Posttranslational modifications optimize the ability of SARS-CoV-2 spike for effective interaction with host cell receptors.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein is the prime target for vaccines, diagnostics, and therapeutic antibodies against the virus. While anchored in the viral envelope, for effective virulence, the spike needs to maintain structural flexibility to recognize the host cell surface receptors and bind to them, a property that can heavily depend upon the dynamics of the unresolved domains, most prominently the stalk. Construction of the complete, membrane-bound spike model and the description of its dynamics are critical steps in understanding the inner working of this key element of the viral infection by SARS-CoV-2. Combining homology modeling, protein-protein docking, and molecular dynamics (MD) simulations, we have developed a full spike structure in a native membrane. Multimicrosecond MD simulations of this model, the longest known single trajectory of the full spike, reveal conformational dynamics employed by the protein to explore the surface of the host cell. In agreement with cryogenic electron microscopy (cryo-EM), three flexible hinges in the stalk allow for global conformational heterogeneity of spike in the fully glycosylated system mediated by glycan-glycan and glycan-lipid interactions. The dynamical range of the spike is considerably reduced in its nonglycosylated form, confining the area explored by the spike on the host cell surface. Furthermore, palmitoylation of the membrane domain amplifies the local curvature that may prime the fusion. We show that the identified hinge regions are highly conserved in SARS coronaviruses, highlighting their functional importance in enhancing viral infection, and thereby, provide points for discovery of alternative therapeutics against the virus.

Computational Dissection of Membrane Transport at a Microscopic Level.

Membrane transporters are key gatekeeper proteins at cellular membranes that closely control the traffic of materials. Their function relies on structural rearrangements of varying degrees that facilitate substrate translocation across the membrane. Characterizing these functionally important molecular events at a microscopic level is key to our understanding of membrane transport, yet challenging to achieve experimentally. Recent advances in simulation technology and computing power have rendered molecular dynamics (MD) simulation a powerful biophysical tool to investigate a wide range of dynamical events spanning multiple spatial and temporal scales. Here, we review recent studies of diverse membrane transporters using computational methods, with an emphasis on highlighting the technical challenges, key lessons learned, and new opportunities to illuminate transporter structure and function.

Unsupervised machine learning demonstrates the prognostic value of TAPSE/PASP ratio among hospitalized patients with COVID-19.

BACKGROUND: The ratio of tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (PASP) is a validated index of right ventricular-pulmonary arterial (RV-PA) coupling with prognostic value. We determined the predictive value of TAPSE/PASP ratio and adverse clinical outcomes in hospitalized patients with COVID-19. METHODS: Two hundred and twenty-nine consecutive hospitalized racially/ethnically diverse adults (≥18 years of age) admitted with COVID-19 between March and June 2020 with clinically indicated transthoracic echocardiograms (TTE) that included adequate tricuspid regurgitation (TR) velocities for calculation of PASP were studied. The exposure of interest was impaired RV-PA coupling as assessed by TAPSE/PASP ratio. The primary outcome was in-hospital mortality. Secondary endpoints comprised of ICU admission, incident acute respiratory distress syndrome (ARDS), and systolic heart failure. RESULTS: One hundred and seventy-six patients had both technically adequate TAPSE measurements and measurable TR velocities for analysis. After adjustment for age, sex, BMI, race/ethnicity, diabetes mellitus, and smoking status, log(TAPSE/PASP) had a significantly inverse association with ICU admission (p = 0.015) and death (p = 0.038). ROC analysis showed the optimal cutoff for TAPSE/PASP for death was 0.51 mm mmHg-1 (AUC = 0.68). Unsupervised machine learning identified two groups of echocardiographic function. Of all echocardiographic measures included, TAPSE/PASP ratio was the most significant in predicting in-hospital mortality, further supporting its significance in this cohort. CONCLUSION: Impaired RV-PA coupling, assessed noninvasively via the TAPSE/PASP ratio, was predictive of need for ICU level care and in-hospital mortality in hospitalized patients with COVID-19 suggesting utility of TAPSE/PASP in identification of poor clinical outcomes in this population both by traditional statistical and unsupervised machine learning based methods.

Binding mode of SARS-CoV-2 fusion peptide to human cellular membrane.

