Discovery and In Vitro Characterization of BAY 2686013, an Allosteric Small Molecule Antagonist of the Human Pituitary Adenylate Cyclase-Activating Polypeptide Receptor.

The human pituitary adenylate cyclase-activating polypeptide receptor (hPAC1-R), a class B G-protein-coupled receptor (GPCR) identified almost 30 years ago, represents an important pharmacological target in the areas of neuroscience, oncology, and immunology. Despite interest in this target, only a very limited number of small molecule modulators have been reported for this receptor. We herein describe the results of a drug discovery program aiming for the identification of a potent and selective hPAC1-R antagonist. An initial high-throughput screening (HTS) screen of 3.05 million compounds originating from the Bayer screening library failed to identify any tractable hits. A second, completely revised screen using native human embryonic kidney (HEK)293 cells yielded a small number of hits exhibiting antagonistic properties (4.2 million compounds screened). BAY 2686013 (1) emerged as a promising compound showing selective antagonistic activity in the submicromolar potency range. In-depth characterization supported the hypothesis that BAY 2686013 blocks receptor activity in a noncompetitive manner. Preclinical, pharmacokinetic profiling indicates that BAY 2686013 is a valuable tool compound for better understanding the signaling and function of hPAC1-R. SIGNIFICANCE STATEMENT: Although the human pituitary adenylate cyclase-activating polypeptide receptor (hPAC1-R) is of major significance as a therapeutic target with a well documented role in pain signaling, only a very limited number of small-molecule (SMOL) compounds are known to modulate its activity. We identified and thoroughly characterized a novel, potent, and selective SMOL antagonist of hPAC1-R (acting in an allosteric manner). These characteristics make BAY 2686013 an ideal tool for further studies.

An Early Prospective Clinical Study to Evaluate the Safety and Performance of the Versius Surgical System in Robot-Assisted Cholecystectomy.

OBJECTIVE: The aim of this study was to demonstrate the ability of the Versius Surgical System to successfully and safely complete cholecystectomy. BACKGROUND: The system has been developed in-line with surgeon feedback to overcome limitations of conventional laparoscopy to enhance surgeon experience and patient outcomes. Here we present results from the cholecystectomy cohort from a completed early clinical trial, which was designed to broadly align with Stage 2b of the Idea, Development, Exploration, Assessment, Long-term follow-up framework for surgical innovation. METHODS: Procedures were performed between March 2019 and September 2020 by surgical teams consisting of a lead surgeon and operating room (OR) assistants. Male or female patients aged 18 years and over and requiring cholecystectomy were enrolled. The primary endpoint was the rate of unplanned conversion from robot-assisted surgery to conventional laparoscopic or open surgery. Adverse events (AEs) and serious AEs were adjudicated by video review of the surgery and patient study reports by an independent Clinical Expert Committee. RESULTS: Overall, 134/143 (93.7%) cholecystectomies were successfully completed using the device. Of the 9 (6.3%) conversions to another surgical modality, 7 were deemed to be related to the device. A total of 6 serious AEs and 3 AEs occurred in 8 patients (5.6%), resulting in 4 (2.8%) readmissions to hospital within 30 days of surgery and 1 death. CONCLUSIONS: This study demonstrates cholecystectomy performed using the device is as safe and effective as conventional laparoscopy and supports the implementation of the device on a wider scale, pending instrument modifications, in alignment with Idea, Development, Exploration, Assessment, Long-term follow-up Stage 3 (Assessment).

Safe Implementation of a Next-Generation Surgical Robot: First Analysis of 2,083 Cases in the Versius Surgical Registry.

