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Mitchell Barns, Daniel Magee, Thomas England Department of Urology, Sir Charles Gardiner Hospital, Perth, Western Australia, AustraliaCorrespondence: Mitchell Barns, Sir Charles Gardiner Hospital, Department of Urology, Perth, Western Australia, 6009, Australia, Tel +61 409 439 006, Email Mitchell.barns@health.wa.gov.auBackground: Since its introduction over two decades ago, the surgical laser has served in the lithotripsy of urinary calculi, resection of bladder tumours, bladder neck incisions, and prostate enucleation. Concerns regarding the safe use of holmium lasers have resulted in potentially excessive and overly precautious theatre regulations. We aimed to evaluate the preconceived impressions and practice patterns at a single site surrounding laser use in endourology.Methods: We designed a three-part online questionnaire that could be accessed using a smart device or computer. This survey was distributed to all theatre staff involved in laser surgery at our single site, including surgical, nursing, and anaesthetic staff of varying seniority. It asked questions regarding holmium laser safety, provided an up-to-date summary of published literature surrounding the safe use of lasers, and finally gave participants further option to alter the answers to several previously encountered questions.Results: A total of 54 theatre staff completed the survey, including 17 theatre nurses (31.5%), 10 urology consultants (18.5%), 8 urology registrars (14.8%), 7 anaesthetic registrars (13%), 4 anaesthetic consultants (7.4%). About 51.9% of participants believed that current laser safety protocols were adequate, with 38.9% finding them excessive. After reading recently published information on laser safety, 22.2% thought current laser safety measures were adequate (57% decrease) and 77.8% found them to be excessive (100% increase). About 74.1% of participants found that laser safety goggles impair their vision and that 79.6% would choose not to wear them if they were optional.Conclusion: Strict laser safety guidelines reflect an overestimated risk associated with using holmium laser in operating theatres. Laser safety regulations should be re-evaluated to align with current research and potential hazards inherent to the device. In doing so, a more effective distribution of staff could enable greater access to laser surgery, thereby reducing patient morbidity and hospital wait times.Keywords: endourology, laser surgery, holmium laser

Background We aimed to understand urgent and emergency care pathways for older people and develop a decision support tool using a mixed methods study design. Objective(s), study design, settings and participants Work package 1 identified best practice through a review of reviews, patient, carer and professional interviews. Work package 2 involved qualitative case studies of selected urgent and emergency care pathways in the Yorkshire and Humber region. Work package 3 analysed linked databases describing urgent and emergency care pathways identifying patient, provider and pathway factors that explain differences in outcomes and costs. Work package 4 developed a system dynamics tool to compare emergency interventions. Results A total of 18 reviews summarising 128 primary studies found that integrated social and medical care, screening and assessment, follow-up and monitoring of service outcomes were important. Forty patient/carer participants described emergency department attendances; most reported a reluctance to attend. Participants emphasised the importance of being treated with dignity, timely and accurate information provision and involvement in decision-making. Receiving care in a calm environment with attention to personal comfort and basic physical needs were key. Patient goals included diagnosis and resolution, well-planned discharge home and retaining physical function. Participants perceived many of these goals of care were not attained. A total of 21 professional participants were interviewed and 23 participated in focus groups, largely confirming the review evidence. Implementation challenges identified included the urgent and emergency care environment, organisational approaches to service development, staff skills and resources. Work package 2 involved 45 interviews and 30 hours of observation in four contrasting emergency departments. Key themes relating to implementation included: intervention-related staff: frailty mindset and behaviours resources: workforce, space, and physical environment operational influences: referral criteria, frailty assessment, operating hours, transport. context-related links with community, social and primary care organisation and management support COVID-19 pandemic. approaches to implementation service/quality improvement networks engaging staff and building relationships education about frailty evidence. The linked databases in work package 3 comprised 359,945 older people and 1,035,045 observations. The most powerful