAN and the intercaval line of block (LOB) was analyzed, and right atrial simulations with different degrees of block were created to investigate arrhythmia mechanisms., Results: Fifteen AFL patients and 12 reference patients were enrolled. SACPs were identified in all patients with sinus rhythm maps. An SAN-adjacent LOB was observed in AFL patients. SAN conduction velocity was slower in AFL vs reference (0.60 m/s [0.56-0.78 m/s] vs 1.13 m/s [1.00-1.21 m/s]; P = .0021). Coronary sinus paced maps displayed an intercaval LOB in AFL patients but not in reference patients, which was completed superiorly by the SAN-adjacent LOB. Corrected sinus node recovery time was longer in AFL patients (552.3 ± 182.9 ms vs 325.4 ± 138.3 ms; P < .006) and correlated with degree of intercaval block (r = 0.7236; P = .0003). Computer modeling supported an important role of SAN-associated block in the flutter substrate., Conclusion: Ultrahigh-density mapping accurately identifies SAN activation and SACPs. The LOB important for typical AFL was longer in AFL patients, and when partial, it was always present inferiorly and completed superiorly because of slowed conduction across the SAN. Corrected sinus node recovery time correlated with intercaval block, suggesting a role for SAN disease in the genesis of the typical AFL substrate., Competing Interests: Disclosures K.S. and G.M.M.: research funding (Boston Scientific). J.M.K.: research and fellowship support (Medtronic, Biosense Webster)., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Bradyarrhythmias including sinus bradycardia and atrioventricular (AV) block are frequently encountered in endurance athletes especially at night. While these are well tolerated by the young athlete, there is evidence that generally from the fifth decade of life onward, such arrhythmias can degenerate into pathological symptomatic bradycardia requiring pacemaker therapy. For many years, athletic bradycardia and AV block have been attributed to high vagal tone, but work from our group has questioned this widely held assumption and demonstrated a role for intrinsic electrophysiological remodeling of the sinus node and the AV node. In this article, we argue that bradyarrhythmias in the veteran athlete arise from the cumulative effects of exercise training, the circadian rhythm and aging on the electrical activity of the nodes. We consider contemporary strategies for the treatment of symptomatic bradyarrhythmias in athletes and highlight potential therapies resulting from our evolving mechanistic understanding of this phenomenon., Competing Interests: Disclosures The authors have no conflicts to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Ventricular arrhythmias (VAs) demonstrate a prominent day-night rhythm, commonly presenting in the morning. Transcriptional rhythms in cardiac ion channels accompany this phenomenon, but their role in the morning vulnerability to VAs and the underlying mechanisms are not understood. We investigated the recruitment of transcription factors that underpins transcriptional rhythms in ion channels and assessed whether this mechanism was pertinent to the heart's intrinsic diurnal susceptibility to VA., Methods and Results: Assay for transposase-accessible chromatin with sequencing performed in mouse ventricular myocyte nuclei at the beginning of the animals' inactive (ZT0) and active (ZT12) periods revealed differentially accessible chromatin sites annotating to rhythmically transcribed ion channels and distinct transcription factor binding motifs in these regions. Notably, motif enrichment for the glucocorticoid receptor (GR; transcriptional effector of corticosteroid signaling) in open chromatin profiles at ZT12 was observed, in line with the well-recognized ZT12 peak in circulating corticosteroids. Molecular, electrophysiological, and in silico biophysically-detailed modeling approaches demonstrated GR-mediated transcriptional control of ion channels (including Scn5a underlying the cardiac Na + current, Kcnh2 underlying the rapid delayed rectifier K + current, and Gja1 responsible for electrical coupling) and their contribution to the day-night rhythm in the vulnerability to VA. Strikingly, both pharmacological block of GR and cardiomyocyte-specific genetic knockout of GR blunted or abolished ion channel expression rhythms and abolished the ZT12 susceptibility to pacing-induced VA in isolated hearts., Conclusions: Our study registers a day-night rhythm in chromatin accessibility that accompanies diurnal cycles in ventricular myocytes. Our approaches directly implicate the cardiac GR in the myocyte excitability rhythm and mechanistically link the ZT12 surge in glucocorticoids to intrinsic VA propensity at this time., Competing Interests: Disclosures None.