OBJECTIVE: To present the first report of data from the Versius Surgical Registry, a prospective, multicenter data registry with ongoing collection across numerous surgical indications, developed to accompany the Versius Robotic Surgical System into clinical practice. BACKGROUND: A data registry can be utilized to minimize risk to patients by establishing the safety and effectiveness of innovative medical devices and generating a thorough evidence base of real-world data. METHODS: Surgical outcome data were collected and inputted through a secure online platform. Preoperative data included patient age, sex, body mass index, surgical history, and planned procedures. Intraoperative data included operative time, complications during surgery, conversion from robot-assisted surgery to an alternative surgical technique, and blood loss. Postoperative outcome data included length of hospital stay, complications following surgery, serious adverse events, return to the operating room, readmission to the hospital, and mortality within 90 days of surgery. RESULTS: This registry analysis included 2083 cases spanning general, colorectal, hernia, gynecologic, urological, and thoracic indications. A considerable number of cases were recorded for cholecystectomy (n=539), anterior resection (n=162), and total laparoscopic hysterocolpectomy (n=324) procedures. The rates of conversion to an alternative technique, serious adverse events, and 90-day mortality were low for all procedures across all surgical indications. CONCLUSIONS: We report the large-scale analysis of the first 2083 cases recorded in this surgical registry, with substantial data collected for cholecystectomies, anterior resections, and total laparoscopic hysterectomies. The extensive surgical outcome data reported here provide real-world evidence for the safe implementation of the surgical robot into clinical practice.

Monofilament suture versus braided suture thread to improve pregnancy outcomes after vaginal cervical cerclage (C-STICH): a pragmatic randomised, controlled, phase 3, superiority trial.

BACKGROUND: Miscarriage in the second trimester and preterm birth are significant global problems. Vaginal cervical cerclage is performed to prevent pregnancy loss and preterm birth. We aimed to determine the effectiveness of a monofilament suture thread compared with braided suture thread on pregnancy loss rates in women undergoing a cervical cerclage. METHODS: C-STICH was a pragmatic, randomised, controlled, superiority trial done at 75 obstetric units in the UK. Women with a singleton pregnancy who received a vaginal cervical cerclage due to a history of pregnancy loss or premature birth, or if indicated by ultrasound, were centrally randomised (1:1) using minimisation to receive a monofilament suture or braided suture thread for their cervical cerclage. Women and outcome assessors were masked to allocation as far as possible. The primary outcome was pregnancy loss, defined as miscarriage, stillbirth, or neonatal death in the first week of life, analysed in the intention-to-treat population (ie, all women who were randomly assigned). Safety was also assessed in the intention-to-treat population. The trial was registered with ISRCTN, ISRCTN15373349. FINDINGS: Between Aug 21, 2015, and Jan 28, 2021, 2049 women were randomly assigned to receive a monofilament suture (n=1025) or braided suture (n=1024). The primary outcome was ascertained in 1003 women in the monofilament suture group and 993 women in the braided suture group. Pregnancy loss occurred in 80 (8·0%) of 1003 women in the monofilament suture group and 75 (7·6%) of 993 women in the braided suture group (adjusted risk ratio 1·05 [95% CI 0·79 to 1·40]; adjusted risk difference 0·002 [95% CI -0·02 to 0·03]). INTERPRETATION: Monofilament suture did not reduce rate of pregnancy loss when compared with a braided suture. Clinicians should use the results of this trial to facilitate discussions around the choice of suture thread to optimise outcomes. FUNDING: National Institute of Health Research Health Technology Assessment Programme.

Competency assessment for the Versius surgical robot: a validity investigation study of a virtual reality simulator-based test.

BACKGROUND: When introducing new equipment like robotic surgical systems, it is essential to ensure that surgeons have the basic skills before operating on patients. The objective was to investigate the validity evidence for a competency-based test for basic robotic surgical skills using the Versius® trainer. METHODS: We recruited medical students, residents, and surgeons which were classified based on data on clinical experience with the Versius system as either novices (0 min), intermediates (1-1000 min), or experienced (> 1000 min). All participants completed three rounds of eight basic exercises on the Versius trainer, where the first was used for familiarization and the final two for data analysis. The simulator automatically recorded data. Validity evidence was summarized using Messick's framework, and the contrasting groups' standard-setting method was used to define pass/fail levels. RESULTS: 40 participants completed the three rounds of exercises. The discriminatory abilities of all parameters were tested, and five exercises including relevant parameters were selected to be part of the final test. 26 of 30 parameters could differentiate between novices and experienced surgeons but none of the parameters could discriminate between the intermediate and experienced surgeons. Test-retest reliability analysis using Pearson's r or Spearman's rho showed only 13 of 30 parameters had moderate or higher reliability. Non-compensatory pass/fail levels were defined for each exercise and showed that all novices failed all the exercises and that most experienced surgeons either passed or nearly passed all five exercises. CONCLUSION: We identified relevant parameters for five exercises that could be used to assess basic robotic skills for the Versius robotic system and defined a credible pass/fail level. This is the first step in developing a proficiency-based training program for the Versius system.

