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Whole brain radiotherapy (WBRT) and dexamethasone are widely used to treat brain metastases from non-small cell lung cancer (NSCLC), although there have been no randomised clinical trials showing that WBRT improves either quality of life or overall survival. Even after treatment with WBRT, the prognosis of this patient group is poor. We aimed to establish whether WBRT could be omitted without a significant effect on survival or quality of life. The Quality of Life after Treatment for Brain Metastases (QUARTZ) study is a non-inferiority, phase 3 randomised trial done at 69 UK and three Australian centres. NSCLC patients with brain metastases unsuitable for surgical resection or stereotactic radiotherapy were randomly assigned (1:1) to optimal supportive care (OSC) including dexamethasone plus WBRT (20 Gy in five daily fractions) or OSC alone (including dexamethasone). The dose of dexamethasone was determined by the patients' symptoms and titrated downwards if symptoms improved. Allocation to treatment group was done by a phone call from the hospital to the Medical Research Council Clinical Trials Unit at University College London using a minimisation programme with a random element and stratification by centre, Karnofsky Performance Status (KPS), gender, status of brain metastases, and the status of primary lung cancer. The primary outcome measure was quality-adjusted life-years (QALYs). QALYs were generated from overall survival and patients' weekly completion of the EQ-5D questionnaire. Treatment with OSC alone was considered non-inferior if it was no more than 7 QALY days worse than treatment with WBRT plus OSC, which required 534 patients (80% power, 5% [one-sided] significance level). Analysis was done by intention to treat for all randomly assigned patients. The trial is registered with ISRCTN, number ISRCTN3826061. Between March 2, 2007, and Aug 29, 2014, 538 patients were recruited from 69 UK and three Australian centres, and were randomly assigned to receive either OSC plus WBRT (269) or OSC alone (269). Baseline characteristics were balanced between groups, and the median age of participants was 66 years (range 38–85). Significantly more episodes of drowsiness, hair loss, nausea, and dry or itchy scalp were reported while patients were receiving WBRT, although there was no evidence of a difference in the rate of serious adverse events between the two groups. There was no evidence of a difference in overall survival (hazard ratio 1·06, 95% CI 0·90–1·26), overall quality of life, or dexamethasone use between the two groups. The difference between the mean QALYs was 4·7 days (46·4 QALY days for the OSC plus WBRT group vs 41·7 QALY days for the OSC group), with two-sided 90% CI of −12·7 to 3·3. Although the primary outcome measure result includes the prespecified non-inferiority margin, the combination of the small difference in QALYs and the absence of a difference in survival and quality of life between the two groups suggests that WBRT provides little additional clinically significant benefit for this patient group. Cancer Research UK, Medical Research Council Clinical Trials Unit at University College London, and the National Health and Medical Research Council in Australia.

S-adenosylmethionine (SAM) is the principal methyl donor in cells and is essential for mitochondrial gene expression, influencing RNA modifications, translation, and ribosome biogenesis. Using direct long-read RNA sequencing in mouse tissues and embryonic fibroblasts, we show that processing of the mitochondrial ribosomal gene cluster fails in the absence of mitochondrial SAM, leading to an accumulation of unprocessed precursors. Proteomic analysis of ribosome fractions revealed these precursors associated with processing and assembly factors, indicating stalled biogenesis. Structural analysis by cryo-electron microscopy demonstrated that SAM-dependent methylation is required for peptidyl transferase centre formation during mitoribosome assembly. Our findings identify a critical role for SAM in coordinating mitoribosomal RNA processing and large subunit maturation, linking cellular methylation potential to mitochondrial translation capacity. Here, using long-read RNA sequencing, SILAC proteomics, and cryo-EM, the authors show that loss of mitochondrial methylation impairs rRNA processing and ribosome maturation, leading to unprocessed rRNA accumulation and defective monosome assembly.

