Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility.

Immune checkpoint inhibition has shown success in treating metastatic cutaneous melanoma but has limited efficacy against metastatic uveal melanoma, a rare variant arising from the immune privileged eye. To better understand this resistance, we comprehensively profile 100 human uveal melanoma metastases using clinicogenomics, transcriptomics, and tumor infiltrating lymphocyte potency assessment. We find that over half of these metastases harbor tumor infiltrating lymphocytes with potent autologous tumor specificity, despite low mutational burden and resistance to prior immunotherapies. However, we observe strikingly low intratumoral T cell receptor clonality within the tumor microenvironment even after prior immunotherapies. To harness these quiescent tumor infiltrating lymphocytes, we develop a transcriptomic biomarker to enable in vivo identification and ex vivo liberation to counter their growth suppression. Finally, we demonstrate that adoptive transfer of these transcriptomically selected tumor infiltrating lymphocytes can promote tumor immunity in patients with metastatic uveal melanoma when other immunotherapies are incapable.

Radiotherapy intensification for atypical and malignant meningiomas: A systematic review.

Background: The outcomes of nonbenign (WHO Grades 2 and 3 [G2, G3]) meningiomas are suboptimal and radiotherapy (RT) dose intensification strategies have been investigated. The purpose of this review is to report on clinical practice and outcomes with particular attention to RT doses and techniques. Methods: The PICO criteria (Population, Intervention, Comparison, and Outcomes) were used to frame the research question, directed at outlining the clinical outcomes in patients with G2-3 meningiomas treated with RT. The same search strategy was run in Embase and MEDLINE and, after deduplication, returned 1 807 records. These were manually screened for relevance and 25 were included. Results: Tumor outcomes and toxicities are not uniformly reported in the selected studies since different endpoints and time points have been used by different authors. Many risk factors for worse outcomes are described, the most common being suboptimal RT. This includes no or delayed RT, low doses, and older techniques. A positive association between RT dose and progression-free survival (PFS) has been highlighted by analyzing the studies in this review (10/25) that report the same endpoint (5y-PFS). Conclusions: This literature review has shown that standard practice RT leads to suboptimal tumor control rates in G2-3 meningiomas, with a significant proportion of disease recurring after a relatively short follow-up. Randomized controlled trials are needed in this setting to define the optimal RT approach. Given the increasing data to suggest a benefit of higher RT doses for high-risk meningiomas, novel RT technologies with highly conformal dose distributions are preferential to achieve optimal target coverage and organs at risk sparing.

Minimum data elements for the Australian Particle Therapy Clinical Quality Registry.

INTRODUCTION: Construction of the first Australian particle therapy (PT) centre is underway. Establishment of a national registry, to be known as the Australian Particle Therapy Clinical Quality Registry (ASPIRE), has been identified as a mandatory requirement for PT treatment to be reimbursed by the Australian Medicare Benefits Schedule. This study aimed to determine a consensus set of Minimum Data Elements (MDEs) for ASPIRE. METHODS: A modified Delphi and expert consensus process was completed. Stage 1 compiled currently operational English-language international PT registries. Stage 2 listed the MDEs included in each of these four registries. Those included in three or four registries were automatically included as a potential MDE for ASPIRE. Stage 3 interrogated the remaining data items, and involved three rounds - an online survey to a panel of experts, followed by a live poll session of PT-interested participants, and finally a virtual discussion forum of the original expert panel. RESULTS: One hundred and twenty-three different MDEs were identified across the four international registries. The multi-staged Delphi and expert consensus process resulted in a total of 27 essential MDEs for ASPIRE; 14 patient factors, four tumour factors and nine treatment factors. CONCLUSIONS: The MDEs provide the core mandatory data items for the national PT registry. Registry data collection for PT is paramount in the ongoing global effort to accumulate more robust clinical evidence regarding PT patient and tumour outcomes, quantifying the magnitude of clinical benefit and justifying the relatively higher costs of PT investment.