Early evaluation of a next-generation surgical system in robot-assisted total laparoscopic hysterectomy: A prospective clinical cohort study.

INTRODUCTION: This study aimed to demonstrate the safe and effective use of the Versius surgical system (CMR Surgical, Cambridge, UK) in robot-assisted total laparoscopic hysterectomy. This surgical robot was developed iteratively with input from surgeons to improve surgical outcomes and end-user experience. We report data from the gynecology cohort of an early clinical trial designed in broad alignment with IDEAL-D (Idea, Development, Exploration, Assessment, Long-term follow-up - Devices) stage 2b (Exploration). MATERIAL AND METHODS: The study is registered in the Indian clinical trials register (CTRI/2019/02/017872). Adult women requiring total hysterectomy who provided informed consent and met the eligibility criteria underwent procedures at one of three hospitals in India. Five surgeons performed robot-assisted total laparoscopic hysterectomies using the device from March 2019 to September 2020. The primary endpoint was rate of unplanned conversion to conventional laparoscopic or open surgery. Adverse events were adjudicated by an independent clinical events committee using endoscope video recordings and clinical notes. RESULTS: In total, 144 women underwent surgery (median age: 44 years [range: 28-78]; median body mass index 25.8 kg/m2 [range: 14.3-47.8]). The rate of unplanned conversion to conventional laparoscopy was 2/144 (1.4%); neither conversion was device related. No surgery was converted to open. In total, 13 adverse events occurred among seven (4.9%) patients, comprising seven serious adverse events and six adverse events. One serious adverse event was deemed device-related. Two patients were readmitted to hospital within 30 days; both made a full recovery. No patients died within 90 days of surgery. CONCLUSIONS: The device provides a safe and effective option for total laparoscopic hysterectomy; these findings support its continued implementation in larger patient cohorts and expansion in other major minimal access indications.

Evolving robotic surgery training and improving patient safety, with the integration of novel technologies.

INTRODUCTION: Robot-assisted surgery is becoming increasingly adopted by multiple surgical specialties. There is evidence of inherent risks of utilising new technologies that are unfamiliar early in the learning curve. The development of standardised and validated training programmes is crucial to deliver safe introduction. In this review, we aim to evaluate the current evidence and opportunities to integrate novel technologies into modern digitalised robotic training curricula. METHODS: A systematic literature review of the current evidence for novel technologies in surgical training was conducted online and relevant publications and information were identified. Evaluation was made on how these technologies could further enable digitalisation of training. RESULTS: Overall, the quality of available studies was found to be low with current available evidence consisting largely of expert opinion, consensus statements and small qualitative studies. The review identified that there are several novel technologies already being utilised in robotic surgery training. There is also a trend towards standardised validated robotic training curricula. Currently, the majority of the validated curricula do not incorporate novel technologies and training is delivered with more traditional methods that includes centralisation of training services with wet laboratories that have access to cadavers and dedicated training robots. CONCLUSIONS: Improvements to training standards and understanding performance data have good potential to significantly lower complications in patients. Digitalisation automates data collection and brings data together for analysis. Machine learning has potential to develop automated performance feedback for trainees. Digitalised training aims to build on the current gold standards and to further improve the 'continuum of training' by integrating PBP training, 3D-printed models, telementoring, telemetry and machine learning.

Interim safety analysis of the first-in-human clinical trial of the Versius surgical system, a new robot-assisted device for use in minimal access surgery.

