Clonal fitness inferred from time-series modelling of single-cell cancer genomes.

Progress in defining genomic fitness landscapes in cancer, especially those defined by copy number alterations (CNAs), has been impeded by lack of time-series single-cell sampling of polyclonal populations and temporal statistical models1-7. Here we generated 42,000 genomes from multi-year time-series single-cell whole-genome sequencing of breast epithelium and primary triple-negative breast cancer (TNBC) patient-derived xenografts (PDXs), revealing the nature of CNA-defined clonal fitness dynamics induced by TP53 mutation and cisplatin chemotherapy. Using a new Wright-Fisher population genetics model8,9 to infer clonal fitness, we found that TP53 mutation alters the fitness landscape, reproducibly distributing fitness over a larger number of clones associated with distinct CNAs. Furthermore, in TNBC PDX models with mutated TP53, inferred fitness coefficients from CNA-based genotypes accurately forecast experimentally enforced clonal competition dynamics. Drug treatment in three long-term serially passaged TNBC PDXs resulted in cisplatin-resistant clones emerging from low-fitness phylogenetic lineages in the untreated setting. Conversely, high-fitness clones from treatment-naive controls were eradicated, signalling an inversion of the fitness landscape. Finally, upon release of drug, selection pressure dynamics were reversed, indicating a fitness cost of treatment resistance. Together, our findings define clonal fitness linked to both CNA and therapeutic resistance in polyclonal tumours.

Health consequences of exposure to aircraft contaminated air and fume events: a narrative review and medical protocol for the investigation of exposed aircrew and passengers.

Thermally degraded engine oil and hydraulic fluid fumes contaminating aircraft cabin air conditioning systems have been well documented since the 1950s. Whilst organophosphates have been the main subject of interest, oil and hydraulic fumes in the air supply also contain ultrafine particles, numerous volatile organic hydrocarbons and thermally degraded products. We review the literature on the effects of fume events on aircrew health. Inhalation of these potentially toxic fumes is increasingly recognised to cause acute and long-term neurological, respiratory, cardiological and other symptoms. Cumulative exposure to regular small doses of toxic fumes is potentially damaging to health and may be exacerbated by a single higher-level exposure. Assessment is complex because of the limitations of considering the toxicity of individual substances in complex heated mixtures.There is a need for a systematic and consistent approach to diagnosis and treatment of persons who have been exposed to toxic fumes in aircraft cabins. The medical protocol presented in this paper has been written by internationally recognised experts and presents a consensus approach to the recognition, investigation and management of persons suffering from the toxic effects of inhaling thermally degraded engine oil and other fluids contaminating the air conditioning systems in aircraft, and includes actions and investigations for in-flight, immediately post-flight and late subsequent follow up.

Conducting evaluations of evidence that are transparent, timely and can lead to health-protective actions.

BACKGROUND: In February 2021, over one hundred scientists and policy experts participated in a web-based Workshop to discuss the ways that divergent evaluations of evidence and scientific uncertainties are used to delay timely protection of human health and the environment from exposures to hazardous agents. The Workshop arose from a previous workshop organized by the European Environment Agency (EEA) in 2008 and which also drew on case studies from the EEA reports on 'Late Lessons from Early Warnings' (2001, 2013). These reports documented dozens of hazardous agents including many chemicals, for which risk reduction measures were delayed for decades after scientists and others had issued early and later warnings about the harm likely to be caused by those agents. RESULTS: Workshop participants used recent case studies including Perfluorooctanoic acid (PFOA), Extremely Low Frequency - Electrical Magnetic Fields (ELF-EMF fields), glyphosate, and Bisphenol A (BPA) to explore myriad reasons for divergent outcomes of evaluations, which has led to delayed and inadequate protection of the public's health. Strategies to overcome these barriers must, therefore, at a minimum include approaches that 1) Make better use of existing data and information, 2) Ensure timeliness, 3) Increase transparency, consistency and minimize bias in evidence evaluations, and 4) Minimize the influence of financial conflicts of interest. CONCLUSION: The recommendations should enhance the production of "actionable evidence," that is, reliable evaluations of the scientific evidence to support timely actions to protect health and environments from exposures to hazardous agents. The recommendations are applicable to policy and regulatory settings at the local, state, federal and international levels.