Association Between Skin Acid Mantle, Natural Moisturizing Factors, and Antibacterial Activity Against S. aureus in the Stratum Corneum.

Purpose: The skin has evolved a system to prevent pathogenic microorganism colonization and infection. This study examined the role of natural moisturizing factors (NMFs) and skin pH on Staphylococcus aureus (S. aureus) growth and colonization on the human stratum corneum (SC). Study Population and Methods: A survey study with 82 female participants was performed. Participants maintained their daily hygiene routine, except for refraining from using leave-on products on their forearms on the day of the test. Skin sampling was performed using adhesive tapes. An ex vivo method was developed to study the viability and growth of S. aureus on human SC sampled from normal skin. NMFs, including pyrrolidone carboxylic acid (PCA), urocanic acid (UCA), histidine, and proline in SC samples, were measured by liquid chromatography with tandem mass spectrometry. The impact of PCA and UCA on S. aureus growth and metabolic activity was measured by optical density and isothermal microcalorimetry, respectively. Results: Heterogeneity of S. aureus viability on human SC samples was observed. Skin pH showed a significant negative association (p<0.05) with SC antibacterial activity in the ex vivo assay. One unit of skin pH decrease corresponded to 68.1% of S. aureus cell death. The levels of PCA and histidine were significantly negatively associated (p<0.05) with skin pH. The addition of 5 mM and 10 mM PCA significantly inhibited S. aureus growth by approximately 25% at 20 hours and reduced its metabolic activity in vitro. Conclusion: The results indicate that PCA, one of the NMFs in human skin, plays an important role in regulating the human skin acid mantle in vivo and contributes to antibacterial activity against S. aureus.

Proton Beam Therapy in the Oligometastatic/Oligorecurrent Setting: Is There a Role? A Literature Review.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) and stereotactic radiosurgery (SRS) with conventional photon radiotherapy (XRT) are well-established treatment options for selected patients with oligometastatic/oligorecurrent disease. The use of PBT for SABR-SRS is attractive given the property of a lack of exit dose. The aim of this review is to evaluate the role and current utilisation of PBT in the oligometastatic/oligorecurrent setting. METHODS: Using Medline and Embase, a comprehensive literature review was conducted following the PICO (Patients, Intervention, Comparison, and Outcomes) criteria, which returned 83 records. After screening, 16 records were deemed to be relevant and included in the review. RESULTS: Six of the sixteen records analysed originated in Japan, six in the USA, and four in Europe. The focus was oligometastatic disease in 12, oligorecurrence in 3, and both in 1. Most of the studies analysed (12/16) were retrospective cohorts or case reports, two were phase II clinical trials, one was a literature review, and one study discussed the pros and cons of PBT in these settings. The studies presented in this review included a total of 925 patients. The metastatic sites analysed in these articles were the liver (4/16), lungs (3/16), thoracic lymph nodes (2/16), bone (2/16), brain (1/16), pelvis (1/16), and various sites in 2/16. CONCLUSIONS: PBT could represent an option for the treatment of oligometastatic/oligorecurrent disease in patients with a low metastatic burden. Nevertheless, due to its limited availability, PBT has traditionally been funded for selected tumour indications that are defined as curable. The availability of new systemic therapies has widened this definition. This, together with the exponential growth of PBT capacity worldwide, will potentially redefine its commissioning to include selected patients with oligometastatic/oligorecurrent disease. To date, PBT has been used with encouraging results for the treatment of liver metastases. However, PBT could be an option in those cases in which the reduced radiation exposure to normal tissues leads to a clinically significant reduction in treatment-related toxicities.

Including genotypic information in genetic evaluations increases the accuracy of sheep breeding values.

