Getting it right first time: what have we learnt?

Getting It Right First Time (GIRFT) is a national programme of improvement to identify and reduce unwarranted variation and non-evidence-based practice in healthcare. It aims to improve patient care, increase productivity and reduce costs. Professor Tim Briggs, an orthopaedic surgeon, began the programme with a pilot review visiting every orthopaedic surgery department in England. He used publicly available data to illuminate variation, and worked with the clinicians and management to develop improvements. The impressive initial report in 2015 led to NHS Improvement investing £60m to expand the programme to 40 medical and surgical specialties. The follow-up Orthopaedic report detailed savings of £696m to the NHS. GIRFT is now sharing its data with the CQC and leading the charge with elective recovery following COVID-19. GIRFT differs from previous programmes of improvement through its peer led, supportive approach to promoting change with early engagement of both clinicians and management. Common themes run through the almost 40 specialty reports published to date: variation in procurement and litigation costs, huge variations in patient treatment options (often with a lack of evidence base) and poor data quality. Successfully applied in orthopaedic surgery, it has been taken on enthusiastically by other specialties. Whether it can deliver its objective of £1.4bn savings whilst improving patient outcomes is yet to be seen, but its approach is changing the culture of the NHS.

Randomised controlled trial of intravenous nafamostat mesylate in COVID pneumonitis: Phase 1b/2a experimental study to investigate safety, Pharmacokinetics and Pharmacodynamics.

BACKGROUND: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is nafamostat mesylate. METHODS: We present the findings of a phase Ib/IIa open label, platform randomised controlled trial of intravenous nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2 mg/kg/h for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC. The primary outcomes of our trial were the safety and tolerability of intravenous nafamostat as an add on therapy for patients hospitalised with COVID-19 pneumonitis. FINDINGS: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous nafamostat. 86% of nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The nafamostat group were significantly more likely to experience at least one AE (posterior mean odds ratio 5.17, 95% credible interval (CI) 1.10 - 26.05) and developed significantly higher plasma creatinine levels (posterior mean difference 10.57 micromol/L, 95% CI 2.43-18.92). An average longer hospital stay was observed in nafamostat patients, alongside a lower rate of oxygen free days (rate ratio 0.55-95% CI 0.31-0.99, respectively). There were no other statistically significant differences in endpoints between nafamostat and SoC. PK data demonstrated that intravenous nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. INTERPRETATION: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous nafamostat, and there were additional adverse events. FUNDING: DEFINE was funded by LifeArc (an independent medical research charity) under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230).

Adverse events and overall health and well-being after COVID-19 vaccination: interim results from the VAC4COVID cohort safety study.

OBJECTIVES: To describe the incidence of adverse events (AEs), reactogenicity symptoms, menstrual changes and overall self-rated improvement in health and well-being after COVID-19 vaccination. DESIGN: VAC4COVID is an ongoing prospective, active observational, post-authorisation cohort safety study (PASS) of UK-approved vaccines for COVID-19 disease. SETTING: The study is conducted through a secure website (www.vac4covid.com) by MEMO Research, University of Dundee, UK. PARTICIPANTS: 16 265 adult (18 years or older) UK residents with a valid email address and internet access. INTERVENTIONS: Any UK-authorised COVID-19 vaccination. MAIN OUTCOME MEASURES: The outcomes reported in this interim analysis include AEs, reactogenicity-type AEs (headache, fatigue, muscle or joint pain, fever, nausea, dizziness or local vaccine reaction), menstrual changes and reported improvement in overall health and well-being. RESULTS: 11 475 consented participants (mean age 54.8 years) provided follow-up data between 2 February and 5 October 2021 (mean follow-up duration 184 days), by which date 89.2% of participants had received two vaccine doses. 89.8% of 5222 participants who completed a follow-up questionnaire in the 7 days after any COVID-19 vaccination reported no AEs. The risk of experiencing any event (not necessarily vaccine-related) requiring hospitalisation was less than 0.2%. 43.7% of post-vaccination follow-up records reported improvement in health and well-being. Reactogenicity-type reactions were more common in the week after the first dose of ChAdOx1 than BNT162b2 (7.8% vs 1.6%), but this relationship was reversed after the second dose (1.3% vs 3.1%). 0.3% of women reported menstrual symptoms after vaccination; no differences between vaccine type or dose order were detected. CONCLUSIONS: The study provides reassuring data on low rates of AEs after COVID-19 vaccination. Differences in reactogenicity-type AE profiles between ChAdOx1 and BNT162b2 and between first and second doses of these vaccines were observed. TRIAL REGISTRATION NUMBER: ISRCTN95881792; Pre-results.

The association between mechanical ventilator compatible bed occupancy and mortality risk in intensive care patients with COVID-19: a national retrospective cohort study.