predictors of four-hour wait and transfer to hospital were age, previous attendance, out-of-hours attendance and call handler designation of urgency. Drawing upon the previous work packages and working closely with a wide range of patient and professional stakeholders, we developed an system dynamics tool that modelled five evidence-based urgent and emergency care interventions and their impact on the whole system in terms of reducing admissions, readmissions, and hospital related mortality. Limitations Across the reviews there was incomplete reporting of interventions. People living with severe frailty and from ethnic minorities were under-represented in the patient/carer interviews. The linked databases did not include patient reported outcomes. The system dynamics model was limited to evidence-based interventions, which could not be modelled conjointly. Conclusions We have reaffirmed the poor outcomes frequently experienced by many older people living with urgent care needs. We have identified interventions that could improve patient and service outcomes, as well as implementation tools and strategies to help including clinicians, service managers and commissioners improve emergency care for older people. Future work Future work will focus on refining the system dynamics model, specifically including patient-reported outcome measures and pre-hospital services for older people living with frailty who have urgent care needs. Study registrations This study is registered as PROSPERO CRD42018111461. WP 1.2: University of Leicester ethics: 17525-spc3-ls:healthsciences, WP 2: IRAS 262143, CAG 19/CAG/0194, WP 3: IRAS 215818, REC 17/YH/0024, CAG 17/CAG/0024. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme [project number 17/05/96 (Emergency Care for Older People)] and will be published in full in Health and Social Care Delivery Research; Vol. 11, No. 14. See the NIHR Journals Library website for further project information. Plain language summary Many older people attending emergency care have poor outcomes; this project aimed to: describe best practice in emergency care understand how best practice might be delivered describe outcomes from emergency care, and synthesise this information in a computer simulation tool that can help teams decide which interventions might work best in their setting. The existing literature showed that holistic interventions (caring for the whole person), spanning emergency and community care, designed with the needs of older people in mind, work best. We checked these findings with front line clinicians, who agreed, but identified that implementing best practice in the emergency department was challenging. Limitations included the emergency department environment itself and the lack of staff with the right skillset. We also asked older people and their carers who had recently received emergency care what mattered. They prioritised basic needs such as comfort, communication, and timely care. They also stated that getting better, maintaining their usual level of function, and getting home safely were important outcomes. We then analysed data that linked together ambulance, emergency department, and hospital care in Yorkshire and Humber from 2011–17 for over 1 million emergency department attendances and hospital admissions. We found a novel and accurate predictor of long emergency department waits and hospital admission: the level of urgency according to the ambulance call handler. Drawing upon all the above and guided by a wide range of patient and professionals, we developed a computer model which allows emergency care teams to simulate different best practice emergency department interventions and estimate the impact on reducing admissions, readmissions, and hospital mortality. In summary, we have reaffirmed the poor outcomes experienced by many older people with urgent care needs. We have identified interventions that could improve patient and service outcomes, as well as implementation tools to help including clinicians, hospital managers and funders transform emergency care for older people. Scientific summary Background This study addressed emergency care for people aged 75 years or older, from the point of an ambulance being called through to admission, and/or transfer out from hospital, focusing on emergency department (ED) interventions. We aimed to identify promising care models and guidance derived from best practice and produce guidance on implementation that address the needs of older people accessing urgent and emergency care (UEC) services. Objectives and research questions Work package (WP) 1 – identifying best practice WP 1.1 – review of reviews of UEC interventions for older people, their outcomes and costs and any implementation factors identified Research question (RQ) 1.1.1 – what is the evidence base for UEC interventions for older people, the outcomes of these interventions and the costs associated with these interventions? RQ 1.1.2 – what factors have been described in the evidence base to