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Background: Left bundle branch area pacing (LBBAP) and endocardial resynchronization (Endo-CRT) are alternatives to biventricular pacing for cardiac resynchronization therapy (CRT)., Objective: To compare the outcomes of LBBAP versus Endo-CRT using conventional pacing leads., Methods: Patients with heart failure (HF) undergoing CRT with LBBAP or Endo-CRT were included. The primary efficacy outcome was a composite of HF-related hospitalization and all-cause mortality. The primary safety outcome was any procedure-related complication. Secondary outcomes included procedural characteristics, electrocardiographic, and echocardiographic parameters., Results: A total of 223 patients (LBBAP n = 197, Endo-CRT n = 26; mean age 69 ± 10.3 years, 32.3% female) were included. Patients in the LBBAP group had lower NYHA class, shorter preprocedural QRS durations (161 [142-183] vs. 180 [170-203] msec, p < .001), and a lower preprocedural spironolactone use (57.4% vs. 84.6%, p = .009) than patients in the Endo-CRT group. Fluoroscopy time was significantly shorter in patients undergoing LBBAP (11.4 [7.2-20] vs. 23 [14.2-34.5] min; p < .001). There was no significant difference in the primary efficacy outcome between both groups (Cox proportional HR 1.21, 95% CI 0.635-2.31; p = .56). During follow-up, patients undergoing LBBAP had a lower incidence of stroke than patients in the Endo-CRT group (0% vs. 11.5%, p = .001). Postprocedural LVEF (35% [25-45] vs. 40% [20-55]; p = .307) and change in LVEF (7% [0-20] vs. 11% [2-18]; p = .384) were similar between the LBBAP and the Endo-CRT groups, respectively., Conclusion: LBBAP and Endo-CRT using conventional leads are associated with similar mortality and HF-related hospitalization, as well as improvements in LVEF. Endo-CRT is associated with longer fluoroscopy times and a higher risk of stroke., (© 2024 Wiley Periodicals LLC.)

Background: Left bundle branch area pacing (LBBAP) has emerged as a physiological alternative pacing strategy to biventricular pacing (BIVP) in cardiac resynchronization therapy (CRT). We aimed to assess the impact of LBBAP vs. BIVP on all-cause mortality and heart failure (HF)-related hospitalization in patients undergoing CRT., Methods: Studies comparing LBBAP and BIVP for CRT in patients with HF with reduced left ventricular ejection fraction (LVEF) were included. The coprimary outcomes were all-cause mortality and HF-related hospitalization. Secondary outcomes included procedural and fluoroscopy time, change in QRS duration, and change in LVEF., Results: Thirteen studies (12 observational and 1 RCT, n = 3239; LBBAP = 1338 and BIVP = 1901) with a mean follow-up duration of 25.8 months were included. Compared to BIVP, LBBAP was associated with a significant absolute risk reduction of 3.2% in all-cause mortality (9.3% vs 12.5%, RR 0.7, 95% CI 0.57-0.86, p < 0.001) and an 8.2% reduction in HF-related hospitalization (11.3% vs 19.5%, RR 0.6, 95% CI 0.5-0.71, p < 0.00001). LBBAP also resulted in reductions in procedural time (mean weighted difference- 23.2 min, 95% CI - 42.9 to - 3.6, p = 0.02) and fluoroscopy time (- 8.6 min, 95% CI - 12.5 to - 4.7, p < 0.001) as well as a significant reduction in QRS duration (mean weighted difference:- 25.3 ms, 95% CI - 30.9 to - 19.8, p < 0.00001) and a greater improvement in LVEF of 5.1% (95% CI 4.4-5.8, p < 0.001) compared to BIVP in the studies that reported these outcomes., Conclusion: In this meta-analysis, LBBAP was associated with a significant reduction in all-cause mortality as well as HF-related hospitalization when compared to BIVP. Additional data from large RCTs is warranted to corroborate these promising findings., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Women respond more favorably to biventricular pacing (BIVP) than men. Sex differences in atrioventricular and interventricular conduction have been described in BIVP studies. Left bundle branch area pacing (LBBAP) offers advantages due to direct capture of the conduction