The impact of inclusion of genome-wide genotypes into breeding value predictions for UK Texel sheep is addressed in this article. The main aim was to investigate the level of change in the accuracy values for EBVs when information from animal genotypes is incorporated into the genetic evaluations. New genetic parameters for a range of lamb growth, carcass composition and health traits are described and applied in the estimation of conventional breeding values (EBVs) for almost 822,000 animals as well as genomic breeding values (gEBVs) after adding 10,143 genotypes. Principal component analyses showed that there are no major distinct groups; hence, the population is mainly homogenous and genetically well-linked. Results suggested that the highest change in accuracy was observed for the animals that are not phenotyped but have good links to the reference population. This was seen especially for the lowly heritable health traits thereby proving that the use of genotypes in breeding values estimation may accelerate the genetic gain by producing more accurate values especially for young, un-phenotyped animals.

Late Dental Toxicities After Proton Chemoradiation for Rhabdomyosarcoma: A Pediatric Case Report.

Purpose: Radiation therapy is an independent risk factor for adverse sequelae to the oral cavity and dentition in childhood cancer survivors. However, dental toxicities after radiation therapy often are underreported and there are minimal published data on disturbances in tooth development after proton beam therapy (PBT). We present the long-term clinical and radiographic dental findings 8 years after treatment completion for a patient treated with PBT and chemotherapy for rhabdomyosarcoma. Materials and Methods: Clinical follow-up data of patients treated with PBT within the Proton Overseas Programme (POP) is stored in a National Database and curated by a dedicated outcomes unit at the Christie NHS PBT center. This case report was identified from the extraction and analysis of data for pediatric head and neck cancer patients in this database for a service evaluation project. Results: The permanent dentition in this patient aged 3.5 years at the time of treatment was severely affected with abnormal dental development first observed 3.5 years after treatment completion. PBT delivered mean doses of 30 Gy(RBE = 1.1) to the maxilla and 25.9 Gy(RBE = 1.1) to the mandible. Conclusion: Significant dental development abnormalities occurred in this pediatric patient, despite doses in areas being lower than the proposed thresholds in the literature. Improved descriptions of dental toxicities and routine contouring of the maxilla and mandible are needed to correlate dosimetric data. The dose to teeth should be kept as low as reasonably possible in younger patients until the dose thresholds for dental toxicities are known.

Performance on stochastic figure-ground perception varies with individual differences in speech-in-noise recognition and working memory capacity.

Speech recognition in noisy environments can be challenging and requires listeners to accurately segregate a target speaker from irrelevant background noise. Stochastic figure-ground (SFG) tasks in which temporally coherent inharmonic pure-tones must be identified from a background have been used to probe the non-linguistic auditory stream segregation processes important for speech-in-noise processing. However, little is known about the relationship between performance on SFG tasks and speech-in-noise tasks nor the individual differences that may modulate such relationships. In this study, 37 younger normal-hearing adults performed an SFG task with target figure chords consisting of four, six, eight, or ten temporally coherent tones amongst a background of randomly varying tones. Stimuli were designed to be spectrally and temporally flat. An increased number of temporally coherent tones resulted in higher accuracy and faster reaction times (RTs). For ten target tones, faster RTs were associated with better scores on the Quick Speech-in-Noise task. Individual differences in working memory capacity and self-reported musicianship further modulated these relationships. Overall, results demonstrate that the SFG task could serve as an assessment of auditory stream segregation accuracy and RT that is sensitive to individual differences in cognitive and auditory abilities, even among younger normal-hearing adults.

ESTRO ACROP and SIOPE recommendations for myeloablative Total Body Irradiation in children.

