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Three-Way Interaction Significant Genes

The clinical application of adriamycin, an exceptionally good chemotherapeutic agent, is limited by its dose-related cardiomyopathy. Our recent study showed that tumor necrosis factor-α (TNF-α) receptors mediated cytoprotective signaling against adriamycin-induced mitochondrial injury and cardiomyocyte apoptosis. In the present study, we investigated the potential targets of TNF receptor–mediated cytoprotective signaling by global genome microarray analysis using wild-type and TNF receptor–deficient mice. Microarray analysis revealed that adriamycin treatment induced the down-regulation of several mitochondrial functions and energy production–related genes in double TNF receptor–deficient mice, notably, phospholipase C-δ1, a protein involved in fatty acid metabolism and calcium regulation. The role of phospholipase C-δ1 in TNF receptor–mediated cardioprotection against adriamycin-induced injury was evaluated by measuring changes in cardiac function using high-frequency ultrasound biomicroscopy. Selective inhibition of phospholipase C activity in wild-type mice by its inhibitor, U73122, exacerbated adriamycin-induced cardiac dysfunction. Inhibition of phospholipase C-δ1 resulted in the significant decrease of left ventricular ejection fraction and fractional shortening, and the decreased levels were similar to those observed in adriamycin-treated double TNF receptor–deficient mice. The data derived from the global genome analysis identified phospholipase C-δ1 as an important target for TNF receptors and revealed the critical role of TNF receptor signaling in the protection against adriamycin-induced cardiotoxicity. (Cancer Res 2006; 66(8): 4329-38)

Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms, a devastating vascular disease with a higher prevalence and mortality rate in men than women. However, the molecular mechanism by which androgen mediates aortic aneurysms is largely unknown. Here, we report that male but not female mice develop aortic aneurysms in response to aldosterone and high salt (Aldo-salt). We demonstrate that both androgen and androgen receptors (AR) are crucial for the sexually dimorphic response to Aldo-salt. We identify T cells expressing programmed cell death protein 1 (PD-1), an immune checkpoint molecule important in immunity and cancer immunotherapy, as a key link between androgen and aortic aneurysms. We show that intraperitoneal injection of anti-PD-1 antibody reinstates Aldo-salt-induced aortic aneurysms in orchiectomized mice. Mechanistically, we demonstrate that AR binds to the PD-1 promoter to suppress its expression in the spleen. Hence, our study reveals an important but unexplored mechanism by which androgen contributes to aortic aneurysms by suppressing PD-1 expression in T cells. Our study also suggests that cancer patients predisposed to the risk factors of aortic aneurysms may be advised to screen for aortic aneurysms during immune checkpoint therapy.Graphical Abstract

Background After activation of the Hospital Readmission Reduction Program (HRRP) in 2012, hospitals nationwide experimented broadly with the implementation of Transitional Care (TC) strategies to reduce hospital readmissions. Although numerous evidence-based TC models exist, they are often adapted to local contexts, rendering large-scale evaluation difficult. Little systematic evidence exists about prevailing implementation patterns of TC strategies among hospitals, nor which strategies in which combinations are most effective at improving patient outcomes. We aimed to identify and define combinations of TC strategies, or groups of transitional care activities, implemented among a large and diverse cohort of U.S. hospitals, with the ultimate goal of evaluating their comparative effectiveness. Methods We collected implementation data for 13 TC strategies through a nationwide, web-based survey of representatives from short-term acute-care and critical access hospitals (N = 370) and obtained Medicare claims data for patients discharged from participating hospitals. TC strategies were grouped separately through factor analysis and latent class analysis. Results We observed 348 variations in how hospitals implemented 13 TC strategies, highlighting the diversity of hospitals’ TC strategy implementation. Factor analysis resulted in five overlapping groups of TC strategies, including those characterized by 1) medication reconciliation, 2) shared decision making, 3) identifying high risk patients, 4) care plan, and 5) cross-setting information exchange. We determined that the groups suggested by factor analysis results provided a more logical grouping. Further, groups of TC strategies based on factor analysis performed better than the ones based on latent class analysis in detecting differences in 30-day readmission trends. Conclusions U.S. hospitals uniquely combine TC strategies in ways that require further evaluation. Factor analysis provides a logical method for grouping such strategies for comparative effectiveness analysis when the groups are dependent. Our findings provide hospitals and health systems 1) information about what groups of TC strategies are commonly being implemented by hospitals, 2) strengths associated with the factor analysis approach for classifying these groups, and ultimately, 3) information upon which comparative effectiveness trials can be designed. Our results further reveal promising targets for comparative effectiveness analyses, including groups incorporating cross-setting information exchange.

Elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) are documented in patients with sepsis and levels positively correlate with disease severity and mortality. Our previous work demonstrated that visceral adipose tissues (VAT) are a major source of PAI-1, especially in the aged (murine endotoxemia), that circulating PAI-1 protein levels match the trajectory of PAI-1 transcript levels in VAT (clinical sepsis), and that PAI-1 in both VAT and plasma are positively associated with acute kidney injury (AKI) in septic patients. In the current study utilizing preclinical sepsis models, PAI-1 tissue distribution was examined and cellular sources, as well as mechanisms mediating PAI-1 induction in VAT, were identified. In aged mice with sepsis, PAI-1 gene expression was significantly higher in VAT than in other major organs. VAT PAI-1 gene expression correlated with PAI-1 protein levels in both VAT and plasma. Moreover, VAT and plasma levels of PAI-1 were positively associated with AKI markers, modeling our previous clinical data. Using explant cultures of VAT, we determined that PAI-1 is secreted robustly in response to recombinant transforming growth factor β (TGFβ) and tumor necrosis factor α (TNFα) treatment; however, neutralization was effective only for TNFα indicating that TGFβ is not an endogenous modulator of PAI-1. Within VAT, TNFα was localized to neutrophils and macrophages. PAI-1 protein levels were fourfold higher in stromal vascular fraction (SVF) cells compared with mature adipocytes, and among SVF cells, both immune and nonimmune compartments expressed PAI-1 in a similar fashion. PAI-1 was localized predominantly to macrophages within the immune compartment and preadipocytes and endothelial cells within the nonimmune compartment. Collectively, these results indicate that induction and secretion of PAI-1 from VAT is facilitated by a complex interaction among immune and nonimmune cells. As circulating PAI-1 contributes to AKI in sepsis, understanding PAI-1 regulation in VAT could yield novel strategies for reducing systemic consequences of PAI-1 overproduction.

The number of crashes and fatalities rate in the Commonwealth of Kentucky, U.S., have been higher than the national average for the past decades. It has been hypothesized that the distinct socioeconomic conditions of the state could be contributing to and explaining these trends. This study investigated the influence of socioeconomic characteristics on highway safety in Kentucky and attempted to identify the high-risk driver groups, based on crash data and the socioeconomic and demographic features of their residence zip codes. The quasi-induced exposure technique and binary logistic regression were employed to develop a predictive modeling approach for determining the probability of being the at-fault driver in a single- and two-unit crashes, based on socioeconomic characteristics of the driver residence zip code. The study identified that socioeconomic features such as income, poverty level, employment, age, gender, rurality, and number of traffic-related convictions of a driver’s zip code influence their likelihood to be at fault in a two-unit crash, while for single-unit crashes, in addition to these variables, educational attainment had also an impact. Younger and older drivers living in zip codes with low socioeconomic conditions have a higher probability to be the at-fault driver in both single- and two-unit crashes. The conclusions of the study can be used to determine the regions (zip codes) and driver groups with higher likelihood to be the at-fault driver in a crash and develop effective safety programs for the target groups.

A cornerstone of evidence-based medicine is the randomized controlled trial (RCT). While randomization seeks to balance study groups on potential confounders, this is not always achieved. Especially in orthopedic research where RCTs are often of modest size, imbalances can exist and may be a significant issue. We sought to describe whether orthopedic RCTs assess balancing between study groups, use statistical hypothesis testing to compare baseline characteristics between groups, and have balanced baseline characteristics between groups. All RCTs from four leading orthopedic journals published between July 2019 and June 2020 were identified and those reporting original trial results reviewed for discussion of balancing, use of statistical significance testing to compare baseline characteristics, and patient reported outcome measures (PROMs) at baseline. Standardized mean differences of baseline PROMs were calculated to assess balancing. Of 86 orthopedic RCTs reviewed, 59 (69%) assessed balancing and 50 (58%) used statistical significance testing to compare baseline characteristics. Of 74 articles specifying a primary outcome, 33 (45%) used a PROM with 23 (70%) reporting baseline PROM values. Of these articles, 17 (74%) had a difference of less than 0.25 standard deviations (SDs) between groups, 4 (17%) had a difference of between 0.25 and 0.50 SDs, and 3 (13%) had a difference greater than 0.5 SDs. Orthopedic RCTs usually assess balancing after randomization though there is room for improvement with over half of articles using hypothesis testing to assess baseline differences as opposed to a measure of the magnitude of the difference.

