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BACKGROUND: Treatment resistance (TR) in schizophrenia may be defined by the persistence of positive and/or negative symptoms despite adequate treatment. Whilst previous investigations have focused on positive symptoms, negative symptoms are highly prevalent, impactful, and difficult to treat. In the current study we aimed to develop easily employable prediction models to predict TR in positive and negative symptom domains from first episode psychosis (FEP). METHODS: Longitudinal cohort data from 1027 individuals with FEP was utilised. Using a robust definition of TR, n = 51 (4.97 %) participants were treatment resistant in the positive domain and n = 56 (5.46 %) treatment resistant in the negative domain 12 months after first presentation. 20 predictor variables, selected by existing evidence and availability in clinical practice, were entered into two LASSO regression models. We estimated the models using repeated nested cross-validation (NCV) and assessed performance using discrimination and calibration measures. RESULTS: The prediction model for TR in the positive domain showed good discrimination (AUC = 0.72). Twelve predictor variables (male gender, cannabis use, age, positive symptom severity, depression and academic and social functioning) were retained by each outer fold of the NCV procedure, indicating importance in prediction of the outcome. However, our negative domain model failed to discriminate those with and without TR, with results only just over chance (AUC = 0.56). CONCLUSIONS: Treatment resistance of positive symptoms can be accurately predicted from FEP using routinely collected baseline data, however prediction of negative domain-TR remains a challenge. Detailed negative symptom domains, clinical data, and biomarkers should be considered in future longitudinal studies.

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Childhood-onset type 1 diabetes (T1D) is associated with substantial psychiatric morbidity in later life, but it remains unknown whether these associations are due to common underlying biological mechanisms or the impacts of living with the condition and its treatment. Here, using Czech national register data, we identified children with T1D aged ≤14 years between 1994 and 2007 and estimated the risk of psychiatric disorders up to 24 years later. We found that children diagnosed with T1D had an elevated risk of developing substance use, mood, anxiety and personality disorders, and behavioral syndromes. Conversely, we found that children with T1D had a lower risk of developing psychotic disorders. In Mendelian randomization analysis, we found an association with schizophrenia, which, however, did not persist following multiple testing adjustment. The combined observational and Mendelian randomization evidence suggests that T1D diagnosis in childhood predisposes to far-reaching, extensive psychiatric morbidity, which is unlikely to be explicable by common underlying biological mechanisms. The findings of this study highlight that monitoring and addressing the mental health needs of children with T1D is imperative, whereas glucose dysregulation and/or inflammation implicated in schizophrenia pathogenesis warrants future research.

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OBJECTIVES: To evaluate the impact of persistent opioid use (POU) following surgery or trauma on health outcomes using linked data. SUMMARY BACKGROUND DATA: Surgery and trauma can lead to POU, characterised by continuous opioid consumption following hospital discharge. Outside the US, there is a lack of population-based studies on POU outcomes in opioid-naïve patients following these events. METHOD: We included opioid-naïve patients who were dispensed opioids after being discharged following admission for surgery or trauma to any New Zealand (NZ) hospital from 2007-2019. Differences in outcomes between individuals with and without POU were assessed between 180-360 days after discharge. The primary outcome was all-cause mortality, the secondary outcomes were all-cause and opioid-related hospitalisation, and Days Alive and Out of Hospital (DAOH). Cox and quantile multivariable regression models were used to examine the association between POU and outcomes. RESULTS: Overall, 298,928 surgical and 206,663 trauma patients were included in the final analyses, and 17,779 (5.9%) surgical and 17,867 (8.6%) trauma patients developed POU. POU was significantly associated with increased risk of all-cause mortality (surgical, aHR=6.59; 95% CI 5.82-7.46; trauma, aHR=2.77; 95% CI 2.47-3.11), all-cause hospitalisation (surgical, aHR=2.02; 95% CI 1.95-2.08; trauma, aHR=1.57; 95% CI 1.52-1.62), opioid-related hospitalisation (surgical, aHR=2.49; 95% CI 2.24-2.76; trauma, aHR=1.89; 95% CI 1.73-2.05) and reduced DAOH. CONCLUSIONS: Among opioid-naive patients who received opioids after surgery or trauma, POU was associated with worse outcomes, including increased mortality. Further investigation is warranted to understand the reasons for continued opioid use beyond 90 days and mechanisms associated with harm.

