Emergency department presentations with suicide and self-harm ideation: a missed opportunity for intervention?

AIMS: Suicidal ideation constitutes a central element of most theories of suicide and is the defining facet separating suicide from other causes of death such as accidents. However, despite a high worldwide prevalence, most research has focused on suicidal behaviours, such as completed suicide and suicide attempts, while the greater proportion who experienced ideation, which frequently precedes suicidal behaviour, have received much less attention. This study aims to examine the characteristics of those presenting to EDs with suicidal ideation and quantify the associated risk of suicide and other causes of death. METHODS: Retrospective cohort study was performed based on population-wide health administration data linked to data from the Northern Ireland Registry of Self-Harm and centrally held mortality records from April 2012 to December 2019. Mortality data, coded as suicide, all-external causes and all-cause mortality were analysed using Cox proportional hazards. Additional cause-specific analyses included accidental deaths, deaths from natural causes and drug and alcohol-related causes. RESULTS: There were 1,662,118 individuals aged over 10 years, of whom 15,267 presented to the ED with ideation during the study period. Individuals with ideation had a 10-fold increased risk of death from suicide (hazard ratio [HRadj] = 10.84, 95% confidence interval [CI] 9.18, 12.80) and from all-external causes (HRadj = 10.65, 95% CI 9.66, 11.74) and a threefold risk of death from all-causes (HRadj = 3.01, 95% CI 2.84, 3.20). Further cause-specific analyses indicated that risk of accidental death (HRadj = 8.24, 95% CI 6.29, 10.81), drug-related (HRadj = 15.17, 95% CI 11.36, 20.26) and alcohol-related (HRadj = 10.57, 95% CI 9.07, 12.31) has also significantly increased. There were few socio-demographic and economic characteristics that would identify which of these patients are most at risk of suicide or other causes of death. CONCLUSIONS: Identifying people with suicidal ideation is recognized to be both important but difficult in practice; this study shows that presentations to EDs with self-harm or suicide ideation represent an important potential intervention point for this hard-to-reach vulnerable population. However, and unlike individuals presenting with self-harm, clinical guidelines for the management and recommended best practice and care of these individuals are lacking. Whilst suicide prevention may be the primary focus of interventions aimed at those experiencing self-harm and suicide ideation, death from other preventable causes, especially substance misuse, should also be a cause of concern.

Molecular and cellular signatures of human vaccine adjuvants.

Oil-in-water emulsions are potent human adjuvants used for effective pandemic influenza vaccines; however, their mechanism of action is still unknown. By combining microarray and immunofluorescence analysis, we monitored the effects of the adjuvants MF59 oil-in-water emulsion, CpG, and alum in the mouse muscle. MF59 induced a time-dependent change in the expression of 891 genes, whereas CpG and alum regulated 387 and 312 genes, respectively. All adjuvants modulated a common set of 168 genes and promoted antigen-presenting cell recruitment. MF59 was the stronger inducer of cytokines, cytokine receptors, adhesion molecules involved in leukocyte migration, and antigen-presentation genes. In addition, MF59 triggered a more rapid influx of CD11b+ blood cells compared with other adjuvants. The early biomarkers selected by microarray, JunB and Ptx3, were used to identify skeletal muscle as a direct target of MF59. We propose that oil-in-water emulsions are the most efficient human vaccine adjuvants, because they induce an early and strong immunocompetent environment at the injection site by targeting muscle cells.

Risk of repetition and subsequent self-harm following presentation to hospital with suicidal ideation: A longitudinal registry study.

BACKGROUND: Few studies have focused on those who present to hospital with suicidal thoughts (suicidal ideation). The aim of this study was to establish the risk of repeat presentation to hospital following suicidal ideation and to identify factors which were associated with further ideation or subsequent self-harm. METHODS: Data were obtained from the Northern Ireland Registry of Self-harm. Risk of repeat presentation following hospital-presenting ideation was analysed using Kaplan Meier analyses, specifically cox proportional hazard models. FINDINGS: During the period April 2014 to March 2019, a total of 14,695 presentations to hospital due to suicidal ideation were made in Northern Ireland. The cumulative incidence of repeat presentation to hospital was 40·5% within five years, with an 18·3% risk of subsequent self-harm. Previous ideation had the strongest association with repeat presentation. There was evidence of recidivism considering further ideation, with an increased risk according to number of previous presentations. In contrast, risk of subsequent self-harm was highest after the first or second presentation. Male gender and alcohol were associated with further ideation, while females and young people were more likely to re-present with self-harm. INTERPRETATION: The findings indicate that individuals who present to hospital with suicidal ideation are at risk of repeat presentation and future self-harm, however clinical guidelines do not specifically address hospital-presenting ideation. The transition from ideation to suicidal behaviour is important to consider and research could inform effective screening and early intervention measures. ROLE OF FUNDING: The Northern Ireland Registry of Self-harm is funded by the Public Health Agency, Northern Ireland.