OBJECTIVE: The aim of this study was to provide an interim safety analysis of the first 30 surgical procedures performed using the Versius Surgical System. BACKGROUND: Robot-assisted laparoscopy has been developed to overcome some of the important limitations of conventional laparoscopy. The new system is currently undergoing a first-in-human prospective clinical trial to confirm the safety and effectiveness of the device when performing minimal access surgery (MAS). METHODS: Procedures were performed using Versius by a lead surgeon supported by an operating room (OR) team. Male or female patients aged between 18 and 65 years old and requiring elective minor or intermediate gynaecological or general surgical procedures were enrolled. The primary endpoint was the rate of unplanned conversion of procedures to other MAS or open surgery. RESULTS: The procedures included nine cholecystectomies, six robot-assisted total laparoscopic hysterectomies, four appendectomies, five diagnostic laparoscopy cases, two oophorectomies, two fallopian tube recanalisation procedures, an ovarian cystectomy and a salpingo-oophorectomy procedure. All procedures were completed successfully without the need for conversion to MAS or open surgery. No patient returned to the OR within 24 h of surgery and readmittance rate at 30 and 90 days post-surgery was 1/30 (3.3%) and 2/30 (6.7%), respectively. CONCLUSIONS: This first-in-human interim safety analysis demonstrates that the Versius Surgical System is safe and can be used to successfully perform minor or intermediate gynaecological and general surgery procedures. The cases presented here provide evidence that the Versius clinical trial can continue to extend recruitment and begin to include major procedures, in alignment with the IDEAL-D Framework Stage 2b: Exploration.

Preclinical evaluation of the versius surgical system, a new robot-assisted surgical device for use in minimal access general and colorectal procedures.

OBJECTIVE: To evaluate the utility of a new robot-assisted surgical system (the Versius Surgical System, CMR Surgical, Cambridge, UK) for use in minimal access general and colorectal surgery, in a preclinical setting. Robot-assisted laparoscopy has been developed to overcome some of the important limitations of conventional laparoscopy. The new system is designed to assist surgeons in performing minimal access surgery and overcome some of the challenges associated with currently available surgical robots. METHODS: Cadaveric sessions were conducted to evaluate the ability of the system to provide adequate surgical access and reach required to complete a range of general and colorectal procedures. Port and bedside unit positions were recorded, and surgical access and reach were evaluated by the lead surgeon using a visual analogue scale. A live animal (porcine) model was used to assess the surgical device's safety in performing cholecystectomy or small bowel enterotomy. RESULTS: Nine types of procedure were performed in cadavers by nine lead surgeons; 35/38 procedures were completed successfully. The positioning of ports and bedside units reflected the lead surgeons' preferred laparoscopic set-up and enabled good surgical access and reach. Cholecystectomy (n = 6) and small bowel enterotomy (n = 5) procedures performed in pigs were all completed successfully by two surgeons. There were no device-related intra-operative complications. CONCLUSIONS: This preclinical study of a new robot-assisted surgical system for minimal access general and colorectal surgery demonstrated the safety and effectiveness of the system in cadaver and porcine models. Further studies are required to assess its clinical utility.

Patient factors associated with onabotulinum toxin A treatment outcome in women with detrusor overactivity.

OBJECTIVE: To evaluate potential predictors of non-response to treatment with 200U onabotulinum toxin A (onaBoNTA) in women with refractory detrusor overactivity (DO). SUBJECTS AND METHODS: A secondary analysis of a randomized trial of 200U onaBoNTA versus placebo in women with refractory DO analyzed baseline and 6 week follow-up data. Univariate and multivariate logistic regression were used to assess demographic factors and baseline clinical parameters on non-response to treatment defined as 20% or less improvement in urinary urgency and leakage episodes, 10% or less in voiding frequency, not achieving continence, and "no change" or worse on PGI-I score at 6 weeks. RESULTS: One Hundred and twenty-two women were included. Twenty-nine (23.8%), 24 (19.7%), and 19 (15.6%) were non-responders to treatment for urgency, voiding, and leakage episodes, respectively. Fifty-nine (48.4%) failed to achieve continence, and 28 (23%) were non-responders on the PGI-I scale. Smoking status (OR: 2.89 95%CI 1.08, 7.73, P = 0.034) predicted non-response in urgency episodes, and higher baseline leakage episodes (OR: 1.17 95%CI 1.04, 1.31, P = 0.007) predicted non-response in achieving continence. Increasing age (OR 1.04, 95%CI 1.0, 1.09, P = 0.063) and body mass index (BMI) (OR 1.07, 95%CI 1.0, 1.16, P = 0.065) showed marginal associations with non-response on the PGI-I scale. CONCLUSION: onaBoNTA is an effective treatment for refractory DO, but some fail to respond. For identification of women at risk, our data indicate smokers should be advised of a lesser chance of successful treatment. Older women, those with high BMI and with more severe leakage also have a higher risk of failure. Neurourol. Urodynam. 36:426-431, 2017. © 2016 Wiley Periodicals, Inc.