The rise in infections caused by antibiotic-resistant bacteria is outpacing the development of new antibiotics. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are a group of clinically important bacteria that have developed resistance to multiple antibiotics and are commonly referred to as multidrug resistant (MDR). The medical and research communities have recognized that, without new antimicrobials, infections by MDR bacteria will soon become a leading cause of morbidity and death. Therefore, there is an ever-growing need to expedite the development of novel antimicrobials to combat these infections. Toward this end, we set out to refine an existing mouse model of pulmonary Pseudomonas aeruginosa infection to generate a robust preclinical tool that can be used to rapidly and accurately predict novel antimicrobial efficacy. This refinement was achieved by characterizing the virulence of a panel of genetically diverse MDR P. aeruginosa strains in this model, by both 50% lethal dose (LD

The aim of this retrospective observational study was to characterize the MRI appearance of retinal detachment (RD) in a sample of dogs and cats. Study inclusion was based on the following medical record criteria: (a) had a diagnosis of RD in at least one eye by either funduscopic examination or ocular ultrasound and had an MRI evaluation including the eyes, or (b) had a diagnosis of RD documented in an MRI report for at least one eye and also had a clinical eye examination. Eighteen patients (12 dogs, 6 cats) and 35 eyes met the inclusion criteria, although four eyes that were clinically examined could not be visualized funduscopically and did not have ocular ultrasound performed (criterion 2). The MRI and clinical diagnosis (via either funduscopy or ultrasound) of RD/no RD was concordant in 27 of 31 eyes (87%). Qualitatively, RD appeared as a variable intensity curvilinear structure located internal and adjacent to the sclera on all sequences and was best delineated on T2W sequences. RDs inconsistently contrast enhanced and, although there was no statistical difference, subjectively appeared more clearly delineated on dorsal and parasagittal images. In conclusion, findings from the current study support using MRI as an ancillary diagnostic test for confirmation or further characterization of RD in dogs and cats.

Recently discovered Au in boulder conglomerate between the Mesoarchean West Pilbara superterrane basement and the overlying volcano-sedimentary stratigraphy of the Neoarchean Fortescue Group in Western Australia has renewed comparisons with the Witwatersrand conglomerate Au deposits in South Africa. As such, this has reignited the question of the Pilbara and Kaapvaal cratons being linked as part of the postulated Vaalbara continent during the Archean. However, little is known about the origin of the Pilbara conglomerate Au and its host conglomerates, as they are hitherto unstudied, and their formation and/or source is uncertain. Here we present a detailed study on the textures, composition, and sedimentology of one newly discovered Pilbara conglomerate Au deposit at the base of the Neoarchean Fortescue Group in the northwestern Pilbara craton. The Pilbara conglomerate Au occurrences are characteristically Ag-bearing but Hg-poor polycrystalline discoid masses that are overgrown by Au-poor chloritic halos, which are further enveloped by a hydrothermal alteration halo of disseminated Au within chlorite. Both the discoids and the auriferous chlorite halo are Ag bearing, with up to ~9 wt % Ag, consistent with a hydrothermal (orogenic) origin. The discoids do not display any physical or chemical evidence for sedimentary transport; thus, their formation (placer versus hydrothermal) remains unclear. However, the position of the Au in the conglomerate, limited to the basal section of the conglomerate, is difficult to account for in a purely hydrothermal deposit model. We argue the Pilbara conglomerate Au represents a modified placer deposit from a primary orogenic Au source, with surface evidence for sedimentation removed by partial dissolution during later hydrothermal alteration in the host conglomerate and the crystalline basement. While the basal Fortescue Group conglomerate Au shares commonalities with the time equivalent (>~2.7 Ga) Venterspost Conglomerate Formation, which overlies the Witwatersrand Supergroup, inconsistencies remain, with different Au chemistries and tectonic, magmatic, sedimentary, and metamorphic-metallogenic histories of the Pilbara and Kaapvaal cratons prior to deposition of the >2.7 Ga conglomerate sequences. This collectively indicates the drivers of Au metallogenesis and ultimate Au deposition in conglomerate facies were fundamentally different in the Pilbara and Kaapvaal cratons.