Advances in vaccine adjuvants.

Currently, aluminum salts and MF59 are the only vaccine adjuvants approved for human use. With the development of new-generation vaccines (including recombinant subunit and mucosal vaccines) that are less immunogenic, the search for more potent vaccine adjuvants has intensified. Of the novel compounds recently evaluated in human trials, immunostimulatory molecules such as the lipopolysaccharide derived MPL and the saponin derivative QS21 appear most promising, although doubts have been raised as to their safety in humans. Preclinical work with particulate adjuvants, such as the MF59 microemulsion and lipid-particle immune-stimulating complexes (Iscoms), suggest that these molecules are also potent elicitors of humoral and cellular immune responses. In addition, preclinical data on CpG oligonucleotides appear to be encouraging, particularly with respect to their ability to selectively manipulate immune responses. While all these adjuvants show promise, further work is needed to better define the mechanisms of adjuvant action. Ultimately, the development of more potent adjuvants may allow vaccines to be used as therapeutic, rather than prophylactic, agents.

Delivery systems and adjuvants for oral vaccines.

The oral route is the ideal means of delivering prophylactic and therapeutic vaccines, offering significant advantages over systemic delivery. Most notably, oral delivery is associated with simple administration and improved safety. In addition, unlike systemic immunisation, oral delivery can induce mucosal immune responses. However, the oral route of vaccine delivery is the most difficult because of the numerous barriers posed by the gastrointestinal tract. To facilitate effective immunisation with peptide and protein vaccines, antigens must be protected, uptake enhanced and the innate immune response activated. Numerous delivery systems and adjuvants have been evaluated for oral vaccine delivery, including live vectors, inert particles and bacterial toxins. Although developments in oral vaccines have been disappointing so far, in terms of the generation of products, the availability of a range of novel delivery systems offers much greater hope for the future development of improved oral vaccines.

Targeting of drugs and vaccines to the gut.

Targeted delivery to the gastrointestinal tract requires a multi-disciplinary approach to research involving contributions from polymer and material scientists, gastroenterologists, pharmaceutical scientists and technologists. Intestinal delivery is important not only for drugs that act locally, but also for those with systemic activity. In particular, there is considerable interest in the oral delivery of peptides and it is felt that the colon may provide an advantageous absorption site for such molecules. The different targeting mechanisms available to the pharmaceutical scientist to provide site-specific delivery in the gastrointestinal tract will be critically assessed. Delivery systems and targeting agents, which are being developed for the delivery of drugs, may also be exploited for the delivery of vaccines, since many of the delivery problems are common to both areas. Recent developments in the design of oral antigen formulations will be discussed in this review.

Interferons impair early transgene expression by adenovirus-mediated gene transfer in muscle cells.

Recombinant adenovirus (AVR) promises to be an efficient vector in gene therapy for neuromuscular diseases, but in preclinical experiments the expression of therapeutic genes is shorter lived in immunocompetent animals than in immunocompromised hosts. Interferons (IFN), which are known to have a role both in early antiviral activity and in late cytotoxic immunoreaction against the virus or transduced cells, may influence the efficiency of gene transfer. In this study we investigated the role of IFNs in determining the efficiency of gene transfer by AVR. AVRs expressing beta-galactosidase (beta-gal) from either a cytomegalovirus (CMV) or a troponin-I promoter were used. Muscle cells were infected by AVR after exposure to various IFNs. The alphaIFN treatment significantly reduced (up to fivefold) the CMV promoter-driven gene expression in muscle cells in vitro and in immature muscles in vivo, while the least effective inhibitor was betaIFN. The decrease in gene expression by IFNs was more pronounced with the CMV-driven transgene than troponin-I promoter-driven one and was due to a decrease in transcript level. Intrinsic IFNs that are triggered by AVR administration can decrease the efficiency of gene transfer in muscle cells. Therefore the use of muscle specific promoters in AVR and/or IFN inhibitory agents will likely improve the prospects of effective gene therapy by AVR.