BACKGROUND: The literature paints a complex picture of the association between mortality risk and ICU strain. In this study, we sought to determine if there is an association between mortality risk in intensive care units (ICU) and occupancy of beds compatible with mechanical ventilation, as a proxy for strain. METHODS: A national retrospective observational cohort study of 89 English hospital trusts (i.e. groups of hospitals functioning as single operational units). Seven thousand one hundred thirty-three adults admitted to an ICU in England between 2 April and 1 December, 2020 (inclusive), with presumed or confirmed COVID-19, for whom data was submitted to the national surveillance programme and met study inclusion criteria. A Bayesian hierarchical approach was used to model the association between hospital trust level (mechanical ventilation compatible), bed occupancy, and in-hospital all-cause mortality. Results were adjusted for unit characteristics (pre-pandemic size), individual patient-level demographic characteristics (age, sex, ethnicity, deprivation index, time-to-ICU admission), and recorded chronic comorbidities (obesity, diabetes, respiratory disease, liver disease, heart disease, hypertension, immunosuppression, neurological disease, renal disease). RESULTS: One hundred thirty-five thousand six hundred patient days were observed, with a mortality rate of 19.4 per 1000 patient days. Adjusting for patient-level factors, mortality was higher for admissions during periods of high occupancy (> 85% occupancy versus the baseline of 45 to 85%) [OR 1.23 (95% posterior credible interval (PCI): 1.08 to 1.39)]. In contrast, mortality was decreased for admissions during periods of low occupancy (< 45% relative to the baseline) [OR 0.83 (95% PCI 0.75 to 0.94)]. CONCLUSION: Increasing occupancy of beds compatible with mechanical ventilation, a proxy for operational strain, is associated with a higher mortality risk for individuals admitted to ICU. Further research is required to establish if this is a causal relationship or whether it reflects strain on other operational factors such as staff. If causal, the result highlights the importance of strategies to keep ICU occupancy low to mitigate the impact of this type of resource saturation.

The Dockstore: enhancing a community platform for sharing reproducible and accessible computational protocols.

Dockstore (https://dockstore.org/) is an open source platform for publishing, sharing, and finding bioinformatics tools and workflows. The platform has facilitated large-scale biomedical research collaborations by using cloud technologies to increase the Findability, Accessibility, Interoperability and Reusability (FAIR) of computational resources, thereby promoting the reproducibility of complex bioinformatics analyses. Dockstore supports a variety of source repositories, analysis frameworks, and language technologies to provide a seamless publishing platform for authors to create a centralized catalogue of scientific software. The ready-to-use packaging of hundreds of tools and workflows, combined with the implementation of interoperability standards, enables users to launch analyses across multiple environments. Dockstore is widely used, more than twenty-five high-profile organizations share analysis collections through the platform in a variety of workflow languages, including the Broad Institute's GATK best practice and COVID-19 workflows (WDL), nf-core workflows (Nextflow), the Intergalactic Workflow Commission tools (Galaxy), and workflows from Seven Bridges (CWL) to highlight just a few. Here we describe the improvements made over the last four years, including the expansion of system integrations supporting authors, the addition of collaboration features and analysis platform integrations supporting users, and other enhancements that improve the overall scientific reproducibility of Dockstore content.

Hospital bed capacity and usage across secondary healthcare providers in England during the first wave of the COVID-19 pandemic: a descriptive analysis.

OBJECTIVE: In this study, we describe the pattern of bed occupancy across England during the peak of the first wave of the COVID-19 pandemic. DESIGN: Descriptive survey. SETTING: All non-specialist secondary care providers in England from 27 March27to 5 June 2020. PARTICIPANTS: Acute (non-specialist) trusts with a type 1 (ie, 24 hours/day, consultant-led) accident and emergency department (n=125), Nightingale (field) hospitals (n=7) and independent sector secondary care providers (n=195). MAIN OUTCOME MEASURES: Two thresholds for 'safe occupancy' were used: 85% as per the Royal College of Emergency Medicine and 92% as per NHS Improvement. RESULTS: At peak availability, there were 2711 additional beds compatible with mechanical ventilation across England, reflecting a 53% increase in capacity, and occupancy never exceeded 62%. A consequence of the repurposing of beds meant that at the trough there were 8.7% (8508) fewer general and acute beds across England, but occupancy never exceeded 72%. The closest to full occupancy of general and acute bed (surge) capacity that any trust in England reached was 99.8% . For beds compatible with mechanical ventilation there were 326 trust-days (3.7%) spent above 85% of surge capacity and 154 trust-days (1.8%) spent above 92%. 23 trusts spent a cumulative 81 days at 100% saturation of their surge ventilator bed capacity (median number of days per trust=1, range: 1-17). However, only three sustainability and transformation partnerships (aggregates of geographically co-located trusts) reached 100% saturation of their mechanical ventilation beds. CONCLUSIONS: Throughout the first wave of the pandemic, an adequate supply of all bed types existed at a national level. However, due to an unequal distribution of bed utilisation, many trusts spent a significant period operating above 'safe-occupancy' thresholds despite substantial capacity in geographically co-located trusts, a key operational issue to address in preparing for future waves.