date that influence implementation of UEC interventions for older people? WP 1.2 – patient and carer preferences RQ 1.2.1 – what elements of care are most important to older people and their carers with UEC needs? RQ 1.2.2 – how could UEC interventions be configured to best meet the needs of older people? WP 1.3 – staff perspectives RQ 1.3.1 – what other interventions, not yet reported in the literature, offer promising models for improving outcomes for older people in the UEC pathway? WP2 – qualitative study of delivery of exemplar UEC pathways RQ 2.1 what aspects of interventions, context and approaches to implementation facilitate and hinder delivery of UEC interventions for older people? WP3 – routine patient level data analysis RQ 3.1 Are some UEC pathways associated with better patient outcomes than others? RQ 3.2 Have UEC pathways improved or got worse over time? RQ 3.3 Over and above the UEC pathway, what patient characteristics, demand and supply factors explain differences in outcomes from place to place and over time? RQ 3.4 What is the relationship between outcomes and the costs of the UEC pathway and are some pathways more cost-effective than others? WP4 – improving emergency care pathways WP 4.1 – baseline simulation model development RQ 4.1 what is the best way to build an ‘archetypal’ or baseline model of patient flow into and out of one specific UEC pathway, ensuring that the model is valid and captures all the relevant factors? WP 4.2 – ‘what if’ analyses RQ 4.2 what changes can be made to existing UEC pathways that will lead to greatest improvements, and what might the consequences of such changes be for the wider health-care system? Methods WP1 – identifying best practice WP 1.1 review of reviews of UEC interventions for older people, their outcomes and costs and any implementation factors identified. WP 1.2 interviews of older people and their carers with recent experience of UEC, using the findings to ensure that the patient’s voice is at the centre of this study. WP 1.3 clinician interviews and focus groups about emerging interventions and key elements of high-quality care. WP2 – qualitative study of delivery of exemplar UEC pathways Qualitative fieldwork (interviews, ethnography, documentary analysis) in sites exemplifying promising pathways, to identify aspects relevant to transfer and adaptation of these models to other settings. WP3 – routine patient level data analysis to describe UEC pathways, outcomes and costs Analysis of linked databases to describe UEC pathways experienced by people aged 75+ years across the Yorkshire and Humber region, 2011–17, to assess which pathways deliver better patient outcomes than others, how pathways have changed over time, and what patient characteristics, demand factors and supply factors explain differences in outcomes and costs between patients, from place to place, and over time. WP4 – modelling improvements to UEC pathways We developed a family of system dynamics computer simulation models representing patient flow through the entire care process for different UEC pathways. We used these models to evaluate UEC interventions in different settings, in terms of their impact on patient outcomes and their knock-on effects in the wider care system. Results WP1 – identifying best practice WP 1.1 review of reviews In total, 806 articles were retrieved; 18 eligible reviews were identified, published between 2005 and 2019. These reviewed 128 unique primary studies (published 1994–2018); 25 were included in more than one review. Most reviews defined 65 years as their age threshold for ‘older people’, although some included papers with populations aged 60 years and older, few stratified by condition or severity. Reviews of ED interventions were organised into four evidence clusters: discharge-focused interventions staff-focused interventions population focused interventions intervention component focused reviews. Discharge interventions vary in their components but tend to employ improved linkages between the ED and the community, either through direct linkage or referral interventions. Comprehensive geriatric assessment (CGA) was frequently used. There was limited evidence for its effectiveness – two meta-analyses found no benefit from this intervention, and narrative synthesis reported an increase in ED readmissions in the short term among patients who had received these interventions. Staff-focused interventions described conflicting evidence around the benefits of nurse-led interventions for older people in the ED. Some reported reduced service use and reduced functional decline, but others increased service use. The meta-analysis found no effect from nurse-led interventions. There was evidence of lowered admission rates following geriatrician-led CGA interventions. There was limited evidence for population-focused interventions, such as the identification and management of older people with cognitive impairment in the ED. There was considerable agreement for the components of successful