system. We hypothesized that men could respond better to LBBAP than BIVP., Objectives: This study aims to describe the sex differences in response to LBBAP vs BIVP as the initial cardiac resynchronization therapy (CRT)., Methods: In this multicenter prospective registry, we included patients with left ventricular ejection fraction ≤35% and left bundle branch block or a left ventricular ejection fraction ≤40% with an expected right ventricular pacing exceeding 40% undergoing initial CRT with LBBAP or BIVP. The composite primary outcome was heart failure-related hospitalization and all-cause mortality. The primary safety outcome included all procedure-related complications., Results: There was no significant difference in the primary outcome when comparing men and women receiving LBBAP (P = 0.46), whereas the primary outcome was less frequent in women in the BIVP group than men treated with BIVP (P = 0.03). The primary outcome occurred less frequently in men undergoing LBBAP (29.9%) compared to those treated with BIVP (46.5%) (P = 0.004). In women, the incidence of the primary endpoint was 24.14% in the LBBAP group and 36.2% in the BIVP group; however, this difference was not statistically significant (P = 0.23). Complication rates remained consistent across all groups., Conclusions: Men and women undergoing LBBAP for CRT had similar clinical outcomes. Men undergoing LBBAP showed a lower risk of heart failure-related hospitalizations and all-cause mortality compared to men undergoing BIVP, whereas there was no difference between LBBAP and BIVP in women., Competing Interests: Funding Support and Author Disclosures Dr Diaz has received speaker honoraria and has been a proctor for Medtronic for conduction system pacing. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Left atrial appendage occlusion (LAAO) is a suitable alternative to oral anticoagulant therapy to prevent stroke in patients with AF. Most procedures are performed under transoesophageal echocardiography (TOE) guidance, which facilitates transseptal puncture, reduces the risk of procedurerelated complications and provides an additional method for device selection and real-time monitoring during device deployment. However, TOE has significant shortcomings, including the need for general anaesthesia/deep sedation as well as a significant risk of procedure-related adverse events. More recently, intracardiac echocardiography has been proposed as an alternative to TOE guidance during LAAO procedures. In this review, we summarise the available evidence as well as providing a step-by-step approach for intracardiac echocardiography-guided LAAO., Competing Interests: Disclosure: JD and JR have received speaker honoraria and are proctors for Boston Scientific. All other authors have no conflicts of interest to declare., (Copyright © The Author(s), 2024. Published by Radcliffe Group Ltd.)

Background: Left bundle branch pacing (LBBP) and left ventricular septal pacing (LVSP) are considered to be acceptable as LBBAP strategies. Differences in clinical outcomes between LBBP and LVSP are yet to be determined., Objectives: The purpose of this study was to compare the outcomes of LBBP vs LVSP vs BIVP for CRT., Methods: In this prospective multicenter observational study, LBBP was compared with LVSP and BIVP in patients undergoing CRT. The primary composite outcome was freedom from heart failure (HF)-related hospitalization and all-cause mortality. Secondary outcomes included individual components of the primary outcome, postprocedural NYHA functional class, and electrocardiographic and echocardiographic parameters., Results: A total of 415 patients were included (LBBP: n = 141; LVSP: n = 31; BIVP: n = 243), with a median follow-up of 399 days (Q1-Q3: 249.5-554.8 days). Freedom from the primary composite outcomes was 76.6% in the LBBP group and 48.4% in the LVSP group (HR: 1.37; 95% CI: 1.143-1.649; P = 0.001), driven by a 31.4% absolute increase in freedom from HF-related hospitalizations (83% vs 51.6%; HR: 3.55; 95% CI: 1.856-6.791; P < 0.001) without differences in all-cause mortality. LBBP was also associated with a higher freedom from the primary composite outcome compared with BIVP (HR: 1.43; 95% CI: 1.175-1.730; P < 0.001), with no difference between LVSP and BIVP., Conclusions: In patients undergoing CRT, LBBP was associated with improved outcomes compared with LVSP and BIVP, while outcomes between BIVP and LVSP are similar., Competing Interests: Funding Support and Author Disclosures Dr Diaz has received speaker honoraria from and is a proctor for Medtronic for LBBAP. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Intracardiac echocardiography (ICE) is increasingly used during left atrial appendage occlusion (LAAO) as an alternative to transesophageal echocardiography (TEE). The objective of this study is to evaluate the impact of ICE versus TEE guidance during LAAO on procedural characteristics and acute outcomes, as well the presence of peri-device leaks and residual septal defects during follow-up., Methods: All studies comparing ICE-guided versus TEE-guided LAAO were identified. The primary outcomes were procedural efficacy and occurrence of procedure-related complications. Secondary outcomes included lab efficiency (defined as a reduction in in-room time), procedural time, fluoroscopy time, and presence of peri-device leaks and residual interatrial septal defects (IASD) during follow-up., Results: Twelve studies (n = 5637) were included. There were no differences in procedural success (98.3% vs. 97.8%; OR 0.73, 95% CI 0.42-1.27, p = .27; I 2  = 0%) or adverse events (4.5% vs. 4.4%; OR 0.81 95% CI 0.56-1.16, p = .25; I 2  = 0%) between the ICE-guided and TEE-guided groups. ICE guidance reduced in in-room time (mean-weighted 28.6-min reduction in in-room time) without differences in procedural time or fluoroscopy time. There were no differences in peri-device leak (OR 0.93, 95% CI 0.68-1.27, p = 0.64); however, an increased prevalence of residual IASD was observed with ICE-guided versus TEE-guided LAAO (46.3% vs. 34.2%; OR 2.23, 95% CI 1.05-4.75, p = 0.04)., Conclusion: ICE guidance is associated with similar procedural efficacy and safety, but could result in improved lab efficiency (as established by a significant reduction in in-room time). No differences in the rate of periprocedural leaks were found. A higher prevalence of residual interatrial septal defects was observed with ICE guidance., (© 2023 Wiley Periodicals LLC.)

Cardiac resynchronisation therapy (CRT) reduces the risk of heart failure-related hospitalisations and all-cause mortality, as well as improving quality of life and functional status in patients with persistent heart failure symptoms despite optimal medical treatment and left bundle branch block. CRT has traditionally been delivered by implanting a lead through the coronary sinus to capture the left ventricular epicardium; however, this approach is associated with significant drawbacks, including a high rate of procedural failure, phrenic nerve stimulation, high pacing thresholds and lead dislodgement. Moreover, a significant proportion of patients fail to derive any significant benefit. Left bundle branch area pacing (LBBAP) has recently emerged as a suitable alternative to traditional CRT. By stimulating the cardiac conduction system physiologically, LBBAP can result in a more homogeneous left ventricular contraction and relaxation, thus having the potential to improve outcomes compared with conventional CRT strategies. In this article, the evidence supporting the use of LBBAP in patients with heart failure is reviewed., Competing Interests: Disclosure: JCD has received honoraria and is a proctor for Medtronic for left bundle branch area pacing. JER has received grants from Biosense Webster, Medtronic and MMC; consulting fees from Abbott, AtriCure, Biosense Webster and Sanofi; and has received honoraria from Biosense Webster and Boston Scientific. All other authors have no conflicts of interest to declare., (Copyright © The Author(s), 2023. Published by Radcliffe Group Ltd.)