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Replacement of beta cells through transplantation is a potential therapeutic approach for individuals with pancreas removal or poorly controllable type 1 diabetes. However, stress and death of beta cells pose significant challenges. Circulating miRNA has emerged as potential biomarkers reflecting early beta cell stress and death, allowing for timely intervention. The aim of this study was to identify miRNAs as potential biomarkers for beta cell health. Literature review combined with small RNA sequencing was employed to select islet-enriched miRNA. The release of those miRNA was assessed by RT-qPCR in vivo, using a streptozotocin induced diabetes mouse model and in vitro, through mouse and human islets exposed to varying degrees of hypoxic and cytokine stressors. Utilizing the streptozotocin induced model, we identified 18 miRNAs out of 39 candidate islet-enriched miRNA to be released upon islet stress in vivo. In vitro analysis of culture supernatants from cytokine and/or hypoxia stressed islets identified the release of 45 miRNAs from mouse and 8 miRNAs from human islets. Investigation into the biological pathways targeted by the cytokine- and/or hypoxia-induced miRNA suggested the involvement of MAPK and PI3K-Akt signaling pathways in both mouse and human islets. We have identified miRNAs associated with beta cell health and stress. The findings allowed us to propose a panel of 47 islet-related human miRNA that is potentially valuable for application in clinical contexts of beta cell transplantation and presymptomatic early-stage type 1 diabetes.

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Clinical indicators are increasingly used to improve the quality of care, particularly with the emergence of 'big data', but physicians' views regarding their utility in practice is unclear. We reviewed the published literature investigating physicians' perspectives, focusing on the following objectives in relation to quality improvement: (1) the role of clinical indicators, (2) what is needed to strengthen them, (3) their key attributes, and (4) the best tool(s) for assessing their quality. A systematic literature search (up to November 2022) was carried out using: Medline, EMBASE, Scopus, CINAHL, PsycInfo, and Web of Science. Articles that met all of the following inclusion criteria were included: reported on physicians' perspectives on clinical indicators and/or tools for assessing the quality of clinical indicators, addressing at least one of the four review objectives; the clinical indicators related to care at least partially delivered by physicians; and published in a peer-reviewed journal. Data extracted from eligible studies were appraised using the Critical Appraisal Skills Programme tool. A thematic synthesis of data was conducted using NVivo software. Descriptive themes were inductively derived from codes, which were grouped into analytical themes answering each objective. A total of 14 studies were included, with 17 analytical themes identified for objectives 1-3 and no data identified for objective 4. Results showed that indicators can play an important motivating role for physicians to improve the quality of care and show where changes need to be made. For indicators to be effective, physicians should be involved in indicator development, recording relevant data should be straightforward, indicator feedback must be meaningful to physicians, and clinical teams need to be adequately resourced to act on findings. Effective indicators need to focus on the most important areas for quality improvement, be consistent with good medical care, and measure aspects of care within the control of physicians. Studies cautioned against using indicators primarily as punitive measures, and there were concerns that an overreliance on indicators can lead to narrowed perspective of quality of care. This review identifies facilitators and barriers to meaningfully engaging physicians in developing and using clinical indicators to improve the quality of healthcare.