Impacts of food contact chemicals on human health: a consensus statement.

Food packaging is of high societal value because it conserves and protects food, makes food transportable and conveys information to consumers. It is also relevant for marketing, which is of economic significance. Other types of food contact articles, such as storage containers, processing equipment and filling lines, are also important for food production and food supply. Food contact articles are made up of one or multiple different food contact materials and consist of food contact chemicals. However, food contact chemicals transfer from all types of food contact materials and articles into food and, consequently, are taken up by humans. Here we highlight topics of concern based on scientific findings showing that food contact materials and articles are a relevant exposure pathway for known hazardous substances as well as for a plethora of toxicologically uncharacterized chemicals, both intentionally and non-intentionally added. We describe areas of certainty, like the fact that chemicals migrate from food contact articles into food, and uncertainty, for example unidentified chemicals migrating into food. Current safety assessment of food contact chemicals is ineffective at protecting human health. In addition, society is striving for waste reduction with a focus on food packaging. As a result, solutions are being developed toward reuse, recycling or alternative (non-plastic) materials. However, the critical aspect of chemical safety is often ignored. Developing solutions for improving the safety of food contact chemicals and for tackling the circular economy must include current scientific knowledge. This cannot be done in isolation but must include all relevant experts and stakeholders. Therefore, we provide an overview of areas of concern and related activities that will improve the safety of food contact articles and support a circular economy. Our aim is to initiate a broader discussion involving scientists with relevant expertise but not currently working on food contact materials, and decision makers and influencers addressing single-use food packaging due to environmental concerns. Ultimately, we aim to support science-based decision making in the interest of improving public health. Notably, reducing exposure to hazardous food contact chemicals contributes to the prevention of associated chronic diseases in the human population.

Liver biopsy in assessment of extended criteria donors.

The safety and liver utilization with prerecovery liver biopsy (PLB) in extended criteria liver donors are unclear. We conducted a retrospective cohort study in 1323 brain death donors (PLB = 496) from 3 organ procurement organizations (OPOs). Outcomes were complications, preempted liver recovery (PLR), and liver transplantation (LT). Additional analyses included liver-only and propensity score-matched multiorgan donor subgroups. PLB donors were older (57 versus 53 years; P < 0.001). Hepatitis C antibody positivity (14.3% versus 9.6%, P = 0.01) and liver-only donors (42.6% versus 17.5%; P < 0.001) were more prevalent. The PLB cohort had fewer complications (31.9% versus 42.3%; P < 0.001). In the PLB cohort, PLR was significantly higher (odds ratio [OR], 3.45; 95% confidence interval [CI], 2.42-4.92) and LT lower (OR, 0.69; 95% CI, 0.52-0.91). In liver-only and propensity score-matched multiorgan donor subgroups, PLR was significantly higher (OR, 1.76; 95% CI, 1.06-2.94 and OR, 2.29; 95% CI, 1.37-3.82, respectively) without a decrease in LT (OR, 0.71; 95% CI, 0.43-1.18 and OR, 0.91; 95% CI, 0.63-1.33, respectively) in PLB subgroups. In conclusion, in extended criteria liver donors, PLB is safe and decreases futile liver recovery without decreasing LT. Increased use of PLB, especially in liver-only donors, is likely to save costs to OPOs and transplant centers and improve efficiencies in organ allocation. Liver Transplantation 24 182-191 2018 AASLD.

The influence of adherent cell morphology on hydrodynamic recruitment of leukocytes.

Innate immunity is characterized by the coordinated activity of multiple leukocytes mobilizing at or near the site of tissue injury. Slow rolling and/or adherent leukocytes have been shown to hydrodynamically recruit free-stream leukocytes to a model of inflamed tissue. In this paper, we numerically investigate the hydrodynamic recruitment of free-stream leukocytes due to the presence of a nearby adherent, deformed leukocyte by using a computational model developed from first principles to simulate these types of interactions. For free-stream cells at least one diameter above the surface and subsequently involved in a glancing (out-of-plane) collision with one or more adherent cell, the simulation indicated that the free-stream cell was driven closer to the surface as a function of increasing glancing distance. Further, with increasing deformation of the adherent cell a similar effect was observed beginning at smaller glancing offsets. The influence of binary interactions on the trajectories of free-stream cells that were less than one diameter above the surface was also examined. For fixed glancing distance, increased adherent cell deformation led to enhanced recruiting effectiveness which was quantified by determining the time needed for the free-stream cell to enter the reactive zone; that is, a membrane separation distance such that receptor-ligand binding was possible. This effectiveness was only moderately influenced by variations in shear rate and cell buoyancy. Finally, for large glancing offset the domain of influence of the adherent cell diminished and the trajectory of the free-stream cell was unaffected by the adherent cell, with regard to hydrodynamic recruitment.

