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The COVID-19 pandemic was immediately marked by strong clinical research activity. The French national competent authority presents the data on request for authorization during the first 2 years of COVID-19 pandemic to inform discussions on future clinical research issues. Applications for authorization of interventional COVID-19 trials submitted between March 2020 and February 2022 were analysed. Trials on medicinal products were classified according to market authorization status, mechanism of action of the investigational product, target population and clinical context. In 2 years, 208 clinical trials were submitted. 75% were authorized, 3% refused, 22% withdrawn by the sponsor. Among medicinal products trials, 6% were adaptative, 28% included outpatients and 2% were focused on post COVID-19 symptoms. Vaccines were evaluated in 9% of trials, antivirals in 38% and immunomodulators in 35%; 63% of antiviral and 60% of immunomodulation trials included a drug with a marketing authorization in another indication. The dynamics of authorization prove the involvement of stakeholders but also illustrates the risk of dispersion of research efforts and the risk of decorrelation between trials and the epidemic evolution. The high rate of withdrawal of applications could be explained by changes in the sanitary context and by the dropping of some therapeutic approaches. Most of clinical trials evaluate drugs authorized in another indication and assessment procedures by authorities have to mitigate between the knowledge of safety profile of those drugs and the uncertainty in a new clinical context with rapidly evolving knowledge. COVID-19 experience should now support future evolution in clinical research practices.

InFederalism and Subsidiarity,a distinguished interdisciplinary group of scholars in political science, law, and philosophy address the application and interaction of the concept of federalism within law and government. What are the best justifications for and conceptions of federalism? What are the most useful criteria for deciding what powers should be allocated to national governments and what powers reserved to state or provincial governments? What are the implications of the principle of subsidiarity for such questions? What should be the constitutional standing of cities in federations? Do we need to remap federalism to reckon with the emergence of translocal and transnational organizations with porous boundaries that are not reflected in traditional jurisdictional conceptions? Examining these questions and more, this latest installation in the NOMOS series sheds new light on the allocation of power within federations.

As compared with Europe, the United States generally requires more rigorous clinical testing of high-risk devices, which delays patients' access to new devices but may provide better assurance of device safety. Millions of patients worldwide depend on an ever-widening array of medical devices for the diagnosis and management of disease. In the United States, the Food and Drug Administration (FDA) requires manufacturers of high-risk devices such as heart valves and intraocular lens implants to demonstrate safety and effectiveness before the devices can be marketed. However, some policymakers and device manufacturers have characterized U.S. device regulation as slow, risk-averse, and expensive. 1 , 2 Other experts, such as those at the Institute of Medicine, have suggested that current premarketing procedures may not be comprehensive enough and may be particularly dangerous for devices that have . . .

Mathematical ability: safety in numbers The 'approximate number system' (ANS) is a rough-and-ready number sense that has been demonstrated in societies that have no verbal counting system, in human infants and even in monkeys. A new study reveals that a gift for more elaborate mathematics might also be linked to this evolutionarily ancient ability. Mathematically talented children, aged around 14 years, were found to perform ANS tasks more precisely than those less good with numbers, regardless of IQ or visual-spatial reasoning skills. This raises the question of whether a better background in mathematics has promoted better care at ANS tasks in those children, or whether early coaching in ANS might improve mathematical prowess. The 'Approximate number system' (ANS), a relatively imprecise discrimination of quantities and numbers, has been demonstrated in cultures with no verbal counting system and even in various non-human species. Children with higher symbolic math abilities also do ANS tasks more precisely, and do this regardless of their general verbal IQ or visual–spatial reasoning skills. Human mathematical competence emerges from two representational systems. Competence in some domains of mathematics, such as calculus, relies on symbolic representations that are unique to humans who have undergone explicit teaching 1 , 2 . More basic numerical intuitions are supported by an evolutionarily ancient approximate number system that is shared by adults 3 , 4 , 5 , 6 , infants 7 and non-human animals 8 , 9 , 10 , 11 , 12 , 13 —these groups can all represent the approximate number of items in visual or auditory arrays without verbally counting, and use this capacity to guide everyday behaviour such as foraging. Despite the widespread nature of the approximate number system both across species and across development, it is not known whether some individuals have a more precise non-verbal ‘number sense’ than others. Furthermore, the extent to which this system interfaces with the formal, symbolic maths abilities that humans acquire by explicit instruction remains unknown. Here we show that there are large individual differences in the non-verbal approximation abilities of 14-year-old children, and that these individual differences in the present correlate with children’s past scores on standardized maths achievement tests, extending all the way back to kindergarten. Moreover, this correlation remains significant when controlling for individual differences in other cognitive and performance factors. Our results show that individual differences in achievement in school mathematics are related to individual differences in the acuity of an evolutionarily ancient, unlearned approximate number sense. Further research will determine whether early differences in number sense acuity affect later maths learning, whether maths education enhances number sense acuity, and the extent to which tertiary factors can affect both.

In Federalism and Subsidiarity, a distinguished interdisciplinary group of scholars in political science, law, and philosophy address the application and interaction of the concept of federalism within law and government. What are the best justifications for and conceptions of federalism? What are the most useful criteria for deciding what powers should be allocated to national governments and what powers reserved to state or provincial governments? What are the implications of the principle of subsidiarity for such questions? What should be the constitutional standing of cities in federations? Do we need to \"remap\" federalism to reckon with the emergence of translocal and transnational organizations with porous boundaries that are not reflected in traditional jurisdictional conceptions? Examining these questions and more, this latest installation in the NOMOS series sheds new light on the allocation of power within federations.