The rise in infections caused by antibiotic resistant bacteria is outpacing the development of new antibiotics. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are a group of clinically important bacteria that have developed resistance to multiple antibiotics and are commonly referred to as multidrug resistant (MDR). The medical and research communities have recognized that without new antimicrobials, infections by MDR bacteria will soon become a leading cause of morbidity and mortality. Therefore, there is an ever growing need to expedite the development of novel antimicrobials to combat these infections. Toward this end, we set out to refine an existing murine model of pulmonary Pseudomonas aeruginosa infection to generate a robust preclinical tool that can be used to rapidly and accurately predict novel antimicrobial efficacy. This refinement was achieved by characterizing the virulence of a panel of genetically diverse MDR P. aeruginosa strains in this model, both by LD50 analysis and natural history studies. Further, we defined two antibiotic regimens (aztreonam and amikacin) that can be used a comparators during the future evaluation of novel antimicrobials, and validated that the model can effectively differentiate between successful and unsuccessful treatment as predicted by in vitro inhibitory data. This validated model represents an important tool in our arsenal to develop new therapies to combat MDR P. aeruginosa, with the ability to provide rapid preclinical evaluation of novel antimicrobials that can also serve to support data from clinical studies during the investigational drug development process.

BACKGROUND AND OBJECTIVES: Hypophosphatemia is commonly observed in patients receiving continuous KRT. Patients who develop hypophosphatemia may be at risk of respiratory and neuromuscular dysfunction and therefore subject to prolongation of ventilator support. We evaluated the association of phosphate-containing versus phosphate-free continuous KRT solutions with ventilator dependence in critically ill patients receiving continuous KRT. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our study was a single-center, retrospective, pre-post cohort study of adult patients receiving continuous KRT and mechanical ventilation during their intensive care unit stay. Zero-inflated negative binomial regression with and without propensity score matching was used to model our primary outcome: ventilator-free days at 28 days. Intensive care unit and hospital lengths of stay as well as hospital mortality were analyzed with a t test or a chi-squared test, as appropriate. RESULTS: We identified 992 eligible patients, of whom 649 (65%) received phosphate-containing solutions and 343 (35%) received phosphate-free solutions. In multivariable models, patients receiving phosphate-containing continuous KRT solutions had 12% (95% confidence interval, 0.17 to 0.47) more ventilator-free days at 28 days. Patients exposed to phosphate-containing versus phosphate-free solutions had 17% (95% confidence interval, −0.08 to −0.30) fewer days in the intensive care unit and 20% (95% confidence interval, − 0.12 to −0.32) fewer days in the hospital. Concordant results were observed for ventilator-free days at 28 days in the propensity score matched analysis. There was no difference in hospital mortality between the groups. CONCLUSIONS: The use of phosphate-containing versus phosphate-free continuous KRT solutions was independently associated with fewer ventilator days and shorter stay in the intensive care unit.

Two anionic asymmetric Fe-Fe hydrogenase model compounds containing a single cyano (CN) and five carboxyl (CO) ligands, [Et4N][Fe2(μ-S2C3H6)(CO)5(CN)1] and [Et4N][Fe2(μ-S2C2H4)(CO)5(CN)1], dissolved in room-temperature acetonitrile, are examined. The molecular asymmetry affects the redox potentials of the central iron atoms, thus changing the photophysics and possible catalytic properties of the compounds. Femtosecond ultraviolet excitation with mid-infrared probe spectroscopy of the model compounds was employed to better understand the ultrafast dynamics of the enzyme-active site. Continuous ultraviolet lamp excitation with Fourier transform infrared (FTIR) spectroscopy was also used to explore stable product formation on the second timescale. For both model compounds, two timescales are observed; a 20-30 ps decay and the formation of a long-lived photoproduct. The picosecond decay is assigned to vibrational cooling and rotational dynamics, while the residual spectra remain for up to 300 ps, suggesting the formation of new photoproducts. Static FTIR spectroscopy yielded a different stable photoproduct than that observed on the ultrafast timescale. Density functional theory calculations simulated photoproducts for CO-loss and CN-loss isomers, and the resulting photoproduct spectra suggest that the picosecond transients arise from a complex mixture of isomerization after CO-loss, while dimerization and formation of a CN-containing Fe-CO-Fe bridged species are also considered.

