Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

The Development of Peroxide-Responsive Arylboronic Acids for Antibody-Drug Conjugates and Small-Molecule Prodrugs

Cancer cells exhibit oxidative stress, which results in the over-production of reactive-oxygen species (ROS), such as hydrogen peroxide. Hence, there are elevated levels of hydrogen peroxide in cancer compared to healthy cells, which can be exploited for the targeted delivery of drugs. Section I of this thesis describes the design, synthesis, and evaluation of antibody-drug conjugates (ADCs) comprising arylboronic acid linkers, which give responsive drug release in the presence of the elevated hydrogen peroxide in cancer. ADCs are a continually expanding therapeutic area, and the linker used for the antibody-drug connection is of upmost importance in determining the stability of the conjugate and the specificity of drug release. Arylboronic acids are known to undergo C-B bond oxidation by action of hydrogen peroxide, and when combined with a suitable self-immolative aryl ring, can subsequently undergo spontaneous 1,6-elimination to release a free drug. Hence, initial studies evaluated a panel of model linkers with a fluorescent reporter molecule and confirmed the linker reactivity with peroxide but otherwise high stability. Trastuzumab peroxide-cleavable ADCs were then synthesised and evaluated *in vitro* against a panel of breast cancer cell lines, and preliminary evidence is presented which suggests the ADCs may not require internalisation for payload release. Hence, peroxide-cleavable ADCs comprising anti-PD-L1 antibody durvalumab were also synthesised and evaluated *in vitro*, with preliminary evidence suggesting the generation of an efficacious non-internalising ADC. Section II of this thesis describes the application of peroxide-responsive arylboronic acids towards the generation of small-molecule prodrugs. Non-targeted drugs, such as olaparib and navitoclax, often suffer from poor tolerability and toxicity because they exert their function on healthy cells as well as target cancer cells. Thus, to improve their efficacy and safety profile, inactive prodrugs of olaparib and navitoclax were designed by capping key amines with the arylboronic acid self-immolative motif. This would enable site-specific release of the free drugs upon encounter with the high levels of hydrogen peroxide in cancer. Synthetic efforts and preliminary investigations towards the peroxide-responsive prodrugs is presented

Tuneable thiol exchange linkers for traceless drug release applications in prodrugs and ADCs †

We describe a versatile and tuneable thiol responsive linker system using thiovinylketones, which relies on the conjugate addition–elimination mechanism of Michael acceptors for the traceless release of therapeutics. In a proof-of-principle study, we translate our findings to exhibit potent thiol-cleavable antibiotic prodrugs and antibody–drug conjugates

“Stabilise-reduce, stabilise-reduce”: A survey of the common practices of deprescribing services and recommendations for future services

Background Public Health England recently called for the establishment of services to help people to safely stop prescribed drugs associated with dependence and withdrawal, including benzodiazepines, z-drugs, antidepressants, gabapentinoids and opioids. NICE identified a lack of knowledge about the best model for such service delivery. Therefore, we performed a global survey of existing deprescribing services to identify common practices and inform service development. Methods We identified existing deprescribing services and interviewed key personnel in these services using an interview co-produced with researchers with lived experience of withdrawal. We summarised the common practices of the services and analysed the interviews using a rapid form of qualitative framework analysis. Results Thirteen deprescribing services were included (8 UK, 5 from other countries). The common practices in the services were: gradual tapering of medications often over more than a year, and reductions made in a broadly hyperbolic manner (smaller reductions as total dose became lower). Reductions were individualised so that withdrawal symptoms remained tolerable, with the patient leading this decision-making in most services. Support and reassurance were provided throughout the process, sometimes by means of telephone support lines. Psychosocial support for the management of underlying conditions (e.g. CBT, counselling) were provided by the service or through referral. Lived experience was often embedded in services through founders, hiring criteria, peer support and sources of information to guide tapering. Conclusion We found many common practices across existing deprescribing services around the world. We suggest that these ingredients are included in commissioning guidance of future services and suggest directions for further research to clarify best practice

Red-light modulated <i>ortho</i>-chloro azobenzene photoswitch for peptide stapling via aromatic substitution