A two-step fluorinase enzyme mediated (18)F labelling of an RGD peptide for positron emission tomography.

A two-step radiolabelling protocol of a cancer relevant cRGD peptide is described where the fluorinase enzyme is used to catalyse a transhalogenation reaction to generate [(18)F]-5'-fluoro-5'-deoxy-2-ethynyladenosine, [(18)F]FDEA, followed by a 'click' reaction to an azide tethered cRGD peptide. This protocol offers efficient radiolabelling of a biologically relevant peptide construct in water at pH 7.8, 37 °C in 2 hours, which was metabolically stable in rats and retained high affinity for αVß3 integrin.

Microparticles for intranasal immunization.

Of the several routes available for mucosal immunization, the nasal route is particularly attractive because of ease of administration and the induction of potent immune responses, particularly in the respiratory and genitourinary tracts. However, adjuvants and delivery systems are required to enhance immune responses following nasal immunization. This review focuses on the use of microparticles as adjuvants and delivery systems for protein and DNA vaccines for nasal immunization. In particular we discuss our own work on poly(lactide co-glycolide) (PLG) microparticles with entrapped protein or adsorbed DNA as a vaccine delivery system. The possible mechanisms involved in the enhancement of immune responses through the use of DNA adsorbed onto PLG microparticles are also discussed.

Absorption of peptides and proteins from the respiratory tract and the potential for development of locally administered vaccine.

Since the appearance of the first therapeutic active peptides and proteins produced by genetic engineering, there has been an ever-increasing demand to be able to deliver these drugs by routes other than the parenteral. For most drugs the need for alternative delivery systems is due to short-half lives in the bloodstream, large extents of first pass metabolism, or the possibility of obtaining endogenous-like plasma profiles. A wide variety of drugs have now been tested for bioavailability after respiratory, especially intranasal, administration. A small range of drugs (such as propranolol and progesterone) appears to be absorbed effectively via the nasal route and shows bioavailabilities comparable to the intravenous route. However, most drugs shows a much lower degree of absorption. The present review discusses the critical steps that have to be considered when attempting to deliver drugs effectively via the nasal and pulmonary routes and how it is possible by suitable formulation of delivery systems to overcome some of the most important barriers to drug absorption. Furthermore, the immunological responses to respiratory absorption of exogenous peptides and proteins and the potential for development of locally administered vaccines are reviewed.

Intestinal absorption of proteins and macromolecules and the immunological response.

Progress in the field of biotechnology has renewed interest in the oral delivery of macromolecules, in particular, proteins and peptides. While small quantities of proteins may be absorbed from the gastrointestinal tract intact, enzymatic degradation and poor absorption have historically limited protein administration to the parenteral route. By consideration of the mechanisms of macromolecular absorption from the gut, it may be possible to exploit physiological processes to promote protein uptake. However, the response of the immune system to intestinally absorbed antigen may limit the oral delivery of proteins but could provide an attractive alternative to parenteral immunization.

Recent developments in vaccine delivery systems.

New generation vaccines, particularly those based on recombinant proteins and DNA, are likely to be less reactogenic than traditional vaccines, but are also less immunogenic. Therefore, there is an urgent need for the development of new and improved vaccine adjuvants. Adjuvants can be broadly separated into two classes, based on their principal mechanisms of action; vaccine delivery systems and 'immunostimulatory adjuvants'. Vaccine delivery systems are generally particulate e.g. emulsions, microparticles, iscoms and liposomes, and mainly function to target associated antigens into antigen presenting cells (APC), including macrophages and dendritic cells. This review will focus on recent developments in vaccine delivery systems. Immunostimulatory adjuvants are predominantly derived from pathogens and often represent pathogen associated molecular patterns (PAMP) e.g. LPS, MPL, CpG DNA, which activate cells of the innate immune system. Once activated, cells of innate immunity drive and focus the acquired immune response. In some studies, delivery systems and immunostimulatory agents have been combined for more effective delivery of the immunostimulatory adjuvant into APC. A rational approach to the development of new and more effective vaccine adjuvants will require much further work to better define the mechanisms of action of existing adjuvants. The discovery of more potent adjuvants may allow the development of vaccines against infectious agents such as HIV which do not naturally elicit protective immunity. New adjuvants and delivery system combinations may also allow vaccines to be delivered mucosally.