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BACKGROUND: Involving the public in evidence synthesis research is challenging due to the highly analytic nature of the projects, so it is important that involvement processes are documented, reflected upon, and shared to devise best practices. There is a literature gap on the involvement of the public in individual participant data meta-analyses, particularly in public health projects. We aimed to document and reflect on our collective experiences of involving and being involved as public stakeholders at all stages of a systematic review and individual participant data meta-analysis project. METHODS: We formed a stakeholder group made of four members of the public at the beginning of our evidence synthesis project comprising a systematic review, an aggregate data meta-analysis, and an individual participant data meta-analysis of mindfulness-based programmes for mental health promotion in non-clinical adults. Following each group meeting, members and participating researchers completed written reflections; one group member collected and collated these. At the end of the project, a reflective writing workshop was held before all members completed their final reflections. Everyone completed an adapted, open-ended questionnaire which asked about what did and did not work well, the overall experience, what could be improved, and the felt impact the stakeholder group had on the research. RESULTS: Overall, the stakeholders and researchers reported a positive experience of working together. Positives from the stakeholders' point of view included learning new skills, experiencing research, and making new friends. For the researchers, stakeholders helped them focus on what matters to the public and were reinvigorating research partners. The challenges stakeholders experienced included having long gaps between meetings and feeling overwhelmed. The researchers found it challenging to strike the balance between asking stakeholders to be involved and for them to learn research-related skills without overburdening them and making sure that the learning was engaging. When looking back at their experience, stakeholders described seeing their impact on the project in hindsight but that this was not felt while the project was being carried out. CONCLUSION: Successfully involving the public in complex evidence synthesis projects is possible and valuable from the points of view of the researchers and the stakeholders. However, it requires a significant time, skill, and resource investment that needs to be factored in from project inception. Further guidance and stakeholder training materials would be helpful. Specific suggestions are provided.

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The compounds 2',3',4',6'-tetra-O-acetyl-ß-d-gluco-pyranosyl N'-cyano-N-phenyl-carbamimido-thio-ate (C22H25N3O9S, 5a), 2',3',4',6'-tetra-O-acetyl-ß-d-galacto-pyranosyl N'-cyano-N-phenyl-carbamimido-thio-ate, (C22H25N3O9S, 5b), 2',3',4',6'-tetra-O-acetyl-ß-d-galacto-pyranosyl N'-cyano-N-methyl-carbamimido-thio-ate (C17H23N3O9S, 5c), and 2',3',4',6'-tetra-O-acetyl-ß-d-galacto-pyranosyl N'-cyano-N-p-tolyl-carbamimido-thio-ate (C23H27N3O9S, 5d) all crystallize in P212121 with Z = 4. For all four structures, the configuration across the central (formal) C=N(CN) double bond of the carbamimido-thio-ate group is Z. The torsion angles C5-O1-C1-S (standard sugar numbering) are all close to 180°, confirming the ß position of the substituent. Compound 5b involves an intra-molecular hydrogen bond N-H⋯O1; in 5c this contact is the weaker branch of a three-centre inter-action, whereas in 5a and 5d the H⋯O distances are much longer and do not represent significant inter-actions. The C-N bond lengths at the central carbon atom of the carbamimido-thio-ate group are almost equal. All C-O-C=O torsion angles of the acetyl groups correspond to a synperiplanar geometry, but otherwise all four mol-ecules display a high degree of conformational flexibility, with many widely differing torsion angles for equivalent groups. In the crystal packing, 5a, 5c and 5d form layer structures involving the classical hydrogen bond N-H⋯Ncyano and a variety of 'weak' hydrogen bonds C-H⋯O or C-H⋯S. The packing of 5b is almost featureless and involves a large number of borderline 'weak' hydrogen bonds. In an appendix, a potted history of wavelength preferences for structure determination is presented and it is recommended that, even for small organic crystals in non-centrosymmetric space groups, the use of Mo radiation should be considered.