BACKGROUND AND PURPOSE: Myeloablative Total Body Irradiation (TBI) is an important modality in conditioning for allogeneic hematopoietic stem cell transplantation (HSCT), especially in children with high-risk acute lymphoblastic leukemia (ALL). TBI practices are heterogeneous and institution-specific. Since TBI is associated with multiple late adverse effects, recommendations may help to standardize practices and improve the outcome versus toxicity ratio for children. MATERIAL AND METHODS: The European Society for Paediatric Oncology (SIOPE) Radiotherapy TBI Working Group together with ESTRO experts conducted a literature search and evaluation regarding myeloablative TBI techniques and toxicities in children. Findings were discussed in bimonthly virtual meetings and consensus recommendations were established. RESULTS: Myeloablative TBI in HSCT conditioning is mostly performed for high-risk ALL patients or patients with recurring hematologic malignancies. TBI is discouraged in children <3-4 years old because of increased toxicity risk. Publications regarding TBI are mostly retrospective studies with level III-IV evidence. Preferential TBI dose in children is 12-14.4 Gy in 1.6-2 Gy fractions b.i.d. Dose reduction should be considered for the lungs to <8 Gy, for the kidneys to ≤10 Gy, and for the lenses to <12 Gy, for dose rates ≥6 cGy/min. Highly conformal techniques i.e. TomoTherapy and VMAT TBI or Total Marrow (and/or Lymphoid) Irradiation as implemented in several centers, improve dose homogeneity and organ sparing, and should be evaluated in studies. CONCLUSIONS: These ESTRO ACROP SIOPE recommendations provide expert consensus for conventional and highly conformal myeloablative TBI in children, as well as a supporting literature overview of TBI techniques and toxicities.

Effects of aging and hearing loss on perceptual and electrophysiological measures of pulse-rate discrimination.

Auditory temporal processing declines with age, leading to potential deleterious effects on communication. In young normal-hearing listeners, perceptual rate discrimination is rate limited around 300 Hz. It is not known whether this rate limitation is similar in older listeners with hearing loss. The purpose of this study was to investigate age- and hearing-loss-related rate limitations on perceptual rate discrimination, and age- and hearing-loss-related effects on neural representation of these stimuli. Younger normal-hearing, older normal-hearing, and older hearing-impaired listeners performed a pulse-rate discrimination task at rates of 100, 200, 300, and 400 Hz. Neural phase locking was assessed using the auditory steady-state response. Finally, a battery of non-auditory cognitive tests was administered. Younger listeners had better rate discrimination, higher phase locking, and higher cognitive scores compared to both groups of older listeners. Aging, but not hearing loss, diminished neural-rate encoding and perceptual performance; however, there was no relationship between the perceptual and neural measures. Higher cognitive scores were correlated with improved perceptual performance, but not with neural phase locking. This study shows that aging, rather than hearing loss, may be a stronger contributor to poorer temporal processing, and cognitive factors such as processing speed and inhibitory control may be related to these declines.

Estimating the percentage of patients who might benefit from proton beam therapy instead of X-ray radiotherapy.

OBJECTIVES: High-energy Proton Beam Therapy (PBT) commenced in England in 2018 and NHS England commissions PBT for 1.5% of patients receiving radical radiotherapy. We sought expert opinion on the level of provision. METHODS: Invitations were sent to 41 colleagues working in PBT, most at one UK centre, to contribute by completing a spreadsheet. 39 responded: 23 (59%) completed the spreadsheet; 16 (41%) declined, arguing that clinical outcome data are lacking, but joined six additional site-specialist oncologists for two consensus meetings. The spreadsheet was pre-populated with incidence data from Cancer Research UK and radiotherapy use data from the National Cancer Registration and Analysis Service. 'Mechanisms of Benefit' of reduced growth impairment, reduced toxicity, dose escalation and reduced second cancer risk were examined. RESULTS: The most reliable figure for percentage of radical radiotherapy patients likely to benefit from PBT was that agreed by 95% of the 23 respondents at 4.3%, slightly larger than current provision. The median was 15% (range 4-92%) and consensus median 13%. The biggest estimated potential benefit was from reducing toxicity, median benefit to 15% (range 4-92%), followed by dose escalation median 3% (range 0 to 47%); consensus values were 12 and 3%. Reduced growth impairment and reduced second cancer risk were calculated to benefit 0.5% and 0.1%. CONCLUSIONS: The most secure estimate of percentage benefit was 4.3% but insufficient clinical outcome data exist for confident estimates. The study supports the NHS approach of using the evidence base and developing it through randomised trials, non-randomised studies and outcomes tracking. ADVANCES IN KNOWLEDGE: Less is known about the percentage of patients who may benefit from PBT than is generally acknowledged. Expert opinion varies widely. Insufficient clinical outcome data exist to provide robust estimates. Considerable further work is needed to address this, including international collaboration; much is already underway but will take time to provide mature data.

