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Abstract Histone mutations (H3 K27M, H3 G34R/V) are molecular features defining subtypes of paediatric-type diffuse high-grade gliomas (HGG) (diffuse midline glioma (DMG), H3 K27-altered, diffuse hemispheric glioma (DHG), H3 G34-mutant). The WHO classification recognises in exceptional cases, these mutations co-occur. We report one such case of a 2-year-old female presenting with neurological symptoms; MRI imaging identified a brainstem lesion which was biopsied. Histology showed diffusely infiltrating pleomorphic astrocytes, multinucleated cells, and conspicuous mitotic activity; the diagnosis was DMG, H3 K27-altered (immunohistochemistry: H3K27me3 loss, H3K27M positivity). DNA methylation profiling (Illumina EPIC BeadArrays, brain tumour classifier (MNP v12.5 R package)) classified the tumour as ‘DMG, H3 K27-altered’ (calibrated score = 0.99). Further molecular studies (whole exome, whole genome sequencing) revealed concurrent H3.1 K27M and G34R mutations (clonal, in the same reads) of H3C3, FGF11 and PIK3CA somatic variants, and a pathogenic germline NBN variant. The RNAseq profile clustered with H3K27M-mutant tumours. A patient-derived cell culture was established enabling unbiased in vitro drug screening; no selective sensitivities were identified. Chromatin immunoprecipitation assays with sequencing (ChIP-seq; H3K27ac, H3K27me3, H3K36me3, RNApol2 marks) showed features in keeping with DMG H3 K27M-mutant tumours (H3K27ac loci including OLIG2, IRX1/2, PKDCC). The patient was treated with adjuvant radiotherapy, but progressed and passed away 13 months post-diagnosis. This case is an exceptionally rare, complex variant of histone-mutant paediatric HGG, illustrating that the H3.1 K27M mutation demonstrates a dominance over the molecular and clinical profiles compared to G34R, and highlights the importance of broad molecular profiling to identify such examples for further study.

Full-field transmission X-ray microscopy has been recently implemented at the hard X-ray ROCK–SOLEIL quick-EXAFS beamline, adding micrometre spatial resolution to the second time resolution characterizing the beamline. Benefiting from a beam size versatility due to the beamline focusing optics, full-field hyperspectral XANES imaging has been successfully used at the Fe K-edge for monitoring the pressure-induced spin transition of a 150 µm × 150 µm Fe(o-phen)2(NCS)2 single crystal and the charge of millimetre-sized LiFePO4 battery electrodes. Hyperspectral imaging over 2000 eV has been reported for the simultaneous monitoring of Fe and Cu speciation changes during activation of a FeCu bimetallic catalyst along a millimetre-sized catalyst bed. Strategies of data acquisition and post-data analysis using Jupyter notebooks and multivariate data analysis are presented, and the gain obtained using full-field hyperspectral quick-EXAFS imaging for studies of functional materials under process conditions in comparison with macroscopic information obtained by non-spatially resolved quick-EXAFS techniques is discussed.

Abstract Imaging the internal architecture of fast-vibrating structures at micrometer scale and kilohertz frequencies poses great challenges for numerous applications, including the study of biological oscillators, mechanical testing of materials, and process engineering. Over the past decade, X-ray microtomography with retrospective gating has shown very promising advances in meeting these challenges. However, breakthroughs are still expected in acquisition and reconstruction procedures to keep improving the spatiotemporal resolution, and study the mechanics of fast-vibrating multiscale structures. Thereby, this works aims to improve this imaging technique by minimising streaking and motion blur artefacts through the optimisation of experimental parameters. For that purpose, we have coupled a numerical approach relying on tomography simulation with vibrating particles with known and ideal 3D geometry (micro-spheres or fibres) with experimental campaigns. These were carried out on soft composites, imaged in synchrotron X-ray beamlines while oscillating up to 400 Hz, thanks to a custom-developed vibromechanical device. This approach yields homogeneous angular sampling of projections and gives reliable predictions of image quality degradation due to motion blur. By overcoming several technical and scientific barriers limiting the feasibility and reproducibility of such investigations, we provide guidelines to enhance gated-CT 4D imaging for the analysis of heterogeneous, high-frequency oscillating materials.

Abstract Identifying evidence of human modification of extinct animal remains, such as Pleistocene megafauna, is challenging due to the similarity of anthropogenic and non-anthropogenic taphonomic features observed under optical microscopy. Here, we re-investigate a Late Pleistocene ground sloth tooth from northeast Brazil, previously suggested as human-modified based only on optical observation. To characterize the macro- and micro-morphological characteristics of the marks preserved in this tooth and evaluate potential human modification, we used stereomicroscope and scanning electron microscopy (SEM) supplemented by energy dispersive spectroscopy (EDS), UV photoluminescence (UV/PL), synchrotron-based X-ray fluorescence (SR-XRF), and synchrotron micro-computed tomography (SR-µCT). These methods allowed us to discriminate non-anthropogenic taphonomic features (root and sedimentary damage), anthropogenic marks, and histological features. The latter shows the infiltration of exogenous elements into the dentine from the sediments. Our evidence demonstrates the sequence of anthropogenic and non-anthropogenic taphonomic modification of this tooth and supports its initial intentional modification by humans. We highlight the benefits of emerging imaging and spectral imaging techniques to investigate and diagnose human modification in fossil and archaeological records and propose that human modification of tooth tissues should be further considered when studying possibly anthropogenically altered fossil remains.

This study examines several methods and new ideas for climate analysis, including expanded ensembles, that combine model projections from different greenhouse gas emissions pathways and different time periods. These methods are tested on Australian projections data previously made available based on outputs from the Energy Sector for Climate Information (ESCI) project that included all available dynamical downscaling approaches with bias correction designed with attention to detail on extremes. The expanded ensemble method provides larger sample sizes to help enhance confidence, with results showing that the projected changes per degree of global warming have relatively small differences when calculated using two different emission pathways and different time periods, with smaller differences than variations between individual models in the ensemble. Results include maps of mean values and extremes for temperature and rainfall metrics, as well as for compound events associated with dangerous bushfire weather conditions, providing new insights on climate change in Australia. The results also show that extremely dangerous fire conditions such as those of the Black Summer 2019/2020 and of Black Saturday in February 2009 are currently still very rare, but that climate change has already increased the chance of their occurrence, as well as larger increases projected in the future for higher amounts of greenhouse gas emissions. New analysis is also presented for changes in rainfall-based metrics associated with agriculture and biogeography such as Goyder’s Line, discussed in relation to the use of climate analogues for adaptation decision making.

Purpose: To report two cases of catastrophic retinal vascular occlusion and crystalline retinopathy due to presumed oxalosis and hyperphosphatemia. Observations: We describe two unrelated patients with end-stage kidney failure (ESKD) treated with peritoneal dialysis that developed rapid bilateral vision loss due to severe retinal vascular occlusion. Multi-modal retinal imaging studies demonstrated crystalline deposits. Plasma phosphorus and oxalate levels were markedly elevated compared to persons with normal kidney function. One patient harbored a heterozygous variant of unknown significance in the Alanine--Glyoxylate Aminotransferase (AGXT) gene. Intense hemodialysis and diet modification reduced phosphorus and oxalate levels. Conclusions and importance: This report serves to raise awareness of hyperphosphatemia and oxalosis in dialysis patients to alert providers so that they can act to decrease the potential risk of vision loss.

Abstract The biology of extinct animals is usually reconstructed from external morphological characters and comparison with present-day analogues. Internal soft organs are very rarely preserved in fossils and require high-tech approaches for visualization. Here, we report the internal anatomy of a female and male of the ~ 162 Myr-old lobster Eryma ventrosum from the Jurassic La Voulte-sur-Rhône Konservat-Lagerstätte in France using X-ray synchrotron tomography. The Erymidae is an extinct, species-rich, widespread and ecologically important Mesozoic family of decapod crustaceans. Our investigation revealed the anatomy of the locomotory, respiratory, circulatory, excretory, digestive, nervous and sensory, and reproductive systems at a resolution resembling low-magnification histology. Particularly notable is the detailed preservation of the small brain and the fragile hepatopancreas, the main metabolic organ of decapods that decays rapidly post-mortem. The remarkable preservation shows that the internal anatomy of Eryma ventrosum is closer to that of Nephropidae (clawed lobsters) than Astacidae (freshwater crayfish), their closest living relatives based on skeletal morphology. The microanatomy of the gonads and hepatopancreas indicates that the two specimens investigated were a young, well-nourished female and male prior to sexual maturity. The analysis of the soft anatomy reveals remarkable conservatism over 160 Myr and offers new insights into feeding, reproduction, life history and lifestyle of an important component of the macrozoobenthos of Middle Jurassic seas.