Comparison of Circumference Measures and Height-Weight Tables With Dual-Energy X-Ray Absorptiometry Assessment of Body Composition in R.O.T.C. Cadets.

Mitchell, KM, Pritchett, RC, Gee, DL, and Pritchett, KL. Comparison of circumference measures and height-weight tables with dual-energy X-ray absorptiometry assessment of body composition in R.O.T.C. cadets. J Strength Cond Res 31(9): 2552-2556, 2017-Height-weight tables and circumference measures are used by the U.S. Army to predict body composition because they require little equipment or expertise. However, agreement between the Army's new 2002 circumference equation and an established laboratory technique has not been determined. The purpose of this study was to quantify agreement in body fat percentages between the Army's circumference measures (taping) and dual-energy X-ray absorptiometry (DXA); second to determine categorical agreement between height-weight tables and DXA. Male Reserve Officer Training Corps (R.O.T.C.) cadets (N = 23; 20.6 ± 1.6 years, 179.1 ± 6.6 cm; 81.4 ± 10.3 kg) were taped according to Army protocol to predict body fat. The % body fat prediction was compared with DXA through a Bland-Altman Plot with ±2-4% body fat established as a zone of agreement (ZOA). Thirteen out of 23 cadets fell outside the ZOA. No cadet was over the compliance threshold (20-22% fat) using the tape method, however, with DXA, 7 out of 23 cadets were noncompliant. Height-weight tables provided a moderate level of categorical agreement with DXA. The results depict poor agreement between taping and DXA, as taping generally underestimated % body fat. Compared with taping, height-weight tables were better able to identify excess fat weight.

A proposed framework for the systematic review and integrated assessment (SYRINA) of endocrine disrupting chemicals.

BACKGROUND: The issue of endocrine disrupting chemicals (EDCs) is receiving wide attention from both the scientific and regulatory communities. Recent analyses of the EDC literature have been criticized for failing to use transparent and objective approaches to draw conclusions about the strength of evidence linking EDC exposures to adverse health or environmental outcomes. Systematic review methodologies are ideal for addressing this issue as they provide transparent and consistent approaches to study selection and evaluation. Objective methods are needed for integrating the multiple streams of evidence (epidemiology, wildlife, laboratory animal, in vitro, and in silico data) that are relevant in assessing EDCs. METHODS: We have developed a framework for the systematic review and integrated assessment (SYRINA) of EDC studies. The framework was designed for use with the International Program on Chemical Safety (IPCS) and World Health Organization (WHO) definition of an EDC, which requires appraisal of evidence regarding 1) association between exposure and an adverse effect, 2) association between exposure and endocrine disrupting activity, and 3) a plausible link between the adverse effect and the endocrine disrupting activity. RESULTS: Building from existing methodologies for evaluating and synthesizing evidence, the SYRINA framework includes seven steps: 1) Formulate the problem; 2) Develop the review protocol; 3) Identify relevant evidence; 4) Evaluate evidence from individual studies; 5) Summarize and evaluate each stream of evidence; 6) Integrate evidence across all streams; 7) Draw conclusions, make recommendations, and evaluate uncertainties. The proposed method is tailored to the IPCS/WHO definition of an EDC but offers flexibility for use in the context of other definitions of EDCs. CONCLUSIONS: When using the SYRINA framework, the overall objective is to provide the evidence base needed to support decision making, including any action to avoid/minimise potential adverse effects of exposures. This framework allows for the evaluation and synthesis of evidence from multiple evidence streams. Finally, a decision regarding regulatory action is not only dependent on the strength of evidence, but also the consequences of action/inaction, e.g. limited or weak evidence may be sufficient to justify action if consequences are serious or irreversible.