Investigating the effect of a simplified perfume accord and dilution on the formation of mixed-surfactant microemulsions.

The phase analysis of a mixed surfactant system is much more complex than that for a single surfactant system. The addition of fragrance further enhances the complexity of such colloidal systems. The wide variation in structure and log P values of perfume raw materials influence its partitioning into the micellar phase. Herein, we have created a simplified perfume accord consisting of three perfume raw materials (3-PRM) and investigated its loading within a mixed-surfactant system consisting of sodium trideceth-2 sulfate/ST2S and cocamidopropyl betaine/CAPB, along with citric acid and dipropylene glycol. We performed a systematic phase diagram analysis and identified the isotropic phases and compositions of interest. Select compositions from the phase diagram were further investigated to learn how the geometry of the surfactant self-assembly and the localization of the PRMs within the surfactant self-assembly changed when water or perfume is added. A combined small-angle neutron scattering/SANS and NMR methodology was used to identify variation in colloidal domains and positioning of perfume molecules at varying dilutions/rinse off scenarios. The results obtained were utilized to better distinguish distorted micelles from true microemulsions. The systematic investigation here provides a fundamental understanding about the self-assembly, encapsulation and perfume release from a commercially relevant mixed surfactant system.

Online learning in proton radiation therapy: the future in the post-Covid-19 pandemic era?

Objective: The Covid-19 pandemic placed unprecedented strain on medical education and led to a vast increase in online learning. Subsequently, the Christie International Proton School moved from face-to-face to online. Delegate feedback and current literature were studied to determine benefits, challenges, and potential solutions, for online proton therapy education. Methods: The course was converted to a 6-week online course with twice weekly 2-h sessions. Feedback was studied pre-, during-, and post-course regarding demographics, learning objectives, proton therapy knowledge, ease of engagement, technical difficulties, and course format. Statistical analyses were performed for proton therapy knowledge pre- and post-course. Results: An increase in delegate attendance was seen with increased international and multidisciplinary diversity. Learner objectives included treatment planning, clinical applications, physics, and centre development. Average learner reported scores of confidence in proton therapy knowledge improved significantly from 3, some knowledge, to 4, adequate knowledge after the course (p<0.0001). There were minimal reported difficulties using the online platform, good reported learner engagement, and shorter twice weekly sessions were reported conducive for learning. Recordings for asynchronous learning addressed time zone difficulties. Conclusion: The obligatory switch to online platforms has catalysed a paradigm shift towards online learning with delegates reporting educational benefit. We propose solutions to challenges of international online education, and a pedagogical model for online proton therapy education. Advances in knowledge: Online education is an effective method to teach proton therapy to international audiences. The future of proton education includes a hybrid of online and practical face-to-face learning depending on the level of cognitive skill required.

The smaller general hospital: Delivering joined up cross-specialty working for the benefit of our patients.

Smaller acute general hospitals, especially those in remote and rural locations, provide vital services to their populations who might otherwise struggle to access safe and effective healthcare. By the nature of their location and, often also reputation, these hospitals are challenging to resource in terms of staffing which makes traditional models of care very difficult to sustain. This article proposes adjustments to the conventional model of acute care that is designed to ensure that patients presenting acutely receive a rapid assessment, according to their medical needs. This is delivered by a multiprofessional team of clinicians delivering care focused on the patient. Hand-offs between clinical teams and duplication of clinical assessment is kept to a minimum. The goal is to deliver care from the most appropriate professional or team as rapidly as possible post presentation, with alternatives to hospital admission being prioritised where appropriate. Early evidence is that this model of care is safe and effective, if delivered within a suitable physical environment for its provision. It is designed to deliver a sustainable model of working for the smaller, remote, rural or challenged healthcare system and is likely to be applicable to such systems elsewhere.

