Paediatric radiotherapy in the United Kingdom: an evolving subspecialty and a paradigm for integrated teamworking in oncology.

Many different malignancies occur in children, but overall, cancer in childhood is rare. Survival rates have improved appreciably and are higher compared with most adult tumour types. Treatment schedules evolve as a result of clinical trials and are typically complex and multi-modality, with radiotherapy an integral component of many. Risk stratification in paediatric oncology is increasingly refined, resulting in a more personalized use of radiation. Every available modality of radiation delivery: simple and advanced photon techniques, proton beam therapy, molecular radiotherapy, and brachytherapy, have their place in the treatment of children's cancers. Radiotherapy is rarely the sole treatment. As local therapy, it is often given before or after surgery, so the involvement of the surgeon is critically important, particularly when brachytherapy is used. Systemic treatment is the standard of care for most paediatric tumour types, concomitant administration of chemotherapy is typical, and immunotherapy has an increasing role. Delivery of radiotherapy is not done by clinical or radiation oncologists alone; play specialists and anaesthetists are required, together with mould room staff, to ensure compliance and immobilization. The support of clinical radiologists is needed to ensure the correct interpretation of imaging for target volume delineation. Physicists and dosimetrists ensure the optimal dose distribution, minimizing exposure of organs at risk. Paediatric oncology doctors, nurses, and a range of allied health professionals are needed for the holistic wrap-around care of the child and family. Radiographers are essential at every step of the way. With increasing complexity comes a need for greater centralization of services.

#Menopause: Examining the frequency of communications about menopause on twitter between 2014 and 2022.

This study explored the use of Twitter to communicate about menopause. Tweets in English posted between January 2014 and December 2022 with the hashtag "menopause" were extracted. Total global tweets and those from the UK, USA, Australia and Canada were examined. Globally, there were 314,974 tweets about menopause over this period, with an annual average of 34,997. There were notable differences between countries, with a large increase in use in the UK in 2018 and 2019, a reducing trend in use in the USA with a smaller increase in 2018 and 2019, and low stable usage in Australia and Canada.

Performance, Efficiency, and Flexibility Analysis of a High-Temperature Proton Exchange Membrane Fuel Cell-Based Micro-Combined Heat-and-Power System with Intensification of the Steam Methane Reforming Step by Using a Millistructured Reactor.

The complete simulation model of an existing 1 kW high-temperature proton exchange membrane (HT-PEM) fuel cell-based residential micro-combined heat-and-power process, including a compact intensified heat-exchanger-reactor, is developed in the simulation software ProSimPlus v3.6.16. Detailed simulation models of the heat-exchanger-reactor, a mathematical model of the HT-PEM fuel cell, and other components are presented. The results obtained by the simulation model and by the experimental micro-cogenerator are compared and discussed. To fully understand the behavior of the integrated system and assess its flexibility, a parametric study is performed considering fuel partialization and important operating parameters. The values of the air-to-fuel ratio = [30, 7.5] and steam-to-carbon ratio = 3.5 (corresponding to net electrical and thermal efficiencies of 21.5 and 71.4%) are chosen for the analysis of inlet/outlet component temperatures. Finally, the exchange network analysis of the full process proves that the process efficiencies can still be increased by further improving the process internal heat integration.

Base editing screens map mutations affecting interferon-γ signaling in cancer.

Interferon-γ (IFN-γ) signaling mediates host responses to infection, inflammation and anti-tumor immunity. Mutations in the IFN-γ signaling pathway cause immunological disorders, hematological malignancies, and resistance to immune checkpoint blockade (ICB) in cancer; however, the function of most clinically observed variants remains unknown. Here, we systematically investigate the genetic determinants of IFN-γ response in colorectal cancer cells using CRISPR-Cas9 screens and base editing mutagenesis. Deep mutagenesis of JAK1 with cytidine and adenine base editors, combined with pathway-wide screens, reveal loss-of-function and gain-of-function mutations, including causal variants in hematological malignancies and mutations detected in patients refractory to ICB. We functionally validate variants of uncertain significance in primary tumor organoids, where engineering missense mutations in JAK1 enhanced or reduced sensitivity to autologous tumor-reactive T cells. We identify more than 300 predicted missense mutations altering IFN-γ pathway activity, generating a valuable resource for interpreting gene variant function.

The relationship between subjective socioeconomic status and health in adults with and without intellectual disability.

