Availability of results of clinical trials registered on EU Clinical Trials Register: cross sectional audit study.

Objective: To identify the availability of results for trials registered on the European Union Clinical Trials Register (EUCTR) compared with other dissemination routes to understand its value as a results repository. Design: Cross sectional audit study. Setting: EUCTR protocols and results sections, data extracted 1-3 December 2020. Population: Random sample of 500 trials registered on EUCTR with a completion date of more than two years from the beginning of searches (ie, 1 December 2018). Main outcome measures: Proportion of trials with results across the examined dissemination routes (EUCTR, ClinicalTrials.gov, ISRCTN registry, and journal publications), and for each dissemination route individually. Prespecified secondary outcomes were number and proportion of unique results, and the timing of results, for each dissemination route. Results: In the sample of 500 trials, availability of results on EUCTR (53.2%, 95% confidence interval 48.8% to 57.6%) was similar to the peer reviewed literature (58.6%, 54.3% to 62.9%) and exceeded the proportion of results available on other registries with matched records. Among the 383 trials with any results, 55 (14.4%, 10.9% to 17.9%) were only available on EUCTR. Also, after the launch of the EUCTR results database, median time to results was fastest on EUCTR (1142 days, 95% confidence interval 812 to 1492), comparable with journal publications (1226 days, 1074 to 1551), and exceeding ClinicalTrials.gov (3321 days, 1653 to undefined). For 117 trials (23.4%, 19.7% to 27.1%), however, results were published elsewhere but not submitted to the EUCTR registry, and no results were located in any dissemination route for 117 trials (23.4%, 19.7% to 27.1). Conclusions: EUCTR should be considered in results searches for systematic reviews and can help researchers and the public to access the results of clinical trials, unavailable elsewhere, in a timely way. Reporting requirements, such as the EU's, can help in avoiding research waste by ensuring results are reported. The registry's true value, however, is unrealised because of inadequate compliance with EU guidelines, and problems with data quality that complicate the routine use of the registry. As the EU transitions to a new registry, continuing to emphasise the importance of EUCTR and the provision of timely and complete data is critical. For the future, EUCTR will still hold important information from the past two decades of clinical research in Europe. With increased efforts from sponsors and regulators, the registry can continue to grow as a source of results of clinical trials, many of which might be unavailable from other dissemination routes.

Biosecurity in an age of open science.

The risk of accidental or deliberate misuse of biological research is increasing as biotechnology advances. As open science becomes widespread, we must consider its impact on those risks and develop solutions that ensure security while facilitating scientific progress. Here, we examine the interaction between open science practices and biosecurity and biosafety to identify risks and opportunities for risk mitigation. Increasing the availability of computational tools, datasets, and protocols could increase risks from research with misuse potential. For instance, in the context of viral engineering, open code, data, and materials may increase the risk of release of enhanced pathogens. For this dangerous subset of research, both open science and biosecurity goals may be achieved by using access-controlled repositories or application programming interfaces. While preprints accelerate dissemination of findings, their increased use could challenge strategies for risk mitigation at the publication stage. This highlights the importance of oversight earlier in the research lifecycle. Preregistration of research, a practice promoted by the open science community, provides an opportunity for achieving biosecurity risk assessment at the conception of research. Open science and biosecurity experts have an important role to play in enabling responsible research with maximal societal benefit.

Industry ties and evidence in public comments on the FDA framework for modifications to artificial intelligence/machine learning-based medical devices: a cross sectional study.