Recent developments in adjuvants for vaccines against infectious diseases.

New generation vaccines, particularly those based on recombinant proteins and DNA, are likely to be less reactogenic than traditional vaccines, but are also less immunogenic. Therefore, there is an urgent need for the development of new and improved vaccine adjuvants. Adjuvants can be broadly separated into two classes, based on their principal mechanisms of action; vaccine delivery systems and 'immunostimulatory adjuvants'. Vaccine delivery systems are generally particulate e.g. emulsions, microparticles, iscoms and liposomes, and mainly function to target associated antigens into antigen presenting cells (APC). In contrast, immunostimulatory adjuvants are predominantly derived from pathogens and often represent pathogen associated molecular patterns (PAMP) e.g. LPS, MPL, CpG DNA, which activate cells of the innate immune system. Once activated, cells of innate immunity drive and focus the acquired immune response. In some studies, delivery systems and immunostimulatory agents have been combined to prepare adjuvant delivery systems, which are designed for more effective delivery of the immunostimulatory adjuvant into APC. Recent progress in innate immunity is beginning to yield insight into the initiation of immune responses and the ways in which immunostimulatory adjuvants may enhance this process. However, a rational approach to the development of new and more effective vaccine adjuvants will require much further work to better define the mechanisms of action of existing adjuvants. The discovery of more potent adjuvants may allow the development of vaccines against infectious agents such as HIV which do not naturally elicit protective immunity. New adjuvants may also allow vaccines to be delivered mucosally.

Mice are protected against Bordetella pertussis infection by intra-nasal immunization with filamentous haemagglutinin.

Intra-nasal immunization of mice with purified Bordetella pertussis filamentous haemagglutinin (FHA) or a crude cell sonicate was shown to protect against subsequent B. pertussis aerosol challenge. Immunization with FHA was found to be the most effective and resulted in complete clearance of the bacterial infection from the lungs within 14 days. Serum IgG and lung IgA anti-FHA antibodies were detectable within 4 weeks of the first immunization and anamnestic responses were seen following secondary immunization and subsequent challenge with B. pertussis. Nasal administration of pertussis antigens is a route which induces good systemic serum, as well as local secretory, antibody responses.

A novel bioadhesive intranasal delivery system for inactivated influenza vaccines.

The aim of the current studies was to evaluate a bioadhesive delivery system for intranasal administration of a flu vaccine, in combination with a mucosal adjuvant (LTK63). A commercially available influenza vaccine, containing hemagglutinin (HA) from influenza/A Johannesberg H1N1 1996, and LTK63 or LTR72 adjuvants, which are genetically detoxified derivatives of heat labile enterotoxin from Escherichia coli, were administered IN in a bioadhesive delivery system, which comprised esterified hyaluronic acid (HYAFF) microspheres, to mice, rabbits and micro-pigs at days 0 and 28. For comparison, additional groups of animals were immunized intranasally with the HA vaccine alone, with soluble HA+LTK63, or IM with HA. In all three species, the groups of animals receiving IN immunization with the bioadhesive microsphere formulations, including LT mutants, showed significantly enhanced serum IgG responses (P<0.05) and higher hemagglutination inhibition (HI) titers in comparison to the other groups. In addition, the bioadhesive formulation also showed a significantly enhanced nasal wash IgA response (P<0.05). Most encouragingly, in pigs, the bioadhesive microsphere vaccine delivery system induced serum immune responses following IN immunization, which were significantly more potent than those induced by traditional IM immunization at the same vaccine dose (P<0.05).

Controlled release of recombinant insulin-like growth factor from a novel formulation of polylactide-co-glycolide microparticles.