Summary: Background: Large-scale multicentre studies are needed to understand complex relationships between the gut microbiota, health and disease. Interrogating the mucosal microbiota may identify important biology not captured by stool analysis. Gold standard tissue cryopreservation (‘flash freezing’) limits large-scale study feasibility. We aimed to compare gut microbiota in gold standard and pragmatic mucosal biopsy storage conditions. Methods: We collected endoscopic recto-sigmoid biopsies from 20 adults with inflammatory bowel disease. Biopsies were preserved using three methods: (i) flash freezing (most proximal and distal biopsy sites); (ii) nucleic acid preservative reagents (QIAGEN Allprotect®, Invitrogen RNAlater™, and Zymo DNA/RNA Shield™); and (iii) formalin fixation with paraffin embedding (FFPE), which is used to preserve tissue for clinical histopathology within healthcare settings. Microbiota were sequenced on the MiSeq platform (V4 region, 16S rRNA gene). Findings: Tissue microbiota were consistent between most proximal and distal tissue suggesting any within-patient variation observed reflected storage condition, not biopsy location. There was no significant difference in alpha-diversity or microbial community profiles of reagent-preserved versus gold standard tissue. FFPE community structure was significantly dissimilar to other tissue samples, driven by differential relative abundance of obligate gut anaerobes; Faecalibacterium, Anaerostipes and Lachnospiraceae. Despite these differences, tissue microbiota grouped by participant regardless of preservation and storage conditions. Interpretation: Preservative reagents offer a convenient alternative to flash freezing tissue in prospective large-scale mucosal microbiota studies. Whilst less comparable, FFPE provides potential for retrospective microbiota studies using historical samples. Funding: Medical Research Council (MR/T032162/1) and The Leona M. and Harry B. Helmsley Charitable Trust (G-2002-04255).

Introduction In liver cirrhosis, acute variceal bleeding (AVB) is associated with a 1-year mortality rate of up to 40%. Data on early or pre-emptive transjugular intrahepatic portosystemic stent–shunt (TIPSS) in AVB is inconclusive and may not reflect current management strategies. Randomised controlled trial of EArly transjugular intrahepatiC porTosystemic stent–shunt in AVB (REACT-AVB) aims to investigate the clinical and cost-effectiveness of early TIPSS in patients with cirrhosis and AVB after initial bleeding control.Methods and analysis REACT-AVB is a multicentre, randomised controlled, open-label, superiority, two-arm, parallel-group trial with an internal pilot. The two interventions allocated randomly 1:1 are early TIPSS within 4 days of diagnostic endoscopy or secondary prophylaxis with endoscopic therapy in combination with non-selective beta blockers. Patients aged ≥18 years with cirrhosis and Child-Pugh Score 7–13 presenting with AVB with endoscopic haemostasis are eligible for inclusion. The primary outcome is transplant-free survival at 1 year post randomisation. Secondary endpoints include transplant-free survival at 6 weeks, rebleeding, serious adverse events, other complications of cirrhosis, Child-Pugh and Model For End-Stage Liver Disease (MELD) scores at 6 and 12 months, health-related quality of life, use of healthcare resources, cost-effectiveness and use of cross-over therapies. The sample size is 294 patients over a 4-year recruitment period, across 30 hospitals in the UK.Ethics and dissemination Research ethics committee of National Health Service has approved REACT-AVB (reference number: 23/WM/0085). The results will be submitted for publication in a peer-reviewed journal. A lay summary will also be emailed or posted to participants before publication.Trial registration number ISRCTN85274829; protocol version 3.0, 1 July 2023.

Objective To estimate the cost-effectiveness of craniotomy, compared with decompressive craniectomy (DC) in UK patients undergoing evacuation of acute subdural haematoma (ASDH).Design Economic evaluation undertaken using health resource use and outcome data from the 12-month multicentre, pragmatic, parallel-group, randomised, Randomised Evaluation of Surgery with Craniectomy for Patients Undergoing Evacuation-ASDH trial.Setting UK secondary care.Participants 248 UK patients undergoing surgery for traumatic ASDH were randomised to craniotomy (N=126) or DC (N=122).Interventions Surgical evacuation via craniotomy (bone flap replaced) or DC (bone flap left out with a view to replace later: cranioplasty surgery).Main outcome measures In the base-case analysis, costs were estimated from a National Health Service and Personal Social Services perspective. Outcomes were assessed via the quality-adjusted life-years (QALY) derived from the EuroQoL 5-Dimension 5-Level questionnaire (cost-utility analysis) and the Extended Glasgow Outcome Scale (GOSE) (cost-effectiveness analysis). Multiple imputation and regression analyses were conducted to estimate the mean incremental cost and effect of craniotomy compared with DC. The most cost-effective option was selected, irrespective of the level of statistical significance as is argued by economists.Results In the cost-utility analysis, the mean incremental cost of craniotomy compared with DC was estimated to be −£5520 (95% CI −£18 060 to £7020) with a mean QALY gain of 0.093 (95% CI 0.029 to 0.156). In the cost-effectiveness analysis, the mean incremental cost was estimated to be −£4536 (95% CI −£17 374 to £8301) with an OR of 1.682 (95% CI 0.995 to 2.842) for a favourable outcome on the GOSE.Conclusions In a UK population with traumatic ASDH, craniotomy was estimated to be cost-effective compared with DC: craniotomy was estimated to have a lower mean cost, higher mean QALY gain and higher probability of a more favourable outcome on the GOSE (though not all estimated differences between the two approaches were statistically significant).Ethics Ethical approval for the trial was obtained from the North West—Haydock Research Ethics Committee in the UK on 17 July 2014 (14/NW/1076).Trial registration number ISRCTN87370545.

Abstract In the present study, in-situ observation of Hot Isostatic Pressure (HIP) procedure of laser powder bed fusion manufactured Ti-6Al-4V parts was performed to quantitatively estimate the densification rate of the material and the influence of the defect initial size and shape on such rate. The observations were performed in-situ using the Ultrafast Tomography Paris-Edinburgh Cell and the combination of fast phase-contrast synchrotron X-ray tomography and energy dispersive diffraction. With this strategy, we could quantify how the effectiveness of HIP depends on the characteristics of a defect. Smaller defects showed a higher densification rate, while the defect shape did not have significant effect on such rate.

High-pressure (>1 GPa) torsion apparatus can be coupled with in situ X-ray tomography (XRT) to study microstructures in materials associated with large shear strains. Here, deformation experiments were carried out on multi-phase aggregates at ∼3–5 GPa and ∼300–500°C, using a rotational tomography Paris–Edinburgh press (RoToPEc) with in situ absorption contrast XRT on the PSICHE beamline at Synchrotron SOLEIL. The actual shear strain reached in the samples was quantified with respect to the anvil twisting angles, which is γ ≤ 1 at 90° anvil twist and reaches γ ≃ 5 at 225° anvil twist. 2D and 3D quantifications based on XRT that can be used to study in situ the deformation microfabrics of two-phase aggregates at high shear strain are explored. The current limitations for investigation in real time of deformation microstructures using coupled synchrotron XRT with the RoToPEc are outlined.

Abstract Background We sought to determine the extent to which cortisol suppressed innate and T cell-mediated cytokine production and whether it could be involved in reducing peripheral cytokine production following subarachnoid haemorrhage (SAH). Methods Whole blood from healthy controls, patients with SAH and healthy volunteers was stimulated with lipopolysaccharide (LPS), to stimulate innate immunity, or phytohaemagglutinin (PHA), to stimulate T cell-mediated immunity. Varying concentrations of cortisol were included, with or without the cortisol antagonist RU486. Concentration of interleukin-6 (IL-6), IL-1β and tumour necrosis factor-alpha) TNFα were determined as a measure of innate immunity. IL-6, IL-17 (interferon gamma) IFNƔ and IL-17 were determined as an indicator of T cell-mediated immunity. Results Suppression of innate responses to LPS was apparent in whole blood from SAH patients, relative to healthy controls, and TNFα production was inversely correlated with plasma cortisol concentration. Cytokine production in whole blood from healthy volunteers was inhibited by cortisol concentrations from 0.33 µM, or 1 µM and above, and these responses were effectively reversed by the cortisol antagonist RU-486. In SAH patients, RU-486 reversed suppression of innate TNF-α and IL-6 responses, but not IL-1ß or T cell-mediated responses. Conclusion These data suggest that cortisol may play a role in reducing innate, but not T cell-mediated immune responses in patients with injuries such as SAH and that cortisol antagonists could be effective in boosting early innate responses.

Introduction Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient’s quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments.Methods and analysis This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures.Ethics and dissemination Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk.Trial registration number ISRCTN96296121.

Abstract This study examined the reproducibility of GymAware, PUSH2 and Vmaxpro velocity monitoring devices during resistance training (RT). The sensitivity of these devices to detect the smallest changes in velocity that correspond to true changes in RT performance was also investigated. Fifty-one resistance-trained men and women performed an incremental loading (1RM) test, and two repetitions to failure tests with different loads, 72 h apart. During all repetitions, mean velocity (MV) and peak velocity (PV) were simultaneously recorded by two devices of each brand. Overall, GymAware was the most reliable and sensitive device for detecting the smallest changes in RT performance, regardless of the velocity metric used. Vmaxpro can be considered as an equivalent, cheaper alternative to GymAware for RT monitoring and prescription, but only if the MV metric is used. Caution should be exercised when using PUSH2 in practice due to their comparatively higher, unacceptable measurement error and generally low sensitivity to detect changes in RT performance. Collectively, these findings support the use of MV and PV from GymAware and MV from Vmaxpro devices for RT monitoring and prescription due to their low magnitudes of error; thus, allowing for the detection of meaningful changes in neuromuscular status and functional performance during RT.

