Job retention vocational rehabilitation for employed people with inflammatory arthritis: adaptations to the WORKWELL trial due to the impact of the COVID-19 pandemic.

There are high levels of work disability, absenteeism (sick leave) and presenteeism (reduced productivity) amongst people with inflammatory arthritis. WORKWELL is a multi-centre, randomised controlled trial of job retention vocational rehabilitation for employed people with inflammatory arthritis. The trial tested the effectiveness and cost-effectiveness of the WORKWELL programme compared to the receipt of written self-help information only. Both arms continued to receive usual care. In March 2020, due to the COVID-19 pandemic, the WORKWELL trial paused to recruitment and intervention delivery. To successfully re-start, protocol amendments were rapidly submitted and changes to existing trial procedures were made. The WORKWELL protocol was adapted in response to both the practical issues likely faced by many clinical research studies active across NHS sites during the pandemic and additional trial-specific challenges. A key eligibility criterion for the trial required participants to be in paid work for at least 15 h per week. However, UK national lockdowns led to a substantial proportion of the workforce suddenly being furloughed or unable to work, and many people with arthritis taking immunosuppressive medications were asked to shield themselves. Thus, the number of eligible participants was reduced. Those continuing to work were harder to identify, as hospital clinics moved to remote delivery, and also to then screen, consent and treat, as the hospital research staff and clinical therapists were re-deployed. New recruitment and consent strategies were applied, and where sites had reduced capacity, responsibilities were absorbed by the trial management team. Remote intervention delivery and electronic data capture were also implemented. By rapidly adapting the WORKWELL protocol and procedures, the trial successfully reopened to recruitment in July 2020, only 4 months after the trial pause. We were able to achieve recruitment figures above the pre-COVID target and maintain a high retention rate. In addition, we found many of the protocol changes beneficial, as these streamlined trial procedures, thus improving efficiency. It is likely that many strategies implemented in response to the pandemic may become standard practice in future research within trials of a similar design and methodology.Trial registration: ClinicalTrials.gov NCT03942783 . Retrospectively registered on 08 May 2019. ISRCTN Registry ISRCTN61762297 . Retrospectively registered on 13 May 2019.

Asgard archaea shed light on the evolutionary origins of the eukaryotic ubiquitin-ESCRT machinery.

The ESCRT machinery, comprising of multiple proteins and subcomplexes, is crucial for membrane remodelling in eukaryotic cells, in processes that include ubiquitin-mediated multivesicular body formation, membrane repair, cytokinetic abscission, and virus exit from host cells. This ESCRT system appears to have simpler, ancient origins, since many archaeal species possess homologues of ESCRT-III and Vps4, the components that execute the final membrane scission reaction, where they have been shown to play roles in cytokinesis, extracellular vesicle formation and viral egress. Remarkably, metagenome assemblies of Asgard archaea, the closest known living relatives of eukaryotes, were recently shown to encode homologues of the entire cascade involved in ubiquitin-mediated membrane remodelling, including ubiquitin itself, components of the ESCRT-I and ESCRT-II subcomplexes, and ESCRT-III and Vps4. Here, we explore the phylogeny, structure, and biochemistry of Asgard homologues of the ESCRT machinery and the associated ubiquitylation system. We provide evidence for the ESCRT-I and ESCRT-II subcomplexes being involved in ubiquitin-directed recruitment of ESCRT-III, as it is in eukaryotes. Taken together, our analyses suggest a pre-eukaryotic origin for the ubiquitin-coupled ESCRT system and a likely path of ESCRT evolution via a series of gene duplication and diversification events.