Impact of pretreatment dihydropyrimidine dehydrogenase genotype-guided fluoropyrimidine dosing on chemotherapy associated adverse events

Consensus guidelines exist for genotype-guided fluoropyrimidine dosing based on variation in the gene dihydropyrimidine dehydrogenase (DPYD). However, these guidelines have not been widely implemented in North America and most studies of pretreatment DPYD screening have been conducted in Europe. Given regional differences in treatment practices and rates of adverse events (AEs), we investigated the impact of pretreatment DPYD genotyping on AEs in a Canadian context. Patients referred for DPYD genotyping prior to fluoropyrimidine treatment were enrolled from December 2013 through November 2019 and followed until completion of fluoropyrimidine treatment. Patients were genotyped for DPYD c.1905+1G\u3eA, c.2846A\u3eT, c.1679T\u3eG, and c.1236G\u3eA. Genotype-guided dosing recommendations were informed by Clinical Pharmacogenetics Implementation Consortium guidelines. The primary outcome was the proportion of patients who experienced a severe fluoropyrimidine-related AE (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Secondary outcomes included early severe AEs, severe AEs by toxicity category, discontinuation of fluoropyrimidine treatment due to AEs, and fluoropyrimidine-related death. Among 1394 patients, mean (SD) age was 64 (12) years, 764 (54.8%) were men, and 47 (3.4%) were DPYD variant carriers treated with dose reduction. Eleven variant carriers (23%) and 418 (31.0%) noncarriers experienced a severe fluoropyrimidine-related AE (p = 0.265). Six carriers (15%) and 284 noncarriers (21.1%) experienced early severe fluoropyrimidine-related AEs (p = 0.167). DPYD variant carriers treated with genotype-guided dosing did not experience an increased risk for severe AEs. Our data support a role for DPYD genotyping in the use of fluoropyrimidines in North America

In situ measurements of atmospheric O2 and CO2 reveal an unexpected O2 signal over the tropical Atlantic Ocean

We present the first meridional transects of atmospheric O2 and CO2 over the Atlantic Ocean. We combine these measurements into the tracer atmospheric potential oxygen (APO), which is a measure of the oceanic contribution to atmospheric O2 variations. Our new in situ measurement system, deployed on board a commercial container ship during 2015, performs as well as or better than existing similar measurement systems. The data show small short-term variability (hours to days), a step-change corresponding to the position of the Intertropical Convergence Zone (ITCZ), and seasonal cycles that vary with latitude. In contrast to data from the Pacific Ocean and to previous modeling studies, our Atlantic Ocean APO data show no significant bulge in the tropics. This difference cannot be accounted for by interannual variability in the position of the ITCZ or the Atlantic Meridional Mode Index and appears to be a persistent feature of the Atlantic Ocean system. Modeled APO using the TM3 atmospheric transport model does exhibit a significant bulge over the Atlantic and overestimates the interhemispheric gradient in APO over the Atlantic Ocean. These results indicate that either there are inaccuracies in the oceanic flux data products in the equatorial Atlantic Ocean region, or that there are atmospheric transport inaccuracies in the model, or a combination of both. Our shipboard O2 and CO2 measurements are ongoing and will reveal the long-term nature of equatorial APO outgassing over the Atlantic as more data become available

In-plane dielectric constant and conductivity of confined water

Water is essential for almost every aspect of life on our planet and, unsurprisingly, its properties have been studied in great detail. However, disproportionately little remains known about the electrical properties of interfacial and strongly confined water where its structure deviates from that of bulk water, becoming distinctly layered. The structural change is expected to affect water's conductivity and particularly its polarizability, which in turn modifies intermolecular forces that play a crucial role in many physical and chemical processes. Here we use scanning dielectric microscopy to probe the in-plane electrical properties of water confined between atomically flat surfaces separated by distances down to 1 nm. For confinement exceeding a few nm, water exhibits an in-plane dielectric constant close to that of bulk water and its proton conductivity is notably enhanced, gradually increasing with decreasing water thickness. This trend abruptly changes when the confined water becomes only a few molecules thick. Its in-plane dielectric constant reaches giant, ferroelectric-like values of about 1,000 whereas the conductivity peaks at a few S/m, close to values characteristic of superionic liquids. We attribute the enhancement to strongly disordered hydrogen bonding induced by the few-layer confinement, which facilitates both easier in-plane polarization of molecular dipoles and faster proton exchange. This insight into the electrical properties of nanoconfined water is important for understanding many phenomena that occur at aqueous interfaces and in nanoscale pores

