General practice pharmacist-led antipsychotic physical health monitoring: a prospective intervention scoping study.

BACKGROUND: People with severe mental health illness die prematurely, often due to preventable cardiometabolic disease, which can be exacerbated by antipsychotic medicines that are effective for treating mental illness. Literature demonstrates that physical health monitoring, as recommended in guidelines, for people receiving antipsychotics is substandard. Therefore, we aimed to scope the potential of a general practice clinical pharmacist (GPCP)-led multidisciplinary intervention optimising adherence to cardiometabolic monitoring guidelines and delivering polypharmacy reviews. METHOD: Prospective intervention scoping study in three urban general practices; one usual care, two intervention. Patients 18-65 years old prescribed oral antipsychotics were identified from records, and invited for cardiometabolic monitoring and GPCP medication review, from January to December 2022. Interventions and onward referrals were recorded and collated. Anonymised pre- and post-review data were analysed, and actions were graded for clinical importance. RESULTS: In total 1.5% (210/14,159) of patients aged 18-65 years met inclusion criteria; usual care practice (n = 58); and intervention practices (n = 152). From baseline, the usual care practice achieved an absolute 7% increase in the cardiometabolic monitoring care bundle (glucose/glycosylated haemoglobin, lipids, blood pressure plus body mass index) versus 19-58% in the intervention practices. Two-thirds (92/152) of patients participated in medication reviews, requiring pharmacological and/or non-pharmacological clinical actions. The majority of actions were graded as moderate importance. Seven percentage of patients were identified as new pre-diabetic/diabetic and 6% were at high risk of cardiovascular disease requiring statin initiation. CONCLUSION: A pharmacist-led multidisciplinary general practice-based approach may be effective at optimising cardiometabolic monitoring; identifying and treating diabetic and cardiovascular risk factors.

People with severe mental illness die 15­20 years earlier than the general population, many due to preventable and/or treatable heart disease. While antipsychotic medicines are effective for treating mental illness they are associated with potential adverse effects; weight gain, increased blood pressure, blood sugar, and cholesterol. Therefore, guidelines advise regular physical health checks for people with severe mental illness, and those receiving antipsychotics, to reduce avoidable harms and optimise preventative treatments. However, routine monitoring is substandard. This study aimed to explore the potential of a general practice pharmacist-led intervention to optimise physical health monitoring and medication reviews, from January to December 2022. Three practices participated; one providing usual care, and two the pharmacist intervention. The usual care practice achieved a 7% increase in all monitoring parameters (weight, blood pressure, blood sugars plus cholesterol), whereas the pharmacist-led practices achieved a 19­58% increase in monitoring. Two in three patients (92/152) participated in a medication review with the pharmacists that addressed a range of mental and physical health issues. Of the 152 patients in the intervention practices 6% were identified as being at high risk of heart disease requiring preventative medicines, and 7% were identified as having new diabetes and/or pre-diabetes.

Pharmacological Characterization of the Novel and Selective α7 Nicotinic Acetylcholine Receptor-Positive Allosteric Modulator BNC375.