Background: Infection is the most dreaded complication of cardiac implantable electronic devices (CIEDs), particularly in patients undergoing high-risk procedures (eg, generator change, device upgrade, lead/pocket revision)., Objective: The purpose of this study was to describe the impact of chlorhexidine gluconate (CHG) pocket lavage in high-risk procedures., Methods: Patients from a prospective multicenter registry undergoing high-risk procedures were included. CHG lavage was performed by irrigating the generator pocket with 20 cc of 2% CHG without alcohol followed by and normal saline (NS) irrigation. Only NS irrigation was performed in the comparison group. The primary efficacy outcome was CIED-related infection at 12 months. The primary safety outcome was any CHG-associated adverse event. The secondary outcome was CIED infection during long-term follow-up. Propensity score matching (PSM) analysis was performed for the primary efficacy outcome., Results: A total of 1504 patients were included. At 12-month follow-up, the primary efficacy outcome occurred in 4 of 904 CHG (0.4%) and 14 of 600 NS (2.3%) subjects (log-rank P = .005). On multivariate analysis, the use of CHG irrigation was associated with a lower risk of infection at 1-year follow-up (Cox proportional hazard ratio [HR] 0.138; 95% confidence interval [CI] 0.04-0.45; P = .001). This effect persisted during long-term follow-up. PSM demonstrated a significant reduction in CIED-related infection for the CHG group (0.2% vs 2.5%; Cox proportional HR 0.08; 95% CI 0.01-0.59; P = .014). No adverse events were associated with the use of CHG., Conclusion: CHG lavage during high-risk procedures was associated with a reduction in CIED-related infections without any adverse events reported. The benefits of CHG lavage were observed even during long-term follow up and in PSM analysis., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Left bundle branch area pacing (LBBAP) for cardiac resynchronization therapy (CRT) is an alternative to biventricular pacing (BiVp)., Objectives: The purpose of this study was to compare the outcomes between LBBAP and BiVp as an initial implant strategy for CRT., Methods: In this prospective multicenter, observational, nonrandomized study, first-time CRT implant recipients with LBBAP or BiVp were included. The primary efficacy outcome was a composite of heart failure (HF)-related hospitalization and all-cause mortality. The primary safety outcomes were acute and long-term complications. Secondary outcomes included postprocedural New York Heart Association functional class and electrocardiographic and echocardiographic parameters., Results: A total of 371 patients (median follow-up of 340 days [IQR: 206-477 days]) were included. The primary efficacy outcome occurred in 24.2% in the LBBAP vs 42.4% in the BiVp (HR: 0.621 [95% CI: 0.415-0.93]; P = 0.021) group, driven by a reduction in HF-related hospitalizations (22.6% vs 39.5%; HR: 0.607 [95% CI: 0.397-0.927]; P = 0.021) without significant difference in all-cause mortality (5.5% vs 11.9%; P = 0.19) or differences in long-term complications (LBBAP: 9.4% vs BiVp: 15.2%; P = 0.146). LBBAP resulted in shorter procedural (95 minutes [IQR: 65-120 minutes] vs 129 minutes [IQR: 103-162 minutes]; P < 0.001) and fluoroscopy times (12 minutes [IQR: 7.4-21.1 minutes] vs 21.7 minutes [IQR: 14.3-30 minutes]; P < 0.001), shorter QRS duration (123.7 ± 18 milliseconds vs 149.3 ± 29.1 milliseconds; P < 0.001), and higher postprocedural left ventricular ejection fraction (34.1% ± 12.5% vs 31.4% ± 10.8%; P = 0.041)., Conclusions: LBBAP as an initial CRT strategy resulted in a lower risk of HF-related hospitalizations compared to BiVp. A reduction in procedural and fluoroscopy times, shorter paced QRS duration, and improvements in left ventricular ejection fraction compared with BiVp were observed., Competing Interests: Funding Support and Author Disclosures Dr Diaz has received speaker honoraria and is a proctor for Medtronic for conduction system pacing. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Epicardial access (EA) has emerged as an increasingly important approach for the treatment of ventricular arrhythmias and to perform other interventional cardiology procedures. EA is frequently underutilized because the current approach is challenging and carries a high risk of life-threatening complications., Objective: The purpose of this study was to determine the efficacy and safety of the SAFER (Sustained Apnea for Epicardial Access With Right Ventriculography) epicardial approach., Methods: Consecutive patients who underwent EA with the SAFER technique were included in this multicenter study. The primary efficacy outcome was the successful achievement of EA. The primary safety outcomes included right ventricular (RV) perforation, major hemorrhagic pericardial effusion (HPE), and bleeding requiring surgical intervention. Secondary outcomes included procedural characteristics and any complications. Our results were compared