A novel class of protein misfolding characterized by either the formation of non-native noncovalent lasso entanglements in the misfolded structure or loss of native entanglements has been predicted to exist and found circumstantial support through biochemical assays and limited-proteolysis mass spectrometry data. Here, we examine whether it is possible to design small molecule compounds that can bind to specific folding intermediates and thereby avoid these misfolded states in computer simulations under idealized conditions (perfect drug-binding specificity, zero promiscuity, and a smooth energy landscape). Studying two proteins, type III chloramphenicol acetyltransferase (CAT-III) and D-alanyl-D-alanine ligase B (DDLB), that were previously suggested to form soluble misfolded states through a mechanism involving a failure-to-form of native entanglements, we explore two different drug design strategies using coarse-grained structure-based models. The first strategy, in which the native entanglement is stabilized by drug binding, failed to decrease misfolding because it formed an alternative entanglement at a nearby region. The second strategy, in which a small molecule was designed to bind to a non-native tertiary structure and thereby destabilize the native entanglement, succeeded in decreasing misfolding and increasing the native state population. This strategy worked because destabilizing the entanglement loop provided more time for the threading segment to position itself correctly to be wrapped by the loop to form the native entanglement. Further, we computationally identified several FDA-approved drugs with the potential to bind these intermediate states and rescue misfolding in these proteins. This study suggests it is possible for small molecule drugs to prevent protein misfolding of this type., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Jiang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The last few years have seen the development of numerous deep learning-based protein-ligand docking methods. They offer huge promise in terms of speed and accuracy. However, despite claims of state-of-the-art performance in terms of crystallographic root-mean-square deviation (RMSD), upon closer inspection, it has become apparent that they often produce physically implausible molecular structures. It is therefore not sufficient to evaluate these methods solely by RMSD to a native binding mode. It is vital, particularly for deep learning-based methods, that they are also evaluated on steric and energetic criteria. We present PoseBusters, a Python package that performs a series of standard quality checks using the well-established cheminformatics toolkit RDKit. The PoseBusters test suite validates chemical and geometric consistency of a ligand including its stereochemistry, and the physical plausibility of intra- and intermolecular measurements such as the planarity of aromatic rings, standard bond lengths, and protein-ligand clashes. Only methods that both pass these checks and predict native-like binding modes should be classed as having "state-of-the-art" performance. We use PoseBusters to compare five deep learning-based docking methods (DeepDock, DiffDock, EquiBind, TankBind, and Uni-Mol) and two well-established standard docking methods (AutoDock Vina and CCDC Gold) with and without an additional post-prediction energy minimisation step using a molecular mechanics force field. We show that both in terms of physical plausibility and the ability to generalise to examples that are distinct from the training data, no deep learning-based method yet outperforms classical docking tools. In addition, we find that molecular mechanics force fields contain docking-relevant physics missing from deep-learning methods. PoseBusters allows practitioners to assess docking and molecular generation methods and may inspire new inductive biases still required to improve deep learning-based methods, which will help drive the development of more accurate and more realistic predictions., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property-free knowledge base for future anticoronavirus drug discovery.

Background: Atrial myopathy may underlie the progression of atrial fibrillation (AF) from a treatable disease to an irreversible condition with poor ablation outcomes. Electrophysiological methods to unmask areas prone to re-entry initiation could be key to defining latent atrial myopathy., Methods: Consecutive patients referred for AF ablation were prospectively included at four institutions. Decrement evoked potential mapping (DEEP) was performed in eight left atrial sites and five right atrial sites, from two different pacing locations (endocardially from the left atrial appendage, epicardially from the proximal coronary sinus). The electrograms (EGMs) during S1 600 ms drive and after an extra stimulus (S2 at +30 ms above atrial refractoriness) were studied at each location and assessed for decremental properties. Follow-up was 12 months., Results: Seventy-four patients were included and 85% had persistent AF. A total of 17,614 EGMs were individually analysed and measured. Nine percent of the EGMs showed DEEP properties (local delay of >10 ms after S2) with a mean decrement of 33±26 ms. DEEPs were more frequent in the left atrium than the right atrium (9.4% vs 8.0%; p<0.001) and more prevalent in persistent AF patients than paroxysmal AF patients (9.8% vs 4.6% p=0.001). Atrial DEEPs were more frequently unmasked in normal bipolar voltage areas and by epicardial pacing than endocardial pacing (9.6% vs 8.4%, respectively; p=0.004). Within the left atrium, the roof had the highest prevalence of DEEP EGMs., Conclusions: DEEP mapping of both atria is useful for highlighting areas with a tendency for unidirectional block and re-entry initiation. Those areas are more easily unmasked by epicardial pacing from the coronary sinus and more prevalent in persistent AF patients than in paroxysmal AF patients., (Copyright © 2023 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

