Peptide macrocyclisation via intramolecular interception of visible-light-mediated desulfurisation.

Synthetic methods that enable the macrocyclisation of peptides facilitate the development of effective therapeutic and diagnostic tools. Herein we report a peptide cyclisation strategy based on intramolecular interception of visible-light-mediated cysteine desulfurisation. This method allows cyclisation of unprotected peptides in an aqueous solution via the installation of a hydrocarbon linkage. We explore the limits of this chemistry using a range of model peptides of increasing length and complexity, including peptides of biological/therapeutic relevance. The method is applied to replace the native disulfide of the peptide hormone, oxytocin, with a proteolytically/redox-stable hydrocarbon, and internal macrocyclisation of an MCL-1-binding peptide.

Advance decisions to refuse treatment and suicidal behaviour in emergency care: 'it's very much a step into the unknown'.

BACKGROUND: Complex challenges may arise when patients present to emergency services with an advance decision to refuse life-saving treatment following suicidal behaviour. AIMS: To investigate the use of advance decisions to refuse treatment in the context of suicidal behaviour from the perspective of clinicians and people with lived experience of self-harm and/or psychiatric services. METHOD: Forty-one participants aged 18 or over from hospital services (emergency departments, liaison psychiatry and ambulance services) and groups of individuals with experience of psychiatric services and/or self-harm were recruited to six focus groups in a multisite study in England. Data were collected in 2016 using a structured topic guide and included a fictional vignette. They were analysed using thematic framework analysis. RESULTS: Advance decisions to refuse treatment for suicidal behaviour were contentious across groups. Three main themes emerged from the data: (a) they may enhance patient autonomy and aid clarity in acute emergencies, but also create legal and ethical uncertainty over treatment following self-harm; (b) they are anxiety provoking for clinicians; and (c) in practice, there are challenges in validation (for example, validating the patient's mental capacity at the time of writing), time constraints and significant legal/ethical complexities. CONCLUSIONS: The potential for patients to refuse life-saving treatment following suicidal behaviour in a legal document was challenging and anxiety provoking for participants. Clinicians should act with caution given the potential for recovery and fluctuations in suicidal ideation. Currently, advance decisions to refuse treatment have questionable use in the context of suicidal behaviour given the challenges in validation. Discussion and further patient research are needed in this area. DECLARATION OF INTEREST: D.G., K.H. and N.K. are members of the Department of Health's (England) National Suicide Prevention Advisory Group. N.K. chaired the National Institute for Health and Care Excellence (NICE) guideline development group for the longer-term management of self-harm and the NICE Topic Expert Group (which developed the quality standards for self-harm services). He is currently chair of the updated NICE guideline for Depression. K.H. and D.G. are NIHR Senior Investigators. K.H. is also supported by the Oxford Health NHS Foundation Trust and N.K. by the Greater Manchester Mental Health NHS Foundation Trust.

Predictive accuracy of risk scales following self-harm: multicentre, prospective cohort study.

BackgroundScales are widely used in psychiatric assessments following self-harm. Robust evidence for their diagnostic use is lacking.AimsTo evaluate the performance of risk scales (Manchester Self-Harm Rule, ReACT Self-Harm Rule, SAD PERSONS scale, Modified SAD PERSONS scale, Barratt Impulsiveness Scale); and patient and clinician estimates of risk in identifying patients who repeat self-harm within 6 months.MethodA multisite prospective cohort study was conducted of adults aged 18 years and over referred to liaison psychiatry services following self-harm. Scale a priori cut-offs were evaluated using diagnostic accuracy statistics. The area under the curve (AUC) was used to determine optimal cut-offs and compare global accuracy.ResultsIn total, 483 episodes of self-harm were included in the study. The episode-based 6-month repetition rate was 30% (n = 145). Sensitivity ranged from 1% (95% CI 0-5) for the SAD PERSONS scale, to 97% (95% CI 93-99) for the Manchester Self-Harm Rule. Positive predictive values ranged from 13% (95% CI 2-47) for the Modified SAD PERSONS Scale to 47% (95% CI 41-53) for the clinician assessment of risk. The AUC ranged from 0.55 (95% CI 0.50-0.61) for the SAD PERSONS scale to 0.74 (95% CI 0.69-0.79) for the clinician global scale. The remaining scales performed significantly worse than clinician and patient estimates of risk (P<0.001).ConclusionsRisk scales following self-harm have limited clinical utility and may waste valuable resources. Most scales performed no better than clinician or patient ratings of risk. Some performed considerably worse. Positive predictive values were modest. In line with national guidelines, risk scales should not be used to determine patient management or predict self-harm.