Lessons from studies of medication reduction in psychosis: giving participants accurate information about risk in psychiatric research trials.

All research needs ethical regulation, which is institutionalized in research ethics committees. The patient information sheet, approved by a research ethics committee, sets out what patients need to know to make an informed choice about research participation. However, guidance from research ethics committees is much less explicit about risk communication. In this commentary, the balance of risk in the patient information sheets from protocols of 2 randomized controlled trials (RCTs) of medication reduction in psychosis was compared with numbers needed to treat and harm from the literature. The patient information sheet omitted risk of excess death and incomplete recovery following relapse, and overestimated the anticipated benefits. All of these risks were demonstrated in the published results of 1 of the 2 RCTs. Quantifying and tabulating risk might improve patient information sheets.

Charge Inversion of Mono- and Dianions to Cations via Triply Charged Metal Complexes: Application to Lipid Mixtures.

Electrospray ionization (ESI) of mixtures can give rise to ions with different masses and charges with overlapping mass-to-charge (m/z) ratios. Such a scenario can be particularly problematic for the detection of low-abundance species in the presence of more highly abundant mixture components. For example, negative mode ESI of polar lipid extracts can result in highly abundant singly charged glyerophospholipids (GPLs), such as phosphatidylethanolamines (PE) and phosphatidylglycerols (PG), that can obscure much less abundant cardiolipins (CLs), which are complex phospholipids with masses roughly double those of GPLs that mostly form doubly charged anions. Despite their low relative abundance, CLs are lipidome components that perform vital biological functions. To facilitate the study of CLs in lipid mixtures without resorting to offline or online separations, we have developed a gas-phase approach employing ion/ion reactions to charge invert anionic lipid species using a trivalent metal-complex. Specifically, ytterbium(III) is shown to readily complex with three neutral ligands, N,N,N',N'-tetra-2-ethylhexyl diglycolamide (TEHDGA), to form [Yb(TEHDGA3)]3+ using ESI. Herein, we describe pilot studies to evaluate [Yb(TEHDGA)3]3+ as an ion/ion reagent to allow for chemical separation of doubly and singly charged anions, using lipid mixtures as examples, without neutralizing ions of either charge state.

Valet Parking for Protein Ion Charge State Concentration: Ion/Molecule Reactions in Linear Ion Traps.

There are several analytical applications in which it is desirable to concentrate analyte ions generated over a range of charge states into a single charge state. This has been demonstrated in the gas phase via ion/ion reactions in conjunction with a technique termed ion parking, which can be implemented in electrodynamic ion traps. Ion parking depends upon the selective inhibition of the reaction of a selected charge state or charge states. In this work, we demonstrate a similar charge state concentration effect using ion/molecule reactions rather than ion/ion reactions. The rates of ion/molecule reactions cannot be affected in the manner used in conventional ion parking. Rather, to inhibit the progression of ion/molecule proton transfer reactions, the product ions must be removed from the reaction cell as they are formed and transferred to an ion trap where no reactions occur. This is accomplished here with mass-selective axial ejection (MSAE) from one linear ion trap to another. The application of MSAE to inhibit ion/molecule reactions is referred to as "valet parking" as it entails the transport of the ions of interest to a remote location for storage. Valet parking is demonstrated using model proteins to concentrate ion signal dispersed over multiple charge states into largely one charge state. Additionally, it has been applied to a simple two-protein mixture of cytochrome c and myoglobin.

Generating Fatty Acid Profiles in the Gas Phase: Fatty Acid Identification and Relative Quantitation Using Ion/Ion Charge Inversion Chemistry.

Representing the most fundamental lipid class, fatty acids (FA) play vital biological roles serving as energy sources, cellular signaling molecules, and key architectural components of complex lipids. Direct infusion electrospray ionization spectrometry, also known as shotgun lipidomics, has emerged as a rapid and powerful toolbox for lipid analysis. While shotgun lipidomics can be a sensitive approach to FA detection, the diverse molecular structure of FA presents challenges for unambiguous identification and the relative quantification of isomeric contributors. In particular, pinpointing double bond position(s) in unsaturated FA and determining the relative contribution of double bond isomers has limited the application of the shotgun approach. Recently, we reported the use of gas-phase ion/ion reactions to facilitate the identification of FA. Briefly, singly deprotonated FA anions undergo charge inversion when reacted in the gas phase with tris-phenanthroline magnesium dications by forming [FA - H + MgPhen]+ complex ions. These charge-inverted FA complex cations fragment upon ion-trap collision-induced dissociation (CID) to generate product ion spectra unique to individual FA isomers. Herein, we report the development of a mass spectral library comprised of [FA - H + MgPhen]+ product ion spectra. The developed FA library permits confident FA identification, including polyunsaturated FA isomers. Furthermore, we demonstrate the ability to determine relative contributions of isomeric FA using multiple linear regression analysis paired with gas-phase ion/ion reactions. We successfully applied the presented method to generate a FA profile for bovine liver phospholipidome based entirely on gas-phase chemistries.