CC and CXC-chemokines are the primary drivers of chemotaxis in inflammation, but chemokine network redundancy thwarts pharmacological intervention. Tick evasins promiscuously bind CC and CXC-chemokines, overcoming redundancy. Here we show that short peptides that promiscuously bind both chemokine classes can be identified from evasins by phage-display screening performed with multiple chemokines in parallel. We identify two conserved motifs within these peptides and show using saturation-mutagenesis phage-display and chemotaxis studies of an exemplar peptide that an anionic patch in the first motif and hydrophobic, aromatic and cysteine residues in the second are functionally necessary. AlphaFold2-Multimer modelling suggests that the peptide occludes distinct receptor-binding regions in CC and in CXC-chemokines, with the first and second motifs contributing ionic and hydrophobic interactions respectively. Our results indicate that peptides with broad-spectrum anti-chemokine activity and therapeutic potential may be identified from evasins, and the pharmacophore characterised by phage display, saturation mutagenesis and computational modelling., (© 2023. Springer Nature Limited.)

This review summarizes the evidence for left atrial appendage closure (LAAC) as an alternative to oral anticoagulation (OAC) for stroke prevention in atrial fibrillation. LAAC reduces hemorrhagic stroke and mortality versus warfarin, but is inferior for ischemic stroke reduction based on randomized data. Whilst a feasible treatment in OAC-ineligible patients, questions remain over procedural safety, and the improvement in complications observed in nonrandomized registries is uncorroborated by contemporary randomized trials. Management of device-related thrombus and peridevice leak remain unclear, and robust randomized data versus direct OACs are required before recommendations can be made for widespread adoption in OAC-eligible populations., Competing Interests: Disclosure K. Saraf has received research funding from Boston Scientific. G.M. Morris has received research funding and honoraria from Boston Scientific and Medtronic, honoraria from Biosense Webster., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The learning curve for the novel RHYTHMIA HDx™ 3-dimensional electroanatomic system is unknown. Retrospective data collection was carried out at 3 U.K. centers from the introduction of RHYTHMIA HDx™ (Boston Scientific, Marlborough, MA, USA) and associated mapping and ablation catheters. Patients were matched with controls using the CARTO ® 3 mapping system (Biosense Webster Inc., Diamond Bar, CA, USA). Fluoroscopy, radiofrequency ablation, and procedure times; acute and long-term success; and complications were assessed. A total of 253 study patients along with 253 controls were included. Significant correlations existed between procedural efficiency metrics and center experience for de novo atrial fibrillation (AF) ablation (procedure time, Spearman's ρ = -0.624; ablation time, ρ = -0.795; both P < .0005) and de novo atrial flutter (AFL) ablation (ablation time, ρ = -0.566; fluoroscopy time, ρ = -0.520; both P = .001). No correlations existed for other assessed atrial arrhythmias. For de novo AF and AFL, metrics significantly improved after 10 procedures in each center (procedure time [AF only, P = .001], ablation time [AF, P < .0005; AFL, P < .0005], and fluoroscopy time [AFL only, P = .0022]) and became comparable to those of controls. Acute success and long-term success did not experience significant improvements with experience, but they were comparable to the control group throughout. Complications with RHYTHMIA HDx™ were comparable to those associated with CARTO ® 3. In conclusion, a short learning curve exists with the use of RHYTHMIA HDx™ for standardized procedures (de novo AF/AFL). Procedural performance improved and became comparable to that seen with CARTO ® 3 following 10 cases at each center. Clinical outcomes at 6 and 12 months and complications were no different from those observed in controls., Competing Interests: Dr. Ullah has received research funding from Biosense Webster, Inc., Boston Scientific, and Abbott. The other authors report no conflicts of interest for the published content. No funding information was provided., (Copyright: © 2023 Innovations in Cardiac Rhythm Management.)