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The structures of seven gold(III) halide derivatives of general formula LAuX 3 (L = methyl-pyridines or di-methyl-pyridines, X = Cl or Br) are presented: tri-chlorido-(2-methyl-pyridine)-gold(III), [AuCl3(C6H7N)], 1 (as two polymorphs 1a and 1b); tri-bromido-(2-methyl-pyridine)-gold(III), [AuBr3(C6H7N)], 2; tri-bromido-(3-methyl-pyridine)-gold(III), [AuBr3(C6H7N)], 3; tri-bromido-(2,4-di-meth-yl-pyridine)-gold(III), [AuBr3(C7H9N)], 4; tri-chlorido-(3,5-di-methylpyridine)-gold(III), [AuCl3(C7H9N)], 5; tri-bromido-(3,5-di-methyl-pyridine)-gold(III), [AuBr3(C7H9N)], 6, and tri-chlorido-(2,6-di-methyl-pyridine)-gold(III), [AuCl3(C7H9N)], 7. Additionally, the structure of 8, the 1:1 adduct of 2 and 6, [AuBr3(C6H7N)]·[AuBr3(C7H9N)], is included. All the structures crystallize solvent-free, and all have Z' = 1 except for 5 and 7, which display crystallographic twofold rotation symmetry, and 4, which has Z' = 2. 1a and 2 are isotypic. The coordination geometry at the gold(III) atoms is, as expected, square-planar. Four of the crystals (1a, 1b, 2 and 8) were non-merohedral twins, and these structures were refined using the 'HKLF 5' method. The largest inter-planar angles between the pyridine ring and the coordination plane are observed for those structures with a 2-methyl substituent of the pyridine ring. The Au-N bonds are consistently longer trans to Br (average 2.059 Å) than trans to Cl (average 2.036 Å). In the crystal packing, a frequent feature is the offset-stacked and approximately rectangular dimeric moiety (Au-X)2, with anti-parallel Au-X bonds linked by Au⋯X contacts at the vacant positions axial to the coordination plane. The dimers are connected by further secondary inter-actions (Au⋯X or X⋯X contacts, 'weak' C-H⋯X hydrogen bonds) to form chain, double chain ('ladder') or layer structures, and in several cases linked again in the third dimension. Only 1b and 7 contain no offset dimers; these structures instead involve C-H⋯Cl hydrogen bonds combined with Cl⋯Cl contacts (1b) or Cl⋯π contacts (7). The packing patterns of seven further complexes LAuX 3 involving simple pyridines (taken from the Cambridge Structural Database) are compared with those of 1-8.

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BACKGROUND: It remains unknown whether severe mental disorders contribute to fatally harmful effects of physical illness. AIMS: To investigate the risk of all-cause death and loss of life-years following the onset of a wide range of physical health conditions in people with severe mental disorders compared with matched counterparts who had only these physical health conditions, and to assess whether these associations can be fully explained by this patient group having more clinically recorded physical illness. METHOD: Using Czech national in-patient register data, we identified individuals with 28 physical health conditions recorded between 1999 and 2017, separately for each condition. In these people, we identified individuals who had severe mental disorders recorded before the physical health condition and exactly matched them with up to five counterparts who had no recorded prior severe mental disorders. We estimated the risk of all-cause death and lost life-years following each of the physical health conditions in people with pre-existing severe mental disorders compared with matched counterparts without severe mental disorders. RESULTS: People with severe mental disorders had an elevated risk of all-cause death following the onset of 7 out of 9 broadly defined and 14 out of 19 specific physical health conditions. People with severe mental disorders lost additional life-years following the onset of 8 out 9 broadly defined and 13 out of 19 specific physical health conditions. The vast majority of results remained robust after considering the potentially confounding role of somatic multimorbidity and other clinical and sociodemographic factors. CONCLUSIONS: A wide range of physical illnesses are more likely to result in all-cause death in people with pre-existing severe mental disorders. This premature mortality cannot be fully explained by having more clinically recorded physical illness, suggesting that physical disorders are more likely to be fatally harmful in this patient group.