Treatments for cognitive deficits associated with central nervous system (CNS) disorders such as Alzheimer disease and schizophrenia remain significant unmet medical needs that incur substantial pressure on the health care system. The α7 nicotinic acetylcholine receptor (nAChR) has garnered substantial attention as a target for cognitive deficits based on receptor localization, robust preclinical effects, genetics implicating its involvement in cognitive disorders, and encouraging, albeit mixed, clinical data with α7 nAChR orthosteric agonists. Importantly, previous orthosteric agonists at this receptor suffered from off-target activity, receptor desensitization, and an inverted U-shaped dose-effect curve in preclinical assays that limit their clinical utility. To overcome the challenges with orthosteric agonists, we have identified a novel selective α7 positive allosteric modulator (PAM), BNC375. This compound is selective over related receptors and potentiates acetylcholine-evoked α7 currents with only marginal effect on the receptor desensitization kinetics. In addition, BNC375 enhances long-term potentiation of electrically evoked synaptic responses in rat hippocampal slices and in vivo. Systemic administration of BNC375 reverses scopolamine-induced cognitive deficits in rat novel object recognition and rhesus monkey object retrieval detour (ORD) task over a wide range of exposures, showing no evidence of an inverted U-shaped dose-effect curve. The compound also improves performance in the ORD task in aged African green monkeys. Moreover, ex vivo 13C-NMR analysis indicates that BNC375 treatment can enhance neurotransmitter release in rat medial prefrontal cortex. These findings suggest that α7 nAChR PAMs have multiple advantages over orthosteric α7 nAChR agonists for the treatment of cognitive dysfunction associated with CNS diseases. SIGNIFICANCE STATEMENT: BNC375 is a novel and selective α7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator (PAM) that potentiates acetylcholine-evoked α7 currents in in vitro assays with little to no effect on the desensitization kinetics. In vivo, BNC375 demonstrated robust procognitive effects in multiple preclinical models across a wide exposure range. These results suggest that α7 nAChR PAMs have therapeutic potential in central nervous system diseases with cognitive impairments.

Seeds tend to disperse further in the tropics.

Despite the importance of seed dispersal in a plant's life cycle, global patterns in seed dispersal distance have seldom been studied. This paper presents the first geographically and taxonomically broad quantification of the latitudinal gradient in seed dispersal distance. Although there is substantial variation in the seed dispersal distances of different species at a given latitude, seeds disperse on average more than an order of magnitude further at the equator than towards the poles. This pattern is partially explained by plant life-history traits that simultaneously associate with seed dispersal distance and latitude, including dispersal mode and plant height. The extended seed shadow of tropical plants could increase the distance between conspecific individuals. This could facilitate species coexistence and contribute to the maintenance of high plant diversity in tropical communities. The latitudinal gradient in dispersal distance also has implications for species' persistence in the face of habitat fragmentation and climate change.

Pharmacodynamic Therapeutic Drug Monitoring for Cancer: Challenges, Advances, and Future Opportunities.

In the modern era of cancer treatment, with targeted agents superseding more traditional cytotoxic chemotherapeutics, it is becoming increasingly important to use stratified medicine approaches to ensure that patients receive the most appropriate drugs and treatment schedules. In this context, there is significant potential for the use of pharmacodynamic biomarkers to provide pharmacological information, which could be used in a therapeutic drug monitoring setting. This review focuses on discussing some of the challenges faced to date in translating preclinical pharmacodynamic biomarker approaches to a clinical setting. Recent advances in important areas including circulating biomarkers and pharmacokinetic/pharmacodynamic modeling approaches are discussed, and selected examples of anticancer drugs where there is existing evidence to potentially advance pharmacodynamic therapeutic drug monitoring approaches to deliver more effective treatment are discussed. Although we may not yet be in a position to systematically implement therapeutic drug monitoring approaches based on pharmacodynamic information in a cancer patient setting, such approaches are likely to become more commonplace in the coming years. Based on ever-increasing levels of pharmacodynamic information being generated on newer anticancer drugs, facilitated by increasingly advanced and accessible experimental approaches available to researchers to collect these data, we can now look forward optimistically to significant advances being made in this area.

Can dispersal investment explain why tall plant species achieve longer dispersal distances than short plant species?

Tall plant species disperse further distances than do short species, within and across dispersal syndromes, yet the driver underpinning this relationship is unclear. The ability of taller plants to invest more in dispersal structures may explain the positive relationship between plant height and dispersal distance. Here, we quantify the cross-species relationships between presence of dispersal structures, dispersal investment plant height and dispersal distance. Plant height, dispersal syndrome and dispersal investment data were collated for 1613 species from the literature, with dispersal distance data collated for 114 species. We find that species with high dispersal investment disperse further than do species with low dispersal investment. Tall species have a greater probability of having dispersal structures on their seeds compared with short species. For species with dispersal structures on their seeds, plant height is very weakly related to dispersal investment. Our results provide the first global confirmation of the dispersal investment-distance hypothesis, and show dispersal investment can be used for predicting species dispersal distances. However, our results and those of previous studies indicate plant height is still the best proxy for estimating species dispersal distances due to it being such a readily available plant trait.