Machine learning scoring functions for protein-ligand binding affinity have been found to consistently outperform classical scoring functions when trained and tested on crystal structures of bound protein-ligand complexes. However, it is less clear how these methods perform when applied to docked poses of complexes. We explore how the use of docked rather than crystallographic poses for both training and testing affects the performance of machine learning scoring functions. Using the PDBbind Core Sets as benchmarks, we show that the performance of a structure-based machine learning scoring function trained and tested on docked poses is lower than that of the same scoring function trained and tested on crystallographic poses. We construct a hybrid scoring function by combining both structure-based and ligand-based features, and show that its ability to predict binding affinity using docked poses is comparable to that of purely structure-based scoring functions trained and tested on crystal poses. We also present a new, freely available validation set─the Updated DUD-E Diverse Subset─for binding affinity prediction using data from DUD-E and ChEMBL. Despite strong performance on docked poses of the PDBbind Core Sets, we find that our hybrid scoring function sometimes generalizes poorly to a protein target not represented in the training set, demonstrating the need for improved scoring functions and additional validation benchmarks.

TRIM33 is a member of the tripartite motif (TRIM) family of proteins, some of which possess E3 ligase activity and are involved in the ubiquitin-dependent degradation of proteins. Four of the TRIM family proteins, TRIM24 (TIF1α), TRIM28 (TIF1β), TRIM33 (TIF1γ) and TRIM66, contain C-terminal plant homeodomain (PHD) and bromodomain (BRD) modules, which bind to methylated lysine (KMe n ) and acetylated lysine (KAc), respectively. Here we investigate the differences between the two isoforms of TRIM33, TRIM33α and TRIM33β, using structural and biophysical approaches. We show that the N1039 residue, which is equivalent to N140 in BRD4(1) and which is conserved in most BRDs, has a different orientation in each isoform. In TRIM33β, this residue coordinates KAc, but this is not the case in TRIM33α. Despite these differences, both isoforms show similar affinities for H3 1-27 K18Ac, and bind preferentially to H3 1-27 K9Me 3 K18Ac. We used this information to develop an AlphaScreen assay, with which we have identified four new ligands for the TRIM33 PHD-BRD cassette. These findings provide fundamental new information regarding which histone marks are recognized by both isoforms of TRIM33 and suggest starting points for the development of chemical probes to investigate the cellular function of TRIM33.

Drug resistance caused by mutations is a public health threat for existing and emerging viral diseases. A wealth of evidence about these mutations and their clinically associated phenotypes is scattered across the literature, but a comprehensive perspective is usually lacking. This work aimed to produce a clinically relevant view for the case of Hepatitis B virus (HBV) mutations by combining a chronic HBV clinical study with a compendium of genetic mutations systematically gathered from the scientific literature. We enriched clinical mutation data by systematically mining 2,472,725 scientific articles from PubMed Central in order to gather information about the HBV mutational landscape. By performing this analysis, we were able to identify mutational hotspots for each HBV genotype (A-E) and gene (C, X, P, S), as well as the location of disulfide bonds associated with these mutations. Through a modelling study, we also identified a mutation position common in both the clinical data and the literature that is located at the binding pocket for a known anti-HBV drug, namely entecavir. The results of this novel approach show the potential of integrated analyses to assist in the development of new drugs for viral diseases that are more robust to resistance. Such analyses should be of particular interest due to the increasing importance of viral resistance in established and emerging viruses, such as for newly developed drugs against SARS-CoV-2., (© 2022. The Author(s).)