Hypertension Prevalence and Related Risk Factors Among Mexican American Adults Are Increasing: National Health and Nutrition Examination Survey 1999 to 2018.

BACKGROUND: Acculturation affects hypertension prevalence among Hispanic people, but there have been no recent analyses specifically focused on Mexican American (MA) people. We sought to determine age-adjusted hypertension prevalence, abdominal obesity, and acculturation trends among MA adults and non-Hispanic White adults. METHODS AND RESULTS: Data from the NHANES (National Health and Nutrition Examination Survey) were analyzed in 2-year increments to observe trends in hypertension and risk factors (age, sex, body mass index, smoking status, abdominal obesity, waist-to-height ratio (WHtR), education, and income). Acculturation was based on three commonly used measures. The sample included 30 920 adults. Age-adjusted hypertension prevalence is higher in MA adults (52.7%) than White adults (48.3%). Hypertension risk factors-age, obesity prevalence, WHtR, acculturation-all significantly increased among MA adults, while smoking declined. Higher acculturation scores increased hypertension likelihood (odds ratio [OR], 1.44 [95% CI, 0.91-1.97]) for MA adults compared with those with lower acculturation scores. White adults with elevated WHtR >0.5 had a 40% higher risk of hypertension than those with WHtR <0.5, but among MA adults, elevated WHtR did not increase risk for hypertension. There was a significant increase in hypertension prevalence among MA adults from 2003 to 2018 at an average biennial rate of 2.23%. There was no change in hypertension prevalence among White adults from 1999 to 2018. CONCLUSIONS: Over 20 years of NHANES, more highly acculturated MA adults were at greater risk for hypertension, despite declines in smoking and controlling for age, sex, obesity status, education, and income. Finding ways to promote more traditional lifestyle and eating habits for MA adults could be a beneficial approach to reducing hypertension risk factors in this population.

Potential of APSIS-InSAR for measuring surface oscillations of tropical peatlands.

Tropical peatland across Southeast Asia is drained extensively for production of pulpwood, palm oil and other food crops. Associated increases in peat decomposition have led to widespread subsidence, deterioration of peat condition and CO2 emissions. However, quantification of subsidence and peat condition from these processes is challenging due to the scale and inaccessibility of dense tropical peat swamp forests. The development of satellite interferometric synthetic aperture radar (InSAR) has the potential to solve this problem. The Advanced Pixel System using Intermittent Baseline Subset (APSIS, formerly ISBAS) modelling technique provides improved coverage across almost all land surfaces irrespective of ground cover, enabling derivation of a time series of tropical peatland surface oscillations across whole catchments. This study aimed to establish the extent to which APSIS-InSAR can monitor seasonal patterns of tropical peat surface oscillations at North Selangor Peat Swamp Forest, Peninsular Malaysia. Results showed that C-band SAR could penetrate the forest canopy over tropical peat swamp forests intermittently and was applicable to a range of land covers. Therefore the APSIS technique has the potential for monitoring peat surface oscillations under tropical forest canopy using regularly acquired C-band Sentinel-1 InSAR data, enabling continuous monitoring of tropical peatland surface motion at a spatial resolution of 20 m.

Single-cell decoding of drug induced transcriptomic reprogramming in triple negative breast cancers.

BACKGROUND: The encoding of cell intrinsic drug resistance states in breast cancer reflects the contributions of genomic and non-genomic variations and requires accurate estimation of clonal fitness from co-measurement of transcriptomic and genomic data. Somatic copy number (CN) variation is the dominant mutational mechanism leading to transcriptional variation and notably contributes to platinum chemotherapy resistance cell states. Here, we deploy time series measurements of triple negative breast cancer (TNBC) single-cell transcriptomes, along with co-measured single-cell CN fitness, identifying genomic and transcriptomic mechanisms in drug-associated transcriptional cell states. RESULTS: We present scRNA-seq data (53,641 filtered cells) from serial passaging TNBC patient-derived xenograft (PDX) experiments spanning 2.5 years, matched with genomic single-cell CN data from the same samples. Our findings reveal distinct clonal responses within TNBC tumors exposed to platinum. Clones with high drug fitness undergo clonal sweeps and show subtle transcriptional reversion, while those with weak fitness exhibit dynamic transcription upon drug withdrawal. Pathway analysis highlights convergence on epithelial-mesenchymal transition and cytokine signaling, associated with resistance. Furthermore, pseudotime analysis demonstrates hysteresis in transcriptional reversion, indicating generation of new intermediate transcriptional states upon platinum exposure. CONCLUSIONS: Within a polyclonal tumor, clones with strong genotype-associated fitness under platinum remained fixed, minimizing transcriptional reversion upon drug withdrawal. Conversely, clones with weaker fitness display non-genomic transcriptional plasticity. This suggests CN-associated and CN-independent transcriptional states could both contribute to platinum resistance. The dominance of genomic or non-genomic mechanisms within polyclonal tumors has implications for drug sensitivity, restoration, and re-treatment strategies.

