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Photocathode laser pulse shaping is a crucial technology for enhancing the performance of X-ray free-electron lasers by optimizing the quality of electron beams generated from photocathodes within high-gradient radio frequency guns. By precisely shaping these laser pulses, it is possible to significantly reduce the transverse emittance of produced electron bunches. The optimal pulse shape is an ellipsoidal distribution, commonly referred to as the Kapchinskij–Vladimirskij profile. A pulse-shaping scheme utilizing a commercial Yb:KGW laser operating at 514 nm with a repetition rate of 1 MHz and duration of 260 fs has been developed for generating electron bunches with high peak and average power. This study presents the experimental realization of ellipsoidal pulses via three-dimensional amplitude shaping using spatial light modulators at 514 nm, followed by conversion to UV (257 nm) suitable for Cs 2Te photocathodes. The preservation of pulse shape and a high conversion efficiency during this process are investigated and our experiments pave the way for future emittance minimization for X-ray free-electron lasers.

Introduction Online adaptive MR-guided radiotherapy allows for dose escalation to pancreatic cancer while sparing surrounding critical organs. We seek to evaluate the safety of delivering hypofractionated five-fraction, three-fraction and single-fraction MR-guided stereotactic ablative radiotherapy (SABR) to the pancreas.Methods and analysis This is a single-centre three-arm phase 1 non-randomised safety study. Patients with localised pancreatic cancer will receive either 50 Gy in five (biological equivalent dose (BED10)=100 Gy), 39 Gy in three (BED10=90 Gy) or 25 Gy in a single fraction (BED10=87.5 Gy) MR-guided daily online adaptive radiotherapy. Each fractionation regimen will be assessed as independent cohorts to determine tolerability, assessed continuously using Bayesian conjugate posterior beta distributions. The primary endpoint of the study is to establish the safety of five-fraction, three-fraction and single-fraction MR-guided hypofractionation SABR in localised pancreatic cancer by assessing dose-limiting toxicities. Secondary endpoints include overall survival, progression-free survival, local control rates, overall control rate, resection rates, long-term toxicities and freedom from second-line chemotherapy. This study plans to also explore imaging and immune biomarkers that may be useful to predict outcome and personalise treatment. The trial will recruit up to 60 patients with a safety run-in.Ethics and dissemination The trial is approved by the West Midlands—Black Country Research Ethics Committee 22/WM/0122. The results will be disseminated via conference presentations, peer-reviewed scientific journals and submission to regulatory authorities. The data collected for the study, including individual participant data, will be made available to researchers on request to the study team and with appropriate reason, via octo-enquiries@oncology.ox.ac.uk. The shared data will be deidentified participant data and will be available for 3 years following publication of the study. Data will be shared with investigator support, after approval of a proposal and with a signed data access agreement.Trial registration number ISRCTN10557832

A key issue of X-ray free-electron lasers is the quality of the photoelectron beams generated from a photocathode by laser pulses in the high-gradient RF gun. Controlling the shape of these laser pulses can strongly reduce the transverse emittance of the generated electron bunch. For this purpose, a laser pulseshaper at 515 nm is presented that can be used directly with alkali antimonide photocathodes for photoemission. The first results regarding generation and measurement of flattop and parabolic pulses as well as introduction of modulations for THz generation are presented and show the potential for emittance optimization with 3D ellipsoidal pulses with the proposed pulseshaper. The experiments are carried out for Cs2Te photocathodes, which require second harmonic generation of the shaped pulses and thus allow investigation of pulseshape preservation in nonlinear frequency conversion processes.

Abstract Background Chemoradiotherapy remains the standard of care for locally advanced rectal cancer. Efforts to intensify treatment and increase response rates have yet to yield practice changing results due to increased toxicity and/or absence of increased radiosensitization. Enadenotucirev (EnAd) is a tumour selective, oncolytic adenovirus which can be given intravenously. Pre-clinical evidence of synergy with radiation warrants further clinical testing and assessment of safety with radiation. Methods Eligibility include histology confirmed locally advanced rectal cancer that require chemoradiation. The trial will use a Time-to-Event Continual Reassessment Model-based (TiTE-CRM) approach using toxicity and efficacy as co-primary endpoints to recommend the optimal dose and treatment schedule 30 patients will be recruited. Secondary endpoints include pathological complete response the neoadjuvant rectal score. A translational program will be based on a mandatory biopsy during the second week of treatment for ‘proof-of-concept’ and exploration of mechanism. The trial opened to recruitment in July 2019, at an expected rate of 1 per month for up to 4 years. Discussion Chemoradiation with Enadenotucirev as a radiosensitiser in locally Advanced Rectal cancer (CEDAR) is a prospective multicentre study testing a new paradigm in radiosensitization in rectal cancer. The unique ability of EnAd to selectively infect tumour cells following intravenous delivery is an exciting opportunity with a clear translational goal. The novel statistical design will make efficient use of both toxicity and efficacy data to inform subsequent studies. Trial registration ClinicalTrial.gov, NCT03916510 . Registered 16th April 2019.

