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Associations between ATM c.7271T>G and cancer risk: Analysis of Breast Cancer Association Consortium and UK Biobank data
No full textPrevious studies have suggested the missense variant NM_000051.4(ATM):c.7271T>G is associated with a high risk of breast cancer (BC), but the magnitude of the association, and the associations with other cancer types, are unclear. Cancer associations were evaluated using sequence data linked to cancer registration data (348 488 participants, 56 640 cancer cases) from UK Biobank (UKB), and targeted sequence or genome-wide array data (126 428 cases, 115 495 controls) from the Breast Cancer Association Consortium (BCAC). The magnitudes of the association of c.7271T>G with invasive BC were similar using UKB (relative risk (RR): 4.57, 95% CI: 2.25 to 9.30, p=2.7×10-5) and BCAC (OR: 4.11, 2.05 to 8.26, p=6.9×10-5). In UKB, c.7271T>G was associated with increased risks of prostate cancer (4.84, 2.27 to 10.33, p=4.54×10-5), and any other cancer (males 2.79, 1.33 to 5.85, p=0.0066; females 3.15, 1.49 to 6.63, p=0.0026). Estimated cumulative risks of all cancers to age 80 years were 87% in males (prostate cancer 43%) and 84% in females (BC 43%). The estimated RRs are consistent with c.7271T>G being associated with a risk of more than twice that for Ataxia-Telangiectasia Mutated protein-truncating variants, for all cancers. These data justify specific management of c.7271T>G carriers
Statistical documentation for multi-disease, multi-domain platform trials: our experience with the Staphylococcus aureus Network Adaptive Platform trial
No full textPlatform trials have become widely adopted across multiple disease areas over recent years, however, guidelines for operationalising these trials have not kept pace. We outline a series of documents that summarise the statistical components, and implicit processes, of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial to provide an informal template for other researchers and reviewers of platform trials. We briefly summarise the content and role of the core protocol, statistical appendix, domain-specific appendices, simulation report, statistical implementation guides, data safety and monitoring committee (DSMC) reports, and domain-specific statistical analysis plans and final reports, and a transparent governance structure that ensures separate blinded and unblinded statistical teams. In the absence of guidelines or checklists for platform trial statistical documents, we hope to provide useful guidance to others in terms of what has worked so far for the SNAP trial, stimulate discussion, and inform a future consensus.Trial registration NCT05137119 . Registered on 30 November 2021
The effectiveness of telemedicine in the prevention of type 2 diabetes mellitus: a systematic review and meta-analysis of interventions
No full textOBJECTIVE: To evaluate the effectiveness of telemedicine-delivered diet and/or exercise interventions to prevent type 2 diabetes (T2D) in people at risk. METHODS: Embase (via Ovid), Medline (via Ovid), Web of Science, CINAHL, Scopus and SciELO were searched from January 2010-December 2020 for intervention studies using a diet and/or exercise intervention delivered through telemedicine for T2D prevention in people at risk. Parallel randomised controlled trials were meta-analysed, and other intervention designs narratively synthesized. RESULTS: We identified 11,645 studies via database searches, of which 226 were full-text screened, and 52 interventions included; 32 were included in the meta-analysis and 20 in the narrative synthesis. Telemedicine interventions reduced body weight (mean difference (MD): -1.66 kg, 95 % confidence interval (CI) -2.48,-0.90, I2 = 81 %, nstudies = 17), body mass index (MD -0.71 kg/m2, 95 % CI -1.06,-0.37, I2 = 70 %, nstudies = 11), waist circumference (MD -2.82 cm, 95 % CI -5.16,-2.35, I2 = 84 %, nstudies = 8) and HbA1c (MD -0.07 %, 95 % CI -0.14,0.00, I2 = 71 %, nstudies = 11). No significant effects were found for other clinical outcomes. The narrative synthesis supported the results. The longest follow-up time was up to 24 months. CONCLUSIONS: Our study demonstrates effectiveness for telemedicine-delivered interventions in preventing T2D in people at risk, specifically in people with overweight/obesity
Single-cell transcriptomics redefines focal neuroendocrine differentiation as a distinct prostate cancer pathology