Infection of human cells by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) relies on its binding to a specific receptor and subsequent fusion of the viral and host cell membranes. The fusion peptide (FP), a short peptide segment in the spike protein, plays a central role in the initial penetration of the virus into the host cell membrane, followed by the fusion of the two membranes. Here, we use an array of molecular dynamics simulations that take advantage of the highly mobile membrane mimetic model to investigate the interaction of the SARS-CoV2 FP with a lipid bilayer representing mammalian cellular membranes at an atomic level and to characterize the membrane-bound form of the peptide. Six independent systems were generated by changing the initial positioning and orientation of the FP with respect to the membrane, and each system was simulated in five independent replicas, each for 300 ns. In 73% of the simulations, the FP reaches a stable, membrane-bound configuration, in which the peptide deeply penetrated into the membrane. Clustering of the results reveals three major membrane-binding modes (binding modes 1-3), in which binding mode 1 populates over half of the data points. Taking into account the sequence conservation among the viral FPs and the results of mutagenesis studies establishing the role of specific residues in the helical portion of the FP in membrane association, the significant depth of penetration of the whole peptide, and the dense population of the respective cluster, we propose that the most deeply inserted membrane-bound form (binding mode 1) represents more closely the biologically relevant form. Analysis of FP-lipid interactions shows the involvement of specific residues, previously described as the "fusion-active core residues," in membrane binding. Taken together, the results shed light on a key step involved in SARS-CoV2 infection, with potential implications in designing novel inhibitors.

Understanding Immigration as a Social Determinant of Health: Cardiovascular Disease in Hispanics/Latinos and South Asians in the United States.

PURPOSE OF REVIEW: The main purpose of this review is to summarize the epidemiology of cardiovascular disease and its risk factors among two of the largest and most diverse immigrant groups in the United States (Hispanics/Latinos and South Asians). RECENT FINDINGS: While the migration process generates unique challenges for individuals, there is a wide heterogeneity in the characteristics of immigrant populations, both between and within regions of origin. Hispanic/Latino immigrants to the United States have lower levels of cardiovascular risk factors, prevalence, and mortality, but this assessment is limited by issues related to the "salmon bias." South Asian immigrants to the United States generally have higher levels of risk factors and higher mortality. In both cases, levels of risk factors and mortality generally increase with time of living in the United States (US). While immigration acts as a social determinant of health, associations between immigration and cardiovascular disease and its risk factors are complex and vary across subpopulations.

The evolving role of coronary artery calcium in preventive cardiology 30 years after the Agatston score.

PURPOSE OF REVIEW: On the brink of the 30th anniversary of the Agatston score we summarize the epidemiological data that shaped the recommendations relevant to coronary artery calcium (CAC) included in the 2018/2019 US and European guidelines for the primary prevention of atherosclerotic cardiovascular disease (ASCVD). We also discuss the implications of novel CAC research conducted in asymptomatic populations within the past 2 years. RECENT FINDINGS: Based on a wealth of observational evidence, CAC has emerged as a mainstay in personalized risk assessment and is now endorsed as a class IIa tool in both US and European guidelines. In the past 2 years, data supporting the prognostic power of CAC has kept mounting, with longer term follow-up data now available. CAC has been evaluated in a variety of patient populations including individuals with severe hypercholesterolemia, diabetes mellitus and younger adults with family history of ASCVD, in all of whom it may be able to inform a more personalized management. Novel CAC scoring approaches are also discussed. SUMMARY: Despite a strong endorsement in recent guidelines, active research in the last 2 years has provided further insights on the potential utility of CAC in informing a more individualized preventive management in broader populations.

Non-contrast coronary magnetic resonance angiography: current frontiers and future horizons.

Coronary magnetic resonance angiography (coronary MRA) is advantageous in its ability to assess coronary artery morphology and function without ionizing radiation or contrast media. However, technical limitations including reduced spatial resolution, long acquisition times, and low signal-to-noise ratios prevent it from clinical routine utilization. Nonetheless, each of these limitations can be specifically addressed by a combination of novel technologies including super-resolution imaging, compressed sensing, and deep-learning reconstruction. In this paper, we first review the current clinical use and motivations for non-contrast coronary MRA, discuss currently available coronary MRA techniques, and highlight current technical developments that hold unique potential to optimize coronary MRA image acquisition and post-processing. In the final section, we examine the various research-based coronary MRA methods and metrics that can be leveraged to assess coronary stenosis severity, physiological function, and atherosclerotic plaque characterization. We specifically discuss how such technologies may contribute to the clinical translation of coronary MRA into a robust modality for routine clinical use.