Comparison of the effectiveness of repeated injections of onabotulinum toxin A for refractory idiopathic detrusor overactivity: analysis of an open label extension of a randomized trial (the RELAX study).

AIMS: To assess effects of repeat treatment with onabotulinumtoxin A (onaBoNT-A) in women with refractory idiopathic detrusor overactivity (DO). METHODS: Analysis of an open-label extension study of a large randomized placebo controlled trial of onaBoNT-A. Participants had been randomized to receive 200 IU onaBoNTA or placebo and were offered up to two further onaBoNTA injections over a 5-year period. For this analysis, the primary outcome was duration of treatment effect by patient-reported symptom return. Weibull proportional hazards regression models were fitted in a Bayesian framework to estimate missing times. Multivariable hazard regression analysis (hazard ratio, 95% credible intervals (HR, 95% CrI) compared repeated injections adjusting for differences in baseline symptom severity. Secondary outcomes included inter-injection interval, incontinence, urgency, and voiding episodes 6 weeks after injection. RESULTS: Four hundred and forty-two active injections were administered: 228 patients had one, 155 had two, and 59 had three injections. Time to symptom return for injection number 1 and 2 was 84 (95%CI: 63, 112) and 180 (95%CI: 135, 223) days, respectively. Median inter-injection intervals for receiving second and third injection were 266 days (range: 130, 1400) and 372 days (range: 134, 1283). No statistically significant differences in symptom outcomes or time to symptom return (HR 0.88, 95% CrI 0.37, 2.07 for injection 2, HR 0.33, 95% CrI 0.09, 1.03 for injection 3) were observed. CONCLUSIONS: Repeated onaBoNT-A injections have consistent efficacy and duration of action. There appears to be long-term placebo effects in both groups of randomized patients, with implications for open-label extension studies.

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.

Toward an understanding of agonist binding to human Orexin-1 and Orexin-2 receptors with G-protein-coupled receptor modeling and site-directed mutagenesis.

The class A G-protein-coupled receptors (GPCRs) Orexin-1 (OX1) and Orexin-2 (OX2) are located predominantly in the brain and are linked to a range of different physiological functions, including the control of feeding, energy metabolism, modulation of neuro-endocrine function, and regulation of the sleep-wake cycle. The natural agonists for OX1 and OX2 are two neuropeptides, Orexin-A and Orexin-B, which have activity at both receptors. Site-directed mutagenesis (SDM) has been reported on both the receptors and the peptides and has provided important insight into key features responsible for agonist activity. However, the structural interpretation of how these data are linked together is still lacking. In this work, we produced and used SDM data, homology modeling followed by MD simulation, and ensemble-flexible docking to generate binding poses of the Orexin peptides in the OX receptors to rationalize the SDM data. We also developed a protein pairwise similarity comparing method (ProS) and a GPCR-likeness assessment score (GLAS) to explore the structural data generated within a molecular dynamics simulation and to help distinguish between different GPCR substates. The results demonstrate how these newly developed methods of structural assessment for GPCRs can be used to provide a working model of neuropeptide-Orexin receptor interaction.

Preclinical evaluation of the Versius surgical system: A next-generation surgical robot for use in minimal access prostate surgery.