Skin benefits of moisturising body wash formulas for children with atopic dermatitis: A randomised controlled clinical study in China.

BACKGROUND: It acknowledged that skin care is an important part of atopic dermatitis therapy. However, clinical evidences are limited for the best bathing practices, especially the skin health performance of cleansing products on children's atopic dermatitis skin. METHODS: A randomised controlled clinical study was conducted in China among 4- to 18-year-old children with mild-to-moderate atopic dermatitis to evaluate the skin health effect of three cleansing systems (a mild synthetic bar, an ultra-mild body wash with lipids, and an ultra-mild body wash with lipids and zinc pyrithione) by measuring SCORing of Atopic Dermatitis (SCORAD), consumption of topical corticosteroid and the characteristics of microbiome. RESULTS: Increased Staphylococcus aureus abundance and decreased microbial diversity were observed in atopic dermatitis lesion sites compared with healthy control sites. After 4 weeks of treatment, all three treatments showed clinically important improvement from baseline in SCORAD. Four-week corticosteroid consumption was significantly lower for the two body wash groups than the bar group. A significant decrease in S. aureus abundance and increase in microbial diversity were observed in the lesion sites for the two body wash formulas, while the microbial diversity was statistically insignificant for the mild cleansing bar group. However, there were no incremental benefits provided by the body wash formulas based on the assessment of SCORAD. CONCLUSIONS: These results demonstrated the safety and efficacy of using the investigational body wash formulas with lipids in reducing the needs for corticosteroid and improving the healthy composition of skin microbiome vs. the mild synthetic bar soap.

Proton beam therapy: perspectives on the National Health Service England clinical service and research programme.

The UK has an important role in the evaluation of proton beam therapy (PBT) and takes its place on the world stage with the opening of the first National Health Service (NHS) PBT centre in Manchester in 2018, and the second in London coming in 2020. Systematic evaluation of the role of PBT is a key objective. By September 2019, 108 patients had started treatment, 60 paediatric, 19 teenagers and young adults and 29 adults. Obtaining robust outcome data is vital, if we are to understand the strengths and weaknesses of current treatment approaches. This is important in demonstrating when PBT will provide an advantage and when it will not, and in quantifying the magnitude of benefit.The UK also has an important part to play in translational PBT research, and building a research capability has always been the vision. We are perfectly placed to perform translational pre-clinical biological and physical experiments in the dedicated research room in Manchester. The nature of DNA damage from proton irradiation is considerably different from X-rays and this needs to be more fully explored. A better understanding is needed of the relative biological effectiveness (RBE) of protons, especially at the end of the Bragg peak, and of the effects on tumour and normal tissue of PBT combined with conventional chemotherapy, targeted drugs and immunomodulatory agents. These experiments can be enhanced by deterministic mathematical models of the molecular and cellular processes of DNA damage response. The fashion of ultra-high dose rate FLASH irradiation also needs to be explored.

A Microbiome-Based Index for Assessing Skin Health and Treatment Effects for Atopic Dermatitis in Children.

A quantitative and objective indicator for skin health via the microbiome is of great interest for personalized skin care, but differences among skin sites and across human populations can make this goal challenging. A three-city (two Chinese and one American) comparison of skin microbiota from atopic dermatitis (AD) and healthy pediatric cohorts revealed that, although city has the greatest effect size (the skin microbiome can predict the originated city with near 100% accuracy), a microbial index of skin health (MiSH) based on 25 bacterial genera can diagnose AD with 83 to ∼95% accuracy within each city and 86.4% accuracy across cities (area under the concentration-time curve [AUC], 0.90). Moreover, nonlesional skin sites across the bodies of AD-active children (which include shank, arm, popliteal fossa, elbow, antecubital fossa, knee, neck, and axilla) harbor a distinct but lesional state-like microbiome that features relative enrichment of Staphylococcus aureus over healthy individuals, confirming the extension of microbiome dysbiosis across body surface in AD patients. Intriguingly, pretreatment MiSH classifies children with identical AD clinical symptoms into two host types with distinct microbial diversity and treatment effects of corticosteroid therapy. These findings suggest that MiSH has the potential to diagnose AD, assess risk-prone state of skin, and predict treatment response in children across human populations.IMPORTANCE MiSH, which is based on the skin microbiome, can quantitatively assess pediatric skin health across cohorts from distinct countries over large geographic distances. Moreover, the index can identify a risk-prone skin state and compare treatment effect in children, suggesting applications in diagnosis and patient stratification.