Using a transcriptome sequencing approach to explore candidate resistance genes against stemphylium blight in the wild lentil species Lens ervoides.

BACKGROUND: Stemphylium blight (SB), caused by Stemphylium botryosum, is a devastating disease in lentil production. Although it is known that accessions of Lens ervoides possess superior SB resistance at much higher frequency than the cultivated lentil species, very little is known about the molecular basis regulating SB resistance in L. ervoides. Therefore, a comprehensive molecular study of SB resistance in L. ervoides was needed to exploit this wild resource available at genebanks for use by plant breeders in resistance breeding. RESULTS: Microscopic and qPCR quantification of fungal growth revealed that 48, 96, and 144 h post-inoculation (hpi) were interesting time points for disease development in L. ervoides recombinant inbred lines (RILs) LR-66-637 (resistant to SB) and LR-66-577 (susceptible to SB). Results of transcriptome sequencing at 0, 48, 96 and 144 hpi showed that 8810 genes were disease-responsive genes after challenge by S. botryosum. Among them, 7526 genes displayed a similar expression trend in both RILs, and some of them were likely involved in non-host resistance. The remaining 1284 genes were differentially expressed genes (DEGs) between RILs. Of those, 712 DEGs upregulated in LR-66-637 were mostly enriched in 'carbohydrate metabolic process', 'cell wall organization or biogenesis', and 'polysaccharide metabolic process'. In contrast, there were another 572 DEGs that were upregulated in LR-66-577, and some of them were enriched in 'oxidation-reduction process', 'asparagine metabolic process' and 'asparagine biosynthetic process'. After comparing DEGs to genes identified in previously described quantitative trait loci (QTLs) for resistance to SB, nine genes were common and three of them showed differential gene expression between a resistant and a susceptible bulk consisting of five RILs each. Results showed that two genes encoding calcium-transporting ATPase and glutamate receptor3.2 were candidate resistance genes, whereas one gene with unknown function was a candidate susceptibility gene. CONCLUSION: This study provides new insights into the mechanisms of resistance and susceptibility in L. ervoides RILs responding to S. botryosum infection. Furthermore, we identified candidate resistance or susceptibility genes which warrant further gene function analyses, and which could be valuable for resistance breeding, if their role in resistance or susceptibility can be confirmed.

Anticoagulation risk assessment for patients with non-valvular atrial fibrillation and venous thromboembolism: A clinical review.

Non-valvular atrial fibrillation and venous thromboembolism anticoagulation risk assessment tools have been increasingly utilized to guide implementation and duration of anticoagulant therapy. Anticoagulation significantly reduces stroke and recurrent venous thromboembolism risk, but comes at the cost of increased risk of major and clinically relevant non-major bleeding. The decision for anticoagulation in high-risk patients is complicated by the fact that many risk factors associated with increased thromboembolic risk are simultaneously associated with increased bleeding risk. Traditional risk assessment tools rely heavily on age, sex, and presence of cardiovascular comorbidities, with newer tools additionally taking into account changes in risk factors over time and novel biomarkers to facilitate more personalized risk assessment. These tools may help counsel and inform patients about the risks and benefits of starting or continuing anticoagulant therapy and can identify patients who may benefit from more careful management. Although the ability to predict anticoagulant-associated hemorrhagic risk is modest, ischemic and bleeding risk scores have been shown to add significant value to therapeutic management decisions. Ultimately, further work is needed to optimally implement accurate and actionable risk stratification into clinical practice.

Evaluation of Different Preosteotomy Determinants as Affecting the Success of Implant Therapy: A "CBCT"-based Clinical Study.