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The polynuclear complex [{µ-C1,C4,N,N″-C6H2{C(H)=N(nBu)}2-2,5}{Pd(µ-OAc)}]2 (I) reacts with tbbpy (4,4'-di-tert-butyl-2,2'-bipyridine) and TlOTf to form the dinuclear complex [{µ-C1,C4,N,N″-C6H2{C(H)=N(nBu)}2-2,5}{Pd(tbbpy)}2] (1). The hydrolysis of I with acetic acid in a 5:1 acetone/water mixture, in the presence of two equivalents of tbbpy and excess NaX (X = Br, I), yields the dipalladated terephthalaldehyde complexes [C6H2{PdX(tbbpy)}2-1,4-(CHO)2-2,5] [X = Br (2a), X = I (2b)], which are the first fully characterized complexes of this type. The reaction of 2a,b with CO results in the insertion of CO into both aryl-Pd bonds, forming [C6H2{C(O){PdX(tbbpy)}}2-1,4-(CHO)2-2,5] [X = Br (3a), X = I (3b)], which are the first examples of complexes with CO inserted into two separate aryl-metal bonds involving the same ligand. The bromo complex 2a reacts with excess XylNC in acetone, causing the precipitation of the dinuclear complex 2,3,6,7-tetrahydrobenzo[1,2-c:4,5-c']dipyrrole-1,5-dione-2,6-dixylyl-3,7-bis{=C(NHXyl)-C(=NXyl)-[PdBr(CNXyl)2]} (4), which is the result of the insertion of three molecules of the isocyanide into each aryl-Pd bond and the nucleophilic attack of one of them at each formyl group. When complex 4 reacts with TlOTf and residual water in 1,2-dichloroethane at 70 °C, depalladation occurs, and the organic compound 2,3,6,7-tetrahydrobenzo[1,2-c:4,5-c']dipyrrole-1,5-dione-2,6-dixylyl-3,7-bis{=C(NHXyl)-C(O)NHXyl} (5) can be isolated. The crystal structures of 1·4CHCl3, 4·2CH2Cl2·3hexane, and 5·2CDCl3 have been determined by X-ray crystallography.

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BACKGROUND: A clinical tool to estimate the risk of treatment-resistant schizophrenia (TRS) in people with first-episode psychosis (FEP) would inform early detection of TRS and overcome the delay of up to 5 years in starting TRS medication. AIMS: To develop and evaluate a model that could predict the risk of TRS in routine clinical practice. METHOD: We used data from two UK-based FEP cohorts (GAP and AESOP-10) to develop and internally validate a prognostic model that supports identification of patients at high-risk of TRS soon after FEP diagnosis. Using sociodemographic and clinical predictors, a model for predicting risk of TRS was developed based on penalised logistic regression, with missing data handled using multiple imputation. Internal validation was undertaken via bootstrapping, obtaining optimism-adjusted estimates of the model's performance. Interviews and focus groups with clinicians were conducted to establish clinically relevant risk thresholds and understand the acceptability and perceived utility of the model. RESULTS: We included seven factors in the prediction model that are predominantly assessed in clinical practice in patients with FEP. The model predicted treatment resistance among the 1081 patients with reasonable accuracy; the model's C-statistic was 0.727 (95% CI 0.723-0.732) prior to shrinkage and 0.687 after adjustment for optimism. Calibration was good (expected/observed ratio: 0.999; calibration-in-the-large: 0.000584) after adjustment for optimism. CONCLUSIONS: We developed and internally validated a prediction model with reasonably good predictive metrics. Clinicians, patients and carers were involved in the development process. External validation of the tool is needed followed by co-design methodology to support implementation in early intervention services.

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BACKGROUND: Mindfulness-based programmes (MBPs) have shown beneficial effects on mental health. There is emerging evidence that MBPs may also be associated with marked deviations in the subjective experience of waking consciousness. We aimed to explore whether MBPs can have a causal role in different types of such states. METHODS: We conducted a pragmatic randomised controlled trial (ACTRN12615001160527). University of Cambridge students without severe mental illness were randomised to an 8-week MBP plus mental health support as usual (SAU), or to SAU alone. We adapted the Altered States of Consciousness Rating Scale (OAV, 0-100-point range) to assess spontaneous experiences in daily life, and included it as a post-hoc secondary outcome at the end of the one-year follow-up questionnaire. Two-part model analyses compared trial arms, and estimated dose-response effects of formal (meditation) and informal (daily activities) mindfulness practice during the year. Sensitivity analyses correcting for multiple comparisons were conducted. RESULTS: We randomised 670 participants; 205 (33%) completed the OAV. In comparison with SAU, MBP participants experienced unity more frequently and intensively (two-part marginal effect (ME) = 6.26 OAV scale points, 95% confidence interval (CI) = 2.24, 10.27, p = 0.006, Cohen's d = 0.33) and disembodiment more frequently (ME = 4.84, 95% CI = 0.86, 8.83, p = 0.019, Cohen's d = 0.26). Formal practice predicted spiritual, blissful and unity experiences, insightfulness, disembodiment, and changed meanings. Informal practice predicted unity and blissful experiences. Trial arm comparisons and informal practice effects lost significance after corrections for multiple comparisons, but formal practice dose-response effects remained significant. CONCLUSIONS: Results provide a novel suggestion of causal links between mindfulness practice and specific altered states of consciousness. To optimise their impact, practitioners and teachers need to anticipate and handle them appropriately. Future studies need to confirm findings and assess mechanisms and clinical implications.