In 2000, seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in the USA and resulted in dramatic reductions in invasive pneumococcal disease (IPD) and moderate increases in non-PCV7 type IPD. In 2010, PCV13 replaced PCV7 in the US immunisation schedule. We aimed to assess the effect of use of PCV13 in children on IPD in children and adults in the USA. We used laboratory-based and population-based data on incidence of IPD from the Active Bacterial Core surveillance (part of the Centers for Disease Control and Prevention's Emerging Infections Program) in a time-series model to compare rates of IPD before and after the introduction of PCV13. Cases of IPD between July 1, 2004, and June 30, 2013, were classified as being caused by the PCV13 serotypes against which PCV7 has no effect (PCV13 minus PCV7). In a time-series model, we used an expected outcomes approach to compare the reported incidence of IPD to that which would have been expected if PCV13 had not replaced PCV7. Compared with incidence expected among children younger than 5 years if PCV7 alone had been continued, incidence of IPD overall declined by 64% (95% interval estimate [95% IE] 59–68) and IPD caused by PCV13 minus PCV7 serotypes declined by 93% (91–94), by July, 2012, to June, 2013. Among adults, incidence of IPD overall also declined by 12–32% and IPD caused by PCV13 minus PCV7 type IPD declined by 58–72%, depending on age. We estimated that over 30 000 cases of IPD and 3000 deaths were averted in the first 3 years after the introduction of PCV13. PCV13 reduced IPD across all age groups when used routinely in children in the USA. These findings provide reassurance that, similar to PCV7, PCVs with additional serotypes can also prevent transmission to unvaccinated populations. Centers for Disease Control and Prevention.

Wild Pacific salmon, including Coho salmon Onchorynchus kisutch, have been supplemented with hatchery propagation for over 50 years in support of increased ocean harvest and conservation of threatened populations. In Canada, the Wild Salmon Policy for Pacific salmon was established with the goal of maintaining and restoring healthy and diverse Pacific salmon populations, making conservation of wild salmon and their habitats the highest priority for resource management decision‐making. A new approach to the assessment and management of wild coho salmon, and the associated hatchery production and fishery management is needed. Implementation of parentage‐based tagging (PBT) may overcome problems associated with coded‐wire tag‐based (CWT) assessment and management of coho salmon fisheries, providing at a minimum information equivalent to that derived from the CWT program. PBT and genetic stock identification (GSI) were used to identify coho salmon sampled in fisheries (8,006 individuals) and escapements (1,692 individuals) in British Columbia to specific conservation units (CU), populations, and broodyears. Individuals were genotyped at 304 single nucleotide polymorphisms (SNPs) via direct sequencing of amplicons. Very high accuracy of assignment to population (100%) via PBT for 543 jack (age 2) assigned to correct age and collection location and 265 coded‐wire tag (CWT, age 3) coho salmon assigned to correct age and release location was observed, with a 40,774—individual, 267—population baseline available for assignment. Coho salmon from un‐CWTed enhanced populations contributed 65% of the catch in southern recreational fisheries in 2017. Application of a PBT‐GSI system of identification to individuals in 2017 fisheries and escapements provided high‐resolution estimates of stock composition, catch, and exploitation rate by CU or population, providing an alternate and more effective method in the assessment and management of Canadian‐origin coho salmon relative to CWTs, and an opportunity for a genetic‐based system to replace the current CWT system for coho salmon assessment.

Collect Earth is a free and open source software for land monitoring developed by the Food and Agriculture Organization of the United Nations (FAO). Built on Google desktop and cloud computing technologies, Collect Earth facilitates access to multiple freely available archives of satellite imagery, including archives with very high spatial resolution imagery (Google Earth, Bing Maps) and those with very high temporal resolution imagery (e.g., Google Earth Engine, Google Earth Engine Code Editor). Collectively, these archives offer free access to an unparalleled amount of information on current and past land dynamics for any location in the world. Collect Earth draws upon these archives and the synergies of imagery of multiple resolutions to enable an innovative method for land monitoring that we present here: augmented visual interpretation. In this study, we provide a full overview of Collect Earth’s structure and functionality, and we present the methodology used to undertake land monitoring through augmented visual interpretation. To illustrate the application of the tool and its customization potential, an example of land monitoring in Papua New Guinea (PNG) is presented. The PNG example demonstrates that Collect Earth is a comprehensive and user-friendly tool for land monitoring and that it has the potential to be used to assess land use, land use change, natural disasters, sustainable management of scarce resources and ecosystem functioning. By enabling non-remote sensing experts to assess more than 100 sites per day, we believe that Collect Earth can be used to rapidly and sustainably build capacity for land monitoring and to substantively improve our collective understanding of the world’s land use and land cover.