Introduction: - Local impedance (LI) guided ablation as a method of judging lesion effectiveness for cavotricuspid isthmus dependent atrial flutter (CTI-AFL), and ultra-high density (UHD) mapping when breakthrough occurred across an ablation line has not previously been assessed., Methods: This retrospective observational study evaluated patients undergoing CTI-AFL ablation using conventional, contact force (CF) and LI guided strategies. Ablation metrics were collected, and in the LI cohort, the use of UHD mapping for breakthrough evaluated., Results: 30 patients were included, 10 per group. Mean total ablation time was significantly shorter with LI (3.2 ± 1.3min) vs conventional (5.6 ± 2.7min) and CF (5.7 ± 2.0min, p = 0.0042). Time from start of ablation to CTI block was numerically shorter with LI (14.2 ± 8.0min) vs conventional and CF (19.7 ± 14.1 and 22.5 ± 19.1min, p = 0.4408). Mean lesion duration was significantly shorter with LI, but there were no differences in the number of lesions required to achieve block, procedural success, complication rates or recurrence. 15/30 patients did not achieve block following first-pass ablation. UHD mapping rapidly identified breakthrough in the five LI patients, including epicardial-endocardial breakthrough (EEB)., Conclusion: - The use of LI during ablation for real-time lesion assessment was as efficacious as the conventional and CF methods. UHD mapping rapidly identified breakthrough, including EEB., Competing Interests: Declaration of competing interest Karan Saraf: research funding from Boston Scientific. Nicholas Black: None. Clifford J Garratt: None. Sahrkaw Muhyaldeen: sponsorship for conference attendance from Biosense Webster. Gwilym M Morris: research funding from Boston Scientific, Honoraria from Boston Scientific and Biosense Webster., (Copyright © 2022 Indian Heart Rhythm Society. Published by Elsevier B.V. All rights reserved.)

Purpose: Cardiac catheter ablations are an established treatment for supraventricular tachycardia (SVT) involving prolonged cannulation of the common femoral vein with multiple catheters. This study aimed to identify the risk of deep vein thrombosis (DVT) by studying the frequency of this complication after catheter ablation., Methods: This was a prospective multi-centre cohort study of patients undergoing cardiac ablation for atrioventricular nodal re-entry tachycardia or right-sided accessory atrioventricular connection. Those taking anticoagulation or antiplatelet therapy prior to the procedure were excluded. Following the procedure, bilateral venous duplex ultrasonography from the popliteal vein to the inferior vena cava for DVT was undertaken at 24 hours and between 10 to 14 days., Results: Eighty (80) patients (mean age 47.6 yrs [SD 13.4] with 67% female) underwent cardiac ablation (median duration 70 mins). Seven (7) patients developed acute DVT in either the femoral or external iliac vein of the intervention leg, giving a frequency of 8.8% (95% CI 3.6-17.2%). No thrombus was seen in the contralateral leg (p=0.023). An elevated D-dimer prior to the procedure was significantly more frequent in patients developing DVT (42.9% vs 4.1%, p=0.0081; OR 17.0). No other patient or procedural characteristics significantly influenced the risk of DVT., Conclusion: In patients without peri-procedural anticoagulation catheter ablation precipitated DVT in the catheterised femoral or iliac veins in 8.8% of patients. Peri-procedure prophylactic anticoagulation may be considered for all patients undergoing catheter ablation for SVT., Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03877770., (Copyright © 2022 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

The rapid and accurate in silico prediction of protein-ligand binding free energies or binding affinities has the potential to transform drug discovery. In recent years, there has been a rapid growth of interest in deep learning methods for the prediction of protein-ligand binding affinities based on the structural information of protein-ligand complexes. These structure-based scoring functions often obtain better results than classical scoring functions when applied within their applicability domain. Here we review structure-based scoring functions for binding affinity prediction based on deep learning, focussing on different types of architectures, featurization strategies, data sets, methods for training and evaluation, and the role of explainable artificial intelligence in building useful models for real drug-discovery applications., Competing Interests: Conflict of Interest Statement The 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.