AIM: The success of implant therapy is of greatest concern for clinicians because a minor negligence can lead to ultimate failure of treatment. However, comprehensive and precise treatment planning can ensure high success rate of implant therapy. Cone-beam computed tomography (CBCT) is an innovation that allows clinicians to explore all related factors in details. This study was conducted to evaluate different preosteotomy determinants as affecting the success of implant therapy in the maxillary anterior region using CBCT. MATERIALS AND METHODS: This study was conducted on 98 partially or complete denture patients willing for artificial replacement of their missing teeth by implant or implant over-denture. Demographic details of participating patients were collected. Furthermore, comprehensive local examination was also done to finalize the site of placement of implant. Cone-beam computed tomography was attempted in all patients for determining accurate implant location, status of bone, and other interrelated determinants of implant success. Cone-beam computed tomography was also prescribed for patients so as to have presurgical idea of implant dimensions as shown in virtual placement of implant. To rule out any interobserver bias, the interpretations of CBCT images were completed by two independent experienced observers. RESULTS: In the 98 studied patients, 61 were males and 37 were females. The study was restricted to the maxillary anterior region only. The studied preosteotomy determinants were available bone height and width in the edentulous region from ridge crest up to the maxillary sinus floor or the nasal fossa floor. A total of 107 implants were placed virtually (on CBCT) in the maxillary anterior region and compared quantitatively in postosteotomy phases. Implant placement sites were the maxillary central incisor region (39), the lateral incisor region (31), and canine (37). Authors also noticed that the relative length and width of virtual implant remained unaffected in 97% of the cases. CONCLUSION: Cone-beam computed tomography showed accurate status of various presurgical determinants like trabeculae, peri-ridiculer pathology, and amount of horizontal and vertical bone losses. Hence, it was further concluded that all these presurgical determinants greatly affect the final success rate of implant therapy. It is therefore deemed necessary to judiciously consider and clinically manage such factors before attempting implant in the maxillary anterior region. CLINICAL SIGNIFICANCE: Presurgical evaluation of factors associated with implant dimensions significantly assists clinicians in deciding the finest treatment option. All additional information provided by CBCT genuinely led to a change in the treatment plan that provides enhanced clinical outcome with lesser postoperative complications. How to cite this article: Jain S, Kapoor K, Sethi K, et al. Evaluation of Different Preosteotomy Determinants as Affecting the Success of Implant Therapy: A "CBCT"-based Clinical Study. J Contemp Dent Pract 2019;20(10):1212-1216.

Communication issues in nutritional observational research.

Observational epidemiological studies involving foods and nutrients often attract great attention from both the press and the public as they involve substances that are part of the daily lives of millions of individuals. In the digital era, findings of this research can be disseminated to very large audiences almost instantaneously, informing health beliefs and potentially triggering lifestyle changes. In this context, communication of results from observational nutritional epidemiology often involves specific issues that may limit the accuracy of the information ultimately being delivered to the public. In this narrative review we discuss some of these issues, with a special attention to the selective reporting of research studies by the media, the presentation of study findings as if they were free of bias, the reporting of inconsistent study results, and the issues related to the real-life uptake of research findings presented in the press. Collaborative efforts by all stakeholders involved in the dissemination process may help ameliorate this situation, and with this purpose we discuss some innovative approaches that may help reduce these issues.

Health Literacy: Readability of ACC/AHA Online Patient Education Material.

OBJECTIVES: To determine whether the online patient education material offered by the American College of Cardiology (ACC) and the American Heart Association (AHA) is written at a higher level than the 6th-7th grade level recommended by the National Institute of Health (NIH). METHODS: Online patient education material from each website was subjected to reading grade level (RGL) analysis using the Readability Studio Professional Edition. One-sample t testing was used to compare the mean RGLs obtained from 8 formulas to the NIH-recommended 6.5 grade level and 8th grade national mean. RESULTS: In total, 372 articles from the ACC website and 82 from the AHA were studied. Mean (±SD) RGLs for the 454 articles were 9.6 ± 2.1, 11.2 ± 2.1, 11.9 ± 1.6, 10.8 ± 1.6, 9.7 ± 2.1, 10.8 ± 0.8, 10.5 ± 2.6, and 11.7 ± 3.5 according to the Flesch-Kincaid grade level (FKGL), Simple Measure of Gobbledygook (SMOG Index), Coleman-Liau Index (CLI), Gunning-Fog Index (GFI), New Dale-Chall reading level formula (NDC), FORCAST, Raygor Readability Estimate (RRE), and Fry Graph (Fry), respectively. All analyzed articles had significantly higher RGLs than both the NIH-recommended grade level of 6.5 and the national mean grade level of 8 (p < 0.00625). CONCLUSIONS: Patient education material provided on the ACC and AHA websites is written above the NIH-recommended 6.5 grade level and 8th grade national mean reading level. Additional studies are required to demonstrate whether lowering the RGL of this material improves outcomes among patients with cardiovascular disease.