BACKGROUND: This study investigated if subjective socioeconomic status (SSS) is related to self-rated health (SRH) and objective indicators of health in people with and without intellectual disability. METHODS: Participants were 217 adults with, and 2350 adults without intellectual disability in Jersey. In the intellectual disability sample, 85 (39.2%) participants consented independently, while 132 (60.8%) participants consented through proxy procedures. The MacArthur Scale of Subjective Social Status was used to measure SSS. The Euro-Qol EQ-5D-5L and a five-point scale ranging from poor to excellent health were used to measure SRH. RESULTS: Higher SSS and younger age were predictors of better SRH for the proxy-report intellectual disability group. Being employed was associated with higher EQ-5D-5L index values for all intellectual disability groups. CONCLUSION: As SSS was only related to SRH in the proxy intellectual disability group, further research with a larger intellectual disability sample is needed to explore its utility further.

The longitudinal dynamics and natural history of clonal haematopoiesis.

Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis1-4. The understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression remains limited5,6. Here we track 697 clonal haematopoiesis clones from 385 individuals 55 years of age or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A and TP53) to more than 50% per year (SRSF2P95H). Growth rates of clones with the same mutation differed by approximately ±5% per year, proportionately affecting slow drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole-genome sequences of haematopoietic colonies from 7 individuals from an older age group, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations drove expansion only later in life, whereas TET2-mutant clones emerged across all ages. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterize the lifelong natural history of clonal haematopoiesis and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.

The essential menopause curriculum for healthcare professionals: A European Menopause and Andropause Society (EMAS) position statement.

INTRODUCTION: The menopause, or the cessation of menstruation, is a stage of the life cycle which will occur in all women. Managing perimenopausal and postmenopausal health is a key issue for all areas of healthcare, not just gynecology. AIM: To provide recommendations for the curriculum of education programs for healthcare professionals worldwide, so that all can receive high quality training on menopause. MATERIALS AND METHODS: Literature review and consensus of expert opinion. SUMMARY RECOMMENDATIONS: Training programs for healthcare professionals worldwide should include menopause and postmenopausal health in their curriculum. It should include assessment, diagnosis and evidence-based management strategies.

Global consensus recommendations on menopause in the workplace: A European Menopause and Andropause Society (EMAS) position statement.

INTRODUCTION: Worldwide, there are 657 million women aged 45-59 and around half contribute to the labor force during their menopausal years. There is a diversity of experience of menopause in the workplace. It is shaped not only by menopausal symptoms and context but also by the workplace environment. It affects quality of life, engagement, performance, motivation and relations with employers. AIM: To provide recommendations for employers, managers, healthcare professionals and women to make the workplace environment more menopause supportive, and to improve women's wellbeing and their ability to remain in work. MATERIALS AND METHODS: Literature review and consensus of expert opinion. SUMMARY RECOMMENDATIONS: Workplace health and wellbeing frameworks and policies should incorporate menopausal health as part of the wider context of gender and age equality and reproductive and post-reproductive health. Workplaces should create an open, inclusive and supportive culture regarding menopause, involving, if available, occupational health professionals and human resource managers working together. Women should not be discriminated against, marginalized or dismissed because of menopausal symptoms. Health and allied health professionals should recognize that, for some women, menopausal symptoms can adversely affect the ability to work, which can lead to reduction of working hours, underemployment or unemployment, and consequently financial insecurity in later life.

Premenstrual Symptoms and Work: Exploring Female Staff Experiences and Recommendations for Workplaces.

Most women experience some premenstrual symptoms during their reproductive years. Yet, this is an under-researched health issue, particularly in the context of work. This study aimed to: (i) understand the prevalence and severity of premenstrual symptoms experienced by working females, and their association with key work outcomes; (ii) explore factors that may be influencing these symptoms and their severity; and (iii) examine how organizations might help staff with premenstrual symptoms that may be impacting their working lives. An online, anonymous survey collected quantitative and qualitative data from 125 working women in the UK. Over 90% of the sample reported some premenstrual symptoms; 40% experienced premenstrual symptoms moderately or severely. Higher symptom severity was significantly (p < 0.05) associated with poor presenteeism, intention to reduce working hours, and higher work absence (time off work, being late, leaving early). Moderate/severe symptoms were significantly associated with several individual-related variables: lower perceived general health, higher alcohol consumption, poorer sleep quality, anxiety, depression, hormonal contraception, and using fewer coping approaches towards premenstrual symptoms (avoiding harm, adjusting energy levels); and work-related variables: poorer work-life balance, lower levels of psychological resilience, higher perceived work demands, less control over work. Disclosure of premenstrual symptoms and sickness absence because of premenstrual symptoms was very low, typically because of perceptions of appropriateness as a reason for work absence, gender of line managers (male), and it being a personal or embarrassing topic. Staff with moderate to severe premenstrual symptoms were statistically more likely to disclose reason for absence than those with milder symptoms. Recommendations and suggestions for employers and line managers include the need to train staff to improve knowledge about women's experience of premenstrual symptoms, to be able to communicate effectively with women and to provide tailored support and resources for those who need it. Implications for future research, policy and practice are discussed.