Background Lumbar puncture is an essential tool for diagnosing meningitis. Neonatal lumbar puncture, although frequently performed, has low success rates (50–60%). Standard technique includes lying infants on their side and removing the stylet ‘late’, that is, after the needle is thought to have entered the cerebrospinal fluid. Modifications to this technique include holding infants in the sitting position and removing the stylet ‘early’, that is, following transection of the skin. To the best of our knowledge, modified techniques have not previously been tested in adequately powered trials. Objectives The aim of the Neonatal Champagne Lumbar punctures Every time – An RCT (NeoCLEAR) trial was to compare two modifications to standard lumbar puncture technique, that is, use of the lying position rather than the sitting position and of ‘early’ rather than ‘late’ stylet removal, in terms of success rates and short-term clinical, resource and safety outcomes. Methods This was a multicentre 2 × 2 factorial pragmatic non-blinded randomised controlled trial. Infants requiring lumbar puncture (with a working weight ≥ 1000 g and corrected gestational age from 27+0 to 44+0 weeks), and whose parents provided written consent, were randomised by web-based allocation to lumbar puncture (1) in the sitting or lying position and (2) with early or late stylet removal. The trial was powered to detect a 10% absolute risk difference in the primary outcome, that is, the percentage of infants with a successful lumbar puncture (cerebrospinal fluid containing < 10,000 red cells/mm3). The primary outcome was analysed by modified intention to treat. Results Of 1082 infants randomised (sitting with early stylet removal, n = 275; sitting with late stylet removal, n = 271; lying with early stylet removal, n = 274; lying with late stylet removal, n = 262), 1076 were followed up until discharge. Most infants were term born (950/1076, 88.3%) and were aged < 3 days (936/1076, 87.0%) with a working weight > 2.5 kg (971/1076, 90.2%). Baseline characteristics were balanced across groups. In terms of the primary outcome, the sitting position was significantly more successful than lying [346/543 (63.7%) vs. 307/533 (57.6%), adjusted risk ratio 1.10 (95% confidence interval 1.01 to 1.21); p = 0.029; number needed to treat = 16 (95% confidence interval 9 to 134)]. There was no significant difference in the primary outcome between early stylet removal and late stylet removal [338/545 (62.0%) vs. 315/531 (59.3%), adjusted risk ratio 1.04 (95% confidence interval 0.94 to 1.15); p = 0.447]. Resource consumption was similar in all groups, and all techniques were well tolerated and safe. Limitations This trial predominantly recruited term-born infants who were < 3 days old, with working weights > 2.5 kg. The impact of practitioners’ seniority and previous experience of different lumbar puncture techniques was not investigated. Limited data on resource use were captured, and parent/practitioner preferences were not assessed. Conclusion Lumbar puncture success rate was higher with infants in the sitting position but was not affected by timing of stylet removal. Lumbar puncture is a safe, well-tolerated and simple technique without additional cost, and is easily learned and applied. The results support a paradigm shift towards sitting technique as the standard position for neonatal lumbar puncture, especially for term-born infants during the first 3 days of life. Future work The superiority of the sitting lumbar puncture technique should be tested in larger populations of premature infants, in those aged > 3 days and outside neonatal care settings. The effect of operators’ previous practice and the impact on family experience also require further investigation, alongside in-depth analyses of healthcare resource utilisation. Future studies should also investigate other factors affecting lumbar puncture success, including further modifications to standard technique. Trial registration This trial is registered as ISRCTN14040914 and as Integrated Research Application System registration 223737. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/188/106) and is published in full in Health Technology Assessment; Vol. 27, No. 33. See the NIHR Funding and Awards website for further award information. Plain language summary Newborn babies are more susceptible to getting meningitis, and this can be fatal or have lifelong complications. A lumbar puncture is an essential test for diagnosing meningitis. Lumbar puncture involves taking a small amount of spinal fluid from the lower back using a needle. Analysing the fluid confirms or excludes meningitis, allowing the right treatment to be given. Lumbar punctures are commonly performed in newborns, but are technically difficult. In 50–60% of lumbar punctures in newborns, either no fluid is obtained or the sample is mixed with blood, making analysis less reliable. No-one knows which is the best technique, and so practice varies. The baby can be held lying on their side or sat up, and the ‘stylet’, which is a thin piece of metal that sits inside (and aids insertion of) the needle, can be removed either soon after passing through the skin (i.e. ‘early stylet removal’) or once the tip is thought to have reached the spinal fluid (i.e. ‘late stylet removal’). We wanted to find the best technique for lumbar puncture in newborns. Therefore, we compared sitting with lying position, and ‘early’ with ‘late’ stylet removal. We carried out a large trial in newborn care and maternity wards in 21 UK hospitals. With parental consent, we recruited 1082 full-term and premature babies who needed a lumbar puncture. Our results demonstrated that the sitting position was more successful than lying position, but the timing of stylet removal did not affect success. In summary, the sitting position is an inexpensive, safe, well-tolerated and easily learned way to improve lumbar puncture success rates in newborns. Our results strongly support using this technique in newborn babies worldwide. Scientific summary Background The neonatal period carries the highest risk of bacterial meningitis (≈ 1 per 4000–5000 births), which is associated with significant mortality (≈ 10%) and morbidity (20–50%). Meningitis is diagnosed by analysis of cerebrospinal fluid (CSF), obtained via lumbar puncture (LP). LPs are frequently performed in newborns because of the non-specific clinical features of neonatal meningitis. However, LP success rates in newborns are much lower (50–60%) than in older children (78–87%). Unsuccessful LPs include those with heavily blood-stained CSF or LPs that fail to obtain CSF at all. Treatment for suspected or confirmed neonatal meningitis involves intravenous antibiotics, typically for 14–21 days. Unsuccessful LPs lead to repeated attempts, whereas LPs with equivocal or uninterpretable CSF results often prompt cautious treatment with extended courses of antibiotics. Prolonged antibiotic use is associated with a range of complications, including induced antimicrobial resistance. Consequently, interventions to improve neonatal LP success rates should allow more accurate diagnosis of meningitis, which will help reduce unnecessary courses of antibiotic therapy and extended hospitalisation, and will save healthcare resources. There have been few modifications to the original LP technique. Thus far, the sitting position, as employed for older patients, and ‘early stylet removal’ (ESR) have been suggested. ESR promises advantages because, in neonates, a ‘loss of resistance’ on entering the CSF is often indistinguishable and a needle advanced too far can cause venous puncture and a blood-stained tap, impairing CSF interpretation. We conducted the Neonatal Champagne Lumbar punctures Every time – An RCT (NeoCLEAR) trial to determine the optimal LP technique in neonates in terms of the effect of infant position (sitting vs. lying) and timing of stylet removal [ESR vs. late stylet removal (LSR)] on success [i.e. a CSF red blood cell (RBC) count of < 10,000/mm3] of first LP. Methods Trial design and oversight The NeoCLEAR trial was a 2 × 2 factorial open-label multicentre randomised controlled trial (RCT), with an internal pilot. The study protocol was published previously. The NeoCLEAR trial was co-ordinated by the National Perinatal Epidemiology Unit – Clinical Trials Unit. The University of Oxford (Oxford, UK) sponsored the trial. Trial oversight was conducted by the Trial Steering Committee and an independent Data Monitoring Committee. The funder [i.e. the National Institute for Health and Care Research (NIHR)] did not have a role in study design, conduct, data collection, analysis or interpretation. Ethics approval was obtained. Trial population Eligible infants were inpatients in UK neonatal units and maternity wards who required a LP at a corrected gestational age (CGA) of 27+0 to 44+0 weeks and with a working weight of ≥ 1000 g. Infants were excluded if they had already had a LP for the same indication, if they were unable to be held in sitting position or if sitting was deemed unsafe. Trial procedures Infants whose parents had provided consent were randomised 1 : 1 : 1 : 1 by a one-based system to the following four groups: (1) lying position and LSR, (2) lying position and ESR, (3) sitting position and LSR or (4) sitting position and ESR. Block randomisation was stratified according to site and CGA (four categories: 27+0 to 31+6 weeks, 32+0 to 36+6 weeks, 37+0 to 40+6 weeks and ≥ 41 weeks). Staff were trained in all four techniques. Any second LP required followed the same allocated technique. The need for any further LPs and the techniques used were determined by the clinical team. Blinding of practitioners was impossible, but the primary outcome was based on laboratory tests performed blinded to allocation. Outcomes Participants were followed up until discharge. The primary outcome was the proportion of infants with a successful first LP, defined as a CSF RBC count of < 10,000/mm3. Secondary outcomes included short-term clinical measures (e.g. number of procedures/attempts per infant, proportions with different CSF-based diagnoses, time taken per procedure, infant movement), resources (e.g. duration of antibiotics, length of stay) and safety (e.g. complications, adverse event reporting). Statistics and analysis The NeoCLEAR trial was designed with 90% power to detect a 10% absolute difference in the primary outcome (estimated comparator group event rate 59%), with a 5% two-sided significance level. Four hundred and eighty-three infants were required for each arm of each comparison (i.e. sitting vs. lying position and ESR vs. LSR). Allowing for 5% attrition, the recruitment target was 1020 infants. Outcomes were analysed by modified intention to treat (excluding participants who were withdrawn before collection of trial data or who did not undergo LP). For infant positioning, we compared groups (1) lying/LSR plus (2) lying/ESR with groups (3) sitting/LSR plus, (4) sitting/ESR. To assess the timing of stylet removal, we compared groups (1) plus (3) with groups (2) plus (4). We estimated risk ratios (RRs) for the primary outcome and all other dichotomous outcomes, the mean difference for normally distributed continuous outcomes and the median difference (Med D) for skewed continuous variables. The 95% confidence intervals (CIs) were calculated for all effect estimates. Groups were compared using regression analysis, adjusting for the stratification factors used at randomisation (i.e. centre and CGA) and allocation to the other intervention. The latter adjustment was advised after the final statistical analysis plan was signed off and is a noted deviation. Adjusted risk ratios (aRRs) were estimated using log-binomial regression, or using a Poisson regression model with a robust variance estimator in the event of non-convergence. Linear regression was used for normally distributed outcomes and quantile regression for skewed continuous outcomes. To mitigate multiple testing, inference was restricted to prespecified tested outcomes. A descriptive multiarm analysis was also performed for the primary outcome, other tested outcomes and baseline characteristics (i.e. for each of the four randomised groups). Effect modification between position (i.e. sitting/lying) and the timing of stylet removal (i.e. ESR/LSR) was investigated for the primary outcome using the statistical test for interaction. Prespecified subgroup analyses were conducted for working weight, day of life and CGA at trial entry. Two-sided p-values of ≤ 0.05 were considered to indicate statistical significance. Results From August 2018 to August 2020, 1082 participants from 21 centres in the UK were randomised in a 2 × 2 factorial design, resulting in two principal comparisons: (1) sitting position (n = 546) compared with lying position (n = 536) and (2) ESR (n = 549) compared with LSR (n = 533). A total of 1079 infants had a ‘first’ LP, and 166 (15.4%) infants had a second LP (each of these LP ‘procedures’ involved one or more ‘attempts’). Nine infants were withdrawn during the trial, but in the case of only one of these participants was consent withdrawn before data collection for the primary outcome. Three infants did not receive a LP, and in the case of a further two infants the consent form was missing. Overall, six infants were excluded, leaving 1076 infants for the final (modified intention-to-treat) analysis: (1) sitting position (n = 543) compared with lying position (n = 533) and (2) ESR (n = 545) compared with LSR (n = 531). All infants were followed up until discharge. Baseline characteristics were similar for the two groups in both comparisons, as recorded at trial entry and at time of first LP. The majority of infants were born at term, were < 3 days old and were not receiving respiratory support. Raised C-reactive protein was the most common indication for LP. First comparison: sitting position compared with lying position The primary outcome – a successful first LP – was achieved in 346 of 543 (63.7%) infants in the sitting arm and 307 of 533 (57.6%) infants in the lying arm [aRR 1.10 (95% CI 1.01 to 1.21); p = 0.03; adjusted absolute risk difference 6.1% (95% CI 0.7% to 11.4%), adjusted number needed to treat (NNT) 16 (95% CI 9 to 134)]. Infants allocated to the sitting position were less likely than infants allocated to the lying position to exhibit moderate or severe struggling at the time of needle insertion [169/541 (31.2%) vs. 202/527 (38.4%), aRR 0.82 (95% CI 0.71 to 0.94); p = 0.006]. Other secondary outcomes did not reach statistical significance, but predominantly favoured the sitting position. Based on microscopy of CSF extracted from the first and second LPs (and any culture/polymerase chain reaction results), infants who were sitting were more likely to be ‘negative’ for meningitis than infants who were lying [396/537 (73.7%) vs. 359/521 (68.9%)], and a result of ‘uninterpretable CSF’ (i.e. no sample obtained or CSF not possible to analyse, usually due to a heavily blood contaminated or clotted sample) was more likely to be recorded for infants who were lying than for infants who were sitting [139/521 (26.7%) vs. 114/537 (21.2%)]. Median duration of antibiotic treatment and length of stay were not significantly different in the sitting and lying arms {median 5 [interquartile range (IQR) 4–6] days in each arm, for both duration of antibiotic treatment and length of stay}. Four (0.3%) of 1241 first or second LPs, 1 in ESR and 1 in LSR arms, respectively, were abandoned because of cardiovascular deterioration. Lowest oxygen saturation (SpO2) during the first LP averaged 93% (IQR 89–96%) in the sitting arm and 90% (IQR 85–94%) in the lying arm (adjusted Med D 3.0%, 95% CI 2.1% to 3.9%; p < 0.001). Three of 1075 (0.3%) infants required increased respiratory support within 1 hour of their first LP (sitting arm, n = 1; lying arm, n = 2; not significantly different). The proportion of infants whose lowest SpO2 fell below 80% during the first LP (analysed post hoc) was 6.6% (35 of 532) in the sitting arm and 14.2% (72 of 508) in the lying LP arm, and this pattern was consistent in preterm and term-born babies. In 47 of 543 (8.7%) first LPs in infants allocated to the sitting position, at least one attempt involved switching to the lying position [compared with 4/533 (0.8%) infants allocated to the lying allocation, who were switched to sitting]. Of the 47 LPs where there was at least one attempt in which the allocated technique was not adhered to, the decision to change position was mostly made on the second (22/247) or third (24/257) attempt. The decision to change position was usually made by a clinical (45/47). Similarly, for the second LP, the sitting allocation was less often followed [for at least one attempt in 16/76 (22.5%) of infants allocated to sitting vs. 6/90 (7.0%) of infants allocated to lying]. There were no obvious differences in baseline infant characteristics between LPs that were carried out in the allocated position and those that were not. In prespecified subgroup analyses, the effect of position on the proportion of infants with a successful first LP was consistent across working weight and CGA at trial entry, but a difference in effect was observed between infants enrolled within 3 days of life (n = 836, RR 1.14, 95% CI 1.04 to 1.25) and those enrolled after 3 days (n = 140, RR 0.9, 95% CI 0.78 to 1.05; p = 0.001). Second comparison: early stylet removal compared with late stylet removal The primary outcome was achieved in 338 of 545 (62.0%) infants following ESR and in 315 of 531 (59.3%) infants following LSR. There was no significant difference between the groups (aRR 1.04, 95% CI 0.94 to 1.15; p = 0.45). There were also no obvious differences between the groups in any of the secondary outcomes. Either the first or the second LP (4/1242, 0.3%) was abandoned in four infants receiving LP (two in each arm) because of cardiovascular deterioration. Three of 1076 (0.3%) infants required increased respiratory support within 1 hour of their first LP (ESR, n =1; LSR, n =2; not significantly different). There were no differences in lowest SpO2, lowest heart rate (HR) or highest HR between the two arms. The allocated technique was not adhered to in 35 of 1076 (3.3%) first LPs, with similar numbers in each arm (untested outcome). In 13 of 78 infants allocated to ESR, the second LP involved at least one attempt without ESR, compared with 6 of 79 allocated to LSR; however, denominators were small and this was an untested outcome. The effect of timing of stylet removal on the proportion of infants with successful first LP was consistent across working weight at trial entry, CGA at randomisation and day of life at trial entry. Multiarm analysis: comparing four randomised groups (sitting plus early stylet removal, sitting plus late stylet removal, lying plus early stylet removal and lying plus late stylet removal) No significant interaction between infant position and timing of stylet removal was detected (p = 0.14). Multiarm baseline characteristics and analyses did not reveal any new obvious differences (only those previously described for the sitting position compared with the lying position; see First comparison: sitting position compared with lying position). Serious adverse events Four serious adverse events (SAEs) were reported during the trial. Three SAEs were deemed unrelated to LP. One infant, from the sitting/LSR group, developed a scrotal haematoma 2 days after LP. The infant did not undergo further investigations to identify a cause for this, and so a relationship with the LP could not be ruled out. Therefore, this event was deemed ‘possibly related’. Discussion The NeoCLEAR trial is, to the best of our knowledge, the first adequately powered RCT examining different LP techniques in newborns. The sitting position was superior to the lying position for achieving a successful first LP, with a NNT of 16. Sitting LP was also better tolerated in terms of infant struggling, SpO2 and HR. Timing of stylet removal did not influence LP success. Our results might be explained by the anatomical advantages of sitting position described in neonates: (1) the intervertebral spaces widen when the infants lean forward to adopt a (natural) kyphotic position; (2) the CSF passively sinks to the lowest point of the spinal canal and close to the entry site of the needle; and (3) this position is more comfortable for the baby, as evidenced by the reduced struggling we observed. At the time of the study, the only other paediatric RCT of sitting compared with lying position, by Hanson et al., involved 168 infants who were < 90 days of age in a paediatric emergency room setting.32 In that trial, the success rate did not differ significantly between groups (lateral group 63/82, 77%; sitting group, 61/85, 72%; difference 5.1%, 95% CI −8.2% to 18.3%). The suggestion that higher LP success rates could be achieved with ESR was based on reports of increased success rates with non-styletted needles. However, non-styletted needles are associated with iatrogenic intraspinal epidermoid tumour formation and, therefore, the technique of ESR was introduced. Subsequent observational studies suggested that ESR was associated with increased success rates in infants. At the time of the study, to the best of our knowledge, the NeoCLEAR trial is the first RCT to have investigated ESR and has demonstrated no significant benefit in it for neonatal LP. Therefore, we cannot advise for or against early or late stylet removal in neonates. Our safety analysis showed greater physiological stability for sitting LP, in keeping with previous observations. Other secondary outcomes lacked statistical significance, including resource outcomes. The NeoCLEAR trial has several strengths. To the best of our knowledge, it is the largest RCT, to date, investigating modifications to traditional LP technique, and the only such RCT in newborns. We chose to investigate modifications that came at no additional cost and were easily learned. The results are clear-cut, showing a significantly higher success rate for LPs with more interpretable CSF results when infants were held in a sitting position. Limitations include the fact that many practitioners were unfamiliar with sitting LP before the NeoCLEAR training sessions, and this may have led to more practitioners switching from the allocated sitting position to the lying position following an initially unsuccessful attempt. It could be speculated that success rates would have been even higher if there had been more experience of sitting position LP among practitioners, and if fewer practitioners had switched position. We did not investigate LPs carried out in infants with a CGA of under 27 weeks or over 44 weeks. Furthermore, most infants were born at or near term and had working weights above 2.5 kg and, therefore, we cannot extrapolate our results to infants born extremely pre or post term or to those of significantly different working weights. In addition, in the subgroup analyses of gestational ages, although the inconsistent effect of sitting position may well be a chance finding and/or due to confounders, the NeoCLEAR trial was underpowered to detect a significant difference for those beyond day 3 of life. In conclusion, the NeoCLEAR trial demonstrates that sitting position is superior to lying position for neonatal LP success rates (NNT 16), with no significant benefit for ESR. Adopting the sitting position is cost neutral, safe, well tolerated, and easy to learn. The results would be applicable in similar settings worldwide and should promote the sitting technique becoming the standard for neonatal lumbar puncture. Trial registration This trial is registered as ISRCTN14040914 and as Integrated Research Application System registration 223737. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/188/106) and is published in full in Health Technology Assessment; Vol. 27, No. 33. See the NIHR Funding and Awards website for further award information.

