Tikhonov adaptively regularized gamma variate fitting to assess plasma clearance of inert renal markers

The Tk-GV model fits Gamma Variates (GV) to data by Tikhonov regularization (Tk) with shrinkage constant, λ, chosen to minimize the relative error in plasma clearance, CL (ml/min). Using 169Yb-DTPA and 99mTc-DTPA (n = 46, 8–9 samples, 5–240 min) bolus-dilution curves, results were obtained for fit methods: (1) Ordinary Least Squares (OLS) one and two exponential term (E1 and E2), (2) OLS-GV and (3) Tk-GV. Four tests examined the fit results for: (1) physicality of ranges of model parameters, (2) effects on parameter values when different data subsets are fit, (3) characterization of residuals, and (4) extrapolative error and agreement with published correction factors. Test 1 showed physical Tk-GV results, where OLS-GV fits sometimes-produced nonphysical CL. Test 2 showed the Tk-GV model produced good results with 4 or more samples drawn between 10 and 240 min. Test 3 showed that E1 and E2 failed goodness-of-fit testing whereas GV fits for t > 20 min were acceptably good. Test 4 showed CLTk-GV clearance values agreed with published CL corrections with the general result that CLE1 > CLE2 > CLTk-GV and finally that CLTk-GV were considerably more robust, precise and accurate than CLE2, and should replace the use of CLE2 for these renal markers

Temperature frequency and mortality: Assessing adaptation to local temperature

Assessing the association between temperature frequency and mortality can provide insights into human adaptation to local ambient temperatures. We collected daily time-series data on mortality and temperature from 757 locations in 47 countries/regions during 1979–2020. We used a two-stage time series design to assess the association between temperature frequency and all-cause mortality. The results were pooled at the national, regional, and global levels. We observed a consistent decrease in the risk of mortality as the normalized frequency of temperature increases across the globe. The average increase in mortality risk comparing the 10th to 100th percentile of normalized frequency was 13.03% (95% CI: 12.17–13.91), with substantial regional differences (from 4.56% in Australia and New Zealand to 33.06% in South Europe). The highest increase in mortality was observed for high-income countries (13.58%, 95% CI: 12.56–14.61), followed by lower-middle-income countries (12.34%, 95% CI: 9.27–15.51). This study observed a declining risk of mortality associated with higher temperature frequency. Our findings suggest that populations can adapt to their local climate with frequent exposure, with the adapting ability varying geographically due to differences in climatic and socioeconomic characteristics. © 2024his article appreciates the contribution of MCC network collaborators. This article is published in memory of Simona Fratianni who helped to contribute the data for Romania. Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute. This study was supported by the Australian Research Council (DP210102076) and the Australian National Health and Medical Research Council (GNT2000581). YW and BW were supported by China Scholarship Council [grant numbers 202006010044 and 202006010043]. AU was supported by the Czech Science Foundation (project number 22-24920S); PHNS by the São Paulo Research Foundation (FAPESP); ST by the Science and Technology Commission of Shanghai Municipality (grant number 18411951600); AG and FS by the Medical Research Council UK (grant ID MR/R013349/1), the Natural Environment Research Council UK (grant ID NE/R009384/1), and the EU’s Horizon 2020 project, Exhaustion (grant ID 820655); FdD by the EU’s Horizon 2020 project, Exhaustion (grant ID 820655). SL was supported by an Emerging Leader Fellowship of the Australian National Health and Medical Research Council (GNT2009866). YG was supported by the Career Development Fellowship (GNT1163693) and Leader Fellowship (GNT2008813) of the Australian National Health and Medical Research Council. The funders had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Summary Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Integrated genomic characterization of oesophageal carcinoma