Acknowledgements: M. K. acknowledges EPSRC for funding (SynTech EP/S024220/1). F. J. P. A. gratefully acknowledges both postdoctoral fellowships from Fundación Ramón Areces (reference BEVP31A6160) and Marie Skłodowska-Curie Individual Fellowships (MSCA-IF-2020, grant number 101025271). N. A. acknowledges a studentship from AstraZeneca. T. S. acknowledges EU funding by the H2020-MSCA-RISE-2020 through the ALISE project (grant 101007256). The Spring group research was supported by grants from UKRI. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript (AAM) version arising. Authors are also grateful to Dr Rohan Eapen for the purification of MDM2 protein, Dr Katherine Stott for interpretation of CD spectra and the NMR team at Cambridge for measuring advanced NMR experiments (Andrew Mason, Duncan Howe and Peter Gierth).The application of peptide stapling using photoswitchable linkers has gained notable interest for potential therapeutic applications. However, many existing methodologies of photoswitching still rely on the use of tissue-damaging and...</jats:p

Explanation of context, mechanisms and outcomes in adult community mental health crisis care: the MH-CREST realist evidence synthesis

Background Mental health crises cause significant disruption to individuals and families and can be life threatening. The number of community crisis services operating in an interagency landscape complicate access to help. It is unclear which underpinning mechanisms of crisis care work, for whom and in which circumstances. Aim To identify mechanisms to explain how, for whom and in what circumstances adult community crisis services work. Objectives To develop, test and synthesise programme theory via: (1) Stakeholder expertise, current evidence; (2) A Context, Intervention, Mechanisms, Outcome framework; (3) Consultation with experts; (4) Development of pen portraits; (5) Synthesis and refinement of programme theories, including mid-range theory; (6) Identification and dissemination of mechanisms needed to trigger desired context-specific crisis outcomes. Design This study is a realist evidence synthesis, comprising (i) identification of initial programme theories; (ii) prioritisation, testing and refinement of programme theory; (iii) focused realist reviews of prioritised initial programme theories; (iv) synthesis to mid-range theory. Main outcome To explain context, mechanisms, and outcomes in adult community mental health crisis care. Data Sources Data were sourced via academic and grey literature searches; Expert Stakeholder Group consultations and n = 20 individual realist interviews with experts. Review Methods A realist evidence synthesis with primary data was conducted to test and refine three initial programme theories: (1) urgent and accessible crisis care; (2) compassionate leadership; (3) interagency working. \ud Results Community crisis services operate best within an interagency system. This requires compassionate leadership and shared values that enable staff to be supported, retain their compassion and in turn facilitate compassionate interventions for people in crisis. The complex interface between agencies is best managed through greater clarity at the boundaries of services making referral and transition seamless and timely. This would facilitate ease of access and guaranteed responses that are trusted by the communities they serve. Strengths and limitations Strengths include the identification of mechanisms for effective interagency community crisis care and meaningful stakeholder consultation that grounded the theories in real-life experience. Limitations include the evidence being heavily weighted towards England and the review scope excluding full analysis of ethnic and cultural diversity. Conclusions Multiple interpretations of crises and diverse population needs present challenges for improving the complex pathways to help in a crisis. Interagency working requires clear policy guidance with local commissioning.. Seamless transitions between services generate trust through guaranteed responses and ease of navigation. This is best achieved where there is interagency affiliation that supports co-production. Compassionate leaders engender staff trust and outcomes for people in crisis improve when staff are supported to retain their compassion. Future Work Further work might explore interagency models of crisis delivery particularly rural communities. A focus on evaluating outcomes across agencies with a focus on individual recovery outcomes rather than limiting the focus to service effectiveness. The implementation and effect of mental health triage could be explored further, including via telehealth. Barriers to access for marginalised populations warrant a specific focus in future research

Peroxide-cleavable linkers for antibody–drug conjugates †

Antibody–drug conjugates containing peroxide-cleavable arylboronic acid linkers are described, which target the high levels of reactive oxygen species (ROS) in cancer. The arylboronic acid linkers rapidly release a payload in the presence of hydrogen peroxide, but remain stable in plasma. Anti-HER2 and PD-L1 peroxide-cleavable ADCs exhibited potent cytotoxicity in vitro