Incorporating patient partner scores into high stakes assessment: an observational study into opinions and attitudes.

BACKGROUND: Volunteer patients (also known as patient partners (PPs)) play a vital role in undergraduate healthcare curricula. They frequently take part in objective structured clinical examinations (OSCE) and rate aspects of students' performance. However, the inclusion and weighting of PP marks varies, while attitudes and opinions regarding how (and if) they should contribute towards the pass/fail outcome are uncertain. METHODS: A prospective observational study was conducted to explore beliefs of PPs regarding inclusion of their scores in a high stakes undergraduate OSCE in a single UK medical school. All PPs delivering components of the local MBChB curriculum were asked to participate in the questionnaire study. Quantitative and qualitative data were analysed using descriptive statistics and framework analysis respectively. RESULTS: Fifty out of 160 (31% response rate) PPs completed the questionnaire; 70% had participated in a final year OSCE. Thirty (60%) felt their marks should be incorporated into a student's overall score, while 28% were uncertain. The main reasons for inclusion were recognition of the patient perspective (31%) and their ability to assess attitudes and professionalism (27%), while reasons against inclusion included lack of PP qualification/training (18%) and concerns relating to consistency (14%). The majority of PPs were uncertain what proportion of the total mark they should contribute, although many felt that 5-10% of the total score was reasonable. Most respondents (70%) felt that globally low PP scores should not result in an automatic fail and many (62%) acknowledged that prior to mark inclusion, further training was required. CONCLUSION: These data show that most respondents considered it reasonable to "formalise their expertise" by contributing marks in the overall assessment of students in a high stakes OSCE, although what proportion they believe this should represent was variable. Some expressed concerns that using marks towards progress decisions may alter PP response patterns. It would therefore seem reasonable to compare outcomes (i.e. pass/fail status) using historical data both incorporating and not incorporating PP marks to evaluate the effects of doing so. Further attention to existing PP training programmes is also required in order to provide clear instruction on how to globally rate students to ensure validity and consistency.

Patient and public understanding of antimicrobial resistance: a systematic review and meta-ethnography.

Objectives: To further develop an understanding of laypeople's (adult patients and public) beliefs and attitudes toward antimicrobial resistance (AMR) by developing a conceptual model derived from identifying and synthesizing primary qualitative research. Methods: A systematic search of 12 electronic databases, including CINAHL, MEDLINE, PsycINFO, PubMed and Web of Science to identify qualitative primary studies exploring patient and public understanding of AMR published between 2012 and 2022. Included studies were quality appraised and synthesized using Noblit and Hare's meta-ethnographic approach and reported using eMERGe guidance. Results: Thirteen papers reporting 12 qualitative studies were synthesized. Studies reported data from 466 participants aged 18-90 years. Five themes were identified from these original studies: the responsible patient; when words become meaningless; patient-prescriber relationship; past experience drives antibiotic use; and reframing public perception. These themes supported the development of a conceptual model that illustrates the tension between two different assumptions, that is, how can antibiotics be used for the collective good whilst balancing the immediate needs of individual patients. Conclusions: Findings suggest that AMR is a distinct ethical issue and should not be viewed purely as a prescribing problem. The meta-ethnography-generated conceptual model illustrates many factors affecting the public's perception of AMR. These include laypeople's own knowledge, beliefs and attitudes around antibiotic use, the relationship with the healthcare provider and the wider context, including the overwhelming influence of the media and public health campaigns. Future research is needed to explore effective health messaging strategies to increase laypeople's baseline awareness of AMR as a public threat.

Greening procurement: Exploring evolving practices in an Irish university.