Image-based consensus molecular subtype (imCMS) classification of colorectal cancer using deep learning.

OBJECTIVE: Complex phenotypes captured on histological slides represent the biological processes at play in individual cancers, but the link to underlying molecular classification has not been clarified or systematised. In colorectal cancer (CRC), histological grading is a poor predictor of disease progression, and consensus molecular subtypes (CMSs) cannot be distinguished without gene expression profiling. We hypothesise that image analysis is a cost-effective tool to associate complex features of tissue organisation with molecular and outcome data and to resolve unclassifiable or heterogeneous cases. In this study, we present an image-based approach to predict CRC CMS from standard H&E sections using deep learning. DESIGN: Training and evaluation of a neural network were performed using a total of n=1206 tissue sections with comprehensive multi-omic data from three independent datasets (training on FOCUS trial, n=278 patients; test on rectal cancer biopsies, GRAMPIAN cohort, n=144 patients; and The Cancer Genome Atlas (TCGA), n=430 patients). Ground truth CMS calls were ascertained by matching random forest and single sample predictions from CMS classifier. RESULTS: Image-based CMS (imCMS) accurately classified slides in unseen datasets from TCGA (n=431 slides, AUC)=0.84) and rectal cancer biopsies (n=265 slides, AUC=0.85). imCMS spatially resolved intratumoural heterogeneity and provided secondary calls correlating with bioinformatic prediction from molecular data. imCMS classified samples previously unclassifiable by RNA expression profiling, reproduced the expected correlations with genomic and epigenetic alterations and showed similar prognostic associations as transcriptomic CMS. CONCLUSION: This study shows that a prediction of RNA expression classifiers can be made from H&E images, opening the door to simple, cheap and reliable biological stratification within routine workflows.

Health information work and the enactment of care in couples and families affected by Multiple Sclerosis.

Given the considerable emphasis placed on informed choice, the management of health information has become an increasingly important part of living with chronic illness. This paper explores the intra-familial dynamics of managing health information in the context of chronic illness. Drawing on 77 interviews with people affected by Multiple Sclerosis in the UK (patients, partners, family members and close friends), we show how families develop their own idiosyncratic information practices, including the careful, at times strategic, seeking, sharing and withholding of information. We describe how one individual, most commonly either the patient or their partner, often takes primary responsibility for managing growing quantities of health information. Doing this is a complex task, yet its dynamics within the family unit remain invisible and unacknowledged. In this paper we: (a) stress the importance of understanding information management in chronic illness as a collective process across all those affected, patients as well as carers; (b) conceptualise the process of managing health information in this context as 'health information work'; and (c) analyse it as part of the wider care practices families engage in and as a form of care in its own right.

Development and evaluation of online menopause awareness training for line managers in UK organizations.

OBJECTIVES: To develop and evaluate a 30-min online training for managers, in order to improve menopause-related knowledge, attitudes and confidence in having supportive discussions with women experiencing menopausal symptoms at work. The study also explored intentions and behaviour in terms of having conversations. STUDY DESIGN: A prospective, pre-post design involved collecting data at three time points: pre-training, immediately after training, and four weeks post-training. Three UK organizations (one public, two private sector) participated. On-line questionnaires collected sociodemographic and background data. Qualitative and quantitative evaluation data were collected in post-intervention questionnaires. Paired t-tests and McNemar tests examined statistical differences pre- and post-training; thematic content analysis was performed on qualitative data. MAIN OUTCOME MEASURES: Menopause knowledge, attitudes and confidence in talking about the menopause at work, intentions, and actual behaviour. RESULTS: 270 staff were invited and 98 consented to participate; 62 and 61 provided data immediately and 4 weeks post training, respectively. Compared to pre-training scores, statistically significant improvements were found in menopause-related knowledge, attitude (not viewing the menopause as an embarrassing topic to talk about at work), confidence in talking about the menopause with staff, and intentions to discuss menopause, at both follow-up assessments. Over 90% of respondents reported that they found the training useful and would recommend it to others. CONCLUSIONS: A brief menopause awareness training may be a feasible and effective way to help managers become more knowledgeable about menopause-related problems and more confident in discussing and exploring solutions with their staff.