Remote monitoring of minewater rebound and environmental risk using satellite radar interferometry.

The cessation of dewatering following coalfield abandonment results in the rise of minewater, which can create significant changes in the local and regional hydrogeological regime. Monitoring such change is challenging but essential to avoiding detrimental consequences such as groundwater contamination and surface flooding. Inverse modelling methods using satellite radar interferometry (InSAR) have proven capable for retrospectively mapping minewater level changes, however, there is a need for the capability to remotely monitor changes as they occur. In this study, ground deformation measurements obtained from InSAR are used to develop a method to remotely monitor the spatio-temporal rise of minewater, which could be implemented in near real-time. The approach is demonstrated over the Horlivka mining agglomeration, Ukraine, where there is no other feasible approach possible due to a lack of safe ground access. The results were blindly validated against in-situ measurements before being used to forecast the time until minewater will reach the natural water table and Earth's surface. The findings reveal that, as a result of military conflict in Donbas, an environmental catastrophe could occur where potentially radioactive minewater is forecast to reach the natural water table between May and August of 2024.

A Datasheet for the INSIGHT Birmingham, Solihull, and Black Country Diabetic Retinopathy Screening Dataset.

Purpose: Diabetic retinopathy (DR) is the most common microvascular complication associated with diabetes mellitus (DM), affecting approximately 40% of this patient population. Early detection of DR is vital to ensure monitoring of disease progression and prompt sight saving treatments as required. This article describes the data contained within the INSIGHT Birmingham, Solihull, and Black Country Diabetic Retinopathy Dataset. Design: Dataset descriptor for routinely collected eye screening data. Participants: All diabetic patients aged 12 years and older, attending annual digital retinal photography-based screening within the Birmingham, Solihull, and Black Country Eye Screening Programme. Methods: The INSIGHT Health Data Research Hub for Eye Health is a National Health Service (NHS)-led ophthalmic bioresource that provides researchers with safe access to anonymized, routinely collected data from contributing NHS hospitals to advance research for patient benefit. This report describes the INSIGHT Birmingham, Solihull, and Black Country DR Screening Dataset, a dataset of anonymized images and linked screening data derived from the United Kingdom's largest regional DR screening program. Main Outcome Measures: This dataset consists of routinely collected data from the eye screening program. The data primarily include retinal photographs with the associated DR grading data. Additional data such as corresponding demographic details, information regarding patients' diabetic status, and visual acuity data are also available. Further details regarding available data points are available in the supplementary information, in addition to the INSIGHT webpage included below. Results: At the time point of this analysis (December 31, 2019), the dataset comprised 6 202 161 images from 246 180 patients, with a dataset inception date of January 1, 2007. The dataset includes 1 360 547 grading episodes between R0M0 and R3M1. Conclusions: This dataset descriptor article summarizes the content of the dataset, how it has been curated, and what its potential uses are. Data are available through a structured application process for research studies that support discovery, clinical evidence analyses, and innovation in artificial intelligence technologies for patient benefit. Further information regarding the data repository and contact details can be found at https://www.insight.hdrhub.org/. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Ultrahigh-viscosity hydroxypropylmethylcellulose blunts postprandial glucose after a breakfast meal in women.