with those from previous studies describing other EA techniques to assess differences in outcomes., Results: A total of 105 patients undergoing EA with the SAFER approach from June 2021 to February 2023 were included. EA was used for ventricular tachycardia ablation in 98 patients (93.4%), left atrial appendage closure in 6 patients (5.7%), and phrenic nerve displacement in 1 patient (0.9%). EA was successful in all subjects (100%). The median time to EA was 7 minutes (IQR: 5-14 minutes). No cases of RV perforation, HPE, or need of surgical intervention were observed in this cohort. Comparing our results with previous studies about EA, the SAFER epicardial approach resulted in a significant reduction in major pericardial bleeding., Conclusions: The SAFER epicardial approach is a simple, efficient, effective, and low-cost technique easily reproducible across multiple centers. It is associated with lower complication rates than previously reported techniques for EA., Competing Interests: Funding Support and Author Disclosures All authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Capsulectomy is recommended in patients with cardiac implantable electronic device (CIED) infection after transvenous lead extraction (TLE) but is time-consuming and requires extensive tissue debridement. In this study, we describe the outcomes of chlorhexidine gluconate (CHG) lavage in lieu of capsulectomy for the treatment of CIED infections., Methods: This retrospective study included patients who underwent TLE for CIED-related infections in two institutions in Colombia. In the capsulectomy group, complete capsulectomy was performed after hardware removal. In the CHG group, exhaustive lavage of the generator pocket with 20 cc of CHG at 2% followed by irrigation with approximately 500 cc of normal saline (0.9% sodium chloride) was performed. The primary outcomes included reinfection and hematoma formation in the generator pocket. Secondary outcomes included the occurrence of any adverse reaction to chlorhexidine, the need for reintervention, infection-related mortality, and total procedural time., Results: A total of 102 patients (mean age 67.2 ± 13 years, 32.4% female) underwent CIED extraction with either total capsulectomy (n = 54) or CHG (n = 48) lavage. Hematoma formation was significantly higher in the capsulectomy group versus the CHG group (13% vs. 0%, p = .014), with no significant differences in the reinfection rate. Capsulectomy was associated with longer procedural time (133.7 ± 78.5 vs. 89.9 ± 51.8 min, p = .002). No adverse reactions to CHG were found. Four patients (4.3%) died from worsening sepsis: three in the capsulectomy group and one in the CHG group (p = .346)., Conclusions: In patients with CIED infections, the use of CHG without capsulectomy resulted in a lower risk of hematoma formation and shorter procedural times without an increased risk of reinfection or adverse events associated with CHG use., (© 2023 Wiley Periodicals LLC.)

Background: Patients with cardiac implantable electronic devices (CIEDs) living in rural areas have difficulty obtaining follow-up visits for device interrogation and programming in specialized healthcare facilities., Objective: To describe the use of an assisted reality device designed to provide front-line workers with real-time online support from a remotely located specialist (Realwear HTM-1; Realwear) during CIED assistance in distant rural areas., Methods: This is a prospective study of patients requiring CIED interrogation using the Realwear HMT-1 in a remote rural population in Colombia between April 2021 and June 2022. CIED interrogation and device programming were performed by a general practitioner and guided by a cardiac electrophysiologist. Non-CIED-related medical interventions were allowed and analyzed. The primary objective was to determine the incidence of clinically significant CIED alerts. Secondary objectives were the changes medical interventions used to treat the events found in the device interrogations regarding non-CIED related conditions., Results: A total of 205 CIED interrogations were performed on 139 patients (age 69 ± 14 years; 54% female). Clinically significant CIED alerts were reported in 42% of CIED interrogations, consisting of the detection of significant arrhythmias (35%), lead malfunction (3%), and device in elective replacement interval (3.9%). Oral anticoagulation was initiated in 8% of patients and general medical/cardiac interventions unrelated to the CIED were performed in 52% of CIED encounters., Conclusion: Remote assistance using a commercially available assisted reality device has the potential to provide specialized healthcare to patients in difficult-to-reach areas, overcoming current difficulties associated with RM, including the inability to change device programming. Additionally, these interactions provided care beyond CIED-related interventions, thus delivering significant social and clinical impact to remote rural populations., (© 2023 Wiley Periodicals LLC.)