The microstructure of polycrystals is known to govern the performance of structural materials. This drives the need for mechanical characterization methods capable of probing large representative volumes at the grain and sub-grain scales. In this paper, the use of in situ diffraction contrast tomography (DCT) along with far-field 3D X-ray diffraction (ff-3DXRD) at the Psiché beamline of Soleil is presented and applied to study crystal plasticity in commercially pure titanium. A tensile stress rig was modified to comply with the DCT acquisition geometry and used for in situ testing. DCT and ff-3DXRD measurements were carried out during a tensile test of a tomographic Ti specimen up to 1.1% strain. The evolution of the microstructure was analyzed in a central region of interest comprising about 2000 grains. Using the 6DTV algorithm, DCT reconstructions were successfully obtained and allowed the characterization of the evolution of lattice rotation in the entire microstructure. The results are backed up by comparisons with EBSD and DCT maps acquired at ESRF-ID11 that allowed the validation of the orientation field measurements in the bulk. Difficulties at the grain boundaries are highlighted and discussed in line with increasing plastic strain during the tensile test. Finally, a new outlook is provided on the potential of ff-3DXRD to enrich the present dataset with access to average lattice elastic strain data per grain, on the possibility of performing crystal plasticity simulations from DCT reconstructions, and ultimately on comparisons between experiments and simulations at the scale of the grain.