Highly Dynamic Anion-Quadrupole Networks in Proteins.

The dynamics of anion-quadrupole (or anion-π) interactions formed between negatively charged (Asp/Glu) and aromatic (Phe) side chains are for the first time computationally characterized in RmlC (Protein Data Bank entry 1EP0 ), a homodimeric epimerase. Empirical force field-based molecular dynamics simulations predict anion-quadrupole pairs and triplets (anion-anion-π and anion-π-π) are formed by the protein during the simulated trajectory, which suggests that the anion-quadrupole interactions may provide a significant contribution to the overall stability of the protein, with an average of -1.6 kcal/mol per pair. Some anion-π interactions are predicted to form during the trajectory, extending the number of anion-quadrupole interactions beyond those predicted from crystal structure analysis. At the same time, some anion-π pairs observed in the crystal structure exhibit marginal stability. Overall, most anion-π interactions alternate between an "on" state, with significantly stabilizing energies, and an "off" state, with marginal or null stabilizing energies. The way proteins possibly compensate for transient loss of anion-quadrupole interactions is characterized in the RmlC aspartate 84-phenylalanine 112 anion-quadrupole pair observed in the crystal structure. A double-mutant cycle analysis of the thermal stability suggests a possible loss of anion-π interactions compensated by variations of hydration of the residues and formation of compensating electrostatic interactions. These results suggest that near-planar anion-quadrupole pairs can exist, sometimes transiently, which may play a role in maintaining the structural stability and function of the protein, in an otherwise very dynamic interplay of a nonbonded interaction network as well as solvent effects.

Discovery of Novel Nonactive Site Inhibitors of the Prothrombinase Enzyme Complex.

The risk of serious bleeding is a major liability of anticoagulant drugs that are active-site competitive inhibitors targeting the Factor Xa (FXa) prothrombin (PT) binding site. The present work identifies several new classes of small molecule anticoagulants that can act as nonactive site inhibitors of the prothrombinase (PTase) complex composed of FXa and Factor Va (FVa). These new classes of anticoagulants were identified, using a novel agnostic computational approach to identify previously unrecognized binding pockets at the FXa-FVa interface. From about three million docking calculations of 281,128 compounds in a conformational ensemble of FXa heavy chains identified by molecular dynamics (MD) simulations, 97 compounds and their structural analogues were selected for experimental validation, through a series of inhibition assays. The compound selection was based on their predicted binding affinities to FXa and their ability to successfully bind to multiple protein conformations while showing selectivity for particular binding sites at the FXa/FVa interface. From these, thirty-one (31) compounds were experimentally identified as nonactive site inhibitors. Concentration-based assays further identified 10 compounds represented by four small-molecule families of inhibitors that achieve dose-independent partial inhibition of PTase activity in a nonactive site-dependent and self-limiting mechanism. Several compounds were identified for their ability to bind to protein conformations only seen during MD, highlighting the importance of accounting for protein flexibility in structure-based drug discovery approaches.

Ensemble-based docking: From hit discovery to metabolism and toxicity predictions.

This paper describes and illustrates the use of ensemble-based docking, i.e., using a collection of protein structures in docking calculations for hit discovery, the exploration of biochemical pathways and toxicity prediction of drug candidates. We describe the computational engineering work necessary to enable large ensemble docking campaigns on supercomputers. We show examples where ensemble-based docking has significantly increased the number and the diversity of validated drug candidates. Finally, we illustrate how ensemble-based docking can be extended beyond hit discovery and toward providing a structural basis for the prediction of metabolism and off-target binding relevant to pre-clinical and clinical trials.

Cardiovascular Outcomes Trials in Type 2 Diabetes Mellitus.