OBJECTIVE: To determine the effects of two water-soluble dietary fibers, ultrahigh-viscosity hydroxypropylmethylcellulose (UHV-HPMC, nonfermentable) and psyllium fiber (fermentable), on postprandial glucose and second meal effects. METHODS: In a single-blind crossover design, 12 healthy adult subjects were given standardized, premeasured breakfast and lunch meals with either 4 g of the fiber supplements or a placebo. Blood glucose was measured with a continuous blood glucose monitoring system (DexCom Seven Plus, San Diego, CA). RESULTS: Subjects consuming UHV-HPMC had significantly (p < 0.05) lower blood glucose area under the curve (AUC) 2 hours after breakfast than those receiving a placebo. Subjects consuming psyllium also tended to have lower glucose levels than the placebo group. Peak glucose concentration following breakfast was significantly (p < 0.01) less with UHV-HPMC when compared with the placebo. No significant differences in AUC or peak glucose concentration between treatments following the second meal (lunch) were detected, suggesting no residual effect from the fiber supplements. CONCLUSIONS: Supplementation with viscous water-soluble fibers may be an effective means of reducing the glycemic response of a meal in healthy adults.

Late Lessons from Early Warnings: Towards realism and precaution with EMF?

The histories of some well-known public and environmental hazards, from the first scientifically based early warnings about potential harm, to the subsequent precautionary and preventive measures, have been reviewed by the European Environment Agency in their report "Late Lessons from Early Warnings: The Precautionary Principle 1896-2000". This paper summarises some of the definitional and other issues that arise from the report and subsequent debates, such as the contingent nature of knowledge; the definitions of precaution, prevention, risk, uncertainty, and ignorance; the use of different strengths of evidence for different purposes; the nature and main direction of the methodological and cultural biases within the environmental health sciences; the need for transparency in evaluating risks; and public participation in risk analysis. These issues are relevant to the risk assessment of electro-magnetic fields (EMF). Some implications of these issues and of the "late lessons" for the evaluation and reduction of risks from EMF are indicated.

Timescales of developmental toxicity impacting on research and needs for intervention.

Much progress has happened in understanding developmental vulnerability to preventable environmental hazards. Along with the improved insight, the perspective has widened, and developmental toxicity now involves latent effects that can result in delayed adverse effects in adults or at old age and additional effects that can be transgenerationally transferred to future generations. Although epidemiology and toxicology to an increasing degree are exploring the adverse effects from developmental exposures in human beings, the improved documentation has resulted in little progress in protection, and few environmental chemicals are currently regulated to protect against developmental toxicity, whether it be neurotoxicity, endocrine disruption or other adverse outcome. The desire to obtain a high degree of certainty and verification of the evidence used for decision-making must be weighed against the costs and necessary duration of research, as well as the long-term costs to human health because of delayed protection of vulnerable early-life stages of human development and, possibly, future generations. Although two-generation toxicology tests may be useful for initial test purposes, other rapidly emerging tools need to be seriously considered from computational chemistry and metabolomics to CLARITY-BPA-type designs, big data and population record linkage approaches that will allow efficient generation of new insight; epigenetic mechanisms may necessitate a set of additional regulatory tests to reveal such effects. As reflected by the Prenatal Programming and Toxicity (PPTOX) VI conference, the current scientific understanding and the timescales involved require an intensified approach to protect against preventable adverse health effects that can harm the next generation and generations to come. While further research is needed, the main emphasis should be on research translation and timely public health intervention to avoid serious, irreversible and perhaps transgenerational harm.

Children's environmental health and the precautionary principle.

The concept of precaution has a long history in medicine and public health. The modern precautionary principle (PP), originating from environmental debates in Germany in the 1970s, has been included in many international agreements, such as the Treaty on European Union. PP is a public policy tool that justifies actions, which protect human health and the environment in face of uncertain risks. The outcome of the application of PP depends on the level, nature, and distribution of acceptable risks and on the availability of alternatives, and can range from taking no action to banning of substances or the activities of concern. Given the complex nature and uncertainty of environmental risks to children's health, a precautionary approach is warranted. Public health professionals and clinical practitioners could adopt such an approach within the wider context of considering the environment as a source of risks to children's health. Relevant knowledge and skills are needed to enable health care professionals to address these issues. New methodological and scientific approaches are necessary to make use of scattered, but potentially relevant clinical evidence in providing 'early warnings' of health hazards.