Objectives: To evaluate the Versius surgical system for robot-assisted prostatectomy in a preclinical cadaveric model using varying system setups and collect surgeon feedback on the performance of the system and instruments, in line with IDEAL-D recommendations. Materials and methods: Procedures were performed in cadaveric specimens by consultant urological surgeons to evaluate system performance in completing the surgical steps required for a prostatectomy. Procedures were conducted using either a 3-arm or 4-arm bedside unit (BSU) setup. Optimal port placements and BSU layouts were determined and surgeon feedback collected. Procedure success was defined as the satisfactory completion of all steps of the procedure, according to the operating surgeon. Results: All four prostatectomies were successfully completed; two were completed with a 3-arm BSU setup and two using a 4-arm BSU setup. Small adjustments were made to the port and BSU positioning, according to surgeon preference, in order to complete the surgical steps. The surgeons noted some instrument difficulties with the Monopolar Curved Scissor tip and the Needle Holders, which were subsequently refined between the first and second sessions of the study, in line with surgeon feedback. Three cystectomies were also successfully completed, demonstrating the capability of the system to perform additional urological procedures. Conclusions: This study provides a preclinical assessment of a next-generation surgical robot for prostatectomies. All procedures were completed successfully, and port and BSU positions were validated, thus supporting the progression of the system to further clinical development according to the IDEAL-D framework.

Safe implementation of surgical innovation: a prospective registry of the Versius Robotic Surgical System.

Objectives: To describe a new, international, prospective surgical registry developed to accompany the clinical implementation of the Versius Robotic Surgical System by accumulating real-world evidence of its safety and effectiveness. Interventions: This robotic surgical system was introduced in 2019 for its first live-human case. With its introduction, cumulative database enrollment was initiated across several surgical specialties, with systematic data collection via a secure online platform. Main outcome measures: Pre-operative data include diagnosis, planned procedure(s), characteristics (age, sex, body mass index and disease status) and surgical history. Peri-operative data include operative time, intra-operative blood loss and use of blood transfusion products, intra-operative complications, conversion to an alternative technique, return to the operating room prior to discharge and length of hospital stay. Complications and mortality within 90 days of surgery are also recorded. Results: The data collected in the registry are analyzed as comparative performance metrics, by meta-analyses or by individual surgeon performance using control method analysis. Continual monitoring of key performance indicators, using various types of analyses and outputs within the registry, have provided meaningful insights that help institutions, teams and individual surgeons to perform most effectively and ensure optimal patient safety. Conclusions: Harnessing the power of large-scale, real-world registry data for routine surveillance of device performance in live-human surgery from first use will enhance the safety and efficacy outcomes of innovative surgical techniques. Data are crucial to driving the evolution of robot-assisted minimal access surgery while minimizing risk to patients. Trial registration number: CTRI/2019/02/017872.

Study of human Orexin-1 and -2 G-protein-coupled receptors with novel and published antagonists by modeling, molecular dynamics simulations, and site-directed mutagenesis.

The class A G-protein-coupled receptors (GPCRs) Orexin-1 (OX1) and Orexin-2 (OX2) are located predominantly in the brain and are linked to a range of different physiological functions, including the control of feeding, energy metabolism, modulation of neuro-endocrine function, and regulation of the sleep-wake cycle. Site-directed mutagenesis (SDM) and domain exchange (chimera) studies have provided important insight into key features of the OX1 and OX2 binding sites. However, the precise determinants of antagonist binding and selectivity are still not fully known. In this work, we used homology modeling of OX receptors to direct further SDM studies. These SDM studies were followed by molecular dynamics (MD) simulations to rationalize the full scope of the SDM data and to explain the role of each mutated residue in the binding and selectivity of a set of OX antagonists: Almorexant (dual OX1 and OX2 antagonist), SB-674042 (OX1 selective antagonist), EMPA (OX2 selective antagonist), and others. Our primary interest was focused on transmembrane helix 3 (TM3), which is identified as being of great importance for the selectivity of OX antagonists. These studies revealed conformational differences between the TM3 helices of OX1 and OX2, resulting from differences in amino acid sequences of the OX receptors that affect key interhelical interactions formed between TM3 and neighboring TM domains. The MD simulation protocol used here, which was followed by flexible docking studies, went beyond the use of static models and allowed for a more detailed exploration of the OX structures. In this work, we have demonstrated how even small differences in the amino acid sequences of GPCRs can lead to significant differences in structure, antagonist binding affinity, and selectivity of these receptors. The MD simulations allowed refinement of the OX receptor models to a degree that was not possible with static homology modeling alone and provided a deeper rationalization of the SDM data obtained. To validate these findings and to demonstrate that they can be usefully applied to the design of novel, very selective OX antagonists, we show here two examples of antagonists designed in house: EP-109-0092 (OX1 selective) and EP-009-0513 (OX2 selective).