DNA hypomethylation has been suggested to cause genomic instability and increase cancer risk. We aimed to test the hypothesis that DNA hypomethylation is associated with increased risk of bladder cancer. We measured cytosine methylation (5-mC) content in genomic DNA from blood cells from patients with bladder cancer enrolled in a large case–control study in Spain between Jan 1, 1998, and Dec 31, 2001. Cases were men and women with newly diagnosed and histologically confirmed urothelial carcinoma of the bladder. Controls were selected from patients admitted to the same hospital for diseases or conditions unrelated to smoking or other known risk factors for bladder cancer. Controls were individually matched to cases on age (within 5 years), sex, race, and area of hospital referral. 5-mC content was measured in leucocyte DNA by use of a combination of high-performance capillary electrophoresis, Hpa II digestion, and densitometry. Data on demographics, 34 polymorphisms in nine folate metabolism genes, and nutritional intake of six B vitamins (including folate), alcohol, and smoking were assessed as potential confounders. Relative 5-mC content was expressed as a percentage (%5-mC) with respect to the total cytosine content (the sum of methylated and non-methylated cytosines). The primary endpoint was median %5-mC DNA content. %5-mC was measured in leucocyte DNA from 775 cases and 397 controls. Median %5-mC DNA was significantly lower in cases (3·03% [IQR 2·17–3·56]) than in controls (3·19% [2·46–3·68], p=0·0002). All participants were subsequently categorised into quartiles by %5-mC content in controls. When the highest quartile of %5-mC content was used as the reference category (Q4), the following adjusted odds ratios (OR) and 95% CI were recorded for decreasing methylation quartiles: OR (Q3) 2·05 (95% CI 1·37–3·06); OR (Q2) 1·62 (1·07–2·44); and OR (Q1) 2·67 (1·77–4·03), p for trend <0·0001. The lowest cancer risk was noted in never smokers in the highest methylation quartile (never smokers in Q4). By comparison with never smokers in the highest quartile, current smokers in the lowest methylation quartile had the highest risk of bladder cancer (Q1: OR 25·51 [9·61–67·76], p for interaction 0·06). In analyses stratified by smoking, hypomethylation was a strong risk factor in never smokers (OR 6·39 [2·37–17·22]). Amount of methylation in controls were not associated with baseline characteristics, micronutrients, or selected genotypes in folate metabolism pathways. For the first time, to our knowledge, we have shown in a large case–control study that leucocyte DNA hypomethylation is associated with increased risk of developing bladder cancer, and this association is independent of smoking and the other assessed risk factors. Amount of global methylation in genomic DNA could provide a useful biomarker of susceptibility to certain cancer types and further research is warranted. Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA, and Fondo de Investigacion Sanitaria, Spain (G03/174).

Background Project DAIRE was a randomised-controlled, factorial design trial which aimed to improve children’s health-related quality of life, wellbeing, food knowledge and dietary habits via two multi-component interventions: Nourish and Engage. Nourish was an intervention aiming to alter the school food environment, provide food-based experiences and expose pupils to locally produced foods. Engage was an age-appropriate cross-curricular food education intervention incorporating food, agriculture, nutrition science and related careers. The purpose of this study was to conduct a process evaluation to evaluate DAIRE implementation, mechanisms of impact (MOI) and context to elucidate trial results, and inform scalable implementation of the DAIRE approach for successful future rollout. Methods The Medical Research Council’s (MRC) framework for process evaluation was followed. Formal (questionnaires designed for process evaluation) and informal (researcher records and communications) methods were used to collect quantitative and qualitative data during the DAIRE trial in relation to process evaluation. Quantitative data were analysed using descriptive statistics and qualitative data via thematic analysis to identify key themes. Results Fifteen schools and 983 pupils ( n  = 495 6–7 year olds/Year 3 and n  = 488 10–11 year olds/Year 7) were recruited for the 6-month DAIRE intervention; a 100% retention rate was observed at the school level and the interventions had a high level of pupil and teacher acceptability. Nourish schools delivered a higher mean dose of intervention elements (61.4%) than Engage (50%) schools but, overall, mixed implementation of both interventions occurred. DAIRE produced change through four key MOI: social learning, experimental learning, interactive engaging content and real-life connections. Lack of time was the main contextual barrier to implementation and lack of financial cost to schools indicated as a potential facilitator. Conclusions This process evaluation helped to identify important findings related to implementation, MOI and context. The most effective elements of the interventions which should be maintained include provision of interactive and engaging intervention elements at no financial cost to the school. Findings also identified suggestions for improvement including provision of increased teacher training, support and planning time, content reduction to facilitate easy integration, and implementation across the full academic year. A sustainable funding and resourcing mechanism is required for successful future roll-out across the UK and beyond. Trial registrations The original trial referenced in this process evaluation is registered as follows: National Institute of Health (NIH) U.S. National Library of Medicine Clinical Trials.gov (ID: NCT04277312; retrospectively registered 11th February 2020).