Photoinjectors are the main high brightness electron sources for x-ray free electron lasers (XFELs). Photoinjector emittance reduction is one of the key knobs for improving XFEL lasing, so precise emittance measurement is critical. It is well known that rms emittance is very sensitive to low intensity tails of particle distributions in the phase space, whose measurement depends on the signal to noise ratio and image processing procedures. Such sensitivities make the interpretations of beam transverse brightness challenging, leading to different emittance definitions to reduce the impact of tail particles. In this paper, transverse phase space is analyzed in action and phase coordinates for both analytical models and experiments, which gives a more intuitive way to calculate the beam core brightness.

Slice energy spread is one of the key parameters in free electron laser optimizations, but its accurate measurement is not straightforward. Two recent studies from high energy (≥100 MeV) photoinjectors at SwissFEL and European x-ray free electron laser (XFEL) have reported much higher slice energy spread than expected at their XFEL working points (200–250 pC). In this paper, a new method for measuring slice energy spread at lower beam energy (∼20 MeV) is proposed and demonstrated at the PhotoInjector Test facility at DESY Zeuthen, and the results for 250 pC are much lower than those measured at high energy injectors.

The function of Sprouty2 (Spry2) in T cells is unknown. Using 2 different (inducible and T cell-targeted) knockout mouse strains, we found that Spry2 positively regulated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling by modulating the activity of LCK. Spry2-/- CD4+ T cells were unable to activate LCK, proliferate, differentiate into T helper cells, or produce cytokines. Spry2 deficiency abrogated type 2 inflammation and airway hyperreactivity in a murine model of asthma. Spry2 expression was higher in blood and airway CD4+ T cells from patients with asthma, and Spry2 knockdown impaired human T cell proliferation and cytokine production. Spry2 deficiency up-regulated the lipid raft protein caveolin-1, enhanced its interaction with CSK, and increased CSK interaction with LCK, culminating in augmented inhibitory phosphorylation of LCK. Knockdown of CSK or dislodgment of caveolin-1-bound CSK restored ERK1/2 activation in Spry2-/- T cells, suggesting an essential role for Spry2 in LCK activation and T cell function.

Introduction Patients with head and neck squamous cell carcinoma with locally advanced disease often require multimodality treatment with surgery, radiotherapy and/or chemotherapy. Adjuvant radiotherapy with concurrent chemotherapy is offered to patients with high-risk pathological features postsurgery. While cure rates are improved, overall survival remains suboptimal and treatment has a significant negative impact on quality of life.Cell cycle checkpoint kinase inhibition is a promising method to selectively potentiate the therapeutic effects of chemoradiation. Our hypothesis is that combining chemoradiation with a WEE1 inhibitor will affect the biological response to DNA damage caused by cisplatin and radiation, thereby enhancing clinical outcomes, without increased toxicity. This trial explores the associated effect of WEE1 kinase inhibitor adavosertib (AZD1775).Methods and analysis This phase I dose-finding, open-label, multicentre trial aims to determine the highest safe dose of AZD1775 in combination with cisplatin chemotherapy preoperatively (group A) as a window of opportunity trial, and in combination with postoperative cisplatin-based chemoradiation (group B).Modified time-to-event continual reassessment method will determine the recommended dose, recruiting up to 21 patients per group. Primary outcomes are recommended doses with predefined target dose-limiting toxicity probabilities of 25% monitored up to 42 days (group A), and 30% monitored up to 12 weeks (group B). Secondary outcomes are disease-free survival times (groups A and B). Exploratory objectives are evaluation of pharmacodynamic (PD) effects, identification and correlation of potential biomarkers with PD markers of DNA damage, determine rate of resection status and surgical complications for group A; and quality of life in group B.Ethics and dissemination Research Ethics Committee, Edgbaston, West Midlands (REC reference 16/WM/0501) initial approval received on 18/01/2017. Results will be disseminated via peer-reviewed publication and presentation at international conferences.Trial registration number ISRCTN76291951 and NCT03028766.