OBJECTIVES: To determine the extent and disclosure of financial ties to industry and use of scientific evidence in comments on a US Food and Drug Administration (FDA) regulatory framework for modifications to artificial intelligence/machine learning (AI/ML)-based software as a medical device (SaMD). DESIGN: Cross-sectional study. SETTING: We searched all publicly available comments on the FDA 'Proposed Regulatory Framework for Modifications to Artificial Intelligence/Machine Learning (AI/ML)-Based Software as a Medical Device (SaMD)-Discussion Paper and Request for Feedback' from 2 April 2019 to 8 August 2019. MAIN OUTCOME MEASURES: The proportion of articles submitted by parties with financial ties to industry, disclosing those ties, citing scientific articles, citing systematic reviews and meta-analyses, and using a systematic process to identify relevant literature. RESULTS: We analysed 125 comments submitted on the proposed framework. 79 (63%) comments came from parties with financial ties; for 36 (29%) comments, it was not clear and the absence of financial ties could only be confirmed for 10 (8%) comments. No financial ties were disclosed in any of the comments that were not from industry submitters. The vast majority of submitted comments (86%) did not cite any scientific literature, just 4% cited a systematic review or meta-analysis and no comments indicated that a systematic process was used to identify relevant literature. CONCLUSIONS: Financial ties to industry were common and undisclosed, and scientific evidence, including systematic reviews and meta-analyses, were rarely cited. To ensure regulatory frameworks best serve patient interests, the FDA should mandate disclosure of potential conflicts of interest (including financial ties) in comments, encourage the use of scientific evidence, and encourage engagement from non-conflicted parties.

A Dynamic Compliance Cervix Phantom Robot for Latent Labor Simulation.

Physical simulation systems are commonly used in training of midwifery and obstetrics students, but none of these systems offers a dynamic compliance aspect that would make them more truly representative of cervix ripening. In this study, we introduce a unique soft robot phantom that simulates the cervix softening during the latent labor phase of birth. This proof-of-concept robotic phantom can be dilated by 1 cm and effaced by 35% through the application of a Foley catheter-like loading mechanism. Furthermore, psychophysics trials demonstrate how untrained subjects can identify hard and soft states of the phantom with specificities of 91% and 87%, respectively. Both results indicated the appropriateness for application of this soft robot technology to birth training simulators.

Nitrate enhancement of CAM activity in two Kalanchoë species is associated with increased vacuolar proton transport capacity.

Among species that perform CAM photosynthesis, members of the genus Kalanchoë have been studied frequently to investigate the effect of environmental factors on the magnitude of CAM activity. In particular, different nitrogen sources have been shown to influence the rate of nocturnal CO2 fixation and organic-acid accumulation in several species of Kalanchoë. However, there has been little investigation of the interrelationship between nitrogen source (nitrate versus ammonium), concentration and the activity of the vacuolar proton pumps responsible for driving nocturnal organic-acid accumulation in these species. In the present study with Kalanchoë laxiflora and Kalanchoë delagoensis cultivated on different nitrogen sources, both species were found to show highest total nocturnal organic-acid accumulation and highest rates of ATP- and PPi-dependent vacuolar proton transport on 2.5 mM nitrate, whereas plants cultivated on 5.0 mM ammonium showed the lowest values. In both species malate was the principal organic-acid accumulated during the night, but the second-most accumulated organic-acid was fumarate for K. laxiflora and citrate for K. delagoensis. Higher ATP- and PPi-dependent vacuolar proton transport rates and greater nocturnal acid accumulation were observed in K. delagoensis compared with K. laxiflora. These results show that the effect of nitrogen source on CAM activity in Kalanchoë species is reflected in corresponding differences in activity of the tonoplast proton pumps responsible for driving sequestration of these acids in the vacuole of CAM-performing cells.

Proton and anion transport across the tonoplast vesicles in bromeliad species.

Crassulacean acid metabolism (CAM) is one of the key innovations in the Neotropical family Bromeliaceae that has enabled many of its species to occupy seasonally water-limited terrestrial environments or microclimatically arid epiphytic niches. However, the relationship between CAM activity and the transport processes responsible for vacuolar organic-acid accumulation at night has not been systematically explored in this family. In the present investigation, ATP- and PPi-dependent proton transport rates were studied in tonoplast membrane vesicles isolated from leaves of six CAM and one C3 species of bromeliads. A consistent feature of these species was the high activity of the tonoplast ATP-driven H+ pump, which, when averaged across the seven species tested, showed a higher specific activity than the tonoplast PPi-driven H+ pump. For all CAM species, the rate of ATP-dependent proton transport into the tonoplast vesicles was strongly influenced by the nature of the balancing organic-acid anion, which displayed the following order of effectiveness: fumarate>malate>citrate. Measurements of leaf organic-acid content in six CAM bromeliads at dusk and dawn showed that nocturnal accumulation of malate exceeded citrate by a factor of ~2.4-20.0-fold in five of six bromeliad species used in this study, demonstrating a close correlation between the CAM rhythm and the intrinsic properties of the vacuolar membrane across which these organic acids are transported.