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Adeno-associated virus-mediated gene therapies for certain muscle disorders require regulatory cassettes that provide high-level, striated muscle-specific activity. However, cardiotoxicity has emerged as a serious concern in clinical trials for Duchenne muscular dystrophy and X-linked myotubular myopathy. While this may be caused by systemic inflammatory effects of the treatment, high transgene expression in the heart may also play a role. Thus, certain muscle disorders may require a modulated level of therapeutic expression in the heart, while others may not require any cardiac expression at all. Additionally, the size of some cargos requires regulatory cassettes to be small enough that large cDNAs and other therapeutic payloads can be accommodated. Thus, we have performed enhancer/promoter optimization to develop highly minimized regulatory cassettes that are active in skeletal muscles, with either low or no detectable activity in cardiac muscle. Our No-heart (NH) cassette is active in most skeletal muscles, but exhibits only very low activity in extensor digitorum longus (EDL), soleus, and diaphragm, and no activity in the heart. By contrast, our Have a Little Heart (HLH) cassette displays high activity in most skeletal muscles, comparable to the ∼800-bp CK8 cassette, with increased activity in EDL, soleus, and diaphragm, and low activity in the heart. Due to their small size, these cassettes can be used in therapeutic strategies with both flexible (e.g., antisense) and stringent (e.g., CRISPR/Cas or bicistronic) size limitations. Thus, our new cassettes may be useful for gene therapies of muscle disorders in which the need for low or almost no expression in cardiac muscle would outweigh the need for high levels of therapeutic product in certain skeletal muscles.

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The Industrial Revolution precipitated a pivotal shift from waterpower to coal-fueled steam power in British textile mills. Although it is now widely accepted that steam was chosen to power factories despite the availability of sufficient waterpower resources across most of Britain, the location and suitability of that waterpower during the early 19th century remain underexplored. Here, we employ quantitative fluvial geomorphology alongside historical climate data, factory records, and a catalog of over 26,000 mill sites to reveal that waterpower was abundant for most of early 19th century Britain, except in the central hub of British cotton production: Greater Manchester in the Mersey Basin. Our findings show that surging factory mechanization and overcrowding on key waterways in the Mersey Basin compounded waterpower scarcity arising from a drier 19th century climate. Widespread adoption of coal-fueled steam engines in certain key industrial centers of Britain was a strategy aimed at ameliorating some of the reduced reliability of waterpower. The fact that steam engines were frequently used in water-powered factories in many industrial regions until the third quarter of the 19th century to recirculate water to provide that power, or as a power supplement when waterpower availability was restricted, adds further weight to our argument. Rapid adoption of coal-powered steam engines reshaped the social and structural landscape of industrial work, firmly established Britain's prominence as an industrial powerhouse, and had lasting global industrial and environmental impacts.

