Does clinical management improve outcomes following self-Harm? Results from the multicentre study of self-harm in England

Background Evidence to guide clinical management of self-harm is sparse, trials have recruited selected samples, and psychological treatments that are suggested in guidelines may not be available in routine practice. Aims To examine how the management that patients receive in hospital relates to subsequent outcome. Methods We identified episodes of self-harm presenting to three UK centres (Derby, Manchester, Oxford) over a 10 year period (2000 to 2009). We used established data collection systems to investigate the relationship between four aspects of management (psychosocial assessment, medical admission, psychiatric admission, referral for specialist mental health follow up) and repetition of self-harm within 12 months, adjusted for differences in baseline demographic and clinical characteristics. Results 35,938 individuals presented with self-harm during the study period. In two of the three centres, receiving a psychosocial assessment was associated with a 40% lower risk of repetition, Hazard Ratios (95% CIs): Centre A 0.99 (0.90–1.09); Centre B 0.59 (0.48–0.74); Centre C 0.59 (0.52–0.68). There was little indication that the apparent protective effects were mediated through referral and follow up arrangements. The association between psychosocial assessment and a reduced risk of repetition appeared to be least evident in those from the most deprived areas. Conclusion These findings add to the growing body of evidence that thorough assessment is central to the management of self-harm, but further work is needed to elucidate the possible mechanisms and explore the effects in different clinical subgroups

Effect of withdrawal of co-proxamol on prescribing and deaths from drug poisoning in England and Wales: time series analysis

Objective To assess the effect of the UK Committee on Safety of Medicines’ announcement in January 2005 of withdrawal of co-proxamol on analgesic prescribing and poisoning mortality

Variation by ethnic group in premature mortality risk following self-harm: a multicentre cohort study in England

Background: Incidence and risk factors for self-harm vary according to ethnicity. People who self-harm have been shown to have increased risk of premature death, but little is known about mortality following self-harm in ethnic minority groups. Methods: A prospective cohort study of self-harm presentations to three English cities (Derby, Manchester, Oxford) between 2000 and 2010. We linked to a national mortality dataset to investigate premature death in South Asian and Black people in comparison with White people to the end of 2012. Results: Ethnicity was known for 72 % of the 28,512 study cohort members: 88 % were White, 5 % were South Asian, and 3 % were Black. After adjusting for age, gender and area-level socioeconomic deprivation, the risk of all-cause mortality was lower in South Asian (hazard ratio [HR] 0.51, 95 % confidence interval [CI] 0.42 – 0.62) and Black people (HR 0.46, 95 % CI 0.39 – 0.55) versus White people. Suicide risk was significantly lower in Black people (HR 0.43, 95 % CI 0.19 – 0.97) than in White people. Prevalence of risk factors for premature death, such as previous self-harm, psychiatric treatment or concurrent alcohol misuse, was lower in South Asian and Black people than in White people. Conclusions: The risk of death following self-harm is lower in South Asian and Black people than White people in the UK, and they also have lower prevalence of risk factors for premature death. Awareness of both protective and risk factors might help to inform clinical decisions following assessment.</p

Engineered Knottin Peptide Enables Noninvasive Optical Imaging of Intracranial Medulloblastoma

Central nervous system tumors carry grave clinical prognoses due to limited effectiveness of surgical resection, radiation, and chemotherapy. Thus, improved strategies for brain tumor visualization and targeted treatment are critically needed. We demonstrate that mouse cerebellar medulloblastoma (MB) can be targeted and illuminated with a fluorescent, engineered cystine knot (knottin) peptide that binds with high affinity to α β , α β , and α β integrin receptors. This integrin-binding knottin peptide, denoted EETI 2.5F, was evaluated as a molecular imaging probe in both orthotopic and genetic models of MB. Following tail vein injection, fluorescence arising from dye-conjugated EETI 2.5F was localized to the tumor compared with the normal surrounding brain tissue, as measured by optical imaging. The imaging signal intensity correlated with tumor volume. Due to its unique ability to bind to α β integrin, EETI 2.5F showed superior in vivo and ex vivo brain tumor imaging contrast compared with other engineered integrin-binding knottin peptides and with c(RGDfK), a well-studied integrin-binding peptidomimetic. Next, EETI 2.5F was fused to an antibody fragment crystallizable (Fc) domain (EETI 2.5F-Fc) to determine if a larger integrin-binding protein could also target intracranial brain tumors. EETI 2.5F-Fc, conjugated to a fluorescent dye, illuminated MB following i.v. injection and was able to distribute throughout the tumor parenchyma. In contrast, brain tumor imaging signals were not detected in mice injected with EETI 2.5F proteins containing a scrambled integrin-binding sequence, demonstrating the importance of target specificity. These results highlight the potential of using EETI 2.5F and EETI 2.5-Fc as targeted molecular probes for brain tumor imaging

Switching methods of self-harm at repeat episodes: Findings from a multicentre cohort study.