Background Adverse events (AEs) are under‐reported in veterinary medicine. The ability to report AEs directly from the practice management system (PMS) has been suggested to facilitate reporting. The Small Animal Veterinary Surveillance Network (SAVSNET) informatics system provides an opportunity to integrate reporting into the workflow such that reports can be submitted directly to the National Competent Authority, the Veterinary Medicines Directorate (VMD). Objectives Develop an AE reporting form linked to the PMS allowing for pre‐population of some fields from the electronic health record (EHR). Analyze the quality of submitted reports. Animals Animals attending United Kingdom (UK) first‐opinion veterinary practices participating in SAVSNET. Methods An AE “reporting button” was developed and available in the normal clinical workflow for SAVSNET enrolled practices using the Robovet PMS. The button facilitated capture of pertinent information relating to AEs, including the ability to append clinical notes from the associated EHR. After submission, reports were automatically submitted daily to the VMD. Report quality was assessed using an adapted version of the vigiGrade scoring system, which was used to compare the quality of reports submitted to the VMD via standard routes to those submitted via SAVSNET. Assessment of reports submitted via SAVSNET, was conducted twice. First, considering only information contained in the report and second, considering information contained in both the report and associated clinical notes. Results Sixty reports were submitted during the first 18 months by 42 different veterinary practices. The quality of SAVSNET reports was significantly improved by information contained within the clinical notes. These reports were more likely to be well‐documented than those submitted via standard routes. Conclusions and Clinical Importance Adverse event reports populated using EHR data are well documented and can support efficient reporting of AEs in veterinary medicine.

During the beginning of the COVID-19 pandemic there was an urgent need for accelerated review of COVID-19 research by Medical Research Ethics Committees (MRECs). In the Netherlands this led to the implementation of so-called 'fast-track-review-procedures' (FTRPs) to enable a swift start of urgent and relevant research. The objective of this study is to evaluate FTRPs of MRECs in the Netherlands during the COVID-19 pandemic and to compare them with the regular review procedures (RRPs). An explanatory sequential mixed method study was conducted. Online questionnaires and four group interviews were conducted among MREC representatives and investigators of COVID-19 research. In addition, data from a national research registration system was requested. Main outcome measures are differences in timelines, quality of the review and satisfaction between FTRPs and RRPs. The total number of review days was shorter in FTRP (median 10.5) compared to RRPs (median 98.0). Review days attributable to the MRECs also declined in FTRPs (median 8.0 versus 50.0). This shortening can be explained by installing ad hoc (sub)committees, full priority given to COVID-19 research, regular research put on hold, online review meetings and administrative leniency. The shorter timelines did not affect the perceived quality of the review and ethical and legal aspects were not weighted differently. Both MREC representatives and investigators were generally satisfied with the review of COVID-19 research. Weaknesses identified were the lack of overview of COVID-19 research and central collaboration and coordination, the delay of review of regular research, and limited reachability of secretariats. This study shows that accelerated review is feasible during emergency situations. We did not find evidence that review quality was compromised and both investigators and MRECs were content with the FTRP. To improve future medical ethical review during pandemic situations and beyond, distinguishing main and side issues, working digitally, and (inter)national collaboration and coordination are important.

Master protocols combine several sub-trials, each with their own research objectives, which is usually presented as one single clinical trial application. Master protocols have become increasingly popular in oncology and haematology, as either basket, umbrella, or platform trials. Although master protocols are intended to accelerate drug development and to reduce futility, their use poses challenges to ethics committees, patients, study investigators, and competent authorities during the review and authorisation process of a clinical trial application. In this Personal View, we review the experiences of clinical trial applications from two European medical regulators—the Danish Medicines Agency and the German Federal Institute for Drugs and Medical Devices. We view master protocols as a good opportunity to identify new treatment options more quickly, particularly for patients with cancer. However, the complexity of trial documentation, the amount of information resulting from sub-trials, and the volume of changes and amendments made to clinical trial applications can cause issues during trial supervision, and during the analysis and review of a corresponding application for marketing authorisation. We draw attention to the potential issues arising from these trial concepts and propose possible solutions to avoid problems during clinical trial authorisation and trial conduct.

Cardiac resynchronization therapy (CRT) improves outcomes, functional capacity and quality of life in patients with heart failure. Despite two decades of experience with CRT, the rate of non-response remains approximately 30%. CRT efficacy is impacted by pacing location, which is anatomically limited in conventional systems. A new wireless endocardial left ventricular (LV) pacing system allows CRT without such limitations and has shown promise in open-label studies. The purpose of this study is to evaluate its use in a patient population with poor therapeutic alternatives. The SOLVE CRT study is an international, multi-center, randomized, double-blind, sham-controlled trial of patients with Class I and IIa indications for CRT who have either failed to respond to or have been unable to receive conventional CRT. Enrollment will comprise 350 patients implanted with the wireless CRT system randomized 1:1 to therapy on (Treatment) or therapy off (Control) for the six-month period over which trial primary endpoints will be evaluated. The primary safety endpoint will measure the proportion of patients free from system- and procedure-related complications. Primary efficacy endpoints will assess absolute change in LV end-systolic volume LVESV, proportion of patients reducing LVESV by ≥15% and clinical composite score for Treatment versus Control patients. Primary endpoints will be evaluated on an intention-to-treat basis, though per-protocol and as-treated analysis will also be performed. SOLVE-CRT will quantify the safety and effectiveness of wireless CRT in non-responders to conventional CRT and indicated patients who have been unable to receive CRT via the usual transvenous approach.