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Bis(2-methyl-pyridine)-gold(I) di-bromido-aurate(I), [Au(C6H7N)2][AuBr2], (1), crystallizes in space group C2/c with Z = 4. Both gold atoms lie on twofold axes and are connected by an aurophilic contact. A second aurophilic contact leads to infinite chains of alternating cations and anions parallel to the b axis, and the residues are further connected by a short H⋯Au contact and a borderline Br⋯Br contact. Bis(3-methyl-pyridine)-gold(I) di-bromido-aurate(I), [Au(C6H7N)2][AuBr2], (2), crystallizes in space group C2/m with Z = 2. Both gold atoms lie on special positions with symmetry 2/m and are connected by an aurophilic contact; all other atoms except for one methyl hydrogen lie in mirror planes. The extended structure is closely analogous to that of 1, although the structures are formally not isotypic. Bis(3,5-di-methyl-pyridine)-gold(I) di-chlor-ido-aurate(I), [Au(C7H9N)2][AuCl2], (3) crystallizes in space group P with Z = 2. The cation lies on a general position, and there are two independent anions in which the gold atoms lie on inversion centres. The cation and one anion associate via three short H⋯Cl contacts to form a ribbon structure parallel to the b axis; aurophilic contacts link adjacent ribbons. Bis(3,5-di-methyl-pyridine)-gold(I) di-bromido-aurate(I), [Au(C7H9N)2][AuBr2], (4) is isotypic to 3. Attempts to make similar compounds involving 2-bromo-pyridine led instead to 2-bromopyridinium di-bromido-aurate(I)-2-bromo-pyridine (1/1), (C5H5BrN)[AuBr2]·C5H4BrN, (5), which crystallizes in space group P with Z = 2; all atoms lie on general positions. The 2-bromo-pyridinium cation is linked to the 2-bromo-pyridine mol-ecule by an N-H⋯N hydrogen bond. Two formula units aggregate to form inversion-symmetric dimers involving Br⋯Br, Au⋯Br and H⋯Br contacts.

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PURPOSE: To document the 2-year mortality and seizure recurrence rate of a prospective cohort of patients identified with status epilepticus (SE). METHODS: Patients presenting to any hospital in the Auckland region between April 6 2015, and April 5 2016, with a seizure lasting 10 min or longer were identified. Follow up was at 2 years post index SE episode via telephone calls and detailed review of clinical notes. RESULTS: We identified 367 patients with SE over the course of one year. 335/367 (91.3 %) were successfully followed up at the 2-year mark. Two-year all-cause mortality was 50/335 (14.9 %), and 49/267 (18.4 %) when febrile SE was excluded. Two-year seizure recurrence was 197/335 (58.8 %). On univariate analyses, children (preschoolers 2 to < 5 years and children 5 to < 15 years), Asian ethnicity, SE duration <30 mins and acute (febrile) aetiology were associated with lower mortality, while older age >60 and progressive causes were associated with higher mortality on both univariate and multivariate analyses. Age < 2 years and acute aetiology were associated with lower seizure recurrence, while non convulsive status epilepticus (NCSE) with coma and a history of epilepsy were associated with higher seizure recurrence. On multivariate analyses, a history of epilepsy, as well as having both acute and remote causes were associated with higher seizure recurrence. CONCLUSIONS: All-cause mortality in both the paediatric and adult populations at 2 years was lower than most previous reports. Older age, SE duration ≥30 mins and progressive aetiologies were associated with the highest 2-year mortality, while febrile SE had the lowest mortality. A history of epilepsy, NCSE with coma, and having both acute and remote causes were associated with higher seizure recurrence at 2 years. Future studies should focus on functional measures of outcome and long-term quality of life.

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ABSTRACT: Persistent opioid use (POU) is a common marker of harm related to opioid use after trauma. This study determined the incidence and risk factors for POU after hospitalisation due to trauma in New Zealand, among opioid-naïve patients. This was a population-based, retrospective cohort study, using linked data, involving all trauma patients of any age admitted to all NZ hospitals between 2007 and 2019. We included all patients who received opioids after discharge and were considered opioid naïve, defined as not having received opioids or not having a prior diagnosis of opioid-use disorder up to 365 days preceding the discharge date. The primary outcome was the incidence of POU defined as opioid use after discharge between 91 and 365 days. We used a multivariable logistic regression to identify independent risk factors for POU. A total of 177,200 patients were included in this study. Of these, 15.3% (n = 27,060) developed POU based on criteria used for the primary analysis, with sensitivity analyses showing POU incidence ranging from 14.3% to 0.8%. The opioid exposure risk factors associated with POU included switching between different opioids (adjusted odds ratio [aOR] 2.62; 95% confidence interval [CI] 2.51-2.73), prescribed multiple opioids (vs codeine, aOR 1.44; 95% CI 1.37-1.53), slow-release opioid formulations (aOR 1.32; 95% CI 1.26-1.39), and dispensed higher total doses of on the initial discharge prescription (aOR 1.26; 95% CI 1.20-1.33). Overall, 1 in 7 opioid-naïve patients who were exposed to opioids after trauma developed POU. Our findings highlight clinicians should be aware of these factors when continuing opioids on discharge.