Background As health systems transition to value-based care, improving transitional care (TC) remains a priority. Hospitals implementing evidence-based TC models often adapt them to local contexts. However, limited research has evaluated which groups of TC strategies, or transitional care activities, commonly implemented by hospitals correspond with improved patient outcomes. In order to identify TC strategy groups for evaluation, we applied a data-driven approach informed by literature review and expert opinion. Methods Based on a review of evidence-based TC models and the literature, focus groups with patients and family caregivers identifying what matters most to them during care transitions, and expert review, the Project ACHIEVE team identified 22 TC strategies to evaluate. Patient exposure to TC strategies was measured through a hospital survey (N = 42) and prospective survey of patients discharged from those hospitals (N = 8080). To define groups of TC strategies for evaluation, we performed a multistep process including: using ACHIEVE’S prior retrospective analysis; performing exploratory factor analysis, latent class analysis, and finite mixture model analysis on hospital and patient survey data; and confirming results through expert review. Machine learning (e.g., random forest) was performed using patient claims data to explore the predictive influence of individual strategies, strategy groups, and key covariates on 30-day hospital readmissions. Results The methodological approach identified five groups of TC strategies that were commonly delivered as a bundle by hospitals: 1) Patient Communication and Care Management, 2) Hospital-Based Trust, Plain Language, and Coordination, 3) Home-Based Trust, Plain language, and Coordination, 4) Patient/Family Caregiver Assessment and Information Exchange Among Providers, and 5) Assessment and Teach Back. Each TC strategy group comprises three to six, non-mutually exclusive TC strategies (i.e., some strategies are in multiple TC strategy groups). Results from random forest analyses revealed that TC strategies patients reported receiving were more important in predicting readmissions than TC strategies that hospitals reported delivering, and that other key co-variates, such as patient comorbidities, were the most important variables. Conclusion Sophisticated statistical tools can help identify underlying patterns of hospitals’ TC efforts. Using such tools, this study identified five groups of TC strategies that have potential to improve patient outcomes.

OBJECTIVENeonatal intraventricular hemorrhage (IVH) leads to posthemorrhagic hydrocephalus (PHH), brain injury, and long-term disability. Current therapy for IVH is based on treating PHH but does not address the underlying brain injury. In order to develop pharmacological treatment for IVH, there must be a better understanding of the underlying pathology of this disease. This study was designed to determine the time course of the acute inflammation and oxidative stress that may underlie the progressive pathology of IVH. The authors sought to understand the temporal relationships among inflammation, oxidative stress, and white matter pathology in a rat model of IVH.METHODSA rat model of IVH consisting of hemoglobin injection into the lateral ventricle was used. Tissue was analyzed via biochemical and histological methods to map the spatiotemporal distribution of innate immune activation and oxidative stress. White matter was quantified using both immunohistochemistry and Western blot for myelin basic protein (MBP) in the corpus callosum.RESULTSIVH led to acute induction of inflammatory cytokines, followed by oxidative stress. Oxidative stress was concentrated in white matter, adjacent to the lateral ventricles. Animals with IVH initially gained weight at a lower rate than control animals and had larger ventricles and less MBP than control animals.CONCLUSIONSExperimental IVH induces global inflammation throughout the brain and oxidative stress concentrated in the white matter. Both of these phenomena occur early after IVH. This has implications for human neonates with immature white matter that is exquisitely sensitive to inflammation and oxidative stress. Antiinflammatory or antioxidant therapy for IVH may need to be initiated early in order to protect developing white matter.