Co-Housing Rodents with Different Coat Colours as a Simple, Non-Invasive Means of Individual Identification:Validating Mixed-Strain Housing for C57BL/6 and DBA/2 Mice

Standard practice typically requires the marking of laboratory mice so that they can be individually identified. However, many of the common methods compromise the welfare of the individuals being marked (as well as requiring time, effort, and/or resources on the part of researchers and technicians). Mixing strains of different colour within a cage would allow them to be readily visually identifiable, negating the need for more invasive marking techniques. Here we assess the impact that mixed strain housing has on the phenotypes of female C57BL/6 (black) and DBA/2 (brown) mice, and on the variability in the data obtained from them. Mice were housed in either mixed strain or single strain pairs for 19 weeks, and their phenotypes then assessed using 23 different behavioural, morphological, haematological and physiological measures widely used in research and/or important for assessing mouse welfare. No negative effects of mixed strain housing could be found on the phenotypes of either strain, including variables relevant to welfare. Differences and similarities between the two strains were almost all as expected from previously published studies, and none were affected by whether mice were housed in mixed- or single-strain pairs. Only one significant main effect of housing type was detected: mixed strain pairs had smaller red blood cell distribution widths, a measure suggesting better health (findings that now need replicating in case they were Type 1 errors resulting from our multiplicity of tests). Furthermore, mixed strain housing did not increase the variation in data obtained from the mice: the standard errors for all variables were essentially identical between the two housing conditions. Mixed strain housing also made animals very easy to distinguish while in the home cage. Female DBA/2 and C57BL/6 mice can thus be housed in mixed strain pairs for identification purposes, with no apparent negative effects on their welfare or the data they generate. This suggests that there is much value in exploring other combinations of strains

A Trivers-Willard Effect in Contemporary Humans: Male-Biased Sex Ratios among Billionaires

BACKGROUND: Natural selection should favour the ability of mothers to adjust the sex ratio of offspring in relation to the offspring's potential reproductive success. In polygynous species, mothers in good condition would be advantaged by giving birth to more sons. While studies on mammals in general provide support for the hypothesis, studies on humans provide particularly inconsistent results, possibly because the assumptions of the model do not apply. METHODOLOGY/PRINCIPAL FINDINGS: Here, we take a subset of humans in very good condition: the Forbe's billionaire list. First, we test if the assumptions of the model apply, and show that mothers leave more grandchildren through their sons than through their daughters. We then show that billionaires have 60% sons, which is significantly different from the general population, consistent with our hypothesis. However, women who themselves are billionaires have fewer sons than women having children with billionaires, suggesting that maternal testosterone does not explain the observed variation. Furthermore, paternal masculinity as indexed by achievement, could not explain the variation, since there was no variation in sex ratio between self-made or inherited billionaires. CONCLUSIONS/SIGNIFICANCE: Humans in the highest economic bracket leave more grandchildren through sons than through daughters. Therefore, adaptive variation in sex ratios is expected, and human mothers in the highest economic bracket do give birth to more sons, suggesting similar sex ratio manipulation as seen in other mammals

Mixed-strain housing for female C57BL/6, DBA/2, and BALB/c mice: validating a split-plot design that promotes refinement and reduction