Co-producing research with youth: The NeurOx young people's advisory group model.

CONTEXT: The 1989 UN Convention on the Rights of the Child states that children have the right to be heard in all matters affecting them. The Convention inspired a surge in research that investigates young people's perspectives on health and wellness-related concerns and that involves children as 'co-researchers'. Young people's advisory groups (YPAGs) are a widely used method to enable young people's involvement in all research stages, but there is a lack of academic literature to guide researchers on how to set up, run and evaluate the impact of such groups. OBJECTIVE: In this paper, we provide a step-by-step model, grounded in our own experience of setting up and coordinating the Oxford Neuroscience, Ethics and Society Young People's Advisory Group (NeurOx YPAG). This group supports studies at the intersection of ethics, mental health and novel technologies. Our model covers the following stages: deciding on the fit for co-production, recruiting participants, developing collective principles of work, running a meeting and evaluating impact. RESULTS: We emphasize that throughout this process, researchers should take a critical stance by reflecting on whether a co-production model fits their research scope and aims; ensuring (or aspiring to) representativeness within the group; valuing different kinds of expertise; and undertaking on-going evaluations on the impact of the group on both the young people and the research. CONCLUSION: Adopting a critical and reflective attitude can increase researchers' capacity to engage youth in democratic and inclusive ways, and to produce research outputs that are aligned with the target audience's needs and priorities.

A system under pressure.

Activity levels within emergency medicine, and the pressures experienced by individual clinicians working within the specialty, continue to increase year on year. In 2016-17 there were 18 691 546 attendances at UK emergency departments. Attendance numbers continue to increase annually, patients are becoming older and more unwell, departments are more crowded and as a result, emergency care standard performance figures are deteriorating. This article describes the impact of this pressure on the staff working within the emergency department and begins to explore the potential for the development of sustainability within the existing and future workforce.

Behavioral evidence for sex steroids hypersensitivity in castrated male canaries.

In seasonally breeding songbirds such as canaries, singing behavior is predominantly under the control of testosterone and its metabolites. Short daylengths in the fall that break photorefractoriness are followed by increasing daylengths in spring that activate singing via both photoperiodic and hormonal mechanisms. However, we observed in a group of castrated male Fife fancy canaries maintained for a long duration under a short day photoperiod a large proportion of subjects that sang at high rates. This singing rate was not correlated with variation in the low circulating concentrations of testosterone. Treatment of these actively singing castrated male canaries with a combination of an aromatase inhibitor (ATD) and an androgen receptor blocker (flutamide) only marginally decreased this singing activity as compared to control untreated birds and did not affect various measures of song quality. The volumes of HVC and of the medial preoptic nucleus (POM) were also unaffected by these treatments but were relatively large and similar to volumes in testosterone-treated males. In contrast, peripheral androgen-sensitive structures such as the cloacal protuberance and syrinx mass were small, similar to what is observed in castrates. Together these data suggest that after a long-term steroid deprivation singing behavior can be activated by very low concentrations of testosterone. Singing normally depends on the activation by testosterone and its metabolites of multiple downstream neurochemical systems such as catecholamines, nonapeptides or opioids. These transmitter systems might become hypersensitive to steroid action after long term castration as they probably are at the end of winter during the annual cycle in seasonally breeding temperate zone species.