30 Years of Neurosurgical Robots: Review and Trends for Manipulators and Associated Navigational Systems.

This review provides an examination of contemporary neurosurgical robots and the developments that led to them. Improvements in localization, microsurgery and minimally invasive surgery have made robotic neurosurgery viable, as seen by the success of platforms such as the CyberKnife and neuromate. Neurosurgical robots can now perform specific surgical tasks such as skull-base drilling and craniotomies, as well as pedicle screw and cochlear electrode insertions. Growth trends in neurosurgical robotics are likely to continue but may be tempered by concerns over recent surgical robot recalls, commercially-driven surgeon training, and studies that show operational costs for surgical robotic procedures are often higher than traditional surgical methods. We point out that addressing performance issues related to navigation-related registration is an active area of research and will aid in improving overall robot neurosurgery performance and associated costs.

A simplified cervix model in response to induction balloon in pre-labour.

BACKGROUND: Induction of labour is poorly understood even though it is performed in 20% of births in the United States. One method of induction, the balloon dilator applied with traction to the interior os of the cervix, engages a softening process, permitting dilation and effacement to proceed until the beginning of active labour. The purpose of this work is to develop a simple model capable of reproducing the dilation and effacement effect in the presence of a balloon. METHODS: The cervix, anchored by the uterus and the endopelvic fascia was modelled in pre-labour. The spring-loaded, double sliding-joint, double pin-joint mechanism model was developed with a Modelica-compatible system, MapleSoft MapleSim 6.1, with a stiff Rosenbrock solver and 1E-4 absolute and relative tolerances. Total simulation time for pre-labour was seven hours and simulations ended at 4.50 cm dilation diameter and 2.25 cm effacement. RESULTS: Three spring configurations were tested: one pin joint, one sliding joint and combined pin-joint-sliding-joint. Feedback, based on dilation speed modulated the spring values, permitting controlled dilation. Dilation diameter speed was maintained at 0.692 cm·hr-1 over the majority of the simulation time. In the sliding-joint-only mode the maximum spring constant value was 23800 N·m-1. In pin-joint-only the maximum spring constant value was 0.41 N·m·rad-1. With a sliding-joint-pin-joint pair the maximum spring constants are 2000 N·m-1 and 0.41 N·m·rad-1, respectively. CONCLUSIONS: The model, a simplified one-quarter version of the cervix, is capable of maintaining near-constant dilation rates, similar to published clinical observations for pre-labour. Lowest spring constant values are achieved when two springs are used, but nearly identical tracking of dilation speed can be achieved with only a pin joint spring. Initial and final values for effacement and dilation also match published clinical observations. These results provide a framework for development of electro-mechanical phantoms for induction training, as well as dilator testing and development.

Balloon dilators for labor induction: a historical review.

A number of recent articles attribute the origin of the use of cervical balloon dilation in the induction of labor to either Barnes in the 1860s or Embrey and Mollison in the 1960s. This review examines the historical record and reveals that, based on current practice attribution should rather be made to two contemporaries of Barnes: the Storer and Mattei. More importantly, Storer's warning about the rubber used in dilators was ignored, leading to decades of possibly unnecessary deaths following childbirth. To conduct this study key search terms for PubMed, Google Scholar and the website of the University of Ryerson were utilized as "Barnes", "Woodman", "balloon dilation", "balloon catheter", "foley", "colpeurynter", "cervix uteri" and "induction." Subsequent analysis was done on downloaded articles using BibDesk.