Visual Abstract, Highlights • Contractile assays were performed using multicellular preparations isolated from the left and right ventricles of organ donors and patients with heart failure. • Heart failure reduced maximum force and power by approximately 30% in the myocardium from both ventricles. • Heart failure increased the Ca2+ sensitivity of contraction, but the effect was bigger in right ventricular tissue than in left ventricular samples. • The changes in Ca2+ sensitivity may reflect ventricle-specific post-translational modifications to sarcomeric proteins., Summary This study measured how heart failure affects the contractile properties of the human myocardium from the left and right ventricles. The data showed that maximum force and maximum power were reduced by approximately 30% in multicellular preparations from both ventricles, possibly because of ventricular remodeling (e.g., cellular disarray and/or excess fibrosis). Heart failure increased the calcium (Ca2+) sensitivity of contraction in both ventricles, but the effect was bigger in right ventricular samples. The changes in Ca2+ sensitivity were associated with ventricle-specific changes in the phosphorylation of troponin I, which indicated that adrenergic stimulation might induce different effects in the left and right ventricles.

As new technologies permit the generation of hitherto unprecedented volumes of data (e.g. genome-wide association study data), researchers struggle to keep up with the added complexity and time commitment required for its analysis. For this reason, model selection commonly relies on machine learning and data-reduction techniques, which tend to afford models with obscure interpretations. Even in cases with straightforward explanatory variables, the so-called ‘best’ model produced by a given model-selection technique may fail to capture information of vital importance to the domain-specific questions at hand. Herein we propose a new concept for model selection, feasibility, for use in identifying multiple models that are in some sense optimal and may unite to provide a wider range of information relevant to the topic of interest, including (but not limited to) interaction terms. We further provide an R package and associated Shiny Applications for use in identifying or validating feasible models, the performance of which we demonstrate on both simulated and real-life data.

Introduction In women with T1-2 breast cancer and one to two positive axillary lymph nodes (LN) at low risk for recurrence, postmastectomy radiation therapy (PMRT) may provide insufficient benefit to justify its toxicity. This study evaluated the interaction of factors associated with overall survival (OS) after PMRT in these patients. Methods The National Cancer Database was queried for women with T1-2 breast cancer undergoing mastectomy with one to two positive LN identified on lymphadenectomy. Patients were grouped according to number of positive LN and then stratified by PMRT use. Differences in OS were evaluated. Results Multivariable modeling demonstrated an interaction effect of age on the efficacy of PMRT. In patients more than or equal to 60 years old, PMRT was associated with improved survival when adjusting for age and tumor grade in patients with 1 to 2 positive LN (risk ratio = 0.62, 95% confidence interval = 0.40-0.93, P = .018). In patients less than 60 years old, tumor size and grade, but not PMRT, were associated with improved OS. Conclusion For women with T1-2 breast cancer and one to two positive LN, PMRT's association with OS is influenced by age, tumor grade, and number of positive LN. PMRT appears to be associated with improvements in OS in older patients, but not younger patients, regardless of tumor size or nodal status.

Manually interpreting multivariate drill hole data is very time-consuming, and different geologists will produce different results due to the subjective nature of geological interpretation. Automated or semi-automated interpretation of numerical drill hole data is required to reduce time and subjectivity of this process. However, results from machine learning algorithms applied to drill holes, without reference to spatial information, typically result in numerous small-scale units. These small-scale units result not only from the presence of very small rock units, which may be below the scale of interest, but also from misclassification. A novel method is proposed that uses the continuous wavelet transform to identify geological boundaries and uses wavelet coefficients to indicate boundary strength. The wavelet coefficient is a useful measure of boundary strength because it reflects both wavelength and amplitude of features in the signal. This means that boundary strength is an indicator of the apparent thickness of geological units and the amount of change occurring at each geological boundary. For multivariate data, boundaries from multiple variables are combined and multiscale domains are calculated using the combined boundary strengths. The method is demonstrated using multi-element geochemical data from mineral exploration drill holes. The method is fast, reduces misclassification, provides a choice of scales of interpretation and results in hierarchical classification for large scales where domains may contain more than one rock type.