Abstract Background Inefficient experimental designs are common in animal-based biomedical research, wasting resources and potentially leading to unreplicable results. Here we illustrate the intrinsic statistical power of split-plot designs, wherein three or more sub-units (e.g. individual subjects) differing in a variable of interest (e.g. genotype) share an experimental unit (e.g. a cage or litter) to which a treatment is applied (e.g. a drug, diet, or cage manipulation). We also empirically validate one example of such a design, mixing different mouse strains -- C57BL/6, DBA/2, and BALB/c -- within cages varying in degree of enrichment. As well as boosting statistical power, no other manipulations are needed for individual identification if co-housed strains are differentially pigmented, so also sparing mice from stressful marking procedures. Methods The validation involved housing 240 females from weaning to 5 months of age in single- or mixed- strain trios, in cages allocated to enriched or standard treatments. Mice were screened for a range of 26 commonly-measured behavioural, physiological and haematological variables. Results Living in mixed-strain trios did not compromise mouse welfare (assessed via corticosterone metabolite output, stereotypic behaviour, signs of aggression, and other variables). It also did not alter the direction or magnitude of any strain- or enrichment-typical difference across the 26 measured variables, or increase variance in the data: indeed variance was significantly decreased by mixed- strain housing. Furthermore, using Monte Carlo simulations to quantify the statistical power benefits of this approach over a conventional design demonstrated that for our effect sizes, the split- plot design would require significantly fewer mice (under half in most cases) to achieve a power of 80 %. Conclusions Mixed-strain housing allows several strains to be tested at once, and potentially refines traditional marking practices for research mice. Furthermore, it dramatically illustrates the enhanced statistical power of split-plot designs, allowing many fewer animals to be used. More powerful designs can also increase the chances of replicable findings, and increase the ability of small-scale studies to yield significant results. Using mixed-strain housing for female C57BL/6, DBA/2 and BALB/c mice is therefore an effective, efficient way to promote both refinement and the reduction of animal-use in research

Nitrous oxide as a function of oxygen and archaeal gene abundance in the North Pacific

Natural Environment Research Council (NERC) (NE/E01559X/1)

Perspectives and Integration in SOLAS Science

Why a chapter on Perspectives and Integration in SOLAS Science in this book? SOLAS science by its nature deals with interactions that occur: across a wide spectrum of time and space scales, involve gases and particles, between the ocean and the atmosphere, across many disciplines including chemistry, biology, optics, physics, mathematics, computing, socio-economics and consequently interactions between many different scientists and across scientific generations. This chapter provides a guide through the remarkable diversity of cross-cutting approaches and tools in the gigantic puzzle of the SOLAS realm. Here we overview the existing prime components of atmospheric and oceanic observing systems, with the acquisition of ocean–atmosphere observables either from in situ or from satellites, the rich hierarchy of models to test our knowledge of Earth System functioning, and the tremendous efforts accomplished over the last decade within the COST Action 735 and SOLAS Integration project frameworks to understand, as best we can, the current physical and biogeochemical state of the atmosphere and ocean commons. A few SOLAS integrative studies illustrate the full meaning of interactions, paving the way for even tighter connections between thematic fields. Ultimately, SOLAS research will also develop with an enhanced consideration of societal demand while preserving fundamental research coherency. The exchange of energy, gases and particles across the air-sea interface is controlled by a variety of biological, chemical and physical processes that operate across broad spatial and temporal scales. These processes influence the composition, biogeochemical and chemical properties of both the oceanic and atmospheric boundary layers and ultimately shape the Earth system response to climate and environmental change, as detailed in the previous four chapters. In this cross-cutting chapter we present some of the SOLAS achievements over the last decade in terms of integration, upscaling observational information from process-oriented studies and expeditionary research with key tools such as remote sensing and modelling. Here we do not pretend to encompass the entire legacy of SOLAS efforts but rather offer a selective view of some of the major integrative SOLAS studies that combined available pieces of the immense jigsaw puzzle. These include, for instance, COST efforts to build up global climatologies of SOLAS relevant parameters such as dimethyl sulphide, interconnection between volcanic ash and ecosystem response in the eastern subarctic North Pacific, optimal strategy to derive basin-scale CO2 uptake with good precision, or significant reduction of the uncertainties in sea-salt aerosol source functions. Predicting the future trajectory of Earth’s climate and habitability is the main task ahead. Some possible routes for the SOLAS scientific community to reach this overarching goal conclude the chapter