The purpose of the current study was to develop a controlled-release delivery system for recombinant insulin-like growth factor (rhIGF-I). Polylactide-co-glycolide (PLG) microparticles with entrapped rhIGF-I were prepared by a novel emulsion based solvent evaporation process. Microparticles with two loading levels of rhIGF-I were prepared (4 and 20% w/w). The integrity of released rhIGF-I was characterized by RP-HPLC, SDS-PAGE and a bioactivity assay. In vitro and in vivo release profiles of rhIGF-I from these microparticles were also evaluated. Reproducible batches of microparticles with 4% and 20% w/w loading of rhIGF-I were prepared, with excellent encapsulation efficiency (81 and 85% of total protein respectively entrapped). The protein retained integrity after the microencapsulation process as evaluated by RP-HPLC, SDS-PAGE and bioactivity assay. The in vitro profiles exhibited a significant burst release of rhIGF-I (20-30%), followed by controlled release of protein for up to 28 days. A similar level of burst release was observed in vivo, followed by controlled release of protein for 14-18 days. In addition, there was a surprisingly close correlation between in vitro and in vivo release rates. PLG microparticles with entrapped rhIGF-I are a promising delivery system which may allow rhIGF-I to be used for a broad range of therapeutic indications.

Novel anionic microparticles are a potent adjuvant for the induction of cytotoxic T lymphocytes against recombinant p55 gag from HIV-1.

Microparticles with entrapped antigens have recently been shown to possess significant potential as vaccine delivery systems and adjuvants. However, the potential of microparticles as adjuvants has been seriously limited by the common problem of degradation and denaturation of antigens following encapsulation and release. To overcome these problems, we have developed a novel way to use microparticles as adjuvants, by the adsorption of proteins onto their surface. Anionic microparticles were prepared through the inclusion of an anionic detergent, sodium dodecyl sulphate (SDS), in the microparticle preparation process. The anionic microparticles were capable of the efficient and reproducible adsorption of recombinant p55 gag protein from HIV-1. Microparticles with adsorbed p55 were capable of inducing potent cytotoxic T lymphocyte responses in mice following intramuscular immunization. In addition, the microparticles also exhibited a potent adjuvant effect for antibody induction against p55.

Biosynthetic studies on the tropane ring system of the tropane alkaloids from Datura stramonium.

Isotopic labelling experiments have been carried out in Datura stramonium root cultures with the following isotopically labelled precursors; [2H3]- [2-13C, 2H3]-, [1-13C, 18O2]-acetates, 2H2O, [2H3-methyl]-methionine, [2-13C]-phenyllactate, [3-2H]-tropine and [2'-13C, 3-2H]-littorine. The study explored the incorporation of isotope into the tropane ring system of littorine 1 and hyoscyamine 2 and revealed that deuterium from acetate is incorporated only into C-6 and C-7, and not into C-2 and C-4 as previously reported. Oxygen-18 was not retained at a detectable level into the C(3)-O bond from [1-13C, 18O2]-acetate. The intramolecular nature of the rearrangement of littorine 1 to hyoscyamine 2 is revealed again by a labelling study using [2'-13C, 3-2H]-littorine, [2-13C]-phenyllactate and [3-2H]-tropine.

Immunological implications of the use of plant lectins for drug and vaccine targeting to the gastrointestinal tract.

Plant lectins are under consideration as targeting agents to enhance the efficacy of orally administered drugs and vaccines. A significant issue that must be considered is the immunogenicity of these molecules since an immune response to the targeting agent may interfere with its ability to interact with the epithelium. In contrast, the ability of certain lectins to activate the immune system may be exploited in the delivery of vaccines. We previously demonstrated that plant lectins vary widely in their immunogenicity and in particular that mistletoe lectins (ML) I, II and II (MLI, MLII, MLIII) are potent immunogens when administered nasotracheally. Here, we measured immune responses following oral delivery of the MLs and assessed their ability to enhance responses to a co-administered antigen to determine if the molecules possess adjuvant activity. Oral administration of the lectins induced potent lectin-specific systemic and mucosal antibody responses. In addition, each of the three lectins possessed adjuvant activity when delivered orally together with ovalbumin (OVA). The lectins enhanced both serum and mucosal antibody responses to the co-delivered antigen. This shows for the first time that MLI, MLII and MLIII possess adjuvant activity when administered orally and may provide a platform for the generation of effective mucosal adjuvants.