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Strong evidence highlights that sufficient physical activity (PA) has multiple benefits for people living with and beyond cancer. However, many are not meeting PA recommendations. APPROACH is a trial of a theory-driven, app-based behavioral support intervention to promote brisk walking after breast, prostate, or colorectal cancer. The aim of this trial is to evaluate the efficacy and cost-effectiveness of the intervention. APPROACH is a multicenter, phase III, 2-armed, individually randomized controlled trial (N=472). We will recruit patients with localized breast, prostate, or colorectal cancer from hospitals in Yorkshire and surrounding areas in the North of England, United Kingdom, and randomize them 1:1 between the intervention and control arm (usual care). The intervention consists of an app designed for the general population to encourage brisk walking (NHS Active 10), supplemented with habit-based behavioral support, including 2 brief telephone or video calls, a leaflet, website, and walking planners. The primary endpoint is the difference between trial arms in the changes from baseline in activPAL-assessed average minutes of brisk walking (≥100 steps per minute) after 3 months. Demographic and medical characteristics will be collected through self-report and hospital records. Secondary outcomes (assessed at 0, 3, and 6 months) will be the other activPAL-assessed outcomes (brisk walking at 6 months, total steps, light PA, standing time, and sitting times, weekly metabolic equivalent of task), self-reported PA, and self-reported BMI and waist circumference. Patient-reported outcome measures of quality of life, fatigue, sleep, anxiety, depression, self-efficacy, habit strength for walking, and social support will also be collected. Interviews will explore experiences of receiving the intervention. We will use health economic modeling to estimate the cost-effectiveness of the intervention over a lifetime horizon. The study was funded in June 2019. Trial recruitment commenced in November 2023 and is planned to be completed in 2025. As of December 2025, a total of 473 participants have been randomized. The publication of the main results is expected in autumn 2027 after all follow-up data collection and analysis are complete. Overall findings will determine the clinical and cost-effectiveness of the intervention for patients diagnosed with breast, prostate, or colorectal cancer. If successful, APPROACH provides a potential model of supportive care to increase PA among people living with and beyond cancer. ISRCTN Registry ISRCTN14149329; https://www.isrctn.com/ISRCTN14149329. DERR1-10.2196/77096.

Spirituality may be the most contentious and poorly understood dimension of Native American communities today. For generations the religious beliefs and practices of Native Americans have been the subject of public fascination and scholarly inquiry. Unfortunately, this ongoing interest has all too frequently been fueled by facile generalizations, inaccurate information, or inappropriate methods of investigation. Given the legacy of misrepresentation and mistrust, is it possible to fully appreciate the religious meanings and experiences of Native Americans? This volume offers a stimulating, multidisciplinary set of essays by noted Native and non-Native scholars that explore the problems and prospects of understanding and writing about Native American spirituality in the twenty-first century. Considerable attention is given to the appropriateness and value of different interpretive paradigms for Native religion, including both \"\"traditional\"\" religion and Native Christianity. The book also investigates the ethics of religious representation, issues of authenticity, the commodification of spirituality, and pedagogical practices. Of special interest is the role of dialogue in expressing and understanding Native American religious beliefs and practices. A final set of essays explores the power of and reactions to Native spirituality from a long-term, historical perspective.

The appropriate age range for breast cancer screening remains a matter of debate. We aimed to estimate the effect of mammographic screening at ages 40–48 years on breast cancer mortality. We did a randomised, controlled trial involving 23 breast screening units across Great Britain. We randomly assigned women aged 39–41 years, using individual randomisation, stratified by general practice, in a 1:2 ratio, to yearly mammographic screening from the year of inclusion in the trial up to and including the calendar year that they reached age 48 years (intervention group), or to standard care of no screening until the invitation to their first National Health Service Breast Screening Programme (NHSBSP) screen at approximately age 50 years (control group). Women in the intervention group were recruited by postal invitation. Women in the control group were unaware of the study. The primary endpoint was mortality from breast cancers (with breast cancer coded as the underlying cause of death) diagnosed during the intervention period, before the participant's first NHSBSP screen. To study the timing of the mortality effect, we analysed the results in different follow-up periods. Women were included in the primary comparison regardless of compliance with randomisation status (intention-to-treat analysis). This Article reports on long-term follow-up analysis. The trial is registered with the ISRCTN registry, ISRCTN24647151. 160 921 women were recruited between Oct 14, 1990, and Sept 24, 1997. 53 883 women (33·5%) were randomly assigned to the intervention group and 106 953 (66·5%) to the control group. Between randomisation and Feb 28, 2017, women were followed up for a median of 22·8 years (IQR 21·8–24·0). We observed a significant reduction in breast cancer mortality at 10 years of follow-up, with 83 breast cancer deaths in the intervention group versus 219 in the control group (relative rate [RR] 0·75 [95% CI 0·58–0·97]; p=0·029). No significant reduction was observed thereafter, with 126 deaths versus 255 deaths occurring after more than 10 years of follow-up (RR 0·98 [0·79–1·22]; p=0·86). Yearly mammography before age 50 years, commencing at age 40 or 41 years, was associated with a relative reduction in breast cancer mortality, which was attenuated after 10 years, although the absolute reduction remained constant. Reducing the lower age limit for screening from 50 to 40 years could potentially reduce breast cancer mortality. National Institute for Health Research Health Technology Assessment programme.

Various risk factors have been associated with epithelial ovarian cancer risk in observational epidemiological studies. However, the causal nature of the risk factors reported, and thus their suitability as effective intervention targets, is unclear given the susceptibility of conventional observational designs to residual confounding and reverse causation. Mendelian randomization (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observational studies. We used MR to evaluate the association of 12 previously reported risk factors (reproductive, anthropometric, clinical, lifestyle, and molecular factors) with risk of invasive epithelial ovarian cancer, invasive epithelial ovarian cancer histotypes, and low malignant potential tumours. Genetic instruments to proxy 12 risk factors were constructed by identifying single nucleotide polymorphisms (SNPs) that were robustly (P < 5 × 10-8) and independently associated with each respective risk factor in previously reported genome-wide association studies. These risk factors included genetic liability to 3 factors (endometriosis, polycystic ovary syndrome, type 2 diabetes) scaled to reflect a 50% higher odds liability to disease. We obtained summary statistics for the association of these SNPs with risk of overall and histotype-specific invasive epithelial ovarian cancer (22,406 cases; 40,941 controls) and low malignant potential tumours (3,103 cases; 40,941 controls) from the Ovarian Cancer Association Consortium (OCAC). The OCAC dataset comprises 63 genotyping project/case-control sets with participants of European ancestry recruited from 14 countries (US, Australia, Belarus, Germany, Belgium, Denmark, Finland, Norway, Canada, Poland, UK, Spain, Netherlands, and Sweden). SNPs were combined into multi-allelic inverse-variance-weighted fixed or random effects models to generate effect estimates and 95% confidence intervals (CIs). Three complementary sensitivity analyses were performed to examine violations of MR assumptions: MR-Egger regression and weighted median and mode estimators. A Bonferroni-corrected P value threshold was used to establish strong evidence (P < 0.0042) and suggestive evidence (0.0042 < P < 0.05) for associations. In MR analyses, there was strong or suggestive evidence that 2 of the 12 risk factors were associated with invasive epithelial ovarian cancer and 8 of the 12 were associated with 1 or more invasive epithelial ovarian cancer histotypes. There was strong evidence that genetic liability to endometriosis was associated with an increased risk of invasive epithelial ovarian cancer (odds ratio [OR] per 50% higher odds liability: 1.10, 95% CI 1.06-1.15; P = 6.94 × 10-7) and suggestive evidence that lifetime smoking exposure was associated with an increased risk of invasive epithelial ovarian cancer (OR per unit increase in smoking score: 1.36, 95% CI 1.04-1.78; P = 0.02). In analyses examining histotypes and low malignant potential tumours, the strongest associations found were between height and clear cell carcinoma (OR per SD increase: 1.36, 95% CI 1.15-1.61; P = 0.0003); age at natural menopause and endometrioid carcinoma (OR per year later onset: 1.09, 95% CI 1.02-1.16; P = 0.007); and genetic liability to polycystic ovary syndrome and endometrioid carcinoma (OR per 50% higher odds liability: 0.89, 95% CI 0.82-0.96; P = 0.002). There was little evidence for an association of genetic liability to type 2 diabetes, parity, or circulating levels of 25-hydroxyvitamin D and sex hormone binding globulin with ovarian cancer or its subtypes. The primary limitations of this analysis include the modest statistical power for analyses of risk factors in relation to some less common ovarian cancer histotypes (low grade serous, mucinous, and clear cell carcinomas), the inability to directly examine the association of some ovarian cancer risk factors that did not have robust genetic variants available to serve as proxies (e.g., oral contraceptive use, hormone replacement therapy), and the assumption of linear relationships between risk factors and ovarian cancer risk. Our comprehensive examination of possible aetiological drivers of ovarian carcinogenesis using germline genetic variants to proxy risk factors supports a role for few of these factors in invasive epithelial ovarian cancer overall and suggests distinct aetiologies across histotypes. The identification of novel risk factors remains an important priority for the prevention of epithelial ovarian cancer.