Background Evidence suggests that dietary intake of UK children is suboptimal. As schools provide an ideal natural environment for public health interventions, effective and sustainable methods of improving food knowledge and dietary habits in this population must be identified. Project Daire aimed to improve children’s health-related quality of life, wellbeing, food knowledge and dietary habits via two multi-component interventions. Methods Daire was a randomised-controlled, factorial design trial evaluating two interventions across four arms. Primary schools in Northern Ireland were randomised to one of four 6-month intervention arms: i) ‘Nourish’, ii) ‘Engage’, iii) ‘Nourish’ and ‘Engage’ and iv) Control (Delayed). ‘Nourish’ was an intervention aiming to alter the whole-school food environment, provide food-related experiences and exposure to locally produced foods. ‘Engage’ was an age-appropriate, cross-curricular educational intervention on food, agriculture, nutrition science and related careers. Primary outcomes were emotional and behavioural wellbeing and health-related quality of life. A number of secondary outcomes, including dietary intake, cooking competence and food-related knowledge, were also measured. Results Fifteen schools from areas of varying socio-economic status participated in the randomised trial. A total of 903 ( n  = 445 aged 6–7 years and n  = 458 aged 10–11 years) primary school pupils took part. Total Difficulties Score improved in all pupils (6–7 and 10–11 year old pupils) who received the ‘Nourish’ intervention compared with those that did not (adjusted difference in mean = − 0.82; 95% CI -1.46, − 0.17; P  < 0.02). No statistically significant difference in Health-Related Quality of Life was observed. The ‘Nourish’ intervention also produced some changes in school-based dietary behaviour, which were most apparent in the 10–11 year old pupils. The ‘Nourish’ intervention also produced improvements in understanding of food labels (adjusted difference in mean = 0.15; 95% CI 0.05, 0.25; P  < 0.01) and knowledge of vegetables in season (adjusted difference in mean = 0.29; 95% CI 0.01,0.56; P  = 0.04) whilst an increased willingness to try new foods and improved perceived cooking competence was also observed. Conclusions Improvements in childhood emotional and behavioural wellbeing, dietary intake, knowledge about food, cooking skills and willingness to try new foods were associated with the ‘Nourish’ whole-school food environment intervention. Exploration of the sustainability and long-term effectiveness of such whole-school food interventions should be conducted. Trial registration National Institute of Health (NIH) U.S. National Library of Medicine Clinical Trials.gov (ID: NCT04277312 ).

Wilson's disease (WD) is an autosomal recessive disorder that results in accumulation of copper in the liver as a consequence of mutations in the gene encoding the copper-transporting P-type ATPase (ATP7B). WD is a chronic liver disorder, and individuals with the disease present with a variety of complications, including steatosis, cholestasis, cirrhosis, and liver failure. Similar to patients with WD, Atp7b⁻/⁻ mice have markedly elevated levels of hepatic copper and liver pathology. Previous studies have demonstrated that replacement of zinc in the DNA-binding domain of the estrogen receptor (ER) with copper disrupts specific binding to DNA response elements. Here, we found decreased binding of the nuclear receptors FXR, RXR, HNF4α, and LRH-1 to promoter response elements and decreased mRNA expression of nuclear receptor target genes in Atp7b⁻/⁻ mice, as well as in adult and pediatric WD patients. Excessive hepatic copper has been described in progressive familial cholestasis (PFIC), and we found that similar to individuals with WD, patients with PFIC2 or PFIC3 who have clinically elevated hepatic copper levels exhibit impaired nuclear receptor activity. Together, these data demonstrate that copper-mediated nuclear receptor dysfunction disrupts liver function in WD and potentially in other disorders associated with increased hepatic copper levels.