Queer Theory is a radically deconstructionist perspective within the humanities and social sciences. Since its initial emergence in the late 1980s and early 1990s in the field of sexualities studies, Queer Theory has increasingly been used to challenges normative notions of self, identity, temporality and the nature of being, more broadly. Whilst Queer Theory has been utilized, to some extent, in gerontology and aging studies, this article makes an original contribution to this endeavor, assessing the potentiality and problems with queer(y)ing three aspects of aging: chronology; cognition; and frailty and vulnerability. To achieve this, the article draws on ideas from some key Queer theorical writers, existing studies of queer aging and illustrates theoretical points with qualitative data collected from two LGBTQ+ projects to illustrate. The article also considers problems with Queer Theory in challenging normativities associated with aging. It is concluded that despite problems, Queer Theory remains an important and valuable theoretical approach for disturbing and challenging many of the norms and understandings that shape and constrain older LGBTQ+ people's lives, in particular, and therefore have importance for how we think and understand aging and later life sociologically.

Social value has evolved rapidly over the last decade or so. Legislation has been a key driver, and added value and numerical measurement are emerging as important focal points. An emerging body of literature in this space draws attention to social value in placemaking, infrastructure and construction work. Using deontological principles of ethics, a critical discussion is presented on the problems associated with numerical measurement of social value as added value. Two key questions are addressed: How does mandating social value by legislation and policy impact good practice? How effectively can numerical measuring of social value evidence the range and diversity of activity and outcomes? This responds to a wider call to take a critical view of both policy and the activities of the sector and advocate a move away from solving immediate problems and development of ever more elaborate tools. The development of a holistic appreciation of the long-term need and outcomes of social value is recommended: the contextual, contingent middle ground. Practice relevance This critical essay on social value considers the dangers inherent in recent policy developments, specifically numerical measurement of social value as added value. A critical review of the literature on social value in placemaking, infrastructure and construction work illuminates the diverse nature of social value. It is argued that social value needs to be for re-energised as a concept, i.e. co-creating values-driven practice and achieving social impact that can be supported by considered approaches to measurement. A balanced approach should be employed when considering, creating and delivering social value. This would avoid both the purely critical and the purely practical, and instead stems from the contextual, contingent middle ground.

Introduction: Autologous bone transplantation is successfully used in reconstructive surgery of large/critical-sized bone defects, whereby the microvascular free fibula flap is still regarded as the gold standard for the reconstruction of such defects in the head and neck region. Here, we report the morphological and lacunar properties of patient-paired bone samples from eight patients from the jaw (AB; recipient site) and the fibula (FB; donor site) on the micron length-scale using Synchrotron µ-CT. Insights into differences and similarities between these bone structures could offer a better understanding of the underlying mechanism for successful surgical outcomes and might clear the path for optimized, nature-inspired bone scaffold designs.Methods: Spatial vessel-pore arrangements, bone morphology, fluid-simulation derived permeability tensor, osteocyte lacunar density, and lacunar morphology are compared.Results: The orientation of the vessel system indicates a homogenous vessel orientation for AB and FB. The average mineral distance (50%) to the closest vessel boundary is higher in AB than in FB (the mean is 96 μm for AB vs. 76 μm for FB; p = 0.021). Average osteocyte lacunar density is found to be higher in AB than in FB (mean 22,874 mm3 vs. 19,376 mm3 for FB; p = 0.038), which might compensate for the high distance from the mineral to the nearest vessel. No significant differences in lacunar volume are found between paired AB and FB.Discussion: A comparable vessel network and similar distribution of vessel porosity between AB and FB may allow the FB graft to exhibit a high regeneration potential when connected to AB, and this might correlate with a high osteoinductive and osteoconductive potential of FB when connected to AB. Since widely used and potent synthetic bone grafts exist, new insight into the bone structure of well-established autologous bone grafts, such as the free fibula flap, could help to improve the performance of such materials and therefore the design of 3D scaffolds.

Within medical education, feedback is an invaluable tool to facilitate learning and growth throughout a physician’s training and beyond. Despite the importance of feedback, variations in practice indicate the need for evidence-based guidelines to inform best practices. Additionally, time constraints, variable acuity, and workflow in the emergency department (ED) pose unique challenges to providing effective feedback. This paper outlines expert guidelines for feedback in the ED setting from members of the Council of Residency Directors in Emergency Medicine Best Practices Subcommittee, based on the best evidence available through a critical review of the literature. We provide guidance on the use of feedback in medical education, with a focus on instructor strategies for giving feedback and learner strategies for receiving feedback, and we offer suggestions for fostering a culture of feedback.