This review summarizes the evidence for left atrial appendage closure (LAAC) as an alternative to oral anticoagulation (OAC) for stroke prevention in atrial fibrillation. LAAC reduces hemorrhagic stroke and mortality versus warfarin, but is inferior for ischemic stroke reduction based on randomized data. Whilst a feasible treatment in OAC-ineligible patients, questions remain over procedural safety, and the improvement in complications observed in nonrandomized registries is uncorroborated by contemporary randomized trials. Management of device-related thrombus and peridevice leak remain unclear, and robust randomized data versus direct OACs are required before recommendations can be made for widespread adoption in OAC-eligible populations., Competing Interests: Disclosure K. Saraf has received research funding from Boston Scientific. G.M. Morris has received research funding and honoraria from Boston Scientific and Medtronic, honoraria from Biosense Webster., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This study aimed to explore the impact of health literacy on psychosocial and behavioural outcomes for people who were not at high risk of cardiovascular disease receiving a hypothetical blood pressure reading of 135/85 mmHg. We performed a secondary analysis of data from a national sample of Australians aged 40 to 50 years (n = 1318) recruited online. Health literacy was measured using the validated Newest Vital Sign (inadequate: 0-3; adequate: 4-6). Analysed outcomes included: willingness to increase exercise and accept medication; perceived severity; positive and negative affect; illness perceptions and impacts on life and motivation. Participants with inadequate levels of health literacy perceived a blood pressure reading of 135/85 mmHg to be less serious compared to individuals with adequate health literacy (Mean Difference [MD]:0.21; 95%CI 0.03-0.39; p = .024; d = 0.13), and reported less motivation to eat well (MD:0.44; 95%CI 0.31-0.58; p < .001; d = 0.38) and exercise (MD:0.43; 95%CI 0.31-0.58; p < .001; d = 0.36). However, they were more willing to accept medication (MD:0.20; 95%CI 0.07-0.34; p = .004; d = 0.17). Participants with inadequate health literacy also perceived the condition to have fewer negative impacts on aspects of life and work than individuals with adequate health literacy, but reported greater negative emotion and more negative illness perceptions (all p < .001). Tailored communication and behaviour change support may be needed when communicating blood pressure information to people with lower health literacy and not at high risk of cardiovascular disease given the differential impacts on medication (increased willingness) and healthy exercise and diet behaviours (decreased willingness) observed in this study., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The SARS-CoV-2 coronavirus is the causal agent of the current global pandemic. SARS-CoV-2 belongs to an order, Nidovirales, with very large RNA genomes. It is proposed that the fidelity of coronavirus (CoV) genome replication is aided by an RNA nuclease complex, comprising the non-structural proteins 14 and 10 (nsp14-nsp10), an attractive target for antiviral inhibition. Our results validate reports that the SARS-CoV-2 nsp14-nsp10 complex has RNase activity. Detailed functional characterization reveals nsp14-nsp10 is a versatile nuclease capable of digesting a wide variety of RNA structures, including those with a blocked 3'-terminus. Consistent with a role in maintaining viral genome integrity during replication, we find that nsp14-nsp10 activity is enhanced by the viral RNA-dependent RNA polymerase complex (RdRp) consisting of nsp12-nsp7-nsp8 (nsp12-7-8) and demonstrate that this stimulation is mediated by nsp8. We propose that the role of nsp14-nsp10 in maintaining replication fidelity goes beyond classical proofreading by purging the nascent replicating RNA strand of a range of potentially replication-terminating aberrations. Using our developed assays, we identify drug and drug-like molecules that inhibit nsp14-nsp10, including the known SARS-CoV-2 major protease (Mpro) inhibitor ebselen and the HIV integrase inhibitor raltegravir, revealing the potential for multifunctional inhibitors in COVID-19 treatment., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Colorectal cancer is the second leading cause of cancer-related death in the United States, with a rising incidence, especially in young adults. Care for patients with colorectal cancer is associated with significant healthcare costs and expenditures. We retrospectively interrogated the National Inpatient Sample for admissions in patients with colorectal cancer from 2007 to 2017. A total of 1,962,705 admissions were identified: 50.2% were men, 64.4% were white, and the median age was 68. Most admissions (47.8%) that were coded for anatomical location of malignancy were for ascending colon cancer. The average in-hospital mortality was 4.9%, with a lower mortality in admissions with ascending colon cancer (2.9, P  < 0.001). The median length of stay was 5 days, with a longer stay in admissions with transverse colon cancer (9 days, P  < 0.0001). The median cost of hospitalization was $12,295 and was significantly higher for patients with descending colon malignancy ($16,369, P  < 0.0001). The number of annual hospitalizations stayed steady overall but increased by 98.6% for rectosigmoid cancer. Our findings highlight the high costs of hospitalization and the overall economic burden associated with inpatient admissions among patients with colorectal cancer., (Copyright © 2021 Baylor University Medical Center.)