Including green criteria in the public procurement of goods and services requires increased expertise, new methodologies, more significant monitoring efforts and more support towards innovation. These added complexities influence procurement professionals and their everyday practices. This article explores the under-researched issue of practitioner-led beliefs, attitudes, and their accounts of Green Public Procurement (GPP). We delve into a qualitative case study of University College Cork (UCC) in Ireland to explore the journey of procurement professionals in introducing GPP across the various sectors and departments of the university. We draw from interviews, a horizon scanning workshop, and secondary materials to capture and build on the expertise of a broad range of staff in UCC with experience in this area. We use this collective viewpoint to make sense of GPP and to position such views relative to ongoing policy priorities, looking at past, present, and future outlooks. The research shows that efforts have been made to introduce green criteria in new tenders. These gradually became wider opportunities to develop competencies, skills, and stimuli to implement more impactful strategies. The research also shows underdeveloped practices around supporting innovation, monitoring, and post-award evaluation. Overall, the paper offers a unique perspective based on the day-to-day practice of public procurement practitioners. While the case study is geographically bound and therefore presents difficulties in replicating findings, it provides a new lens for researching GPP adoption through interaction with practitioners.

Identification and optimisation of novel sulfonamide, selective vasopressin V1B receptor antagonists.

The synthesis and preliminary structure-activity relationships (SAR) of a novel class of vasopressin V(1B) receptor antagonists are described. Hit compound 5, identified via high throughput screening of the corporate collection, showed good activity in a V(1B) binding assay (K(i) 63 nM) but did not possess the lead-like physicochemical properties typically required in a hit compound. A 'deletion approach' on the HTS hit 5 was performed, with the focus on improvement of physicochemical properties, yielding the selective V(1B) antagonist 9f (K(i) 190 nM), with improved druglike characteristics.

The discovery of novel 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamides as vasopressin V1A receptor antagonists.

The discovery of a novel series of 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamide antagonists of the vasopressin V(1A) receptor is disclosed. Compounds 47 and 48 were found to be high affinity, selective vasopressin V(1A) antagonists.

Discovery and optimisation of a selective non-steroidal glucocorticoid receptor antagonist.

High-throughput screening of 3.87 million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed progression from a non-selective ligand with a poor ADMET profile to an orally bioavailable, selective, stable, glucocorticoid receptor antagonist.

Synthesis and SAR studies of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl)acetamide vasopressin V1b receptor antagonists.

Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V(1b) (V(3)) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V(1b) receptor and good selectivity with respect to related receptors V(1a), V(2) and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.

Optimisation of an Electrochemical DNA Sensor for Measuring KRAS G12D and G13D Point Mutations in Different Tumour Types.

Circulating tumour DNA (ctDNA) is widely used in liquid biopsies due to having a presence in the blood that is typically in proportion to the stage of the cancer and because it may present a quick and practical method of capturing tumour heterogeneity. This paper outlines a simple electrochemical technique adapted towards point-of-care cancer detection and treatment monitoring from biofluids using a label-free detection strategy. The mutations used for analysis were the KRAS G12D and G13D mutations, which are both important in the initiation, progression and drug resistance of many human cancers, leading to a high mortality rate. A low-cost DNA sensor was developed to specifically investigate these common circulating tumour markers. Initially, we report on some developments made in carbon surface pre-treatment and the electrochemical detection scheme which ensure the most sensitive measurement technique is employed. Following pre-treatment of the sensor to ensure homogeneity, DNA probes developed specifically for detection of the KRAS G12D and G13D mutations were immobilized onto low-cost screen printed carbon electrodes using diazonium chemistry and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride/N-hydroxysuccinimide coupling. Prior to electrochemical detection, the sensor was functionalised with target DNA amplified by standard and specialist PCR methodologies (6.3% increase). Assay development steps and DNA detection experiments were performed using standard voltammetry techniques. Sensitivity (as low as 0.58 ng/µL) and specificity (>300%) was achieved by detecting mutant KRAS G13D PCR amplicons against a background of wild-type KRAS DNA from the representative cancer sample and our findings give rise to the basis of a simple and very low-cost system for measuring ctDNA biomarkers in patient samples. The current time to receive results from the system was 3.5 h with appreciable scope for optimisation, thus far comparing favourably to the UK National Health Service biopsy service where patients can wait for weeks for biopsy results.