interventions. Effective interventions: integrate social and medical care involvement include screening and assessment initiate care in the ED and bridge this with follow-up monitor and evidence successful practices. WP 1.2 patient and carer interviews In total, 40 participants were interviewed: 24 patients and 16 carers who, between them, described ED attendances for 28 patients across the 3 sites. The majority were white British and were living with mild-moderate frailty. Most participants reported a reluctance to attend ED and emphasised the importance of being treated with respect and dignity, the provision of timely and accurate information, involvement in decision-making and the need for clear communication. Receiving care in a calm ED environment with attention to personal comfort, basic physical needs and being supported by family members were also key, as were shorter waiting times. The goals of care for participants accessing emergency care were that their medical problem be diagnosed and resolved; information about tests and treatment be given to them and their relatives; they receive an appropriate well-planned discharge to their own home with support where needed and without readmission or reattendance at ED; and that they retain mobility, function and normal activities. Participants perceived that many of these goals of care were not attained. WP 1.3 clinician interviews A total of 21 professional participants were interviewed and a further 23 participated in focus groups largely confirming the review evidence. Implementation challenges identified included the UEC environment, organisational approaches to service development, staff skills and resource allocation. WP2 – qualitative study of delivery of exemplar UEC pathways Work package 2 involved 45 interviews and 30 hours of observation in four contrasting EDs. Key themes relating to implementation included: intervention-related implementation influences staff: frailty mindset and behaviours resources: workforce, space, and physical environment operational influences: referral criteria, frailty assessment, operating hours, transport. context-related implementation influences links with community, social and primary care organisation and management support COVID-19 pandemic. approaches to implementation service/quality improvement networks engaging staff and building relationships education about frailty evidence. WP3 – routine patient level data analysis to describe UEC pathways, outcomes, and costs The dataset comprises a total of 1,035,045 observations, of which 867,902 were ED attendances and 167,143 were emergency admissions to hospital; 256,215 (29.5%) of the 867,902 ED attendances lasted more than four hours. Following receipt of care, 363,526 (41.9%) were discharged from the ED (of whom 3901, 0.5%, died), while the remaining 504,376 (58.1%) were admitted to hospital; 178,553 (20.6%) reattended the ED within 30 days of discharge. Of the 671,519 patients admitted to hospital, 199,506 (29.7%) had a short length of stay (LoS), 233,600 (34.8%) stayed more than 7 days and 73,665 (11%) stayed more than 21 days; 51,323 (7.6%) patients died in hospital; 129,971 (19.4%) had an emergency readmission within 30 days of being discharged, with 21,579 (3.2%) having three subsequent emergency admissions within 90 days and 90,639 (13.5%) within 365 days. For the 671,519 patients admitted to hospital, the average cost of their hospital care was £2760. For the full sample of 1,034,956 patients, the average cost of the entire UEC pathway amounted to £2,007. Patients in older age categories were more likely to experience poor outcomes. For example, compared with those aged 75–79 years, those aged 95+ years were more likely to stay more than four hours in the ED [odds ratios (OR) 1.146], to be admitted to hospital (OR 1.345) and to reattend the ED within 30 days (OR 1.091). The call handler designation of urgency for those conveyed by ambulance was associated with all three outcomes. Compared with those who made their own way to the ED, the probability of waiting more than four hours was higher for those designated as less urgent (OR 1.238), urgent (OR 1.359), emergency (OR 1.35) and with a life-threatening condition (OR 1.448). There is also clear gradient across urgency categories in the likelihood of hospital admission, increasing from OR 2.155 for those designated less urgent to OR 3.603 for those with life-threatening conditions. For those admitted, frailty risk was more important at explaining LoS than any other patient or pathway characteristic. Those with intermediate and high frailty risk were significantly less likely have a short LoS (OR 0.476 and OR 0.293, respectively) and significantly more likely to have a long LoS (OR 2.909 and OR 5.872, respectively) and excessive LoS (OR 4.25 and OR 11.78, respectively). Frailty risk was also associated with greater likelihood of death [hazard ratio (HR) 1.872 for intermediate risk and HR 2.042 for high risk]. For hospital readmission, the