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies.ope

Practising an explosive eruption in Iceland: outcomes from a European exercise

A 3 day exercise simulating unrest and a large explosive eruption at Katla volcano, Iceland, was conducted in January 2016. A large volume of simulated data based on a complex, but realistic eruption scenario was compiled in advance and then transmitted to exercise participants in near-real time over the course of the exercise. The scenario was designed to test the expertise and procedures of the local institutions in charge of warning and responding to volcanic hazards, namely the volcano observatory, national civil protection, and the local university-science sector, as well as their interactions with the European science community and the London Volcanic Ash Advisory Centre. This exercise was the first of this magnitude and scope in Iceland and has revealed many successful developments introduced since the 2010 Eyjafjallajökull and 2011 Grímsvötn eruptions. Following the exercise, 90% of participants said that they felt better prepared for a future eruption. As with any exercise, it also identified areas where further development is required and improvements can be made to procedures. Seven key recommendations are made to further develop capability and enhance the collaboration between the volcano observatory, volcano research institutions and civil protection authorities. These recommendations cover topics including notification of responders, authoritative messaging, data sharing and media interaction, and are more broadly applicable to volcanic institutions elsewhere. Lessons and suggestions for how to run a large-scale volcanic exercise are given and could be adopted by those planning to rehearse their own response procedures.This work was funded by the European Community’s FP7 Programme grant 308377 (Project FUTUREVOLC).Peer Reviewe

Impact of population aging on future temperature-related mortality at different global warming levels

Data availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Data were collected within the MCC Collaborative Research Network under a data sharing agreement and cannot be made publicly available.Code availability: A sample of the analysis code is available from https://github.com/CHENlab-Yale/MCC_ProjAging_Temp .Supplementary information is available online at: https://link-springer-com.ezproxytest.brunel.ac.uk/article/10.1038/s41467-024-45901-z#Sec15 .Older adults are generally amongst the most vulnerable to heat and cold. While temperature-related health impacts are projected to increase with global warming, the influence of population aging on these trends remains unclear. Here we show that at 1.5 °C, 2 °C, and 3 °C of global warming, heat-related mortality in 800 locations across 50 countries/areas will increase by 0.5%, 1.0%, and 2.5%, respectively; among which 1 in 5 to 1 in 4 heat-related deaths can be attributed to population aging. Despite a projected decrease in cold-related mortality due to progressive warming alone, population aging will mostly counteract this trend, leading to a net increase in cold-related mortality by 0.1%–0.4% at 1.5–3 °C global warming. Our findings indicate that population aging constitutes a crucial driver for future heat- and cold-related deaths, with increasing mortality burden for both heat and cold due to the aging population.We acknowledge the World Climate Research Programme, which, through its Working Group on Coupled Modeling, coordinated and promoted CMIP6. We thank the climate modeling groups for producing and making available their model output, the Earth System Grid Federation (ESGF) for archiving the data and providing access, and the multiple funding agencies who support CMIP6 and ESGF. K.C. was supported by the Yale Planetary Solutions Project seed grant. A.G., A.S., and S.R. were supported by the European Union’s Horizon 2020 Project Exhaustion grant (820655). A.G. was also supported by the Medical Research Council UK grant (MR/V034162/1). J.M. received funding from the Fundação para a Ciência e a Tecnlogia Grant (SFRH/BPD/115112/2016). A.T. was supported by the MCIN/AEI/10.13039/501100011033 grant (CEX2018-000794-S). A.U. and J.K. were supported by the Czech Science Foundation (22-24920S). F.S. was supported by the Italian Ministry of University and Research (MUR), Department of Excellence project 2023-2027 ReDS ‘Rethinking Data Science’ - Department of Statistics, Computer Science and Applications - University of Florence. MNM. was supported by the European Commission (H2020-MSCA-IF-2020) under REA grant agreement no. 101022870. A.V.C. acknowledges the support of the Swiss National Foundation (TMSGI3_211626). V.H. received funding from the European Union’s Horizon 2020 research and innovation program (Marie Skłodowska-Curie Grant Agreement No.: 101032087)