Prediction of acute myeloid leukaemia risk in healthy individuals.

The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure1. The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion2,3. However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH)4-8. Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention.

Self-help cognitive behavior therapy for working women with problematic hot flushes and night sweats (MENOS@Work): a multicenter randomized controlled trial.

OBJECTIVE: The aim of the study was to examine the efficacy of an unguided, self-help cognitive behavior therapy (SH-CBT) booklet on hot flush and night sweat (HFNS) problem rating, delivered in a work setting. METHODS: Women aged 45 to 60 years, having 10 or more problematic HFNS a week, were recruited to a multicenter randomized controlled trial, via the occupational health/human resources departments of eight organizations. Participants were 1:1 randomized to SH-CBT or no treatment waitlist control (NTWC). The primary outcome was HFNS problem rating; secondary outcomes included HFNS frequency, work and social adjustment, sleep, mood, beliefs and behaviors, and work-related variables (absence, performance, turnover intention, and work impairment due to presenteeism). Intention-to-treat analysis was used, and between-group differences estimated using linear mixed models. RESULTS: A total of 124 women were randomly allocated to SH-CBT (n = 60) and NTWC (n = 64). 104 (84%) were assessed for primary outcome at 6 weeks and 102 (82%) at 20 weeks. SH-CBT significantly reduced HFNS problem rating at 6 weeks (SH-CBT vs NTWC adjusted mean difference, -1.49; 95% CI, -2.11 to -0.86; P < 0.001) and at 20 weeks (-1.09; 95% CI, -1.87 to -0.31; P < 0.01). SH-CBT also significantly reduced HFNS frequency, improved work and social adjustment; sleep, menopause beliefs, HFNS beliefs/behaviors at 6 and 20 weeks; improved wellbeing and somatic symptoms and reduced work impairment due to menopause-related presenteeism at 20 weeks, compared with the NTWC. There was no difference between groups in other work-related outcomes. CONCLUSIONS: A brief, unguided SH-CBT booklet is a potentially effective management option for working women experiencing problematic HFNS.

Work outcomes in midlife women: the impact of menopause, work stress and working environment.

BACKGROUND: There is growing research interest in the question of whether menopause impacts upon mid-aged women's work outcomes, but the evidence to date is inconclusive. This paper examines whether: (i) menopausal status, and experience of hot flushes and night sweats (HFNS), and whether (ii) work stress and work environment, are associated with work outcomes (absenteeism, job performance, turnover intention, and intention to leave the labor force). METHODS: An online survey (sociodemographic, menopause, health, well-being and aspects of work) was completed by 216 (pre-, peri- and postmenopausal) women aged 45-60 years. RESULTS: Work outcomes were not associated with menopausal status but were significantly associated with job stress and aspects of the work environment, such as demand, control and support. HFNS presence, frequency and problem-rating were not significantly associated with work outcomes. HF problem rating at work was significantly associated with intention to leave the labor force, after controlling for age (F(2,101), 6.742, p = .002). CONCLUSIONS: The main predictors of work outcomes in this sample of mid-aged women were aspects of the working environment (particularly role clarity and work stress). Menopausal status was not associated with work outcomes but having problematic hot flushes at work was associated with intention to stop working. These results challenge assumptions about the menopause transition by providing evidence that the menopause does not impact on women's self-reported work performance and absence. However, support for women with problematic HFNS at work may be beneficial, as might addressing working environment issues for mid-aged women.

The driver landscape of sporadic chordoma.

Chordoma is a malignant, often incurable bone tumour showing notochordal differentiation. Here, we defined the somatic driver landscape of 104 cases of sporadic chordoma. We reveal somatic duplications of the notochordal transcription factor brachyury (T) in up to 27% of cases. These variants recapitulate the rearrangement architecture of the pathogenic germline duplications of T that underlie familial chordoma. In addition, we find potentially clinically actionable PI3K signalling mutations in 16% of cases. Intriguingly, one of the most frequently altered genes, mutated exclusively by inactivating mutation, was LYST (10%), which may represent a novel cancer gene in chordoma.Chordoma is a rare often incurable malignant bone tumour. Here, the authors investigate driver mutations of sporadic chordoma in 104 cases, revealing duplications in notochordal transcription factor brachyury (T), PI3K signalling mutations, and mutations in LYST, a potential novel cancer gene in chordoma.