number of admissions in the previous year stand out as by far the most important explanatory variables. For example, those who had three or more admissions in the past year are 15% more likely to be readmitted within 30 days and to have more than three admissions within 90 days (OR 7.525) and 365 days (OR 5.156). The most important factor influencing the costs of the overall UEC pathway is whether there is a hospital admission, costs being £4,262 higher for those admitted to hospital compared to those who were not. WP4 – modelling improvements to UEC pathways Drawing upon all the previous WPs, we developed whole system decision support tool focusing upon urgent care for older people. The tool allows users to run one of five evidence-based scenarios to answer the ‘what if’ or ‘so what’ question – what might happen if we implemented this service in our ED? It is configurable to allow users to input their own data or chose from a range of archetypes that reflect their own setting. It takes account not only of the hours of provision, but the population targeted. It should support decisions about which model of urgent care might best suit the setting in question, according to the outcomes (LoS, readmissions, institutionalisation, mortality) that the system wants to address. Conclusions Call handler designation was the most powerful predictor of a four-hour wait and of transfer to hospital. We confirmed that frailty risk was a strong, independent predictor of LoS and in-hospital death, but not 30-day readmission. Changes at the levels of clinical practice and service design are required to deliver person-centred care for older people living with frailty in the ED environment. Holistic interventions initiated in the ED and continued elsewhere can improve outcomes. The evidence-based, clinically validated decision support tool for use by clinicians, service managers and commissioners is available at FutureNHS, which is open to anyone working in or for health and care (https://future.nhs.uk/ECOPDecisionSupportTool). For future service changes, call handler designation of urgency could be relatively easily embedded in EDs, which alongside frailty risk, could identify those at the highest risk of adverse events upon arrival at ED. It might be that frailty expertise in combination with emergency medicine expertise could be usefully deployed to support these individuals. In summary, we have reaffirmed the poor outcomes frequently experienced by older people with urgent care needs. We have identified interventions that could improve patient and service outcomes, as well as implementation tools and strategies to transform emergency care for older people. Future work Future work will focus on refining the system dynamics model, specifically including patient-reported outcome measures and prehospital services for older people living with frailty who have urgent care needs. Study registrations This study is registered as PROSPERO CRD42018111461. WP 1.2: University of Leicester ethics: 17525-spc3-ls:healthsciences, WP 2: IRAS 262143, CAG 19/CAG/0194, WP 3: IRAS 215818, REC 17/YH/0024, CAG 17/CAG/0024. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research; Vol. 11, No. 14. See the NIHR Journals Library website for further project information.

Abstract Background Gender-related factors might affect vulnerability to Covid-19. The aim of this study was to describe the role of gender on clinical features and 28-day mortality in Covid-19 patients. Methods Observational study of Covid-19 patients hospitalized in Bergamo, Italy, during the first three weeks of the outbreak. Medical records, clinical, radiological and laboratory findings upon admission and treatment have been collected. Primary outcome was 28-day mortality since hospitalization. Results 431 consecutive adult patients were admitted. Female patients were 119 (27.6%) with a mean age of 67.0 ± 14.5 years (vs 67.8 ± 12.5 for males, p = 0.54). Previous history of myocardial infarction, vasculopathy and former smoking habits were more common for males. At the time of admission PaO2/FiO2 was similar between men and women (228 [IQR, 134–273] vs 238 mmHg [150–281], p = 0.28). Continuous Positive Airway Pressure (CPAP) assistance was needed in the first 24 h more frequently in male patients (25.7% vs 13.0%; p = 0.006). Overall 28-day mortality was 26.1% in women and 38.1% in men (p = 0.018). Gender did not result an independent predictor of death once the parameters related to disease severity at presentation were included in the multivariable analysis (p = 0.898). Accordingly, the Kaplan–Meier survival analysis in female and male patients requiring CPAP or non-invasive ventilation in the first 24 h did not find a significant difference (p = 0.687). Conclusion Hospitalized women are less likely to die from Covid-19; however, once severe disease occurs, the risk of dying is similar to men. Further studies are needed to better investigate the role of gender in clinical course and outcome of Covid-19.