Meiotic drivers are selfish genes that bias their transmission into gametes, defying Mendelian inheritance. Despite the significant impact of these genomic parasites on evolution and infertility, few meiotic drive loci have been identified or mechanistically characterized. Here, we demonstrate a complex landscape of meiotic drive genes on chromosome 3 of the fission yeasts Schizosaccharomyces kambucha and S. pombe. We identify S. kambucha wtf4 as one of these genes that acts to kill gametes (known as spores in yeast) that do not inherit the gene from heterozygotes. wtf4 utilizes dual, overlapping transcripts to encode both a gamete-killing poison and an antidote to the poison. To enact drive, all gametes are poisoned, whereas only those that inherit wtf4 are rescued by the antidote. Our work suggests that the wtf multigene family proliferated due to meiotic drive and highlights the power of selfish genes to shape genomes, even while imposing tremendous costs to fertility. Animals, plants and fungi produce sex cells – known as gametes – when they are preparing to reproduce. These cells are made when cells containing two copies of every gene in the organism divide to produce new cells that each only have one copy of each gene. Therefore, a particular gene copy usually has a 50% chance of being carried by each gamete. There is a group of genes that selfishly increase their chances of being transmitted to the next generation by destroying the gametes that do not carry them. These “gamete killer” genes can lead to infertility and other health problems. Fission yeast is a fungus that is widely used in research. Previous studies revealed that the yeast are likely to have several gamete killers, but the identities of these genes or how they work were not clear. Nuckolls, Bravo Núñez et al. sought to identify at least one gamete killer gene and understand how it works. The experiments found that a gene called wtf4 acts as a gamete killer in fission yeast. This gene encodes two different proteins, one that acts as a poison and one that acts as an antidote. The antidote remains inside the gametes that contain the wtf4 gene, while the poison is released in the surrounding environment. The poison is capable of killing all of the gametes, but the antidote protects the gametes that contain the wtf4 gene. Further experiments show that wtf4 is just one member of a large family of genes that are also likely to play roles in selectively killing gametes. A separate study by Hu et al. found that two other members of the wtf family also act as gamete killers in fission yeast. Together, these findings expand our understanding of the nature of gamete killers and how they can contribute to infertility. This may guide the search for gamete killers in humans and other organisms. In the future, gamete killers could potentially be used to eradicate populations of pests that damage crops or spread diseases in humans.

High-impact weather events, such as severe thunderstorms, tornadoes, and hurricanes, cause significant disruptions to infrastructure, property loss, and even fatalities. High-impact events can also positively impact society, such as the impact on savings through renewable energy. Prediction of these events has improved substantially with greater observational capabilities, increased computing power, and better model physics, but there is still significant room for improvement. Artificial intelligence (AI) and data science technologies, specifically machine learning and data mining, bridge the gap between numerical model prediction and real-time guidance by improving accuracy. AI techniques also extract otherwise unavailable information from forecast models by fusing model output with observations to provide additional decision support for forecasters and users. In this work, we demonstrate that applying AI techniques along with a physical understanding of the environment can significantly improve the prediction skill for multiple types of high-impact weather. The AI approach is also a contribution to the growing field of computational sustainability. The authors specifically discuss the prediction of storm duration, severe wind, severe hail, precipitation classification, forecasting for renewable energy, and aviation turbulence. They also discuss how AI techniques can process “big data,” provide insights into high-impact weather phenomena, and improve our understanding of high-impact weather.

This large trial of acute lymphoblastic leukemia in children aimed to determine whether intensive systemic and intrathecal chemotherapy could obviate the need for prophylactic central nervous system irradiation, which is associated with distressing late complications. The results show that, with meticulous monitoring of responses and toxic effects, it is possible not only to avoid cranial irradiation but also to improve the overall outcome. This large trial of acute lymphoblastic leukemia in children aimed to determine whether intensive systemic and intrathecal chemotherapy could obviate the need for prophylactic central nervous system irradiation. The results show that it is possible not only to avoid cranial irradiation but also to improve the overall outcome. Clinical trials have yielded 5-year event-free survival rates as high as 79 to 82% among children with acute lymphoblastic leukemia (ALL). 1 – 3 A major challenge is to reduce treatment-related late effects, which can occur in more than two thirds of long-term survivors. 4 In a growing proportion of patients, prophylactic cranial irradiation, once a standard treatment, is being replaced by intrathecal and systemic chemotherapy to reduce radiation-associated late complications such as second cancers, cognitive deficits, and endocrinopathy. 4 – 8 Two pediatric clinical trials tested whether prophylactic cranial irradiation could be completely omitted from treatment. 9 , 10 Although the cumulative risks of isolated central . . .