BACKGROUND: Self-poisoning and self-injury have widely differing incidences in hospitals and in the community, which has led to confusion about the concept of self-harm. Categorising self-harm simply by a method may be clinically misleading because many hospital-attending patients switch from one method of harm to another on subsequent episodes. The study set out to determine the frequency, pattern, determinants and characteristics of method-switching in self-harm episodes presenting to the general hospital. METHODS: The pattern of repeated self-harm was established from over 33,000 consecutive self-harm episodes in a multicentre English cohort, categorising self-harm methods as poisoning, cutting, other injury, and combined methods. RESULTS: Over an average of 30 months of follow-up, 23% of people repeated self-harm and one-third of them switched method, often rapidly, and especially where the person was male, younger, or had self-harmed previously. Self-poisoning was far less likely than other methods to lead on to switching. LIMITATIONS: Self-harm episodes that do not lead to hospital attendance are not included in these findings but people who self-harmed and went to hospital but were not admitted from the emergency department to the general hospital, or did not receive designated psychosocial assessment are included. People in the study were a mix of prevalent as well as incident cases. CONCLUSIONS: Method of self-harm is fluctuating and unpredictable. Clinicians should avoid false assumptions about people׳s risks or needs based simply on the method of harm

Molecular determinants of avoidance and inhibition of Pseudomonas aeruginosa MexB efflux pump

: Transporters of the resistance-nodulation-cell division (RND) superfamily of proteins are the dominant multidrug efflux power of Gram-negative bacteria. The major RND efflux pump of Pseudomonas aeruginosa is MexAB-OprM, in which the inner membrane transporter MexB is responsible for the recognition and binding of compounds. The high importance of this pump in clinical antibiotic resistance made it a subject of intense investigations and a promising target for the discovery of efflux pump inhibitors. This study is focused on a series of peptidomimetic compounds developed as effective inhibitors of MexAB-OprM. We performed multi-copy molecular dynamics simulations, machine-learning (ML) analyses, and site-directed mutagenesis of MexB to investigate interactions of MexB with representatives of efflux avoiders, substrates, and inhibitors. The analysis of both direct and water-mediated protein-ligand interactions revealed characteristic patterns for each class, highlighting significant differences between them. We found that efflux avoiders poorly interact with the access binding site of MexB, and inhibition engages amino acid residues that are not directly involved in binding and transport of substrates. In agreement, machine-learning models selected different residues predictive of MexB substrates and inhibitors. The differences in interactions were further validated by site-directed mutagenesis. We conclude that the substrate translocation and inhibition pathways of MexB split at the interface (between the main putative binding sites) and at the deep binding pocket and that interactions outside of the hydrophobic patch contribute to the inhibition of MexB. This molecular-level information could help in the rational design of new inhibitors and antibiotics less susceptible to the efflux mechanism. IMPORTANCE Multidrug transporters recognize and expel from cells a broad range of ligands including their own inhibitors. The difference between the substrate translocation and inhibition routes remains unclear. In this study, machine learning and computational and experimental approaches were used to understand dynamics of MexB interactions with its ligands. Our results show that some ligands engage a certain combination of polar and charged residues in MexB binding sites to be effectively expelled into the exit funnel, whereas others engage aromatic and hydrophobic residues that slow down or hinder the next step in the transporter cycle. These findings suggest that all MexB ligands fit into this substrate-inhibitor spectrum depending on their physico-chemical structures and properties

The psychology of containment: mis/representing emotional and behavioural difficulties in Australian schools

The number of students in special schools has increased at a rapid rate in some Australian states, due in part to increased enrolment under the categories of emotional disturbance (ED) and behaviour disorder (BD). Nonetheless, diagnostic distinctions between ED and BD are unclear. Moreover, despite international findings that students with particular backgrounds are over-represented in special schools, little is known about the backgrounds of students entering such settings in Australia. This study examined the government school enrolment data from New South Wales, the most populous of the Australian states. Linear and quadratic trends were used to describe the numbers and ages of students enrolled in special schools in the ED and BD categories. Changes between 1997 and 2007 were observed. Results showed an over-representation of boys that increased across the decade and a different pattern across age for boys and girls. Consistent with international findings, these results indicate that trends in special school placements are unrelated to disability prevalence in the population. Rather, it is suggested that schools act to preserve time and resources for others by removing their more challenging students: most typically, boys

Perceived academic performance as an indicator of risk of attempted suicide in young adolescents

This study investigated perceived academic performance and self-reported suicidal behavior in adolescents (n=2,596), mean age 13 years, from 27 South Australian high schools. Groups perceiving their academic performance as failing, below average, average and above average were significantly different on measures of self-esteem, locus of control, depressive symptoms, suicidal thoughts, plans, threats, deliberate self-injury, and suicide attempts. Multivariate logistic regression analyses revealed that failing academic performance (compared to above average) is associated with a fivefold increased likelihood of a suicide attempt, controlling for self-esteem, locus of control and depressive symptoms. Teachers should note that a student presenting with low selfesteem, depressed mood and perceptions of failure may be at increased risk for suicidal thoughts and behaviors, and need referral for clinical assessment

Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts

Peer reviewe

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies