Foot and ankle problems in children and young people: a population-based cohort study.

The aim of this research was to describe the epidemiology, presentation and healthcare use in primary care for foot and ankle problems in children and young people (CYP) across England. We undertook a population-based cohort study using data from the Clinical Practice Research Datalink Aurum database, a database of anonymised electronic health records from general practices across England. Data was accessed for all CYP aged 0-18 years presenting to their general practitioner between January 2015 and December 2021 with a foot and/or ankle problem. Consultation rates were calculated and used to estimate numbers of consultations in an average practice. Hierarchical Poisson regression estimated relative rates of consultations across sociodemographic groups and logistic regression evaluated factors associated with repeat consultations. A total of 416,137 patients had 687,753 foot and ankle events, of which the majority were categorised as "musculoskeletal" (34%) and "unspecified pain" (21%). Rates peaked at 601 consultations per 10,000 patient-years among males aged 10-14 years in 2018. An average practice might observe 132 (95% CI 110 to 155) consultations annually. Odds for repeat consultations were higher among those with pre-existing diagnoses including juvenile arthritis (OR 1.73, 95% CI 1.48 to 2.03).    Conclusions: Consultations for foot and ankle problems were high among CYP, particularly males aged 10 to 14 years. These data can inform service provision to ensure CYP access appropriate health professionals for accurate diagnosis and treatment. What is Known: • Foot and ankle problems can have considerable impact on health-related quality of life in children and young people (CYP). • There is limited data describing the nature and frequency of foot and ankle problems in CYP. What is New: • Foot and ankle consultations were higher in English general practice among CYP aged 10 to 14 years compared to other age groups, and higher among males compared to females. • The high proportion of unspecified diagnoses and repeat consultations suggests there is need for greater integration between general practice and allied health professionals in community-based healthcare settings.

Platelet factor XIII-A regulates platelet function and promotes clot retraction and stability.

Background: Factor XIII (FXIII) is an important proenzyme in the hemostatic system. The plasma-derived enzyme activated FXIII cross-links fibrin fibers within thrombi to increase their mechanical strength and cross-links fibrin to fibrinolytic inhibitors, specifically α2-antiplasmin, to increase resistance to fibrinolysis. We have previously shown that cellular FXIII (factor XIII-A [FXIII-A]), which is abundant in the platelet cytoplasm, is externalized onto the activated membrane and cross-links extracellular substrates. The contribution of cellular FXIII-A to platelet activation and platelet function has not been extensively studied. Objectives: This study aims to identify the role of platelet FXIII-A in platelet function. Methods: We used normal healthy platelets with a cell permeable FXIII inhibitor and platelets from FXIII-deficient patients as a FXIII-free platelet model in a range of platelet function and clotting tests. Results: Our data demonstrate that platelet FXIII-A enhances fibrinogen binding to the platelet surface upon agonist stimulation and improves the binding of platelets to fibrinogen and aggregation under flow in a whole-blood thrombus formation assay. In the absence of FXIII-A, platelets show reduced sensitivity to agonist stimulation, including decreased P-selectin exposure and fibrinogen binding. We show that FXIII-A is involved in platelet spreading where a lack of FXIII-A reduces the ability of platelets to fully spread on fibrinogen and collagen. Our data demonstrate that platelet FXIII-A is important for clot retraction where clots formed in its absence retracted to a lesser extent. Conclusion: Overall, this study shows that platelet FXIII-A functions during thrombus formation by aiding platelet activation and thrombus retraction in addition to its antifibrinolytic roles.

The rate of platelet activation determines thrombus size and structure at arterial shear.

BACKGROUND: The response of platelets to activating stimuli and pharmaceutical agents varies greatly within the normal population. Current platelet function tests are used to measure end-point levels of platelet activation without taking the speed at which platelets activate into account, potentially missing vital metrics to characterize platelet reactivity. OBJECTIVES: To identify variability, to agonists and among individuals, in platelet activation kinetics and assess the impact of this on thrombus formation. METHODS: We have developed a bespoke real-time flow cytometry assay and analysis package to measure the rate of platelet activation over time using 2 parameters of platelet activation, fibrinogen binding and P-selectin exposure. RESULTS: The rate of platelet activation varied considerably within the normal population but did not correlate with maximal platelet activation, demonstrating that platelet activation rate is a separate and novel metric to describe platelet reactivity. The relative rate of platelet response between agonists was strongly correlated, suggesting that a central control mechanism regulates the rate of platelet response to all agonists. CONCLUSION: For the first time, we have shown that platelet response rate corresponds to thrombus size and structure, wherein faster responders form larger, more densely packed thrombi at arterial, but crucially not venous, shear. We have demonstrated that the rate of platelet activation is an important metric in stratifying individual platelet responses and will provide a novel focus for the design and development of antiplatelet therapy, targeting high-shear thrombosis without exacerbating bleeding at low shear.

A cross-sectional assessment of frailty, falls and perceptions of ageing in people living with HIV using an mHealth platform.

OBJECTIVE: To evaluate frailty, falls and perceptions of ageing among clinically stable individuals with HIV, engaged with remote healthcare delivered via a novel smartphone application. METHODS: This was a multi-centre European cross-sectional, questionnaire-based sub-study of EmERGE participants. Frailty was assessed using the five-item FRAIL scale. Present criteria were summed and categorized as follows: 0, robust; 1-2, pre-frail; 3-5, frail. Falls history and EQ-5D-5L quality of life measure were completed. Participants were asked their felt age and personal satisfaction with ageing. RESULTS: A total of 1373 participated, with a mean age of 45 (± 9.8) years. Frailty was uncommon at 2%; 12.4% fell in the previous year, 58.8% of these recurrently. Mood symptoms and pain were prevalent, at 43.3% and 31.8%, respectively. Ageing satisfaction was high at 76.4%, with 74.6% feeling younger than their chronological age; the mean felt age was 39.3 years. In multivariable analysis, mood symptoms and pain were positively associated with frailty, falls and ageing dissatisfaction. An increase in pain severity and mood symptoms were respectively associated with 34% and 63% increased odds of pre-frailty/frailty. An increment in pain symptoms was associated with a 71% increase in odds of falling. Pain was associated with ageing poorly, as were mood symptoms, with odds of dissatisfaction increasing by 34% per increment in severity. CONCLUSIONS: Although uncommon, frailty, falls and ageing dissatisfaction were seen in a younger cohort with medically stable HIV infection using a remote care model, promoting screening as advocated by European guidelines. These were more common in those with pain or mood symptoms, which should be proactively managed in clinical care and explored further in future research.

Spelling Errors in Brief Computer-Mediated Texts Implicitly Lead to Linearly Additive Penalties in Trustworthiness.

Background: Spelling errors in documents lead to reduced trustworthiness, but the mechanism for weighing the psychological assessment (i.e., integrative versus dichotomous) has not been elucidated. We instructed participants to rate content of texts, revealing that their implicit trustworthiness judgments show marginal differences specifically caused by spelling errors. Methods: An online experiment with 100 English-speaking participants were asked to rate 27 short text excerpts (∼100 words) about multiple sclerosis in the format of unmoderated health forum posts. In a counterbalanced design, some excerpts had no typographic errors, some had two errors, and some had five errors. Each participant rated nine paragraphs with a counterbalanced mixture of zero, two or five errors. A linear mixed effects model (LME) was assessed with error number as a fixed effect and participants as a random effect. Results: Using an unnumbered scale with anchors of "completely untrustworthy" (left) and "completely trustworthy" (right) recorded as 0 to 100, two spelling errors resulted in a penalty to trustworthiness of 5.91 ± 1.70 (robust standard error) compared to the reference excerpts with zero errors, while the penalty for five errors was 13.5 ± 2.47; all three conditions were significantly different from each other (P < 0.001). Conclusion: Participants who rated information about multiple sclerosis in a context mimicking an online health forum implicitly assigned typographic errors nearly linearly additive trustworthiness penalties. This contravenes any dichotomous heuristic or local ceiling effect on trustworthiness penalties for these numbers of typographic errors. It supports an integrative model for psychological judgments of trustworthiness.

The efficiency of the EmERGE platform for medically stable people living with HIV in Portugal.

Background: The aim of this study was to calculate the cost-effectiveness of the EmERGE Pathway of Care for medically stable people living with HIV in the Hospital Capuchos, Centro Hospitalar Universitário de Lisboa Central (HC-CHLC). The app enables individuals to receive HIV treatment information and communicate with caregivers. Methods: This before-and-after study collected the use of services data 1 year before implementation and after implementation of EmERGE from November 1, 2016, to October 30, 2019. Departmental unit costs were calculated and linked to mean use of outpatient services per patient-year (MPPY). Annual costs per patient-year were combined with primary (CD4 count; viral load) and secondary outcomes (PAM-13; PROQOL-HIV). Results: Five hundred eighty-six EmERGE participants used HIV outpatient services. Annual outpatient visits decreased by 35% from 3.1 MPPY (95% confidence interval [CI]: 3.0-3.3) to 2.0 (95% CI: 1.9-2.1) as did annual costs per patient-year from €301 (95% CI: €288-€316) to €193 (95% CI: €182-€204). Laboratory tests and costs increased by 2%, and radiology investigations decreased by 40% as did costs. Overall annual cost for HIV outpatient services decreased by 5% from €2093 (95% CI: €2071-€2112) to €1984 (95% CI: €1968-€2001); annual outpatient costs decreased from €12,069 (95% CI: €12,047-€12,088) to €11,960 (95% CI: €11,944-€11,977), with 83% of annual cost because of antiretroviral therapy (ART). Primary and secondary outcome measures did not differ substantially between periods. Conclusions: The EmERGE Pathway produced cost savings after implementation-extended to all people living with HIV additional savings are likely to be produced, which can be used to address other needs. Antiretroviral drugs (ARVs) were the main cost drivers and more expensive in Portugal compared with ARV costs in the other EmERGE sites.

Genome-wide analyses of XRN1-sensitive targets in osteosarcoma cells identify disease-relevant transcripts containing G-rich motifs.

XRN1 is a highly conserved exoribonuclease which degrades uncapped RNAs in a 5'-3' direction. Degradation of RNAs by XRN1 is important in many cellular and developmental processes and is relevant to human disease. Studies in D. melanogaster demonstrate that XRN1 can target specific RNAs, which have important consequences for developmental pathways. Osteosarcoma is a malignancy of the bone and accounts for 2% of all pediatric cancers worldwide. Five-year survival of patients has remained static since the 1970s and therefore furthering our molecular understanding of this disease is crucial. Previous work has shown a down-regulation of XRN1 in osteosarcoma cells; however, the transcripts regulated by XRN1 which might promote osteosarcoma remain elusive. Here, we confirm reduced levels of XRN1 in osteosarcoma cell lines and patient samples and identify XRN1-sensitive transcripts in human osteosarcoma cells. Using RNA-seq in XRN1-knockdown SAOS-2 cells, we show that 1178 genes are differentially regulated. Using a novel bioinformatic approach, we demonstrate that 134 transcripts show characteristics of direct post-transcriptional regulation by XRN1. Long noncoding RNAs (lncRNAs) are enriched in this group, suggesting that XRN1 normally plays an important role in controlling lncRNA expression in these cells. Among potential lncRNAs targeted by XRN1 is HOTAIR, which is known to be up-regulated in osteosarcoma and contributes to disease progression. We have also identified G-rich and GU motifs in post-transcriptionally regulated transcripts which appear to sensitize them to XRN1 degradation. Our results therefore provide significant insights into the specificity of XRN1 in human cells which are relevant to disease.

Correction: Spelling Errors and Shouting Capitalization Lead to Additive Penalties to Trustworthiness of Online Health Information: Randomized Experiment With Laypersons.

[This corrects the article DOI: 10.2196/15171.].

TLR9 expression in chronic lymphocytic leukemia identifies a promigratory subpopulation and novel therapeutic target.

Chronic lymphocytic leukemia (CLL) remains incurable despite B-cell receptor-targeted inhibitors revolutionizing treatment. This suggests that other signaling molecules are involved in disease escape mechanisms and resistance. Toll-like receptor 9 (TLR9) is a promising candidate that is activated by unmethylated cytosine guanine dinucleotide-DNA. Here, we show that plasma from patients with CLL contains significantly more unmethylated DNA than plasma from healthy control subjects (P < .0001) and that cell-free DNA levels correlate with the prognostic markers CD38, ß2-microglobulin, and lymphocyte doubling time. Furthermore, elevated cell-free DNA was associated with shorter time to first treatment (hazard ratio, 4.0; P = .003). We also show that TLR9 expression was associated with in vitro CLL cell migration (P < .001), and intracellular endosomal TLR9 strongly correlated with aberrant surface expression (sTLR9; r = 0.9). In addition, lymph node-derived CLL cells exhibited increased sTLR9 (P = .016), and RNA-sequencing of paired sTLR9hi and sTLR9lo CLL cells revealed differential transcription of genes involved in TLR signaling, adhesion, motility, and inflammation in sTLR9hi cells. Mechanistically, a TLR9 agonist, ODN2006, promoted CLL cell migration (P < .001) that was mediated by p65 NF-κB and STAT3 transcription factor activation. Importantly, autologous plasma induced the same effects, which were reversed by a TLR9 antagonist. Furthermore, high TLR9 expression promoted engraftment and rapid disease progression in a NOD/Shi-scid/IL-2Rγnull mouse xenograft model. Finally, we showed that dual targeting of TLR9 and Bruton's tyrosine kinase (BTK) was strongly synergistic (median combination index, 0.2 at half maximal effective dose), which highlights the distinct role for TLR9 signaling in CLL and the potential for combined targeting of TLR9 and BTK as a more effective treatment strategy in this incurable disease.

Multiplexed gene expression analysis of HLA class II-associated podoconiosis implicates chronic immune activation in its pathogenesis.

BACKGROUND: Podoconiosis is a tropical lymphoedema of the leg resulting from barefoot exposure to irritant volcanic soils. Approximately 4 million people are affected, mainly in African highland regions. The pathogenesis of this neglected tropical disease is still largely unknown, although HLA class II (HLAII) polymorphisms are associated with the disease. METHODS: NanoString technology was used to assess expression of 579 immune-related genes in formalin-fixed and paraffin-embedded lymph node archival samples from podoconiosis patients and unaffected controls. RESULTS: Forty-eight genes were upregulated and 21 downregulated in podoconiosis samples compared with controls. Gene ontology analysis showed differentially expressed genes to be closely related to major histocompatibility complex protein, cytokine and TNF receptor binding genes. Pathway enrichment analysis revealed involvement of lymphocyte activation, adaptive immunity, cytokine signalling, antigen processing and the IL-12 pathways. CONCLUSIONS: This exploratory study reports a multiplex gene expression analysis in podoconiosis and shows upregulation of pro-inflammatory transcripts compatible with the notion of local, chronic immune activation in this HLAII-associated disease. Implicated pathways will inform future research into podoconiosis immunopathogenesis.

Characterization of Lead Adherence Using Intravascular Ultrasound to Assess Difficulty of Transvenous Lead Extraction.

BACKGROUND: Clinical factors associated with development of intravascular lead adherence (ILA) are unreliable predictors. Because vascular injury in the superior vena cava-right atrium during transvenous lead extraction is more likely to occur in segments with higher degrees of ILA, reliable and accurate assessment of ILA is warranted. We hypothesized that intravascular ultrasound (IVUS) could accurately visualize and quantify ILA and degree of ILA correlates with transvenous lead extraction difficulty. METHODS: Serial imaging of leads occurred before transvenous lead extraction using IVUS. ILA areas were classified as high or low grade. Degree of extraction difficulty was assessed using 2 metrics and correlated with ILA grade. Lead extraction difficulty was calculated for each patient and compared with IVUS findings. RESULTS: One hundred fifty-eight vascular segments in 60 patients were analyzed: 141 (89%) low grade versus 17 (11%) high grade. Median extraction time (low=0 versus high grade=97 seconds, P<0.001) and median laser pulsations delivered (low=0 versus high grade=5852, P<0.001) were significantly higher in high-grade segments. Most patients with low lead extraction difficulty score had low ILA grades. Eighty-six percentage of patients with high lead extraction difficulty score had low IVUS grade, and the degree of transvenous lead extraction difficulty was similar to patients with low IVUS grades and lead extraction difficulty scores. CONCLUSIONS: IVUS is a feasible imaging modality that may be useful in characterizing ILA in the superior vena cava-right atrium region. An ILA grading system using imaging correlates with extraction difficulty. Most patients with clinical factors associated with higher extraction difficulty may exhibit lower ILA and extraction difficulty based on IVUS imaging. Graphic Abstract: A graphic abstract is available for this article.

Spelling Errors and Shouting Capitalization Lead to Additive Penalties to Trustworthiness of Online Health Information: Randomized Experiment With Laypersons.

BACKGROUND: The written format and literacy competence of screen-based texts can interfere with the perceived trustworthiness of health information in online forums, independent of the semantic content. Unlike in professional content, the format in unmoderated forums can regularly hint at incivility, perceived as deliberate rudeness or casual disregard toward the reader, for example, through spelling errors and unnecessary emphatic capitalization of whole words (online shouting). OBJECTIVE: This study aimed to quantify the comparative effects of spelling errors and inappropriate capitalization on ratings of trustworthiness independently of lay insight and to determine whether these changes act synergistically or additively on the ratings. METHODS: In web-based experiments, 301 UK-recruited participants rated 36 randomized short stimulus excerpts (in the format of information from an unmoderated health forum about multiple sclerosis) for trustworthiness using a semantic differential slider. A total of 9 control excerpts were compared with matching error-containing excerpts. Each matching error-containing excerpt included 5 instances of misspelling, or 5 instances of inappropriate capitalization (shouting), or a combination of 5 misspelling plus 5 inappropriate capitalization errors. Data were analyzed in a linear mixed effects model. RESULTS: The mean trustworthiness ratings of the control excerpts ranged from 32.59 to 62.31 (rating scale 0-100). Compared with the control excerpts, excerpts containing only misspellings were rated as being 8.86 points less trustworthy, those containing inappropriate capitalization were rated as 6.41 points less trustworthy, and those containing the combination of misspelling and capitalization were rated as 14.33 points less trustworthy (P<.001 for all). Misspelling and inappropriate capitalization show an additive effect. CONCLUSIONS: Distinct indicators of incivility independently and additively penalize the perceived trustworthiness of online text independently of lay insight, eliciting a medium effect size.

Determining the accuracy of zero-flux and ingestible thermometers in the peri-operative setting.

Accurately monitoring peri-operative core temperature is a cornerstone of good practice. Relatively invasive devices such as oesophageal temperature probes and pulmonary artery catheters facilitate this, but are inappropriate for many patients. There remains a need for accurate monitors of core temperature that can be used in awake patients. This study compared the accuracy of two core temperature thermometers that can be used for this purpose: the 3M Bair Hugger™ Temperature Monitoring System Zero Flux Thermometer and the CorTempR™ Wireless Ingestible Temperature Sensor. Readings were compared with the oesophageal probe, the current intraoperative standard. Thirty patients undergoing elective surgical procedures under general anaesthesia were recruited. The ingestible sensor was ingested prior to induction of anaethesia, and post induction, the zero-flux electrode attached above the right eyebrow and oesophageal probe inserted. During surgery, the temperature on each device was recorded every minute. Measurements were compared using Bland-Altman analysis. The ingestible sensor experienced interference from use of diathermy and fluoroscopy in the operating theatre, rendering 39% of its readings unusable. These were removed from analysis. With remaining readings the bias compared with oesophageal probe was + 0.42 °C, with 95% limits of agreement - 2.4 °C to 3.2 °C. 75.4% of readings were within ± 0.5 °C of the OTP reading. The bias for the zero flux electrode compared to oesophageal probe was + 0.02 °C with 95% limits of agreement - 0.5 °C to 0.5 °C. 97.7% of readings were within ± 0.5 °C of the oesophageal probe. The study findings suggest the zero-flux thermometer is sufficiently accurate for clinical use, whereas the ingestible sensor is not.Trial registration The study was registered at http://www.clinicaltrials.gov , NCT Number: NCT02121574.

Functional redundancy between RAP1 isoforms in murine platelet production and function.

RAP GTPases, important regulators of cellular adhesion, are abundant signaling molecules in the platelet/megakaryocytic lineage. However, mice lacking the predominant isoform, RAP1B, display a partial platelet integrin activation defect and have a normal platelet count, suggesting the existence of a RAP1-independent pathway to integrin activation in platelets and a negligible role for RAP GTPases in megakaryocyte biology. To determine the importance of individual RAP isoforms on platelet production and on platelet activation at sites of mechanical injury or vascular leakage, we generated mice with megakaryocyte-specific deletion (mKO) of Rap1a and/or Rap1b Interestingly, Rap1a/b-mKO mice displayed a marked macrothrombocytopenia due to impaired proplatelet formation by megakaryocytes. In platelets, RAP isoforms had redundant and isoform-specific functions. Deletion of RAP1B, but not RAP1A, significantly reduced α-granule secretion and activation of the cytoskeleton regulator RAC1. Both isoforms significantly contributed to thromboxane A2 generation and the inside-out activation of platelet integrins. Combined deficiency of RAP1A and RAP1B markedly impaired platelet aggregation, spreading, and clot retraction. Consistently, thrombus formation in physiological flow conditions was abolished in Rap1a/b-mKO, but not Rap1a-mKO or Rap1b-mKO, platelets. Rap1a/b-mKO mice were strongly protected from experimental thrombosis and exhibited a severe defect in hemostasis after mechanical injury. Surprisingly, Rap1a/b-mKO platelets were indistinguishable from controls in their ability to prevent blood-lymphatic mixing during development and hemorrhage at sites of inflammation. In summary, our studies demonstrate an essential role for RAP1 signaling in platelet integrin activation and a critical role in platelet production. Although important for hemostatic/thrombotic plug formation, platelet RAP1 signaling is dispensable for vascular integrity during development and inflammation.

Toxigenic Clostridium difficile colonization among hospitalised adults; risk factors and impact on survival.

OBJECTIVES: To establish risk factors for Clostridium difficile colonization among hospitalized patients in England. METHODS: Patients admitted to elderly medicine wards at three acute hospitals in England were recruited to a prospective observational study. Participants were asked to provide a stool sample as soon as possible after enrolment and then weekly during their hospital stay. Samples were cultured for C. difficile before ribotyping and toxin detection by PCR. A multivariable logistic regression model of risk factors for C. difficile colonization was fitted from univariable risk factors significant at the p < 0.05 level. RESULTS: 410/727 participants submitted ≥1 stool sample and 40 (9.8%) carried toxigenic C. difficile in the first sample taken. Ribotype 106 was identified three times and seven other ribotypes twice. No ribotype 027 strains were identified. Independent predictors of colonization were previous C. difficile infection (OR 4.53 (95% C.I. 1.33-15.48) and malnutrition (MUST score ≥2) (OR 3.29 (95% C.I. 1.47-7.35)). Although C. difficile colonised patients experienced higher 90-day mortality, colonization was not an independent risk for death. CONCLUSIONS: In a non-epidemic setting patients who have previously had CDI and have a MUST score of ≥2 are at increased risk of C. difficile colonization and could be targeted for active surveillance to prevent C. difficile transmission.

The roles of the exoribonucleases DIS3L2 and XRN1 in human disease.

RNA degradation is a vital post-transcriptional process which ensures that transcripts are maintained at the correct level within the cell. DIS3L2 and XRN1 are conserved exoribonucleases that are critical for the degradation of cytoplasmic RNAs. Although the molecular mechanisms of RNA degradation by DIS3L2 and XRN1 have been well studied, less is known about their specific roles in the development of multicellular organisms or human disease. This review focusses on the roles of DIS3L2 and XRN1 in the pathogenesis of human disease, particularly in relation to phenotypes seen in model organisms. The known diseases associated with loss of activity of DIS3L2 and XRN1 are discussed, together with possible mechanisms and cellular pathways leading to these disease conditions.

Effectiveness of antipsychotics used in first-episode psychosis: a naturalistic cohort study.

BACKGROUND: One year of antipsychotic treatment from symptom remission is recommended following a first episode of psychosis (FEP). AIMS: To investigate the effectiveness of commonly used antipsychotic medications in FEP. METHOD: A retrospective cohort study of naturalistic treatment of patients (N=460) accepted by FEP services across seven UK sites. Treatment initiation to all-cause discontinuation determined from case files. RESULTS: Risk of treatment discontinuation is greatest within 3 months of treatment initiation. Risperidone had longest median survival time. No significant differences were observed in time to discontinuation between commonly used antipsychotics on multivariable Cox regression analysis. Poor adherence and efficacy failure were the most common reasons for discontinuation. CONCLUSIONS: Effectiveness differences appear not to be a current reason for antipsychotic choice in FEP. Adherence strategies and weighing up likely adverse effects should be the clinical focus. DECLARATION OF INTEREST: R.W., A.T. and S.M. have received research grant, speaker honoraria and conference attendance funding from all companies marketing antipsychotics. COPYRIGHT AND USAGE: © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.