A standardized description of graft-containing meshes and recommended steps before the introduction of medical devices for prolapse surgery. Consensus of the 2nd IUGA Grafts Roundtable: optimizing safety and appropriateness of graft use in transvaginal pelvic reconstructive surgery.

Over the past decade, a huge number of new implants and ancillary devices have been introduced to the market. Most of these have become clinically available with little or no clinical data or research. This is a less-than-ideal situation, and this subgroup of the ad hoc IUGA roundtable conference wants to open the discussion to change this, by proposing a pragmatic minimum clearance track for new products being introduced to the market. It consists of an accurate and more standardized product description, data on the biological properties gathered in animal experiments, anatomical cadaveric studies, and upfront clinical studies followed by a compulsory registry on the first 1,000 patients implanted. Ideally, manufacturers should support well-designed prospective (randomized) clinical trials that can support the claimed benefits of the new product.

The Role of the Versius Surgical Robotic System in the Paediatric Population.

The uptake of robot-assisted surgery has continuously grown since its advent in the 1990s. While robot-assisted surgery is well-established in adult surgery, the rate of uptake in paediatric surgical centres has been slower. The advantages of a robot-assisted system, such as improved visibility, dexterity, and ergonomics, could make it a superior choice over the traditional laparoscopic approach. However, its implementation in the paediatric surgery arena has been limited primarily due to the unavailability of appropriately sized instruments as per paediatric body habitus, therefore, requiring more technologically advanced systems. The Versius surgical robotic system is a new modular platform that offers several benefits such as articulated instruments which pass through conventional 5 mm ports, compact arms for easier manoeuvrability and patient access, the ability to mimic conventional port placements, and adaptive machine learning concepts. Prior to its introduction to paediatric surgery, it needs to go through a careful pre-clinical and clinical research program.

Preclinical evaluation of Versius, an innovative device for use in robot-assisted thoracic surgery.

OBJECTIVES: The adoption of robot-assisted thoracic surgery (RATS) has helped to overcome some of the challenges associated with surgeons performing conventional video-assisted thoracic surgery. The Versius Surgical System (CMR Surgical, Cambridge, UK) has been developed iteratively in line with surgical team feedback to improve the surgeon's experience and patient outcomes. The goal of this study was to assess the use of the device in RATS in a preclinical setting and to fulfil Idea, Development, Exploration, Assessment, Long-Term Follow Up-Devices stage 1 (Idea). METHODS: Four cadaveric sessions were conducted between November 2018 and December 2020, during which device performance in a range of thoracic operations was assessed. Procedures were categorized as either completed or not completed, and surgeons evaluated the device's ability to successfully complete necessary surgical steps. Port and bedside unit positions were recorded. RESULTS: In total, 22/24 (91.7%) thoracic procedures were successfully completed, including 17/18 lobectomies, 2/3 thymectomies and 3/3 diaphragm plications, in 9 cadaver specimens. One thymectomy could not be completed due to cadaver anatomy and 1 lobectomy was not completed due a console system fault. Port and bedside unit configurations were successfully validated for all procedures, and lead surgeons deemed the device to be well-suited for thoracic surgery. CONCLUSIONS: This preclinical study demonstrated the successful use of the device in RATS in cadaveric models and supports progression to small-scale clinical studies, as part of Idea, Development, Exploration, Assessment, Long-Term Follow Up-Devices stage 2a (Development).