Background: Loneliness and social isolation are recognized as critical public health issues. Older people are at greater risk of loneliness and social isolation as they deal with things like living alone, loss of family or friends, chronic illness, and hearing loss. Loneliness increases a person's risk of premature death from all causes, including dementia, heart disease, and stroke. To address these issues, the inclusion of technological platforms and the use of commercial monitoring devices are vastly increasing in healthcare and elderly care., Objective: The objective of this study is to design and develop a loneliness monitor serverless architecture to obtain real-time data from commercial activity wristbands through an Application Programming Interface., Methods: For the design and development of the architecture, the Amazon Web Services platform has been used. To monitor loneliness, the Fitbit Charge 5 bracelet was selected. Through the web Application Programming Interface offered by the AWS Lambda service, the data is obtained and stored in AWS services with an automated frequency thanks to the event bridge., Results: In the pilot stage in which the system is, it is showing great possibilities in the ease of collecting data and programming the sampling frequency. Once the request is made, the data is automatically analyzed to monitor loneliness., Conclusion: The proposed architecture shows great potential for easy data collection, analysis, security, personalization, real-time inference, and scalability of sensors and actuators in the future. It has powerful benefits to apply in the health sector and reduces cases of depression and loneliness.

This papers presents a comparative study of three different 3D scanning modalities to acquire 3D meshes of stoma barrier rings from ostomized patients. Computerized Tomography and Structured light scanning methods were the digitization technologies studied in this research. Among the Structured Light systems, the Go!Scan 20 and the Structure Sensor were chosen as the handheld 3D scanners. Nineteen ostomized patients took part in this study, starting from the 3D scans acquisition until the printed ostomy patches validation. 3D mesh processing, mesh generation and 3D mesh comparison was carried out using commercial softwares. The results of the presented study show that the Structure Sensor, which is the low cost structured light 3D sensor, has a great potential for such applications. This study also discusses the benefits and reliability of low-cost structured light systems.

The use of mobile fitness apps has been on the rise for the last decade and especially during the worldwide SARS-CoV-2 pandemic, which led to the closure of gyms and to reduced outdoor mobility. Fitness apps constitute a promising means for promoting more active lifestyles, although their attrition rates are remarkable and adherence to their training plans remains a challenge for developers. The aim of this project was to design an automatic classification of users into adherent and non-adherent, based on their training behavior in the first three months of app usage, for which purpose we proposed an ensemble of regression models to predict their behaviour (adherence) in the fourth month. The study was conducted using data from a total of 246 Mammoth Hunters Fitness app users. Firstly, pre-processing and clustering steps were taken in order to prepare the data and to categorize users into similar groups, taking into account the first 90 days of workout sessions. Then, an ensemble approach for regression models was used to predict user training behaviour during the fourth month, which were trained with users belonging to the same cluster. This was used to reach a conclusion regarding their adherence status, via an approach that combined affinity propagation (AP) clustering algorithm, followed by the long short-term memory (LSTM), rendering the best results (87% accuracy and 85% F1&#95;score). This study illustrates the suggested the capacity of the system to anticipate future adherence or non-adherence, potentially opening the door to fitness app creators to pursue advanced measures aimed at reducing app attrition.

Monitoring and strategic response to variants in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represent a considerable challenge in the current pandemic and for future viral outbreaks. Mutations/deletions of the virion's prefusion Spike protein may have significant impact on vaccines and therapeutics that utilize this key structural protein in their mitigation strategies. In this study, we have demonstrated how dominant energetic landscape mappings ("glue points") based on ab inito all-atom force fields coupled with phylogenetic sequence alignment information can identify key residue mutations and deletions associated with variants. We also found several examples of excellent homology of stabilizing residue glue points across the lineages of betacoronavirus Spike proteins that we have called "sequence homologous glue points." SARS-CoV-2 demonstrates the least number of stabilizing glue points associated with interchain interactions among Down-state protomers across lineages. Additionally, we computationally studied variants among the trimeric Spike protein of SARS-CoV-2 using all-atom molecular dynamics to ascertain structural and energetic changes among variants. We examined both a theoretically based triple mutant and the UK or B.1.1.7 variant. For the theoretical triple mutant, we demonstrated through alanine substitutions that three key residues could cause the transition of Down-to-Up protomer states, where the transition is characterized by the "arm" length of the receptor-binding domain (RBD) rather than the hinge angle. For the B.1.1.7 variant, we demonstrated the critical importance of mutations D614G and N501Y on the structure and binding, respectively, of the Spike protein. We note that these same two key mutations are also found in the South African B.1.351 variant. IMPORTANCE Viral variants represent a major challenge to monitoring viral outbreaks and formulating strategic health care responses. Variants represent transmitting viruses that have specific mutations and deletions associated with their genome. In the case of SARS-CoV-2 and other related viruses (betacoronaviruses), many of these mutations and deletions are associated with the Spike protein that the virus uses to infect cells. Here, we have analyzed both SARS-CoV-2 variants and related viruses, such as Middle Eastern respiratory syndrome coronavirus (MERS-CoV), in order to understand not only differences, but also key similarities between them. Understanding similarities can be as important as differences in determining key functional features of a class of viruses, such as the betacoronaviruses. We have used both phylogenetic analysis, which traces genetic similarities and differences, along with independent biophysics analysis, which adds function or behavior, in order to determine possible functional differences and hence possible transmission and infection differences among variants and lineages.