Background Cancer arises through accumulation of somatically acquired genetic mutations. An important question is to delineate the temporal order of somatic mutations during carcinogenesis, which contributes to better understanding of cancer biology and facilitates identification of new therapeutic targets. Although a number of statistical and computational methods have been proposed to estimate the temporal order of mutations, they do not account for the differences in the functional impacts of mutations and thus are likely to be obscured by the presence of passenger mutations that do not contribute to cancer progression. In addition, many methods infer the order of mutations at the gene level, which have limited power due to the low mutation rate in most genes. Results In this paper, we develop a Probabilistic Approach for estimating the Temporal Order of Pathway mutations by leveraging functional Annotations of mutations (PATOPA). PATOPA infers the order of mutations at the pathway level, wherein it uses a probabilistic method to characterize the likelihood of mutational events from different pathways occurring in a certain order. The functional impact of each mutation is incorporated to weigh more on a mutation that is more integral to tumor development. A maximum likelihood method is used to estimate parameters and infer the probability of one pathway being mutated prior to another. Simulation studies and analysis of whole exome sequencing data from The Cancer Genome Atlas (TCGA) demonstrate that PATOPA is able to accurately estimate the temporal order of pathway mutations and provides new biological insights on carcinogenesis of colorectal and lung cancers. Conclusions PATOPA provides a useful tool to estimate temporal order of mutations at the pathway level while leveraging functional annotations of mutations.

The flood basalts and gold-bearing basal sediments of the 2775-2629 Ma Fortescue Group unconformably overlie the Mesoarchean West Pilbara Superterrane to the south of Karratha, Western Australia. F...

Lesniak, AY, Bergstrom, HC, Clasey, JL, Stromberg, AJ, and Abel, MG. The effect of personal protective equipment on firefighter occupational performance. J Strength Cond Res 34(8): 2165-2172, 2020-The purpose of this study was to evaluate the effects of load carriage (LC) and LC plus respirator use (LC + self-contained breathing apparatus [SCBA]) on firefighters' work capacity to enhance our understanding of occupational demands. Twenty-one male structural firefighter recruits (age: 28.6 ± 4.3 years; height: 178.6 ± 7.2 cm; body mass: 94.1 ± 15.4 kg; body fat: 22.9 ± 6.1%) participated. Occupational performance was assessed by time to complete a simulated fire ground test (SFGT). After 2 familiarization trials, recruits performed the following SFGT conditions in a randomized order: PT (physical training clothes), LC only, and LC + SCBA. To describe within-group differences between SFGT conditions, relative difference scores were calculated as follows: % difference = ([experimental trial outcome - PT trial outcome]/PT trial outcome) × 100. Statistical differences between conditions were assessed with repeated-measures analysis of variance. The level of significance was set p < 0.01. Time to complete the LC + SCBA trial (345.9 ± 43.7 seconds; p < 0.001) and LC-only trial (331.2 ± 39.3 seconds; p < 0.001) were significantly greater than the PT trial (241.0 ± 33.3 seconds). Post-SFGT rating of perceived exertion was higher in the LC + SCBA trial (6.7 ± 1.7) and LC trial (6.4 ± 1.5) compared with the PT trial (4.7 ± 1.8; p < 0.001). Heart rate and lactate measures were similar across conditions (p = 0.488; p = 0.287). Personal protective equipment (PPE) significantly decreases the work capacity and increases the perceived effort of occupational tasks. Thus, these findings describe the additional physical demands produced by PPE and indicate that performance of firefighting tasks in an unloaded condition does not reflect work capacity in a bona fide condition.

Adipose tissue dysfunction is strongly linked to the development of chronic inflammation and cardiometabolic disorders in aging. While much attention has been given to the role of resident adipose tissue immune cells in the disruption of homeostasis in obesity, age-specific effects remain understudied. Here, we identified and characterized a population of γδ T cells, which show unique age-dependent accumulation in the visceral adipose tissue (VAT) of both mice and humans. Diet-induced obesity likewise increased γδ T cell numbers; however, the effect was greater in the aged where the increase was independent of fat mass. γδ T cells in VAT express a tissue-resident memory T cell phenotype (CD44hiCD62LlowCD69+) and are predominantly IL-17A-producing cells. Transcriptome analyses of immunomagnetically purified γδ T cells identified significant age-associated differences in expression of genes related to inflammation, immune cell composition, and adipocyte differentiation, suggesting age-dependent qualitative changes in addition to the quantitative increase. Genetic deficiency of γδ T cells in old age improved the metabolic phenotype, characterized by increased respiratory exchange ratio, and lowered levels of IL-6 both systemically and locally in VAT. Decreased IL-6 was predominantly due to reduced production by non-immune stromal cells, primarily preadipocytes, and adipose-derived stem cells. Collectively, these findings suggest that an age-dependent increase of tissue-resident γδ T cells in VAT contributes to local and systemic chronic inflammation and metabolic dysfunction in aging.