Abstract Prior research highlights that rural populations have been historically underrepresented/excluded from clinical research. The primary objective of this study was to describe the inclusion of rural populations within our research enterprise using Clinical Research Management System demographic information at a large academic medical center in the Southeast. This was a cross‐sectional study using participant demographic information for all protocols entered into our Clinical Research Management System between May 2018 and March 2021. Descriptive statistics were used to analyze the representation of rural and non‐rural participants and demographic breakdown by age, sex, race, and ethnicity for our entire enterprise and at the state level. We also compared Material Community Deprivation Index levels between urban and rural participants. Results indicated that 19% of the research population was classified as rural and 81% as non‐rural for our entire sample, and 17.5% rural and 82.5% urban for our state‐level sample. There were significant differences in race, sex, and age between rural and non‐rural participants and Material Community Deprivation Indices between rural and non‐rural participants. Lessons learned and recommendations for increasing the inclusion of rural populations in research are discussed.

In May 2023, the editorial board of Cosmopolitan Civil Societies hosted an online conference on ‘New Conceptualisations of Cosmopolitanism’. Discussions were rich and varied, across two days and several panels. The event was an experiment for the journal. This Special Issue is the result. There are ten papers in this Special Issue, falling into three broad fields of debate: four on themes of cosmopolitics, ethnonationalism and the national state; three on aspects of work, gender and cosmopolitan identification; and three on issues of climate action, land use and environmentalism. The editorial introduction seeks to summarise papers and draw out some common themes for wider debate.

Empowering the Participant Voice (EPV) is an NCATS-funded six-CTSA collaboration to develop, demonstrate, and disseminate a low-cost infrastructure for collecting timely feedback from research participants, fostering trust, and providing data for improving clinical translational research. EPV leverages the validated Research Participant Perception Survey (RPPS) and the popular REDCap electronic data-capture platform. This report describes the development of infrastructure designed to overcome identified institutional barriers to routinely collecting participant feedback using RPPS and demonstration use cases. Sites engaged local stakeholders iteratively, incorporating feedback about anticipated value and potential concerns into project design. The team defined common standards and operations, developed software, and produced a detailed planning and implementation Guide. By May 2023, 2,575 participants diverse in age, race, ethnicity, and sex had responded to approximately 13,850 survey invitations (18.6%); 29% of responses included free-text comments. EPV infrastructure enabled sites to routinely access local and multi-site research participant experience data on an interactive analytics dashboard. The EPV learning collaborative continues to test initiatives to improve survey reach and optimize infrastructure and process. Broad uptake of EPV will expand the evidence base, enable hypothesis generation, and drive research-on-research locally and nationally to enhance the clinical research enterprise.

Abstract Introduction: Latinx populations are underrepresented in clinical research. Asking Latinx research participants about their research experiences, barriers, and facilitators could help to improve research participation for these populations. Methods: The Salud Estres y Resilencia (SER) Hispano cohort study is a longitudinal cohort study of young adult Latinx immigrants whose design and conduct were tailored for their study population. We administered the Research Participant Perception Survey (RPPS) to SER Hispano participants to assess their experiences in the study. We describe overall results from the RPPS and compare results of surveys administered to SER Hispano participants via email versus telephone. Results: Of 340 participants who were contacted with the RPPS, 142 (42%) responded. Among respondents, 53 (37%) responded by initial email contact; and 89 (63%) responded by subsequent phone contact. The majority of respondents were between 35 and 44 years of age (54%), female (76%), and of Cuban origin (50%). Overall, research participants expressed high satisfaction with their research experience; 84% stated that they would “definitely” recommend research participation to friends and family, with no significant difference by method of survey administration (P = 0.45). The most common factor that was chosen that would influence future research participation was having summary results of the research shared with them (72%). Conclusion: We found that culturally tailored studies can be good experiences for Latinx research participants; and we found that use of the RPPS can be administered successfully, particularly when administered by more than one method, including telephone, to evaluate and to improve research experiences for this population.