OBJECTIVES: To review the spectrum of contemporary cardiovascular outcomes trials (CVOTS) in type 2 diabetes mellitus (T2DM), spanning both the pre- and post-ACCORD eras. METHODS: We reviewed a total of 12 CVOTs and delineated the two eras in accordance with the 2008 US Food and Drug Administration (FDA) mandate requiring completion of CVOTs prior the licensing of new glucose-lowering agents. The salient implications regarding macrovascular disease complications were summarized. RESULTS: Five trials in the pre-ACCORD and 7 in the post-ACCORD era were identified. Heterogeneous results pertaining to the degree of glycemic control associated with optimal macrovascular disease risk reduction, as well as the safest pharmacologic means to do so, were observed. CONCLUSIONS: The post-ACCORD era is representative of a significant shift in the landscape of CVOTs in T2DM, with an emphasis on safety of glucose-lowering agents. Recently completed and ongoing trials of dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors will continue to inform clinical practice on safe and effective ways to reduce CV risk in T2DM.

Quantification of lymph nodes in the central compartment of the neck: a cadaveric study.

Differentiated thyroid cancer (DTC) accounts for over 90 % of thyroid malignancies, and is frequently associated with central neck compartment nodal metastasis that requires a therapeutic central compartment neck dissection (CCND) for clinically evident nodes. Current knowledge on the expected lymph node yield from a CCND is limited, compared with data on the lateral neck. The aim of our study was to accurately quantify nodal yield from the cadaveric central neck compartment. Twenty-eight cadaveric necks were dissected and the central neck compartment was subdivided into four regions: pre-laryngeal (delphian), pre-tracheal, right and left para-tracheal regions. Each cadaver had a thyroid gland, which was also removed, and the CCND tissue in each compartment was processed and examined by a consultant histopathologist. Only lymphoid tissue with a defined microscopic fibrous capsule and subcapsular sinus was included in the node count. The median total lymph node count per cadaver was four (range 1-16), with a median of one node detectable in each para-tracheal region (range 0-7) and the pre-tracheal region (range 0-8). The median pre-laryngeal node count was 0 (range 0- 2). The average lymph node size across all compartments was 2.9 mm. This is the first European study to assess cadaveric central neck lymph nodes and establish baseline counts for nodal yield. If a prophylactic or therapeutic CCND is required during thyroid surgery, those involved in DTC management must recognise that there is a wide range, and low median yield of central neck compartment lymph nodes.

Spontaneous mesenteric hematoma: Case report and review literature of a rare clinical entity.

Spontaneous mesenteric hematomas (SMH) are not a common entity. Here we describe a case of 64 year old woman who presented with a vague abdominal pain and diffuse tenderness. Her CT abdomen revealed an ill-defined hyperdense mass like lesion in the mesentery and she underwent exploratory laparotomy which revealed a large hematoma in the mesentery with inflammation of the adjoining small bowel loop. Histopathology revealed findings consistent with hematoma with no evidence of neoplastic lesion.

New robotic platform for transoral robotic surgery: an IDEAL stage 0 study.

Objectives: This study aims to assess the feasibility to perform transoral robotic surgery (TORS) with a new robotic platform, the Versius Surgical System (CMR Surgical, UK) in a preclinical cadaveric setting in accordance to stage 0 of the IDEAL-D framework. Design: IDEAL stage 0 preclinical assessment of the Versius Robotic System in TORS in human cadavers. Setting: All procedures were performed in a simulated operating theatre environment at a UK surgical training centre. Participants: 11 consultant head and neck surgeons from the UK, mainland Europe and the USA took part in TORS procedures on six human cadavers. Interventions: 3 key index procedures were assessed that represent the core surgical workload of TORS: lateral oropharyngectomy, tongue base resection and partial supraglottic laryngectomy. Main outcome measures: The primary outcome was the successful completion of each surgical procedure. Secondary outcomes included the optimisation of system setup, instrumentation and surgeon-reported outcomes for feasibility of each component procedural step. Results: 33 cadaveric procedures were performed and 32 were successfully completed. One supraglottic laryngectomy was not fully completed due to issues dividing the epiglottic cartilage with available instrumentation. Surgeon-reported outcomes met the minimal level of feasibility in all procedures and a consensus that it is feasible to perform TORS with Versius was reached. Available instrumentation was not representative of other robotic platforms used in TORS and further instrument optimisation is recommended before wider dissemination. Conclusions: It is feasible to perform TORS with the Versius Surgical System (CMR Surgical) within a pre-clinical cadaveric setting. Clinical evaluation is needed and appropriate with the system. Further instrument development and optimisation is desirable.