Position Statement: The position of The Society regarding caffeine supplementation and sport performance is summarized by the following seven points: 1.) Caffeine is effective for enhancing sport performance in trained athletes when consumed in low-to-moderate dosages (~3-6 mg/kg) and overall does not result in further enhancement in performance when consumed in higher dosages (≥ 9 mg/kg). 2.) Caffeine exerts a greater ergogenic effect when consumed in an anhydrous state as compared to coffee. 3.) It has been shown that caffeine can enhance vigilance during bouts of extended exhaustive exercise, as well as periods of sustained sleep deprivation. 4.) Caffeine is ergogenic for sustained maximal endurance exercise, and has been shown to be highly effective for time-trial performance. 5.) Caffeine supplementation is beneficial for high-intensity exercise, including team sports such as soccer and rugby, both of which are categorized by intermittent activity within a period of prolonged duration. 6.) The literature is equivocal when considering the effects of caffeine supplementation on strength-power performance, and additional research in this area is warranted. 7.) The scientific literature does not support caffeine-induced diuresis during exercise, or any harmful change in fluid balance that would negatively affect performance.

Uptake in the national colorectal cancer screening programme in England varies by socioeconomic status. We assessed four interventions aimed at reducing this gradient, with the intention of improving the health benefits of screening. All people eligible for screening (men and women aged 60–74 years) across England were included in four cluster-randomised trials. Randomisation was based on day of invitation. Each trial compared the standard information with the standard information plus the following supplementary interventions: trial 1 (November, 2012), a supplementary leaflet summarising the gist of the key information; trial 2 (March, 2012), a supplementary narrative leaflet describing people's stories; trial 3 (June, 2013), general practice endorsement of the programme on the invitation letter; and trial 4 (July–August, 2013) an enhanced reminder letter with a banner that reiterated the screening offer. Socioeconomic status was defined by the Index of Multiple Deprivation score for each home address. The primary outcome was the socioeconomic status gradient in uptake across deprivation quintiles. This study is registered, number ISRCTN74121020. As all four trials were embedded in the screening programme, loss to follow-up was minimal (less than 0·5%). Trials 1 (n=163 525) and 2 (n=150 417) showed no effects on the socioeconomic gradient of uptake or overall uptake. Trial 3 (n=265 434) showed no effect on the socioeconomic gradient but was associated with increased overall uptake (adjusted odds ratio [OR] 1·07, 95% CI 1·04–1·10, p<0·0001). In trial 4 (n=168 480) a significant interaction was seen with socioeconomic status gradient (p=0·005), with a stronger effect in the most deprived quintile (adjusted OR 1·11, 95% CI 1·04–1·20, p=0·003) than in the least deprived (1·00, 0·94–1·06, p=0·98). Overall uptake was also increased (1·07, 1·03–1·11, p=0·001). Of four evidence-based interventions, the enhanced reminder letter reduced the socioeconomic gradient in screening uptake, but further reducing inequalities in screening uptake through written materials alone will be challenging. National Institute for Health Research.

Douglas Higgs and colleagues functionally test the α-globin super-enhancer in mice by genetically deleting its constituent enhancers. They find that the individual regulatory elements seem to act independently and in an additive way with respect to hematological phenotype, gene expression, and chromatin structure and conformation. Many genes determining cell identity are regulated by clusters of Mediator-bound enhancer elements collectively referred to as super-enhancers. These super-enhancers have been proposed to manifest higher-order properties important in development and disease. Here we report a comprehensive functional dissection of one of the strongest putative super-enhancers in erythroid cells. By generating a series of mouse models, deleting each of the five regulatory elements of the α-globin super-enhancer individually and in informative combinations, we demonstrate that each constituent enhancer seems to act independently and in an additive fashion with respect to hematological phenotype, gene expression, chromatin structure and chromosome conformation, without clear evidence of synergistic or higher-order effects. Our study highlights the importance of functional genetic analyses for the identification of new concepts in transcriptional regulation.