Postgraduate engagement in delivering outreach activities is more commonplace than it once was. However, the impact on postgraduate students (typically studying for a Ph.D. degree) of participating in the delivery of these outreach activities has rarely, if ever, been recorded. The Bristol ChemLabS Outreach program has been running for ca. 17 years, and in that time, many postgraduate students have been involved (approximately 500), with around 250 typically for up to 3 years. We sought to investigate the impact of outreach engagement on postgraduate alumni who were involved in the program for over 3 years (32) and how the experiences and training of the outreach program had impacted on their careers postgraduation. Thirty of the 32 postgraduates engaged and ~70% reported that their outreach experience had influenced their decision making on future careers. Many respondents reported that the skills and experiences gained through outreach participation had contributed to success in applying for and interviewing at their future employers. All respondents reported that outreach had helped them to develop key skills that were valued in the workplace, specifically, communication, teamwork, organizational skills, time planning, event planning, and event management. Rather than a pleasant distraction or an opportunity to supplement income, all participants noted that they felt there were many additional benefits and that this was time well spent. Outreach should not be viewed as a distraction to science research but rather an important enhancement to it provided that the program is well constructed and seeks to develop those delivering the outreach activities.

Unsolved Mendelian cases often lack obvious pathogenic coding variants, suggesting potential non-coding etiologies. Here, we present a single cell multi-omic framework integrating embryonic mouse chromatin accessibility, histone modification, and gene expression assays to discover cranial motor neuron (cMN) cis-regulatory elements and subsequently nominate candidate non-coding variants in the congenital cranial dysinnervation disorders (CCDDs), a set of Mendelian disorders altering cMN development. We generate single cell epigenomic profiles for ~86,000 cMNs and related cell types, identifying ~250,000 accessible regulatory elements with cognate gene predictions for ~145,000 putative enhancers. We evaluate enhancer activity for 59 elements using an in vivo transgenic assay and validate 44 (75%), demonstrating that single cell accessibility can be a strong predictor of enhancer activity. Applying our cMN atlas to 899 whole genome sequences from 270 genetically unsolved CCDD pedigrees, we achieve significant reduction in our variant search space and nominate candidate variants predicted to regulate known CCDD disease genes MAFB, PHOX2A, CHN1, and EBF3 - as well as candidates in recurrently mutated enhancers through peak- and gene-centric allelic aggregation. This work delivers non-coding variant discoveries of relevance to CCDDs and a generalizable framework for nominating non-coding variants of potentially high functional impact in other Mendelian disorders.

This paper examines issues relating to the perceptions and adoption of open access (OA) and institutional repositories. Using a survey research design, we collected data from academics and other researchers in the humanities, arts and social sciences (HASS) at a university in Australia. We looked at factors influencing choice of publishers and journal outlets, as well as the use of social media and nontraditional channels for scholarly communication. We used an online questionnaire to collect data and used descriptive statistics to analyse the data. Our findings suggest that researchers are highly influenced by traditional measures of quality, such as journal impact factor, and are less concerned with making their work more findable and promoting it through social media. This highlights a disconnect between researchers’ desired outcomes and the efforts that they put in toward the same. Our findings also suggest that institutional policies have the potential to increase OA awareness and adoption. This study contributes to the growing literature on scholarly communication by offering evidence from the HASS field, where limited studies have been conducted. Based on the findings, we recommend that academic librarians engage with faculty through outreach and workshops to change perceptions of OA and the institutional repository.

Freshwater ecosystems are particularly at risk from climate change due to the intrinsic link between the physical properties of the water environment and those species that live there. Mayflies, stoneflies and caddisflies are key indicators of the health of freshwater environments and their biological traits and ecological preferences determine their vulnerability to climate change. Traits and preferences for 289 British species were analysed, with voltinism, length of flight period, altitudinal preference and affinity to headwaters being the main factors causing vulnerability. Sixteen species were deemed to be at risk from climate change. These species are distributed across Great Britain, but particular hotspots of vulnerability are present in upland areas. These areas should be targeted with mitigation measures to reduce the impacts of climate change on populations of aquatic insects.