Durvalumab (MEDI 4736) in combination with extended neoadjuvant regimens in rectal cancer: a study protocol of a randomised phase II trial (PRIME-RT).

BACKGROUND: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but around 30% of patients will still die from distant metastatic disease. In parallel, there is increasing recognition that with radiotherapy and systemic treatment, some patients achieve a complete response and may avoid surgical resection, including in many cases, the need for a permanent stoma. Extended neoadjuvant regimes have emerged to address these concerns. The inclusion of immunotherapy in the neoadjuvant setting has the potential to further enhance this strategy by priming the local immune microenvironment and engaging the systemic immune response. METHODS: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients will be randomised to receive either: short course radiotherapy (25 Gray in 5 fractions over one week) with concomitant durvalumab (1500 mg administered intravenously every 4 weeks), followed by FOLFOX (85 mg/m2 oxaliplatin, 350 mg folinic acid and 400 mg/m2 bolus 5-fluorouracil (5-FU) given on day 1 followed by 2400 mg/m2 5-FU infusion over 46-48 h, all administered intravenously every 2 weeks), and durvalumab, or long course chemoradiotherapy (50 Gray to primary tumour in 25 fractions over 5 weeks with concomitant oral capecitabine 825 mg/m2 twice per day on days of radiotherapy) with durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Secondary endpoints include treatment compliance, toxicity, safety, overall recurrence, proportion of patients with a permanent stoma, and survival. The study is translationally rich with collection of bio-specimens prior to, during, and following treatment in order to understand the molecular and immunological factors underpinning treatment response. The trial opened and the first patient was recruited in January 2021. The main trial will recruit up to 42 patients with LARC and commence after completion of a safety run-in that will recruit at least six patients with LARC or metastatic disease. DISCUSSION: PRIME-RT will explore if adding immunotherapy to neoadjuvant radiotherapy and chemotherapy for patients with LARC can prime the tumour microenvironment to improve complete response rates and stoma free survival. Sequential biopsies are a key component within the trial design that will provide new knowledge on how the tumour microenvironment changes at different time-points in response to multi-modality treatment. This expectation is that the trial will provide information to test this treatment within a large phase clinical trial. Trial registration Clinicaltrials.gov NCT04621370 (Registered 9th Nov 2020) EudraCT number 2019-001471-36 (Registered 6th Nov 2020).

Serum Proteomics and Plasma Fibulin-3 in Differentiation of Mesothelioma From Asbestos-Exposed Controls and Patients With Other Pleural Diseases.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory. METHODS: A multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure. RESULTS: A total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557-0.664], p = 0.0015) and 0.516 [0.443-0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume. CONCLUSIONS: SOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification.

Identification and optimization of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl)acetamide vasopressin V3 (V1b) receptor antagonists.

The discovery, synthesis, and preliminary structure-activity relationship (SAR) of a novel class of vasopressin V3 (V1b) receptor antagonists is described. Compound 1, identified by high throughput screening of a diverse, three million-member compound collection, prepared using ECLiPS technology, had good activity in a V3 binding assay (IC50=0.20 microM), but less than desirable physicochemical properties. Optimization of compound 1 yielded potent analogs 19 (IC50=0.31 microM) and 24 (IC50=0.12 microM) with improved drug-like characteristics.

The discovery and SAR of indoline-3-carboxamides--a new series of 5-HT6 antagonists.

Antagonists of the 5-HT(6) receptor have been shown to improve cognitive function in a wide range of animal models and as such may prove to be attractive agents for the symptomatic treatment of cognitive disorders such as Alzheimer's disease (AD) and schizophrenia. We report herein the identification and SAR around N-(2-aminoalkyl)-1-(arylsulfonyl)indoline-3-carboxamides-a novel chemotype of 5-HT(6) antagonists.

Developing a Low-Cost, Simple-to-Use Electrochemical Sensor for the Detection of Circulating Tumour DNA in Human Fluids.

