White noise, white heat: A call to action from the frontline

Whilst the Covid-19 pandemic moves into a new phase with the successful roll out of vaccines in adults in the UK, there is an opportunity to reflect, re-evaluate, and reconfigure public health responses. Of importance is the need to defend and protect the frontline workforce who have sacrificed so much over the last 18 months. The present essay summarises key recommendations from frontline workers to policymakers with specific reference to the preparation needed for the Autumn and Winter to come. The participants from the CV19 Heroes Project give voice to concerns over the unique challenges posed by the coming months, and speak of the need to embed evidence into future policy to both compensate existing, and prevent future, occupational exposure to Covid-19, the experience of Long Covid, and the overall psychological and physical scars experienced from what has been a traumatic period of their working lives

Technologies to Support End-of-Life Care

OBJECTIVES: To describe the current level of utilization of informatics systems in hospice and palliative care and to discuss two projects that highlight the role of informatics applications for hospice informal caregivers. DATA SOURCES: Published articles, web resources, clinical practice and ongoing research initiatives. CONCLUSION: There are currently few informatics interventions designed specifically for palliative and hospice care. Challenges such as interoperability, user acceptance, privacy, the digital divide and allocation of resources all affect the diffusion of informatics tools in hospice. IMPLICATIONS FOR NURSING PRACTICE: Caregiver support through use of IT is feasible and may enhance hospice care

A preoperative package of care for osteoarthritis, consisting of weight loss, orthotics, rehabilitation, topical and oral analgesia (OPPORTUNITY): A two centre open label randomised controlled feasibility trial

Background Osteoarthritis of the knee is a major cause of disability worldwide. Non-operative treatments can reduce the morbidity but adherence is poor. We hypothesised that adherence could be optimised if behavioural change was established in the preoperative period. Therefore, we aimed to assess feasibility, acceptability, and recruitment and retention rates of a preoperative package of non-operative care in patients awaiting knee replacement surgery. Methods We did an open-label, randomised controlled, feasibility trial in two secondary care centres in the UK. Eligible participants were aged 15–85 years, on the waiting list for a knee arthroplasty for osteoarthritis, and met at least one of the thresholds for one of the four components of the preoperative package of non-operative care intervention (ie, weight loss, exercise therapy, use of insoles, and analgesia adjustment). Participants were randomly assigned (2:1) to either the intervention group or the standard of care (ie, control) group. All four aspects of the intervention were delivered weekly over 12 weeks. Participants in the intervention group were reviewed regularly to assess adherence. The primary outcome was acceptability and feasibility of delivering the intervention, as measured by recruitment rate, retention rate at follow-up review after planned surgery, health-related quality of life, joint-specific scores, and adherence (weight change and qualitative interviews). This study is registered with ISRCTN, ISRCTN96684272. Findings Between Sept 3 2018, and Aug 30, 2019, we screened 233 patients, of whom 163 (73%) were excluded and 60 (27%) were randomly assigned to either the intervention group (n=40) or the control group (n=20). 34 (57%) of 60 participants were women, 26 (43%) were men, and the mean age was 66·8 years (SD 8·6). Uptake of the specific intervention components varied: 31 (78%) of 40 had exercise therapy, 28 (70%) weight loss, 22 (55%) analgesia adjustment, and insoles (18 [45%]). Overall median adherence was 94% (IQR 79·5–100). At the final review, the intervention group lost a mean of 11·2 kg (SD 5·6) compared with 1·3 kg (3·8) in the control group (estimated difference –9·8 kg [95% CI –13·4 to –6·3]). A clinically significant improvement in health-related quality o life (mean change 0·078 [SD 0·195]) were reported, and joint-specific scores showed greater improvement in the intervention group than in the control group. No adverse events attributable to the intervention occurred. Interpretation Participants adhered well to the non-operative interventions and their health-related quality of life improved. Participant and health professional feedback were extremely positive. These findings support progression to a full-scale effectiveness trial

Osteoarthritis Preoperative Package for care of Orthotics, Rehabilitation, Topical and oral agent Usage and Nutrition to Improve ouTcomes at a Year (OPPORTUNITY); a feasibility study protocol for a randomised controlled trial