Extreme event attribution (EEA) information is increasingly in demand from climate services. EEA messages can: raise awareness about the effect climate change has already imposed, inform climate change liability conversations, and be combined with climate projections to inform adaptation. However, due to limitations in observations, models and methods, there are barriers towards operationalising EEA in practice. Operational services will need EEA to be done transparently and using preset formats. Here we review recent experience and practice in EEA in Australia and New Zealand with a view to inform the design of an EEA component of climate services. We present a flow chart of the processes involved, noting particular care is needed on the trigger, event definition, and climate model evaluation, with effective stage gates. We also promote the use of tailored causal network diagrams as a standard tool to inform an EEA study and communicate results, with particular care needed for messages on events with lower confidence or complex sets of influences, including tropical cyclones and extratropical cyclones. We suggest that extending EEA to impact attribution is essential for making EEA messages salient but requires an uplift in forming interdisciplinary teams and in granular exposure and vulnerability datasets and is likely to raise new interdisciplinary methodological questions. Finally, we suggest communication of EEA messages can learn more from its origins in medical epidemiology.

A high-temperature multi-axial test is carried out to characterize the thermo-mechanical behaviour of a 3D-woven SiC/SiC composite aeronautical part under loads representative of operating conditions. The sample is L-shaped and cut out from the part. It is subjected to severe thermal gradients and a superimposed mechanical load that progressively increases up to the first damage. The sample shape and its associated microstructure, the heterogeneity of the stress field and the limited accessibility to regions susceptible to damage require non-contact imaging modalities. An in situ experiment, conducted with a dedicated testing machine at the SOLEIL synchrotron facility, provides the sample microstructure from computed micro-tomographic imaging and thermal loads from infrared thermography. Experimental constraints lead to non-ideal acquisition conditions for both measurement modalities. This article details the procedure of correcting artefacts to use the volumes for quantitative exploitation (i.e. full-field measurement, model validation and identification). After proper processing, despite its complexity, the in situ experiment provides high-quality data about a part under realistic operating conditions. The influence of the mesostructure on fracture phenomena can be inferred from the tomography in the damaged state. Experiments show that the localization of damage initiation is driven by the geometry, while the woven structure moderates the crack propagation. This study widens the scope of in situ thermo-mechanical experiments to more complex loading states, closer to in-service conditions.

Abstract Rainfall during the monsoon in northwest Australia has increased since the 1950s. Previous studies have explored possible causes of the rainfall increase; however, the trend has not been fully explained. Understanding the cause of this trend is important for interpreting climate projections and local water‐sensitive services. We explore the role of the Madden‐Julian Oscillation (MJO) in explaining the rainfall increase. The MJO, since 1974, has had a longer duration in phases associated with enhanced rainfall in northwest Australia (Phases 5 and 6) during the monsoon. We show that the rainfall trend in northwest Australia is identified only during MJO phases associated with enhanced rainfall, with a large change in daily rainfall distribution in these phases. The increasing occurrence of these MJO phases explains most of the rainfall increase, as opposed to an increase in daily rainfall independent of MJO phase, albeit with some sensitivity to MJO definition.

Abstract There is a growing body of research documenting Indigenous Peoples and Local Communities' observations of changes in climate. The accuracy, efficacy, and transferability of this research depends on its motives and methods. In this paper, we report on research to produce a working knowledge of changes in climate and its impacts on local biophysical systems in the Tiwi Islands in Northern Australia. Interviews with 52 Tiwi people were combined with diverse forms of aerial data to produce a nuanced understanding of climate change in these remote islands. These data show changes in climate‐sensitive biophysical systems that would otherwise remain undetected by instruments conventionally used for monitoring climate change. These include changes in shorelines, which are causing concerns about damage to buildings that are important for Tiwi well‐being, and changes in the marine environment and wetlands, which are causing concerns about damage to natural heritage. We discuss the implications of these findings, arguing that systematic observations collected by networks of people “on Country” can provide excellent monitoring of climate change impacts, and that Indigenous people's interests in the effects of climate change overlap with those of non‐Indigenous people, as do their rights to support from the State for adaptation.

This paper highlights experiences and perceptions of older gay males living with Human Immunodeficiency Virus (HIV) in relation to age, sexual orientation, HIV status and how they perceive health. Participants were gay males aged 50 and over living in England, diagnosed with HIV for longer than 2 years. In total, 19 interviews were conducted between March 2020 and March 2021. Data were analysed using thematic analysis. Three major themes were generated: 1.) Health as holistic and as a balance; 2.) The impact of HIV on people’s lives; 3.) The Intersectionality of stigma: a lifetime of discrimination. Participants highlighted the changing nature of the concept of health through their lifespan while the intersectionality of stigma in different contexts is examined considering the personal journey of living with HIV. The implications of health as a complex concept and intersectional stigma on the planning and delivering of care in this population are discussed.

Abstract The austral spring climate of 2020 was characterised by the occurrence of La Niña, which is the most predictable climate driver of Australian springtime rainfall. Consistent with this La Niña, the Bureau of Meteorology’s dynamical sub-seasonal to seasonal forecast system, ACCESS-S1, made highly confident predictions of wetter-than-normal conditions over central and eastern Australia for spring when initialised in July 2020 and thereafter. However, many areas of Australia received near average to severely below average rainfall, particularly during November. Possible causes of the deviation of rainfall from its historical response to La Niña and causes of the forecast error are explored with observational and reanalysis data for the period 1979–2020 and real-time forecasts of ACCESS-S1 initialised in July to November 2020. Several compounding factors were identified as key contributors to the drier-than-anticipated spring conditions. Although the ocean surface to the north of Australia was warmer than normal, which would have acted to promote rainfall over northern Australia, it was not as warm as expected from its historical relationship with La Niña and its long-term warming trend. Moreover, a negative phase of the Indian Ocean Dipole mode, which typically acts to increase spring rainfall in southern Australia, decayed earlier than normal in October. Finally, the Madden–Julian Oscillation activity over the equatorial Indian Ocean acted to suppress rainfall across northern and eastern Australia during November. While ACCESS-S1 accurately predicted the strength of La Niña over the Niño3.4 region, it over-predicted the ocean warming to the north of Australia and under-predicted the strength of the November MJO event, leading to an over-prediction of the Australian spring rainfall and especially the November-mean rainfall.

A crucial evolutionary change in vertebrate history was the Palaeozoic (Devonian 419–359 million years ago) water-to-land transition, allowed by key morphological and physiological modifications including the acquisition of lungs. Nonetheless, the origin and early evolution of vertebrate lungs remain highly controversial, particularly whether the ancestral state was paired or unpaired. Due to the rarity of fossil soft tissue preservation, lung evolution can only be traced based on the extant phylogenetic bracket. Here we investigate, for the first time, lung morphology in extensive developmental series of key living lunged osteichthyans using synchrotron x-ray microtomography and histology. Our results shed light on the primitive state of vertebrate lungs as unpaired, evolving to be truly paired in the lineage towards the tetrapods. The water-to-land transition confronted profound physiological challenges and paired lungs were decisive for increasing the surface area and the pulmonary compliance and volume, especially during the air-breathing on land.

Background: Freezing all embryos, followed by thawing and transferring them into the uterine cavity at a later stage (freeze-all), instead of fresh-embryo transfer may lead to improved pregnancy rates and fewer complications during in vitro fertilisation and pregnancies resulting from it. Objective: We aimed to evaluate if a policy of freeze-all results in a higher healthy baby rate than the current policy of transferring fresh embryos. Design: This was a pragmatic, multicentre, two-arm, parallel-group, non-blinded, randomised controlled trial. Setting: Eighteen in vitro fertilisation clinics across the UK participated from February 2016 to April 2019. Participants: Couples undergoing their first, second or third cycle of in vitro fertilisation treatment in which the female partner was aged

The development of new technologies drives many aspects of socio-economic development, including the development of education. The behavioural intention of music teachers, particularly in relation to how technology is integrated into the classroom, needs to be understood since it has a direct effect on the pedagogical approach used in classroom learning. Existing theories (the Unified Theory of Acceptance and Use of Technology (UTAUT) and Technological Pedagogical and Content Knowledge (TPACK)) have explored aspects of teachers’ adoption of technologies; this article uses data from a pilot study to develop and test a model that combines the two theories in order to understand more fully the relationship between Individual Beliefs, Technological Competence and Behavioural Prediction of music teachers using technology in the context of the Chinese governmental policy: ‘Internet +’. The participants of this pilot study were 61 music teachers (12 male and 49 female); the proportion of participants in different provincial administrative regions covered more than half of mainland China (18 out of 34). Structural Equation Modelling (SEM) revealed that the overall fit of the model was above the recommended level of acceptable fit. The results showed that Technological Competence has a significant impact on Individual Beliefs; Individual Beliefs have a significant impact on Behavioural Prediction. However, Technological Competence was found to have no significant direct impact on Behavioural Prediction. This study is one of only a few studies that combine the UTAUT and TPACK models into the field of music pedagogy and uses SEM for analysis. This study attempts to fill the gap in the factors influencing the adoption of technology in music education in non-Western cultures and also provides a starting point for understanding Chinese music teachers’ technological beliefs and behavioural intentions.