It is well-known that two major issues, preventing improved outcomes from cancer are late diagnosis and the evolution of drug resistance during chemotherapy, therefore technologies that address these issues can have a transformative effect on healthcare workflows. In this work we present a simple, low-cost DNA biosensor that was developed specifically to detect mutations in a key oncogene (KRAS). The sensor employed was a screen-printed array of carbon electrodes, used to perform parallel measurements of DNA hybridisation. A DNA amplification reaction was developed with primers for mutant and wild type KRAS sequences which amplified target sequences from representative clinical samples to detectable levels in as few as twenty cycles. High levels of sensitivity were demonstrated alongside a clear exemplar of assay specificity by showing the mutant KRAS sequence was detectable against a significant background of wild type DNA following amplification and hybridisation on the sensor surface. The time to result was found to be 3.5 h with considerable potential for optimisation through assay integration. This quick and versatile biosensor has the potential to be deployed in a low-cost, point-of-care test where patients can be screened either for early diagnosis purposes or monitoring of response to therapy.

Discovery of [11C]MK-6884: A Positron Emission Tomography (PET) Imaging Agent for the Study of M4Muscarinic Receptor Positive Allosteric Modulators (PAMs) in Neurodegenerative Diseases.

The measurement of receptor occupancy (RO) using positron emission tomography (PET) has been instrumental in guiding discovery and development of CNS directed therapeutics. We and others have investigated muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs) for the treatment of symptoms associated with neuropsychiatric disorders. In this article, we describe the synthesis, in vitro, and in vivo characterization of a series of central pyridine-related M4 PAMs that can be conveniently radiolabeled with carbon-11 as PET tracers for the in vivo imaging of an allosteric binding site of the M4 receptor. We first demonstrated its feasibility by mapping the receptor distribution in mouse brain and confirming that a lead molecule 1 binds selectively to the receptor only in the presence of the orthosteric agonist carbachol. Through a competitive binding affinity assay and a number of physiochemical properties filters, several related compounds were identified as candidates for in vivo evaluation. These candidates were then radiolabeled with 11C and studied in vivo in rhesus monkeys. This research eventually led to the discovery of the clinical radiotracer candidate [11C]MK-6884.

Emergency management of paediatric status epilepticus in Australia and New Zealand: practice patterns in the context of clinical practice guidelines.

AIMS: To establish current acute seizure management through a review of clinical practice guidelines (CPGs) and reported physician management in the 11 largest paediatric emergency departments in Australia (n= 9) and New Zealand (n= 2) within the Paediatric Research in Emergency Departments International Collaborative (PREDICT) network, and to compare this with Advanced Paediatric Life Support (APLS) guidelines and existing evidence. METHODS: (i) Review of CPGs for acute seizure management at PREDICT sites. (ii) A standardised anonymous survey of senior emergency doctors at PREDICT sites investigating management of status epilepticus (SE). RESULTS: Ten sites used seven different seizure CPGs. One site had no seizure CPG. First line management was with benzodiazepines (10 sites). Second line and subsequent management included phenytoin (10), phenobarbitone (10), thiopentone (9), paraldehyde (6) and midazolam infusion (5). Of 83 available consultants, 78 (94%) responded. First line management of SE without intravenous (IV) access included diazepam per rectum (PR) (49%), and midazolam intramuscular (41%) and via the buccal route (9%). First line management of SE with IV access included midazolam IV (50%) and diazepam IV (44%). The second line agent was phenytoin (88%); third line agents were phenobarbitone (33%), thiopentone and intubation (32%), paraldehyde PR (22%) and midazolam infusion (6%). Fourth line agents were thiopentone and intubation (60%), phenobarbitone (16%), midazolam infusion (13%) and paraldehyde (9%). CONCLUSIONS: Initial seizure management by CPG recommendations and reported physician practice was broadly similar across PREDICT sites and consistent with APLS guidelines. Practice was variable for second/third line SE management. Areas of controversy would benefit from multi-centred trials.