BackgroundPatients’ pre-operative health and physical function is known to influence their post-operative outcomes. In patients with knee osteoarthritis, pharmacological and non-pharmacological options are often not optimised prior to joint replacement. This results in some patients undergoing surgery when they are not as fit as they could be. The aim of this study is to assess the feasibility and acceptability of a pre-operative package of non-operative care versus standard care prior to joint replacement.Methods/designThis is a multicentre, randomised controlled feasibility trial of patients undergoing primary total knee replacement for osteoarthritis. Sixty patients will be recruited and randomised (2:1) to intervention or standard care arms. Data will be collected at baseline (before the start of the intervention), around the end of the intervention period and a minimum of 90 days after the planned date of surgery. Adherence will be reviewed each week during the intervention period (by telephone or in person). Participants will be randomised to a pre-operative package of non-operative care or standard care. The non-operative care will consist of (1) a weight-loss programme, (2) a set of exercises, (3) provision of advice on analgesia use and (4) provision of insoles. The intervention will be started as soon as possible after patients have been added to the waiting list for joint replacement surgery to take advantage of the incentive for behavioural change that this will create. The primary outcomes of this study are feasibility outcomes which will indicate whether the intervention and study protocol is feasible and acceptable and whether a full-scale effectiveness trial is warranted.The following will be measured and used to inform study feasibility: rate of recruitment, rate of retention at 90-day follow-up review after planned surgery date, and adherence to the intervention estimated through review questionnaires and weight change (for those receiving the weight-loss aspect of intervention). In addition the following information will be assessed qualitatively: analysis of qualitative interviews exploring acceptability, feasibility, adherence and possible barriers to implementing the intervention, and acceptability of the different outcome measures.DiscussionThe aims of the study specifically relate to testing the feasibility and acceptability of the proposed effectiveness trial intervention and the feasibility of the trial methods.This study forms the important first step in developing and assessing whether the intervention has the potential to be assessed in a future fully powered effectiveness trial. The findings will also be used to refine the design of the effectiveness trial.Trial registrationISRCTN registry, ID: ISRCTN96684272. Registered on 18 April 2018

Use of a conditional Ubr5 mutant allele to investigate the role an N-end rule ubiquitin-protein ligase in Hedgehog signalling and embryonic limb development

Hedgehog (Hh) signalling is a potent regulator of cell fate and function. While much is known about the events within a Hh-stimulated cell, far less is known about the regulation of Hh-ligand production. Drosophila Hyperplastic Discs (Hyd), a ubiquitin-protein ligase, represents one of the few non-transcription factors that independently regulates both hh mRNA expression and pathway activity. Using a murine embryonic stem cell system, we revealed that shRNAi of the mammalian homologue of hyd, Ubr5, effectively prevented retinoic-acid-induced Sonic hedgehog (Shh) expression. We next investigated the UBR5:Hh signalling relationship in vivo by generating and validating a mouse bearing a conditional Ubr5 loss-of-function allele. Conditionally deleting Ubr5 in the early embryonic limb-bud mesenchyme resulted in a transient decrease in Indian hedgehog ligand expression and decreased Hh pathway activity, around E13.5. Although Ubr5-deficient limbs and digits were, on average, shorter than control limbs, the effects were not statistically significant. Hence, while loss of UBR5 perturbed Hedgehog signalling in the developing limb, there were no obvious morphological defects. In summary, we report the first conditional Ubr5 mutant mouse and provide evidence for a role for UBR5 in influencing Hh signalling, but are uncertain to whether the effects on Hedgehog signaling were direct (cell autonomous) or indirect (non-cell-autonomous). Elaboration of the cellular/molecular mechanism(s) involved may help our understanding on diseases and developmental disorders associated with aberrant Hh signalling

Investigation of the E3 ubiquitin ligase UBR5; a novel regulator of Hh gene expression

The Hedgehog (Hh) signalling pathway is essential for embryogenesis and regulating cellular homeostasis in the adult, however much remains unknown about the molecular mechanisms that control ligand expression. In 2002, Lee et al. demonstrated that conditional mutation of the Drosophila hyperplastic discs gene (hyd) resulted in increased hh levels, suggesting that Hyd can act as a negative regulator of hh gene expression. Based on this evidence, the aim of this project was to investigate the hypothesis that UBR5, the murine homologue of Hyd, acts as a novel regulator of Hh gene expression in mammals. To investigate this hypothesis in vivo, I utilized the developing mouse limb as a model system that is highly sensitive to abnormal Hh expression. Morphological analysis of Ubr5 limb mutant embryos did not reveal an obvious phenotype, however quantitative analysis of Ihh gene expression and its downstream targets at E13.5 demonstrated a significant decrease in levels. In addition, changes in the expression of Runx2 and Msx2 were detected. Therefore, these data indicate that UBR5 can act as a positive regulator of Ihh expression, in addition to regulating other factors involved in chondrogenesis. The role for UBR5 as a positive regulator of Hh expression was also supported by in vitro investigations, demonstrating that UBR5 is required for Shh expression in mouse embryonic stem cells. Morphological analysis of adult Ubr5 limb mutant mice revealed the presence of significantly shorter long bones. These observations support previous reports that interference with IHH during early chondrogenesis can negatively affect long bone growth in the adult. Interestingly, adult Ubr5 limb mutant mice also possess osteophytes, a feature typically observed in osteoarthritis (OA), in addition to sites of ectopic mineralization (EM) near tendons of the knee and ankle. Based on these observations and evidence from the literature, I hypothesize that in addition to the role for UBR5 as a positive regulator of Ihh expression in the bone, UBR5 also plays a role in ligament/tendon development and/or maintenance, whereby its loss results in defective ligaments/tendons that are incapable of stabilizing the joints of the limb, culminating in joint deterioration, as observed in OA, in addition to EM. However, further investigation is required to determine whether this is also related to deregulated Ihh. These experiments suggest that Ubr5 limb mutant mice could provide a novel mouse model in the study of OA and prompt the investigation of the potential role for EDD, the human homologue of UBR5, in OA initiation and progression