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BACKGROUND: Persistent opioid use (POU) can occur with opioid use after surgery or trauma. Current systematic reviews include patients with previous exposure to opioids, meaning their findings may not be relevant to patients who are opioid naïve (i.e. Most recent exposure was from surgery or trauma). The aim of this review was to synthesise narratively the evidence relating to the incidence of, and risk factors for POU in opioid-naïve surgical or trauma patients. METHOD: Structured searches of Embase, Medline, CINAHL, Web of Science, and Scopus were conducted, with final search performed on the 17th of July 2023. Searches were limited to human participants to identify studies that assessed POU following hospital admission due to surgery or trauma. Search terms relating to 'opioid', 'analgesics', 'surgery', 'injury', 'trauma' and 'opioid-related disorder' were combined. The Newcastle-Ottawa Scale for cohort studies was used to assess the risk of bias for studies. RESULTS: In total, 22 studies (20 surgical and two trauma) were included in the analysis. Of these, 20 studies were conducted in the United States (US). The incidence of POU for surgical patients 18 and over ranged between 3.9% to 14.0%, and for those under 18, the incidence was 2.0%. In trauma studies, the incidence was 8.1% to 10.5% among patients 18 and over. Significant risk factors identified across surgical and trauma studies in opioid-naïve patients were: higher comorbidity burden, having pre-existing mental health or chronic pain disorders, increased length of hospital stay during the surgery/trauma event, or increased doses of opioid exposure after the surgical or trauma event. Significant heterogeneity of study design precluded meta-analysis. CONCLUSION: The quality of the studies was generally of good quality; however, most studies were of US origin and used medico-administrative data. Several risk factors for POU were consistently and independently associated with increased odds of POU, primarily for surgical patients. Awareness of these risk factors may help prescribers recognise the risk of POU after surgery or trauma, when considering continuing opioids after hospitalisation. The review found gaps in the literature on trauma patients, which represents an opportunity for future research. TRIAL REGISTRATION: PROSPERO registration: CRD42023397186.

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BACKGROUND: A maturity matrix can be a useful tool for organisations implementing large-system transformation (LST) initiatives in complex systems. Insights from implementation of a local LST initiative using collaborative networks, known as Alliances, highlighted a tool was needed to help health system leaders prompt discussions on how and where to focus their change efforts. In the New Zealand (NZ) health system, Alliances were introduced to integrate the planning and delivery of health care between primary and hospital care. METHODS: The aim of this research was to use insights from Alliance members to develop a learning tool that collaborative networks could use to assess and improve their readiness for change. We constructed a maturity matrix using the knowledge of senior NZ health system leaders, in a workshop setting. The maturity matrix was empirically tested and refined with three Alliances and with feedback from the NZ Ministry of Health Maori Health Strategy and Policy team. RESULTS: The maturity matrix described the 10 key elements that had been found to support successful implementation of LST initiatives in the NZ health system, along with success indicators and different stages of maturity from beginning to excellence. Testing of the maturity matrix with three Alliances suggested that it functioned as a learning tool and stimulated collective thinking and reflection. The Maori Health Strategy and Policy team commented on the importance of such a tool to increase health system leaders' responsiveness to improving Maori health outcomes. Comparisons with similar international matrices revealed common elements with ours. A strength of our maturity matrix is that it is specific to the NZ context and is the first practical tool to implement large-scale change in the health system that incorporates principles of the Government's treaty with Maori, the indigenous people of NZ. CONCLUSIONS: Through a regular self-assessment process, use of the maturity matrix may create feedback loops to support deliberate learning and knowledge sharing for senior health system leaders and collaborative networks. The maturity matrix fills an important gap in the NZ health system and contributes to implementation science literature internationally. OTHER: This study was approved by the Victoria University of Wellington Human Ethics Committee (Ethics Approval Number 27,356). The research was supported by the Victoria University of Wellington research grant (222,809) and from the University of Auckland Department of Medicine research fund (H10779).

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