No full textNeuroendocrine prostate cancer (NEPC) tumours are classified by pathology into several distinct subtypes. Gene expression profiling has revealed transcriptional heterogeneity across NEPC, but this is rarely considered in the context of variation between pathologies. Diagnosis typically relies on immunohistochemical markers (CHGA, SYP, NCAM1) and genomic alterations in RB1, PTEN and TP53. We hypothesized that NEPC pathologies have unique transcriptional features. Single-cell RNA sequencing of 18 632 tumour cells from nine patient-derived xenograft models representing five pathologies (small-cell and large-cell neuroendocrine carcinomas, focal neuroendocrine differentiation (Focal NED), low-grade neuroendocrine and amphicrine) demonstrated pathway-specific enrichment. Focal NED and amphicrine tumours exhibited cellular subpopulations enriched for KRAS, IL2-STAT5 and TNF signalling pathways, absent in small- and large-cell carcinomas, which were instead enriched for Myc and E2F pathways. Furthermore, focal NED cells exhibited minimal clonal divergence from adjacent adenocarcinoma cells, while small cell carcinoma cells were clonally distinct. These data underscore significant transcriptional variation among NEPC pathologies, highlighting focal NED's unique biological context and its clinical implications
Biological features of squamous cell carcinoma of the anus—a deep dive review
No full textSquamous cell carcinoma of the anus (SCCA) is a human papillomavirus (HPV)-associated cancer with an increasing incidence. Localized disease is treated curatively with chemoradiotherapy (CRT) but has substantial toxicities and impact on quality of life. Despite increasing research over the past decade, much of our biological understanding of SCCA is extrapolated from other HPV-associated cancers. Recently launched initiatives aim to connect clinicians and basic researchers working in SCCA to foster collaboration and knowledge sharing and facilitate access to SCCA materials. To improve outcomes for SCCA patients, a better understanding of SCCA-specific biology is required. This review will discuss areas of SCCA biology that are important to developing targets for drug development and biomarker-based individualized precision treatment. It will discuss the current understanding of radiosensitivity, differences in HPV-positive versus HPV-negative disease, hypoxia, immune environment, molecular characteristics, circulating tumor HPV-DNA, and the microbiome. It will detail when this understanding has been extrapolated from other HPV-associated cancers. Finally, it will discuss our current and upcoming preclinical biological models and discuss future models needed to further our understanding of SCCA biology
Pyrogenic carbon production in eucalypt forests under low to moderate fire severities
No full textWildfires play an important role in the global carbon cycle, influencing both atmospheric carbon concentrations and terrestrial carbon storage. The production of pyrogenic carbon (PyC; the C-enriched product of incomplete combustion) is a globally significant buffering mechanism for fire-related carbon emissions. PyC production varies widely with vegetation fuel and fire characteristics, and data on the production rates for PyC for specific ecosystems, fuel components and fire severities remain scarce. This limits our understanding of the quantitative importance of PyC production, its role in the carbon budgets of fire-affected ecosystems, and our ability to modify planned fires towards maximizing this long-term carbon store. Eucalypt forests, which incur frequent wildfires and human-prescribed fires, provide an important context for understanding PyC dynamics. Here we quantify PyC production in experimental fires conducted with low- to moderate fire severities in three Eucalyptus forest types across southern Australia. This involved comprehensive pre and post-fire fuel inventories and quantifying all pyrogenic materials generated in eucalypt forest sites near Sydney, Melbourne, and Perth. We also estimate PyC conversion rates in the main fuel components: forest floor, understory, down wood, and overstory (comprising only tree bark as these surface fires did not affect the crowns). Our results show that, of all the carbon affected by the fire, 2.7 t C ha−1 (2.4 – 3.1 t C ha−1) was transformed into PyC and 9.3 t C ha−1 (7.9 – 11.0 t C ha−1) emitted to the atmosphere. This translates into an average pyrogenic carbon conversion rate of 23 % of carbon affected by fire, underscoring the relevance of PyC in carbon budgets from eucalypt forest fires. The conversion rates varied substantially among fuel components, with the bark exhibiting the highest conversion rate, at approximately 40 %, and the down wood component displaying the lowest rate at around 15 %. Intermediate conversion values were found for forest floor and understory components (20 % and 31 %, respectively). Our findings highlight the critical importance of bark in PyC production in low to moderate fires, an aspect frequently overlooked in general inventories. Given the high fire recurrence in eucalypt forests in Australia, both naturally and under human-prescribed conditions, and the expansion of eucalypt plantations in many regions around the world, our findings are relevant for fire-related carbon budget estimations at both regional and global levels and can inform the optimization of prescribed burning for reducing carbon emissions
Neoliberal pedagogies of Pahari enterprise: Youth in provincial North India
No full textThis paper draws on one year of field research by the primary author in Gopeshwar, North India, to discuss how young men develop ideas of personality development in a university setting. We argue that the young men studied here followed an agenda of developing entrepreneurial selves that differed from pedagogies of neoliberal enterprise in other parts of India. Contrary to widespread calls to overcome provincialism, young men in Gopeshwar tended to arrange their pedagogical programmes around cultural practices that they considered to be ‘authentically’ regional, especially through emphasising regional sociality, the Garhwali language, and spirit possession as a means of cultivating entrepreneurial selves
A rapid review of nutrition and exercise approaches to managing unintentional weight loss, muscle loss, and malnutrition in cancer
No full textPURPOSE: This narrative review summarizes the evidence for nutrition, exercise, and multimodal interventions to maintain weight and muscle mass and prevent malnutrition from meta-analysis, systematic reviews, and randomized controlled trials published within the last 5 years, and in comparison to future research priority areas identified by international guidelines. RECENT FINDINGS: Dietary counseling with oral nutrition support (ONS), escalated to enteral nutrition if weight loss continues, is the gold standard treatment approach to maintaining weight and preventing malnutrition. Recent ONS trials with dietary counseling show promising findings for weight maintenance, extending the literature to include studies in chemoradiotherapy, however, change in body composition is rarely evaluated. Emerging trials have evaluated the impact of isolated nutrients, amino acids, and their derivatives (ie, β-hydroxy β-methylbutyrate) on muscle mass albeit with mixed effects. There is insufficient evidence evaluating the effect of exercise interventions on unintentional weight loss, muscle mass, and malnutrition, however, our knowledge of the impact of multimodal nutrition and exercise interventions is advancing. Prehabilitation interventions may attenuate weight and muscle loss after surgery, particularly for patients having gastrointestinal and colorectal surgery. Multimodal trials that commence during treatment show mixed effects on weight and muscle mass when measured. SUMMARY: This review highlights that the evidence for preventing unintentional weight loss and malnutrition from cancer treatment is strong within nutrition. Multimodal interventions are emerging as effective interventions to prevent unintentional weight loss. Promising interventions are demonstrating improvements in muscle mass, however further exploration through studies designed to determine the effect on muscle is required
Moving beyond the prevalent exposure design for causal inference in dementia research
No full textAs randomised trials are not always feasible or practical, observational studies remain crucial for addressing many causal questions in the dementia prevention field. Through a systematic search, we found that 84 (72%) of the 116 latest observational cohort studies that investigated factors hypothesised to reduce the risk of dementia (hearing aids, physical activity, antihypertensives, antidiabetics, and antidepressants) used a prevalent exposure design. The approach of using a prevalent exposure design, which compares dementia risk between individuals with and without prevalent exposure at the start of follow-up, has several limitations, including ill-defined interventions, selection biases, and challenges in adjusting for confounders. This Personal View discusses these limitations using physical activity as a case study and describes an alternative approach based on the target trial framework that can help to overcome such limitations. This approach aligns observational analyses with the design and analysis principles of randomised trials and can, thereby, improve the robustness and relevance of evidence for dementia prevention, which is the ultimate goal
INTRODUCTION: Navigating faith and tolerance in the Muslim experience
No full textDiscrimination, hatred, and acts of violence towards the religious Other is on the rise, according to a recent Pew report analysing ‘harassment’ of religious groups by governments or social actors. It’s not a good time to be a Christian in North Korea, a Shiʿi Muslim in Afghanistan, or a Falun Gong practitioner in China.
Many Muslim-majority countries do not fare well in the report, and the rise in religiously sourced violence and intolerance by certain governments and groups has raised questions about Islam’s stance on the rights of religious minorities. Many ask: Why does Islam appear to advocate distrust and conflict with people of other faiths? Others point to periods and places of generally peaceful coexistence as a precedent, suggesting intra- and inter-religious tension is an aberration