Gas-Phase Sequencing of Cyclotides: Introduction of Selective Ring Opening at Dehydroalanine via Ion/Ion Reaction.

The gas-phase linearization of cyclotides via site-selective ring opening at dehydroalanine residues and its application to cyclotide sequencing is presented. This strategy relies on the ability to incorporate dehydroalanine into macrocyclic peptide ions, which is easily accomplished through an ion/ion reaction. Triply protonated cyclotide cations are transformed into radical cations via ion/ion reaction with the sulfate radical anion. Subsequent activation of the cyclotide radical cation generates dehydroalanine at a single cysteine residue, which is easily identified by the odd-electron loss of ·SCH2CONH2. The presence of dehydroalanine in cyclotides provides a site-selective ring-opening pathway that, in turn, generates linear cyclotide analogues in the gas phase. Unlike cyclic variants, product ions derived from the linear peptides provide rich sequence information. The sequencing capability of this strategy is demonstrated with four known cyclotides found in Viola inconspicua, where, in each case, greater than 93% sequence coverage was observed. Furthermore, the utility of this method is highlighted by the partial de novo sequencing of an unknown cyclotide with much greater sequence coverage than that obtained with a conventional Glu-C digestion approach. This method is particularly well-suited for cyclotide species that are not abundant enough to characterize with traditional methods.

Gas-Phase Ion/Ion Reactions Involving Tris-Phenanthroline Alkaline Earth Metal Complexes as Charge Inversion Reagents for the Identification of Fatty Acids.

Fatty acids (FA) play vital biological roles as energy sources, signaling molecules and key building blocks of complex lipids in cell membranes. Modifications to FA structure and composition are associated with the onset and progression of a number of chronic diseases. Consequently, the sensitive detection and unambiguous structure elucidation of FA is integral to the advancement of biomedical sciences. Recent advances in FA analysis have taken advantage of wet chemical derivatization to enhance detection and drive unique fragmentation in tandem mass spectrometry protocols. Here, we significantly further this approach through demonstrating gas-phase charge inversion of singly deprotonated FA ions, [M - H]-, using doubly charged tris-phenanthroline alkaline earth metal complexes, [Cat(Phen)3]2+ (Cat = Mg2+, Ca2+, Sr2+, or Ba2+). Metal cationized FA, [M - H + Cat]+ are obtained after the gas-phase ion/ion reaction. Low-energy collision-induced dissociation (CID) of the [M - H + Cat]+ cations facilitates double bond localization for a variety of monounsaturated and polyunsaturated FAs. Ultimately, detailed characterization presented unambiguous distinction among FA double bond positional isomers, such as n-3 and n-6 isomers. The method was successfully used to identify the FA profile of corn oil, including double bond localization for unsaturated FAs present.

Novel Peptide Ion Chemistry Associated with Gold (I) Cationization: Preferential Cleavage at Lysine Residues.

Novel peptide ion chemistry associated with gold (I) cationization is described. Cation switching ion/ion reactions, involving gold dichloride reagent anion, [AuCl2]-, are used to replace protons with a gold (I) cation on a polypeptide. Collision induced dissociation of aurated, lysine-containing peptides results in the elimination of gold hydride and ammonia, generating a [M - H - NH3]+ oxidized species. The oxidized product is likely a cyclic iminium ion. This fragmentation pathway is specific to lysine side-chains as polypeptides containing arginine or histidine in the absence of lysine were not observed to form the oxidized product. While oxidation can occur on N-terminal, internal, and C-terminal lysine residues, it is observed to a lesser extent at lysines found at internal and C-terminal positions. However, isolation and subsequent activation of the [M - H - NH3]+ species derived from the internal or C-terminal positions results in preferential cleavage N-terminal to the oxidized lysine residue. This chemistry has been demonstrated using a variety of model peptides and has also been applied to the analysis of melittin.

Editorial Perspective: The new Special Educational Needs and Disability Code of Practice-an opportunity for school mental health services?

The 2014 English Special Educational Needs and Disability (SEND) Code of Practice, a policy framework for delivery of a range of services including Schools Mental Health Services (SMHS), is considered in the context of international research on the delivery of mental health services in schools. Effective interventions have been reported in poor and middle-income countries, whereas there is less information about routine services in high-income societies, and what they report are equivocal outcomes. In England and the United States, problems with acceptability of routine mental health assessment, together with conflict over resource allocation significantly impede both effectiveness and acceptability. The new Code has been specifically written to support better engagement between Education and Mental Health, but piloting suggests that this has not yet happened. Proactive multiagency planning within the framework of the Code, linked to explicit work on organizational transformation, could provide an effective and acceptable Schools Mental Health Service, with legal protection from subsequent deleterious policy and funding changes. Explicit recommendations for using the Code are appended.

Psychiatry in public mental health: easy to say, but harder to achieve.

Psychiatrists are currently ill equipped to exploit the growing interest in public mental health. Training, service infrastructure and organisational links are deficient, which will impede population-based interventions. However, the potential benefits make correcting this worthwhile.

Dissecting the Heterogeneous Glycan Profiles of Recombinant Coronavirus Spike Proteins with Individual Ion Mass Spectrometry.

Surface-embedded glycoproteins, such as the spike protein trimers of coronaviruses MERS, SARS-CoV, and SARS-CoV-2, play a key role in viral function and are the target antigen for many vaccines. However, their significant glycan heterogeneity poses an analytical challenge. Here, we utilized individual ion mass spectrometry (I2MS), a multiplexed charge detection measurement with similarities to charge detection mass spectrometry (CDMS), in which a commercially available Orbitrap analyzer is used to directly produce mass profiles of these heterogeneous coronavirus spike protein trimers under native-like conditions. Analysis by I2MS shows that glycosylation contributes to the molecular mass of each protein trimer more significantly than expected by bottom-up techniques, highlighting the importance of obtaining complementary intact mass information when characterizing glycosylation of such heterogeneous proteins. Enzymatic dissection to remove sialic acid or N-linked glycans demonstrates that I2MS can be used to better understand the glycan profile from a native viewpoint. Deglycosylation of N-glycans followed by I2MS analysis indicates that the SARS-CoV-2 spike protein trimer contains glycans that are more difficult to remove than its MERS and SARS-CoV counterparts, and these differences are correlated with solvent accessibility. I2MS technology enables characterization of protein mass and intact glycan profile and is orthogonal to traditional mass analysis methods such as size exclusion chromatography-multiangle light scattering (SEC-MALS) and field flow fractionation-multiangle light scattering (FFF-MALS). An added advantage of I2MS is low sample use, requiring 100-fold less than other methodologies. This work highlights how I2MS technology can enable efficient development of vaccines and therapeutics for pharmaceutical development.

Off the RADAR; questions regarding the trial protocol of a randomised controlled trial of antipsychotic reduction and discontinuation.

The randomised controlled trial of antipsychotic reduction and discontinuation addresses essential questions with regard to continued use of antipsychotics in schizophrenia, pertaining to social functioning and continued antipsychotic use. However, significant methodological issues stated in the trial protocol have the potential to confound interpretation of any findings. These include use of a non-blinded outcome measure, treatment as usual comparator and possible sample size issues.

Nurse-delivered and doctor-delivered care in an attention deficit hyperactivity disorder follow-up clinic: a comparative study using propensity score matching.

BACKGROUND: Nurse prescribers may be a cost-effective alternative to doctors in managing attention deficit hyperactivity disorder, but to date there has been no study of their relative effectiveness, and there are concerns about their usage. We therefore undertook a direct comparison of nurse-delivered and doctor-delivered attention deficit hyperactivity disorder care in an attention deficit hyperactivity disorder follow-up clinic. METHOD: Seventy patients were identified between February 2005 and September 2006, 36 managed by an attention deficit hyperactivity disorder specialist nurse, 34 by doctors. Average age at referral was 7·1 years; their duration in the service was 5·5 years. Outcomes included changes since admission in the predicted diagnostic category from Strengths and Difficulties Questionnaire scores, the Commission for Health Improvement patient satisfaction questionnaire and a clinic-developed side-effect questionnaire. Propensity score matching and multiple imputation were used to manage selection bias and missing data. The impact of nurse management was estimated using the Average Treatment effect on the Treated statistic with 95% confidence intervals. RESULTS: All the Average Treatment effects on the Treated approximated zero. Inspecting the confidence intervals suggested that there was, at worst, 2·5% risk of nurses underidentifying emotional disorders with respect to doctors. CONCLUSIONS: There seems little to distinguish the quality of doctor- or nurse-delivered care in ordinary attention deficit hyperactivity disorder follow-up clinics. There seems no clinical impediment to using nurse prescribers to increase clinic capacity. It may be useful to add structured assessment of mood difficulties at follow-up if nurse prescribers are used.

Introducing the new culture section of BJPsych Bulletin.