Abstract Introduction Major surgery accounts for a substantial proportion of health service activity, due not only to the primary procedure, but the longer-term health implications of poor short-term outcome. Data from small studies or from outside the UK indicate that rates of complications and failure to rescue vary between hospitals, as does compliance with best practice processes. Within the UK, there is currently no system for monitoring postoperative complications (other than short-term mortality) in major non-cardiac surgery. Further, there is variation between national audit programmes, in the emphasis placed on quality assurance versus quality improvement, and therefore the principles of measurement and reporting which are used to design such programmes. Methods and analysis The PQIP patient study is a multi-centre prospective cohort study which recruits patients undergoing major surgery. Patient provide informed consent and contribute baseline and outcome data from their perspective using a suite of patient-reported outcome tools. Research and clinical staff complete data on patient risk factors and outcomes in-hospital, including two measures of complications. Longer-term outcome data are collected through patient feedback and linkage to national administrative datasets (mortality and readmissions). As well as providing a uniquely granular dataset for research, PQIP provides feedback to participating sites on their compliance with evidence-based processes and their patients’ outcomes, with the aim of supporting local quality improvement. Ethics and dissemination Ethical approval has been granted by the Health Research Authority in the UK. Dissemination of interim findings (non-inferential) will form a part of the improvement methodology and will be provided to participating centres at regular intervals, including near-real time feedback of key process measures. Inferential analyses will be published in the peer-reviewed literature, supported by a comprehensive multi-modal communications strategy including to patients, policy makers and academic audiences as well as clinicians.

Abstract Background Analysis of Medicare data is often used to determine epidemiology, healthcare utilization and effectiveness of disease treatments. We were interested in whether Medicare data could be used to estimate prevalence of tobacco use. Currently, data regarding tobacco use is derived from Behavioral Risk Factor Surveillance System (BRFSS) survey data. We compare administrative claims data for tobacco diagnosis among Medicare beneficiaries to survey (BRFSS) estimates of tobacco use from 2001 to 2014. Methods Retrospective cross-sectional study comparing tobacco diagnoses using International Classification of Disease, Ninth Revision (ICD-9) codes for tobacco use in Medicare data to BRFSS data from 2001 to 2014 in adults age ≥ 65 years. Beneficiary data included age, gender, race, socioeconomic status, and comorbidities. Tobacco cessation counselling was also examined using Healthcare Common Procedure Coding System codes. Results The prevalence of Medicare enrollees aged ≥65 years who had a diagnosis of current tobacco use increased from 2.01% in 2001 to 4.8% in 2014, while the estimates of current tobacco use from BRFSS decreased somewhat (10.03% in 2001 vs. 8.77% in 2014). However, current tobacco use based on Medicare data remained well below the estimates from BRFSS. Use of tobacco cessation counselling increased over the study period with largest increases after 2010. Conclusions The use of tobacco-related diagnosis codes increased from 2001 to 2014 in Medicare but still substantially underestimated the prevalence of tobacco use compared to BRFSS data.

Background: England, and the UK more generally, has a large burden of winter- and cold-related mortality/morbidity in comparison with nearby countries in continental Europe. Improving the energy efficiency of the housing stock may help to reduce this, as well as being important for climate change and energy security objectives. Objectives: To evaluate the impact of home energy efficiency (HEE) interventions on winter- and cold-related mortality/morbidity, including assessing the impact of winter fuel payments (WFPs) and fuel costs. Design: A mixed-methods study – an epidemiological time-series analysis, an analysis of data on HEE interventions, the development and application of modelling methods including a multicriteria decision analysis and an in-depth interview study of householders. Setting: England, UK. Participants: The population of England. In-depth interviews were conducted with 12 households (2–4 participants each) and 41 individuals in three geographical regions. Interventions: HEE interventions. Main outcome measures: Mortality, morbidity and intervention-related changes to the home indoor environment. Data sources: The Homes Energy Efficiency Database, mortality and hospital admissions data and weather (temperature) data. Results: There has been a progressive decline in cold-related deaths since the mid-1970s. Since the introduction of WFPs, the gradient of association between winter cold and mortality [2.00%, 95% confidence interval (CI) 1.74% to 2.28%] per degree Celsius fall in temperature is somewhat weaker (i.e. that the population is less vulnerable to cold) than in earlier years (2.37%, 95% CI 0.22% to 2.53%). There is also evidence that years with above-average fuel costs were associated with higher vulnerability to outdoor cold. HEE measures installed in England in 2002–10 have had a relatively modest impact in improving the indoor environment. The gains in winter temperatures (around +0.09 °C on a day with maximum outdoor temperature of 5 °C) are associated with an estimated annual reduction of ≈280 cold-related deaths in England (an eventual maximum annual impact of 4000 life-years gained), but these impacts may be appreciably smaller than those of changes in indoor air quality. Modelling studies indicate the potential importance of the medium- and longer-term impacts that HEE measures have on health, which are not observable in short-term studies. They also suggest that HEE improvements of similar annualised cost to current WFPs would achieve greater improvements in health while reducing (rather than increasing) carbon dioxide emissions. In-depth interviews suggest four distinct householder framings of HEE measures (as home improvement, home maintenance, subsidised public goods and contributions to sustainability), which do not dovetail with current ‘consumerist’ national policy and may have implications for the uptake of HEE measures. Limitations: The quantification of intervention impacts in this national study is reliant on various indirect/model-based assessments. Conclusions: Larger-scale changes are required to the housing stock in England if the full potential benefits for improving health and for reaching increasingly important climate change mitigation targets are to be realised. Future work: Studies based on data linkage at individual dwelling level to examine health impacts. There is a need for empirical assessment of HEE interventions on indoor air quality. Funding: This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 6, No. 11. See the NIHR Journals Library website for further project information.

In 2017 the Australian Government announced a raft of measures designed to combat ‘foreign interference’ in the Australian political system. The measures propose new constraints on civil society advocacy and threaten to seriously curtail democratic rights. They form part of global trend towards the increased regulation of International Non-Government Organisations (INGOs), driven by fears of ‘foreign’ political influence. In response to the shrinking ‘civic space’, NGOs are defining new agendas. Recently in Australia and elsewhere NGO advocates have gained some traction in extending the legitimacy and scope for political advocacy. The new rhetoric of countering ‘foreign interference’ threatens NGO advocacy, but also creates new political possibilities. This article surveys the international trends and Australian contexts; it analyses recent legislative proposals in Australia to combat ‘foreign interference’, and outlines the public debate. The double standard for INGOs and multinational corporations is highlighted as a key theme, and the article ends with a concluding discussion about emerging possibilities for new political obligations for corporations in Australia

Problem Ghana’s population is ageing. In 2011, the Government of Ghana requested technical support from the World Health Organization (WHO) to help revise national policies on ageing and health. Approach We applied WHO’s knowledge translation framework on ageing and health to assist evidence based policy-making in Ghana. First, we defined priority problems and health system responses by performing a country assessment of epidemiologic data, policy review, site visits and interviews of key informants. Second, we gathered evidence on effective health systems interventions in low- middle- and high-income countries. Third, key stakeholders were engaged in a policy dialogue. Fourth, policy briefs were developed and presented to the Ghana Health Services. Local setting Ghana has a well-structured health system that can adapt to meet the health care needs of older people. Relevant changes Six problems were selected as priorities, however after the policy dialogue, only five were agreed as priorities by the stakeholders. The key stakeholders drafted evidence-based policy recommendations that were used to develop policy briefs. The briefs were presented to the Ghana Health Service in 2014. Lessons learnt The framework can be used to build local capacity on evidence-informed policy-making. However, knowledge translation tools need further development to be used in low-income countries and in the field of ageing. The terms and language of the tools need to be adapted to local contexts. Evidence for health system interventions on ageing populations is very limited, particularly for low- and middle-income settings.

The 2001 invasion and subsequent occupation consolidated ethnicity as a political force in Afghanistan. Inter-ethnic elite bargaining instituted an ethnocratic oligarchy, grounded in the occupation. Against this, everyday politics in Afghanistan has centred on social clientelism, founded on kinship networks rather than ethnicity. At the same time, formal political structures, expressed in the 2004 Constitution, are grounded in Islam and nationalist statehood rather than ethnicity. In recent years sharp disjunctures have emerged between ethnic elites and would-be constituents, creating some electoral fluidity and ethnic de-alignment. The paper addresses the relationship between occupation and ethnocracy in Afghanistan. It takes an historical perspective on the present, debating contending foundations for political solidarity and identification in the country.