Comparison of published core outcome sets with outcomes recommended in regulatory guidance from the US Food and Drug Administration and European Medicines Agency: cross sectional analysis

ObjectiveTo compare the outcomes in published core outcome sets with the outcomes recommended in corresponding guidance documents from the European Medicines Agency (EMA) and US Food and Drug Administration (FDA), matched by health condition.DesignCross sectional analysis.SettingUS and Europe.PopulationSample of core outcome sets related to drugs, devices, and gene therapy that involved patients in the consensus process, published between 1 January 2015 and 31 December 2019; and corresponding EMA and FDA guidance documents.Main outcome measuresThe extent of matches between outcomes included within core outcome sets and those recommended in corresponding EMA and FDA guidance documents were assessed. Matches were considered to be general (ie, non-specific) or specific (ie, exact). General matches were assessed to determine whether the core outcome set or guidance document outcome was narrower.ResultsRelevant guidance documents were found for for 38 (39%) of 98 eligible published core outcome sets. Among outcomes in core outcome sets, medians of 70% (interquartile range 48-86%) and 52% (33-77%) were matches with outcomes recommended in EMA and FDA documents, respectively. Medians of 46% (27-68%) and 26% (18-46%) were specific matches with outcomes in EMA and FDA documents, respectively. When outcomes were generally matched, the outcomes from core outcome sets were more frequently narrower than the regulatory outcomes (83% and 75% for EMA and FDA, respectively).ConclusionGreater adoption of, and reference to, core outcome sets in regulatory guidance documents can encourage clinical trialists, especially those in industry, to measure and report consistent and agreed outcomes and improve the quality of guidance. Given the overlap between outcomes in core outcome sets and regulatory guidance, and given that most core outcome sets now involve patients in the consensus process, these sets could serve as a useful resource for regulators when recommending outcomes for studies evaluating regulated products. Developers are encouraged to appraise recommended outcomes in salient regulatory documents when planning a core outcome set

The role of prevention in reducing the economic impact of ME/CFS in Europe : A report from the socioeconomics working group of the European network on ME/CFS (EUROMENE)

Funding Information: This research received no external funding. EUROMENE receives funding for networking activities from the COST programme (COST Action 15111), via the COST Association. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.This report addresses the extent to which there may be scope for preventive programmes for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and, if so, what economic benefits may accrue from the implementation of such programmes. We consider the economic case for prevention programmes, whether there is scope for preventive programmes for ME/CFS, and what are the health and economic benefits to be derived from the implementation of such programmes. We conclude that there is little scope for primary prevention programmes, given that ME/CFS is attributable to a combination of host and environmental risk factors, with host factors appearing to be most prominent, and that there are few identified modifiable risk factors that could be the focus of such programmes. The exception is in the use of agricultural chemicals, particularly organophosphates, where there is scope for intervention, and where Europe-wide programmes of health education to encourage safe use would be beneficial. There is a need for more research on risk factors for ME/CFS to establish a basis for the development of primary prevention programmes, particularly in respect of occupational risk factors. Secondary prevention offers the greatest scope for intervention, to minimise diagnostic delays associated with prolonged illness, increased severity, and increased costs.publishersversionPeer reviewe

Perceptions of European ME/CFS experts concerning knowledge and understanding of ME/CFS among primary care physicians in Europe : A report from the European ME/CFS research network (EUROMENE)

Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Background and Objectives: We have conducted a survey of academic and clinical experts who are participants in the European ME/CFS Research Network (EUROMENE) to elicit perceptions of general practitioner (GP) knowledge and understanding of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and suggestions as to how this could be improved. Materials and Methods: A questionnaire was sent to all national representatives and members of the EUROMENE Core Group and Management Committee. Survey responses were collated and then summarized based on the numbers and percentages of respondents selecting each response option, while weighted average responses were calculated for questions with numerical value response options. Free text responses were analysed using thematic analysis. Results: Overall there were 23 responses to the survey from participants across 19 different European countries, with a 95% country-level response rate. Serious concerns were expressed about GPs’ knowledge and understanding of ME/CFS, and, it was felt, about 60% of patients with ME/CFS went undiagnosed as a result. The vast majority of GPs were perceived to lack confidence in either diagnosing or managing the condition. Disbelief, and misleading illness attributions, were perceived to be widespread, and the unavailability of specialist centres to which GPs could refer patients and seek advice and support was frequently commented upon. There was widespread support for more training on ME/CFS at both undergraduate and postgraduate levels. Conclusion: The results of this survey are consistent with the existing scientific literature. ME/CFS experts report that lack of knowledge and understanding of ME/CFS among GPs is a major cause of missed and delayed diagnoses, which renders problematic attempts to determine the incidence and prevalence of the disease, and to measure its economic impact. It also contributes to the burden of disease through mismanagement in its early stages.publishersversionPeer reviewe