Following the impact of the protoplanet Theia, planet Earth likely transformed into a magma ocean. New high temperature and pressure experiments by Xie et al. suggest that a layer enriched in bridgmanite formed during the magma ocean phase of Earth–remnants of this ancient layer today may be responsible for the viscosity peak between 660 and 1500 km in present solid mantle.

Abstract Background Ex-vivo cardiovascular magnetic resonance (CMR) imaging has played an important role in the validation of in-vivo CMR characterization of pathological processes. However, comparison between in-vivo and ex-vivo imaging remains challenging due to shape changes occurring between the two states, which may be non-uniform across the diseased heart. A novel two-step process to facilitate registration between ex-vivo and in-vivo CMR was developed and evaluated in a porcine model of chronic myocardial infarction (MI). Methods Seven weeks after ischemia-reperfusion MI, 12 swine underwent in-vivo CMR imaging with late gadolinium enhancement followed by ex-vivo CMR 1 week later. Five animals comprised the control group, in which ex-vivo imaging was undertaken without any support in the LV cavity, 7 animals comprised the experimental group, in which a two-step registration optimization process was undertaken. The first step involved a heart specific flexible 3D printed scaffold generated from in-vivo CMR, which was used to maintain left ventricular (LV) shape during ex-vivo imaging. In the second step, a non-rigid co-registration algorithm was applied to align in-vivo and ex-vivo data. Tissue dimension changes between in-vivo and ex-vivo imaging were compared between the experimental and control group. In the experimental group, tissue compartment volumes and thickness were compared between in-vivo and ex-vivo data before and after non-rigid registration. The effectiveness of the alignment was assessed quantitatively using the DICE similarity coefficient. Results LV cavity volume changed more in the control group (ratio of cavity volume between ex-vivo and in-vivo imaging in control and experimental group 0.14 vs 0.56, p

Background: Focal ventricular tachycardia (VT) is a life-threating arrhythmia, responsible for high morbidity rates and sudden cardiac death (SCD). Radiofrequency ablation is the only curative therapy against incessant VT; however, its success is dependent on accurate localization of its source, which is highly invasive and time-consuming.Objective: The goal of our study is, as a proof of concept, to demonstrate the possibility of utilizing electrogram (EGM) recordings from cardiac implantable electronic devices (CIEDs). To achieve this, we utilize fast and accurate whole torso electrophysiological (EP) simulations in conjunction with convolutional neural networks (CNNs) to automate the localization of focal VTs using simulated EGMs.Materials and Methods: A highly detailed 3D torso model was used to simulate ∼4000 focal VTs, evenly distributed across the left ventricle (LV), utilizing a rapid reaction-eikonal environment. Solutions were subsequently combined with lead field computations on the torso to derive accurate electrocardiograms (ECGs) and EGM traces, which were used as inputs to CNNs to localize focal sources. We compared the localization performance of a previously developed CNN architecture (Cartesian probability-based) with our novel CNN algorithm utilizing universal ventricular coordinates (UVCs).Results: Implanted device EGMs successfully localized VT sources with localization error (8.74 mm) comparable to ECG-based localization (6.69 mm). Our novel UVC CNN architecture outperformed the existing Cartesian probability-based algorithm (errors = 4.06 mm and 8.07 mm for ECGs and EGMs, respectively). Overall, localization was relatively insensitive to noise and changes in body compositions; however, displacements in ECG electrodes and CIED leads caused performance to decrease (errors 16–25 mm).Conclusion: EGM recordings from implanted devices may be used to successfully, and robustly, localize focal VT sources, and aid ablation planning.

X-ray and neutron imaging are widely employed for battery materials, thanks to the possibility to perform noninvasive in situ and in operando analyses. X-ray tomography can be performed either in synchrotron or in laboratory facilities and is particularly well-suited to analyze bulk materials and electrode/electrolyte interfaces. Several post-lithium-ion (Li-ion) devices, such as Li–sulfur, Li–O2, or all-solid-state Li batteries, have an anode made of metallic Li in common. The main failure mode of Li batteries is the inhomogeneity of the Li electrodeposits onto the Li anode during charge steps, leading to dendrite growth and low Coulombic efficiency. X-ray tomography is a powerful tool for studying dendrites as it provides useful information about their locations, dynamics, and microstructures. So far, the use of neutron tomography is scarcely reported for Li deposit analysis due to the difficulty in reaching sufficient image resolution to capture the deposit microstructure, that is, typically below 10–20 µm. The very different interactions of X-rays and neutrons with Li, which has significantly different opacity in the two cases, make the two techniques highly complementary. Notably, the capacity of neutrons to discern different Li isotopes is pivotal to getting an insight into the composition of Li deposits by distinguishing between Li originating from an electrode (6Li in this study) and Li originating from the Li salt electrolyte (mainly in 7Li here). Indeed, the theoretical linear neutron attenuation coefficient of 6Li is about 15 and 2,000 times larger than that of natural Li and 7Li, respectively. Therefore, a high imaging contrast difference is obtained between 6Li (high attenuation) and natural Li and 7Li (lower attenuations), which could allow a better understanding of the origin of the Li comprising the electrodeposits. In this work, we report, as a proof of concept, an in situ neutron tomography imaging of Li electrodeposits in a cycled Li symmetric cell. The electrochemical cell comprises a natural Li electrode, a 6Li electrode, and a deuterated liquid electrolyte. The neutron tomographies are compared with X-ray tomography images of the same electrochemical cell acquired both at an X-ray synchrotron beamline and at a laboratory X-ray tomograph. Neutron tomography is shown to be compatible with in situ analysis and capable of capturing the overall morphology of the Li deposits in good accordance with X-ray tomography analyses.

The method outlined in this article is a customization of the whole exhaust exposure method generated by Mullins et al. (2016) using reprogrammed primary human airway epithelial cells as described by Martinovich et al. (2017). It has been used successfully to generate recently published data (Landwehr et al. 2021). The goal was to generate an exhaust exposure model where exhaust is collected from a modern engine, real-world exhaust concentrations are used and relevant tissues exposed to assess the effects of multiple biodiesel exposures. Exhaust was generated, gently vacuumed into a dilution chamber where it was diluted 1/15 with air and then vacuumed into an incubator containing the primary cell cultures for exposure. Exhaust physico-chemical properties including combustion gas concentrations and particle spectra were then analyzed using a combustion gas analyzer and a Universal Scanning Mobility Particle Sizer. 24 h after exposure, cellular viability and mediator release were measured using Annexin-V/PI staining and meditator multiplexing kits respectively. This method was generated to test biodiesel exhaust exposures but can be easily adapted for any type of engine exhaust exposure or even potentially other respirable environmental exposures such as woodsmoke.The main customization points for this method are: • Exhaust generated by a diesel engine equipped with EURO VI exhaust after treatment devices including diesel particulate filter and diesel oxidation catalyst. • The generated exhaust was diluted 1/15 with air to replicate real world exposure concentrations. • Used primary human airway epithelial cells obtained from bronchoscope brushings from multiple volunteers and reprogrammed to allow multiple, comparative exposures from the same individual.

Clinical teaching is the primary educational tool use to train learners from day one of medical school all the way to the completion of fellowship. However, concerns over time constraints and patient census have led to a decline in bedside teaching. This paper provides a critical review of the literature on clinical teaching with a focus on instructor teaching strategies, clinical teaching models, and suggestions for incorporating technology. Recommendations for instructor-related teaching factors include adequate preparation, awareness of effective teacher attributes, using evidence-based-knowledge dissemination strategies, ensuring good communication, and consideration of environmental factors. Proposed recommendations for potential teaching strategies include the Socratic method, the One-Minute Preceptor model, SNAPPS, ED STAT, teaching scripts, and bedside presentation rounds. Additionally, this article will suggest approaches to incorporating technology into clinical teaching, including just-in-time training, simulation, and telemedical teaching. This paper provides readers with strategies and techniques for improving clinical teaching effectiveness.

Background: Observational data suggest that slowly advancing enteral feeds in preterm infants may reduce necrotising enterocolitis but increase late-onset sepsis. The Speed of Increasing milk Feeds Trial (SIFT) compared two rates of feed advancement. Objective: To determine if faster (30 ml/kg/day) or slower (18 ml/kg/day) daily feed increments improve survival without moderate or severe disability and other morbidities in very preterm or very low-birthweight infants. Design: This was a multicentre, two-arm, parallel-group, randomised controlled trial. Randomisation was via a web-hosted minimisation algorithm. It was not possible to safely and completely blind caregivers and parents. Setting: The setting was 55 UK neonatal units, from May 2013 to June 2015. Participants: The participants were infants born at

Wheat is one of the most important crops in the world, mainly used for human consumption and animal feed. To overcome the increasing demand in wheat production, it is necessary to better understand the mechanisms involved in the growth of the wheat grain. X-ray computed tomography is an efficient method for the non-destructive investigation of the 3D architecture of biological specimens, which does not require staining, sectioning, or inclusion. In particular, phase-contrast tomography results in images with better contrast and an increased resolution compared to that obtained with laboratory tomography devices. The aim of this study was to investigate the potential of phase-contrast tomography for the study of the anatomy of the wheat grain at early stages of development. We provided 3D images of entire grains at various development stages. The image analysis allowed identifying a large number of tissues, and to visualize individual cells. Using a high-resolution setup, finer details were obtained, making it possible to identify additional tissues. Three-dimensional rendering of the grain also revealed the pattern resulting from the epidermis cells. X-ray phase-contrast tomography appears as a promising imaging method for the study of the 3D anatomy of plant organs and tissues.