Vancomycin is a first-line agent used in the treatment of methicillin-resistant Staphylococcus aureus; however, vancomycin is associated with acute kidney injury (AKI). Previous literature demonstrates decreased incidence of AKI using 24-h area under the concentration-time curve (AUC(24)) monitoring, but its safety is unknown in obese populations. Patients ≥18 years, with body mass indices (BMI) ≥30 kg/m(2), admitted between August 2015 and July 2017 or October 2017 and September 2019, who received vancomycin for ≥72 h and had level(s) drawn within 96 h of initiation were included. The primary outcome was incidence of AKI. Secondary outcomes included inpatient mortality rate, median inpatient length of stay, median vancomycin trough concentration, and median vancomycin AUC(24). AKI was identified using the highest serum creatinine value compared with the value immediately prior to vancomycin initiation based on Kidney Disease Improving Global Outcomes (KDIGO) criteria. Overall, 1,024 patients met inclusion criteria, with 142 out of 626 patients in the trough group and 65 out of 398 patients in the AUC(24) group meeting criteria for AKI (22.7% versus 16.3%, P = 0.008). Logistic regression of the data to account for confounding factors maintained significance for the reduction in incidence of AKI with AUC(24) monitoring compared to trough monitoring (P = 0.010). Monitoring of vancomycin with AUC(24) was associated with a decreased risk of AKI when compared with trough monitoring in obese patients.

Despite the known deleterious effects of obesity, clinical data indicate that overweight or obese patients experience higher rates of sepsis survival compared to normal and underweight patients; a phenomenon called the obesity paradox. Results from preclinical sepsis studies have not been able to replicate these findings. The objective of this study was to test the existence of the obesity paradox in a murine model of cecal slurry (CS)-induced sepsis with insulin-resistant diet-induced obese mice. Male C57BL/6 mice were provided high-fat (HFD) or low-fat (LFD) diets for 20 weeks. HFD-fed mice experienced higher rates of survival compared to LFD-fed mice after septic challenge induced by CS injection (66% vs. 25%, p = 0.01, survival assessed for 14 days). Despite the survival advantage, HFD-fed mice had higher rates of positive bacterial cultures and increased markers of kidney injury. Circulating levels of IL-6, IL-1β, TNFα, and IL-23 were equivalent 24 h after CS-injection; however, IL-17A was uniquely increased in HFD-fed mice. While LFD-fed mice maintained euglycemia, HFD-fed mice were hyperglycemic 6 and 12 h after CS-injection. Stable isotope resolved metabolomics analysis of liver tissue showed diverging pathways of glucose utilization during sepsis, with LFD-fed mice significantly upregulating glycolytic activity and HFD-fed mice decreasing glucose entry into the TCA cycle. This murine study corroborates clinical data that obesity confers a survival benefit in sepsis, albeit at the expense of more significant organ injury. The mechanisms promoting survival in the obese remain unknown; however, this model appears to be well-poised to begin answering this question. Differences in glucose utilization are a novel target to investigate this paradox.

Background: Compare arterial stiffness among law enforcement officers (LEOs) versus general population normative values and identify predictors of arterial stiffness in LEOs. Methods: Seventy male LEOs (age: 24–54 years) completed body composition, blood pressures, physical activity level, and carotid-femoral pulse wave velocity (cfPWV) measurements. T-tests and regression analyses were utilized to compare LEO data to normative data and predict cfPWV, respectively. Results: Compared to similar age strata within the general population, cfPWV was lower among LEO’s under 30-years (mean difference = −0.6 m·s−1), but higher among LEOs 50–55-years (mean difference = 1.1 m·s−1). Utilizing regression, age, relative body fat, and diastolic blood pressure explained the greatest variance in LEO’s cfPWV (adj. R2 = 0.56, p &lt, 0.001). Conclusion: This investigation demonstrated that arterial stiffness may progress more rapidly in LEOs and LEOs’ relative body fat and blood pressure may primarily affect arterial stiffness and risk of CVD.