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the Genomics Research to Elucidate the Genetics of Rare Diseases consortium and analyzed using the seqr platform. The addition of CNV detection to exome analysis identified causal CNVs for 171 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb. The causal CNVs consisted of 140 deletions, 15 duplications, 3 suspected complex structural variants (SVs), 3 insertions, and 10 complex SVs, the latter two groups being identified by orthogonal confirmation methods. To classify CNV variant pathogenicity, we used the 2020 American College of Medical Genetics and Genomics/ClinGen CNV interpretation standards and developed additional criteria to evaluate allelic and functional data as well as variants on the X chromosome to further advance the framework. We interpreted 151 CNVs as likely pathogenic/pathogenic and 20 CNVs as high-interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher-resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs.

Ultrafast electron diffraction (UED) stands as a powerful technique for real-time observation of structural dynamics at the atomic level. In recent years, the use of MeV electrons from radio frequency guns has been widely adopted to take advantage of the relativistic suppression of the space charge effects that otherwise limit the temporal resolution of the technique. Nevertheless, there is not a clear choice for the optimal energy for a UED instrument. Scaling to beam energies higher than a few MeV does pose significant technical challenges, mainly related to the inherent increase in diffraction camera length associated with the smaller Bragg angles. In this study, we report a solution by using a compact post-sample magnetic optical system to magnify the diffraction pattern from a crystal Au sample illuminated by an 8.2 MeV electron beam. Our method employs, as one of the lenses of the optical system, a triplet of compact, high field gradients (>500 T/m), small-gap (3.5 mm) Halbach permanent magnet quadrupoles. Shifting the relative position of the quadrupoles, we demonstrate tuning the magnification by more than a factor of two, a 6× improvement in camera length, and reciprocal space resolution better than 0.1 Å-1 in agreement with beam transport simulations.

BACKGROUND: The effect of transdermal glyceryl trinitrate (GTN, a nitrovasodilator) on clinical outcome when administered before hospital admission in suspected stroke patients is unclear. Here, we assess the safety and efficacy of GTN in the prespecified subgroup of patients who had an ischaemic stroke within the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2). METHODS: RIGHT-2 was an ambulance-based multicentre sham-controlled blinded-endpoint study with patients randomised within 4 hours of onset. The primary outcome was a shift in scores on the modified Rankin scale (mRS) at day 90. Secondary outcomes included death; a global analysis (Wei-Lachin test) containing Barthel Index, EuroQol-5D, mRS, telephone interview for cognitive status-modified and Zung depression scale; and neuroimaging-determined brain frailty markers. Data were reported as n (%), mean (SD), median [IQR], adjusted common OR (acOR), mean difference or Mann-Whitney difference (MWD) with 95% CI. RESULTS: 597 of 1149 (52%) patients had a final diagnosis of ischaemic stroke; age 75 (12) years, premorbid mRS>2 107 (18%), Glasgow Coma Scale 14 (2) and time from onset to randomisation 67 [45, 108] min. Neuroimaging brain frailty was common: median score 2 [2, 3] (range 0-3). At day 90, GTN did not influence the primary outcome (acOR for increased disability 1.15, 95% CI 0.85 to 1.54), death or global analysis (MWD 0.00, 95% CI -0.10 to 0.09). In subgroup analyses, there were non-significant interactions suggesting GTN may be associated with more death and dependency in participants randomised within 1 hour of symptom onset and in those with more severe stroke. CONCLUSIONS: In patients who had an ischaemic stroke, ultra-acute administration of transdermal GTN in the ambulance did not improve clinical outcomes in a population with more clinical and radiological frailty than seen in previous in-hospital trials.