The SARS-CoV-2 virion responsible for the current world-wide pandemic COVID-19 has a characteristic Spike protein (S) on its surface that embellishes both a prefusion state and fusion state. The prefusion Spike protein (S) is a large trimeric protein where each protomer may be in a so-called Up state or Down state, depending on the configuration of its receptor binding domain (RBD) within its distal, prefusion S1 domain. The Up state is believed to allow binding of the virion to ACE-2 receptors on human epithelial cells, whereas the Down state is believed to be relatively inactive or reduced in its binding behavior. We have performed detailed all-atom, dominant energy landscape mappings for noncovalent interactions (charge, partial charge, and van der Waals) of the SARS-CoV-2 Spike protein in its static prefusion state based on two recent and independent experimental structure publications. We included both interchain interactions and intrachain (domain) interactions in our mappings in order to determine any telling differences (different so-called "glue" points) between residues in the Up and Down state protomers. The S2 proximal, fusion domain demonstrated no appreciable energetic differences between Up and Down protomers, including interchain as well as each protomer's intrachain, S1-S2 interactions. However, the S1 domain interactions across neighboring protomers, which include the RBD-NTD cross chain interactions, showed significant energetic differences between Up-Down and Down-Down neighboring protomers. This included, for example, a key RBD residue ARG357 in the Up-Down interaction and a three residue sequence ALA520-PRO521-ALA522, associated with a turn structure in the RBD of the Up state protomer, acting as a stabilizing interaction with the NTD of its neighbor protomer. Additionally, our intra chain dominant energy mappings within each protomer, identified a significant "glue" point or possible "latch" for the Down state protomer between the S1 subdomain, SD1, and the RBD domain of the same protomer that was completely missing in the Up state protomer analysis. Ironically, this dominant energetic interaction in the Down state protomer involved the backbone atoms of the same three residue sequence ALA520-PRO521-ALA522 of the RBD with the amino acid R-group of GLN564 in the SD1 domain. Thus, this same three residue sequence acts as a stabilizer of the RBD in the Up conformation through its interactions with its neighboring NTD chain and a kind of latch in the Down state conformation through its interactions with its own SD1 domain. The dominant interaction energy residues identified here are also conserved across reported variations of SARS-CoV-2, as well as the closely related virions SARS-Cov and the bat corona virus RatG13. We conducted preliminary molecular dynamics simulations across 0.1 μ seconds to see if this latch provided structural stability and indeed found that a single point mutation (Q564G) resulted in the latch releasing transforming the protomer from the Down to the Up state conformation. Full trimeric Spike protein studies of the same mutation across all protomers, however, did not exhibit latch release demonstrating the critical importance of interchain interactions across the S1 domain, including RBD-NTD neighboring chain interactions. Therapies aimed at disrupting these noncovalent interactions could be a viable route for the physico-chemical mitigation of this deadly virion., Competing Interests: V.C.U (M.H.P.) entered an exclusive licensing agreement for "ACE2 Decoy Peptides in the Treatment of COVID-19" with Hoth Therapeutics, NY.