Social stories in mainstream schools for children with autism spectrum disorder : a feasibility randomised controlled trial

OBJECTIVES: To assess the feasibility of recruitment, retention, outcome measures and intervention training/delivery among teachers, parents and children. To calculate a sample size estimation for full trial. DESIGN: A single-centre, unblinded, cluster feasibility randomised controlled trial examining Social Stories delivered within a school environment compared with an attentional control. SETTING: 37 primary schools in York, UK. PARTICIPANTS: 50 participants were recruited and a cluster randomisation approach by school was examined. Participants were randomised into the treatment group (n=23) or a waiting list control group (n=27). OUTCOME MEASURES: Acceptability and feasibility of the trial, intervention and of measurements required to assess outcomes in a definitive trial. RESULTS: An assessment of the questionnaire completion rates indicated teachers would be most appropriate to complete the primary outcome measure. 2 outcome measures: the Social Responsiveness Scale (SRS)-2 and a goal-based measure showed both the highest levels of completion rates (above 80%) at the primary follow-up point (6 weeks postintervention) and captured relevant social and behaviour outcomes. Power calculations were based on these 2 outcome measures leading to a total proposed sample size of 180 participant groups. CONCLUSIONS: Results suggest that a future trial would be feasible to conduct and could inform the policy and practice of using Social Stories in mainstream schools. TRIAL REGISTRATION NUMBER: ISRCTN96286707; Results

A Literature Review of GP Knowledge and Understanding of ME/CFS: A Report from the Socioeconomic Working Group of the European Network on ME/CFS (EUROMENE)

Funding Information: EUROMENE receives funding for networking activities from the COST programme (COST Action 15111), via the COST Association. Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.Background and Objectives: The socioeconomic working group of the European myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) Research Network (EUROMENE) has con-ducted a review of the literature pertaining to GPs’ knowledge and understanding of ME/CFS; Materials and Methods: A MEDLINE search was carried out. The papers identified were reviewed following the synthesis without meta-analysis (SWiM) methodology, and were classified according to the focus of the enquiry (patients, GPs, database and medical record studies, evaluation of a training programme, and overview papers), and whether they were quantitative or qualitative in nature; Results: Thirty-three papers were identified in the MEDLINE search. The quantitative surveys of GPs demonstrated that a third to a half of all GPs did not accept ME/CFS as a genuine clinical entity and, even when they did, they lacked confidence in diagnosing or managing it. It should be noted, though, that these papers were mostly from the United Kingdom. Patient surveys indicated that a similar proportion of patients was dissatisfied with the primary medical care they had received. These findings were consistent with the findings of the qualitative studies that were examined, and have changed little over several decades; Conclusions: Disbelief and lack of knowledge and understanding of ME/CFS among GPs is widespread, and the resultant diagnostic delays constitute a risk factor for severe and prolonged disease. Failure to diagnose ME/CFS renders problematic attempts to determine its prevalence, and hence its economic impact.publishersversionPeer reviewe

Cooperation of local motions in the Hsp90 molecular chaperone ATPase mechanism

The Hsp90 chaperone is a central node of protein homeostasis activating a large number of diverse client proteins. Hsp90 functions as a molecular clamp that closes and opens in response to the binding and hydrolysis of ATP. Crystallographic studies define distinct conformational states of the mechanistic core implying structural changes that have not yet been observed in solution. Here, we engineered one-nanometer fluorescence probes based on photo-induced electron transfer into yeast Hsp90 to observe these motions. We found that the ATPase activity of the chaperone was reflected in the kinetics of specific structural rearrangements at remote positions that acted cooperatively. Nanosecond single-molecule fluorescence fluctuation analysis uncovered that critical structural elements that undergo rearrangement are mobile on a sub-millisecond time scale. We identified a two-step mechanism for lid closure over the nucleotide-binding pocket. The activating co-chaperone Aha1 mobilizes the lid of apo Hsp90, suggesting an early role in the catalytic cycle

Effect of collaborative care vs usual care on depressive symptoms among older adults with sub-threshold depression : the CASPER randomized clinical trial

In the CASPER randomized trial of 705 participants age 65 and older with sub-threshold depression, those randomized to a collaborative care intervention had lower depression scores, measured by the Patient Health 9-item questionnaire at 4 month follow-up, compared to usual care