This editorial launches the new culture section in the journal. Without any unchallengeable definition of 'culture', potential contributors may consider submissions under four headings: the arts and humanities relating to practice; regulatory culture; becoming a cultured practitioner; and psychiatry's cultural context. A new article type, 'Cultural reflections', has been created, and submissions may reflect any appropriate methodology, including those from the arts. Peer review (from methodologies outside psychiatry if appropriate) will assure quality. Our objectives are to establish BJPsych Bulletin as the 'journal of record' for cultural studies relevant to psychiatric service delivery and demonstrate equivalent quality between them and scientific studies.

Is COVID-19 changing psychiatry?

Two articles on the potential impact of the current coronavirus pandemic on psychiatry reveal agreement on many points, but opposing positions on the methodology, philosophy and politics of psychiatry's response. This points to the need for psychiatry to audit its approach to evidence when agility is required.

The Impact of Governmental Guidance on the Time Taken to Receive a Prescription for Medication for ADHD in England.

The National Health Service in England has deployed guidance from the National Institute of Clinical Excellence (NICE) to assist practitioners in the diagnosis and treatment of Attention Deficit Hyperactivity Disorder (ADHD) but, though the number of prescriptions has risen since its introduction, the impact of the guidance on prescribing practice has not been studied. Clinic records of all open ADHD cases (296) in three English Child and Adolescent Mental Health Services were examined. The time from referral to either prescription or data collection was extracted for a survival analysis. It was hypothesised that NICE guidance, clinic, patient and referral characteristics would all influence the speed and likelihood of prescription. Following the introduction of NICE guidance, the median time to start prescribing medication fell from 1262 to 526 days: the minimum realistic time to complete a routine assessment was approximately 70 days. Overall, 70% were prescribed medication. Most of the wait was after face-to-face appointments at the clinic had been initiated. Waiting times differed between clinics and shorter waits were likely for older children and those referred from an educational source. While the introduction of NICE guidance has increased the rate of prescription, the time taken before prescription suggests that the tendency in England is still to postpone treatment by medication. The reasons for this require further research.

Development of dried blood spot quality control materials for adenosine deaminase severe combined immunodeficiency and LC-MS/MS method for their characterization.

Adenosine deaminase severe combined immunodeficiency (ADA-SCID) is an autosomal recessive disorder in which a lack of ADA enzyme prevents the maturation of T- and B-cells; early intervention is crucial for restoring immune function in affected neonates. ADA is responsible for purine metabolism and-in its absence-adenosine, deoxyadenosine, and S-adenosylhomocysteine build up and can be detected in the blood. Preparing dried blood spot (DBS) quality control (QC) materials for these analytes is challenging because enrichments are quickly metabolized by the endogenous ADA in normal donor blood. Adding an inhibitor, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), has been previously reported to minimize enzyme activity, although this adds additional cost and complexity. We describe an alternative method using unnatural L-enantiomer nucleosides (L-adenosine and 2'-deoxy-L-adenosine) which eliminates the need for enzyme inhibition. We also present a novel method for characterization of the materials using liquid chromatography mass spectrometry to quantify the analytes of interest.

Exploring the clinical utility of the Development And Well-Being Assessment (DAWBA) in the detection of hyperkinetic disorders and associated diagnoses in clinical practice.

BACKGROUND: The clinical diagnosis of ADHD is time-consuming and error-prone. Secondary care referral results in long waiting times, but primary care staff may not provide reliable diagnoses. The Development And Well-Being Assessment (DAWBA) is a standardised assessment for common child mental health problems, including attention deficit/hyperactivity disorder (ADHD), which can be rapidly scored by skilled specialist clinicians, who may be remote from the interview, thus avoiding referral. METHOD: A representative clinic sample of routine cases suspected of ADHD underwent an assessment which included the DAWBA alongside a confirmatory assessment with a skilled clinician. Another clinician provided DAWBA-based diagnoses blind to the clinic view. Bayesian statistical modelling was used to include clinic diagnostic uncertainty in the analyses. RESULTS: Eighty-four cases were assessed. For ADHD, the predictive value of a positive or negative DAWBA diagnosis was greater than .8, with negligible bias. Non-hyperkinetic behaviour disorders had higher, emotional and autistic disorders lower predictive values, though all greater than .75: there was, however, evidence of bias. CONCLUSIONS: Diagnoses of ADHD based on senior clinician review of the DAWBA completed by parents, teachers and young people aged 11 plus may be sufficiently accurate to permit clinical diagnosis without direct patient contact by the diagnosing clinician. This could improve access to accurate diagnoses of ADHD in primary care while freeing up senior clinicians to focus on complex and refractory cases in secondary care.