Abstract Background Injections into the tendinous portion of the common extensor origin are a common intervention in the treatment of Lateral Elbow Tendinopathy (LET). Clinical trials report a heterogeneous selection of injectate volumes and delivery techniques, with systematic reviews finding no clear consensus. The aim of this study was to assess the intratendinous distribution and surrounding tissue contamination of ultrasound-guided injections into the Common Extensor Tendon (CET) of the elbow. Methods Twenty cadaveric elbows were injected by a Consultant Radiologist under Ultrasound guidance. Elbows were randomised to equal groups of 1 or 3 mls of methylene blue injection, delivered using single shot or fenestrated techniques. Following injection, each cadaver underwent a dry arthroscopy and dissection of superficial tissues. The CET was excised, set and divided into 1 mm sections using microtome. Each slice was photographed and analysed to assess spread and pixel density of injectate in four colour graduations. The cross-sectional area of distribution was calculated and compared between groups. Results In all 20 cadaveric samples, contamination of the joint was noted on arthroscopy and dissection. Injectate spread through over 97% of the cross-sectional area. No differences were found in intratendinous spread of injectate between differing volumes or techniques. Conclusion This study found that commonly used injection volumes and techniques distribute widely throughout cadaveric CETs. There was no improvement when the volume was increased from 1 to 3 mls or between single shot of fenestrated injection techniques. It should be noted that joint contamination using these techniques and volumes may be inevitable.

Understanding the mechanisms involved in the formation and growth of methane hydrate in marine sandy sediments is crucial for investigating the thermo-hydro-mechanical behavior of gas hydrate marine sediments. In this study, high-resolution optical microscopy and synchrotron X-ray computed tomography were used together to observe methane hydrate growing under excess gas conditions in a coarse sandy sediment. The high spatial and complementary temporal resolutions of these techniques allow growth processes and accompanying redistribution of water or brine to be observed over spatial scales down to the micrometre—i.e., well below pore size—and temporal scales below 1 s. Gas hydrate morphological and growth features that cannot be identified by X-ray computed tomography alone, such as hollow filaments, were revealed. These filaments sprouted from hydrate crusts at water–gas interfaces as water was being transported from their interior to their tips in the gas (methane), which extend in the µm/s range. Haines jumps are visualized when the growing hydrate crust hits a water pool, such as capillary bridges between grains or liquid droplets sitting on the substrate—a capillary-driven mechanism that has some analogy with cryogenic suction in water-bearing freezing soils. These features cannot be accounted for by the hydrate pore habit models proposed about two decades ago, which, in the absence of any observation at pore scale, were indeed useful for constructing mechanical and petrophysical models of gas hydrate-bearing sediments.

Abstract The virulence of chlamydial infection in wild koalas is highly variable between individuals. Some koalas can be infected (PCR positive) with Chlamydia for long periods but remain asymptomatic, whereas others develop clinical disease. Chlamydia in the koala has traditionally been studied without regard to coinfection with other pathogens, although koalas are usually subject to infection with koala retrovirus (KoRV). Retroviruses can be immunosuppressive, and there is evidence of an immunosuppressive effect of KoRV in vitro. Originally thought to be a single endogenous strain, a new, potentially more virulent exogenous variant (KoRV-B) was recently reported. We hypothesized that KoRV-B might significantly alter chlamydial disease outcomes in koalas, presumably via immunosuppression. By studying sub-groups of Chlamydia and KoRV infected koalas in the wild, we found that neither total KoRV load (either viraemia or proviral copies per genome), nor chlamydial infection level or strain type, was significantly associated with chlamydial disease risk. However, PCR positivity with KoRV-B was significantly associated with chlamydial disease in koalas (p = 0.02961). This represents an example of a recently evolved virus variant that may be predisposing its host (the koala) to overt clinical disease when co-infected with an otherwise asymptomatic bacterial pathogen (Chlamydia).

Sponges (Porifera), as one of the earliest-branching animal phyla, are crucial for understanding early metazoan phylogeny. Recent studies of Lower Palaeozoic sponges have revealed a variety of character states and combinations unknown in extant taxa, challenging our views of early sponge morphology. The Herefordshire Konservat–Lagerstätte yields an abundant, diverse sponge fauna with three-dimensional preservation of spicules and soft tissue. Carduispongia pedicula gen. et sp. nov. possesses a single layer of hexactine spicules arranged in a regular orthogonal network. This spicule type and arrangement is characteristic of the reticulosans, which have traditionally been interpreted as early members of the extant siliceous Class Hexactinellida. However, the unusual preservation of the spicules of C. pedicula reveals an originally calcareous composition, which would be diagnostic of the living Class Calcarea. The soft tissue architecture closely resembles the complex sylleibid or leuconid structure seen in some modern calcareans and homoscleromorphs. This combination of features strongly supports a skeletal continuum between primitive calcareans and hexactinellid siliceans, indicating that the last common ancestor of Porifera was a spiculate, solitary, vasiform animal with a thin skeletal wall.

This study investigates the interannual, seasonal, and intraseasonal variation in rainfall extremes (REs) in Jakarta and surroundings. We used datasets of daily rainfall at three sites at coastal, inland and mountainous environments during 1974–2016 (42 years), Sea Surface Temperature, 850-hPa zonal and meridional winds, and Outgoing Longwave Radiation during 1979–2016 (37 years). The results show that intensity and frequency of REs, and their relative contribution to the total rainfall, have strong relationships with the Indian Ocean Dipole and El Niño Southern Oscillation in the dry season (Jun–Nov) but weak relationships in the wet season (Dec–May) at all sites. During active Madden-Julian Oscillation (MJO) period, the daily average rainfall and the number of RE days relative to all days show strong variation between MJO phases at all sites and the MJO signature differs between the three stations. At the coastal and inland sites, there is a less marked variation of the number of RE events relative to all days with MJO phases. Compared to lower altitudes, the high-altitude station has a greater number of RE events relative to all days in the wet season and a lower intensity of REs relative to total rainfall amount in the dry season. The results of the study suggest that the REs vary in each station due to highly localised differences in responses to large-scale conditions. Keywords: Rainfall extremes, ENSO, IOD, MJO, Seasonal dependence

TAR DNA-binding protein 43 (TDP-43) is the major component of the ubiquitin-positive protein aggregates seen in the majority of frontotemporal lobar degeneration and amyotrophic lateral sclerosis cases. TDP-43 belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family that is involved in the regulation of RNA transcription, splicing, transport and translation. There are a great many hnRNPs, which often have overlapping functions and act cooperatively in RNA processing. Here we demonstrate that another hnRNP family member, hnRNP E2, shows a striking accumulation within dystrophic neurites and cytoplasmic inclusions in the frontal cortex and hippocampus of a subset of FTLD-TDP cases belonging to pathological subtypes A and C, where hnRNP E2 was found to co-localize with 87% of TDP-43 immunopositive inclusions. hnRNP E2-positive inclusions were not seen in FTLD-TDP cases with the C9orf72 expansion or in any other neurodegenerative disorders examined. This interaction with TDP-43 in specific FTLD subtypes suggests different underlying neurodegenerative pathways.

Several studies have highlighted the positive effects of group music-making and have suggested that it may be the creative and social aspects of such activities, which have a positive effect on participants’ wellbeing. Collaborative composition offers strong examples of both aspects as participants work together to create new material. However, although it seems likely that participants’ influence over and ownership of the creative material contributes to these positive effects, studies have yet to examine these elements in detail. Through analysis of video observations, pre- and post-project interviews, video recall interviews, and questionnaires, this article aims to: (1) evaluate the impact of participation in collaborative composition workshops on the subjective and psychological wellbeing of older adults and (2) identify skills and approaches employed by the composer-facilitators in order to understand more fully the approach and skills employed to engage participants effectively in the creative process. This second aim is of particular interest given the current movement toward social prescribing and arts and health interventions in the UK. Analysis revealed that all dimensions of the PERMA framework for subjective and psychological wellbeing were present in this collaborative composition project. The specific nature of collaborative composition is considered in comparison with other forms of group musical engagement. For older adults, collaborative composition has much to offer as an activity encouraging social interaction with others with shared interests, increasing positive affect, and enhancing self-esteem. Analysis of workshop videos and interviews with composers identified various facilitation skills employed by the composers to establish safe creative space and to encourage participants to engage in the process of collaborative composition.