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Objective: This study evaluated the association between preoperative education and adherence to downstream components of enhanced recovery programs (ERPs) and surgical outcomes among patients undergoing elective colorectal surgery., Background: ERPs improve outcomes for surgical patients. While preoperative education is an essential component of ERPs, its relationship with other components is unclear., Methods: This was a retrospective cohort study of all ERP patients undergoing elective colorectal surgery from 2019 to 2022. Our institutional ERP database was linked with American College of Surgeons National Surgical Quality Improvement Program data and stratified by adherence to preoperative education. Primary outcomes included adherence to individual ERP components and secondary outcomes included high-level ERP adherence (>70% of components), length of stay (LOS), readmissions, and 30-day complications., Results: A total of 997 patients were included. The mean (SD) age was 56.5 (15.8) years, 686 (57.3%) were female, and 717 (71.9%) were white. On adjusted analysis, patients who received preoperative education (n = 877, 88%) had higher adherence rates for the following ERP components: no prolonged fasting (estimate = +19.6%; P < 0.001), preoperative blocks (+8.0%; P = 0.02), preoperative multimodal analgesia (+18.0%; P < 0.001), early regular diet (+15.9%; P < 0.001), and postoperative multimodal analgesia (+6.4%; P < 0.001). High-level ERP adherence was 13.4% higher ( P < 0.01) and LOS was 2.0 days shorter ( P < 0.001) for those who received preoperative education. Classification and regression tree analysis identified preoperative education as the first-level predictor for adherence to early regular diet, the second-level predictor for LOS, and the third-level predictor for ERP high-level adherence., Conclusion: Preoperative education is associated with adherence to ERP components and improved surgical outcomes., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Cardiovascular disease (CVD) is largely preventable, and the leading cause of death for men and women. Though women have increased life expectancy compared to men, there are marked sex disparities in prevalence and risk of CVD-associated mortality and dementia. Yet, the basis for these and female-male differences is not completely understood. It is increasingly recognized that heart and brain health represent a lifetime of exposures to shared risk factors (including obesity, hyperlipidemia, diabetes, and hypertension) that compromise cerebrovascular health. We describe the process and resources for establishing a new research Center for Women's Cardiovascular and Brain Health at the University of California, Davis as a model for: (1) use of the cy pres principle for funding science to improve health; (2) transdisciplinary collaboration to leapfrog progress in a convergence science approach that acknowledges and addresses social determinants of health; and (3) training the next generation of diverse researchers. This may serve as a blueprint for future Centers in academic health institutions, as the cy pres mechanism for funding research is a unique mechanism to leverage residual legal settlement funds to catalyze the pace of scientific discovery, maximize innovation, and promote health equity in addressing society's most vexing health problems., (© The Author(s) 2024.)

Background: Delta-8 tetrahydrocannabinol (THC) is a psychoactive cannabinoid found in small amounts naturally in the cannabis plant; it can also be synthetically produced in larger quantities from hemp-derived cannabidiol. Most states permit the sale of hemp and hemp-derived cannabidiol products; thus, hemp-derived delta-8 THC products have become widely available in many state hemp marketplaces, even where delta-9 THC, the most prominently occurring THC isomer in cannabis, is not currently legal. Health concerns related to the processing of delta-8 THC products and their psychoactive effects remain understudied., Objective: The goal of this study is to implement a novel topic modeling approach based on transformers, a state-of-the-art natural language processing architecture, to identify and describe emerging trends and topics of discussion about delta-8 THC from social media discourse, including potential symptoms and adverse health outcomes experienced by people using delta-8 THC products., Methods: Posts from January 2008 to December 2021 discussing delta-8 THC were isolated from cannabis-related drug forums on Reddit (Reddit Inc), a social media platform that hosts the largest web-based drug forums worldwide. Unsupervised topic modeling with state-of-the-art transformer-based models was used to cluster posts into topics and assign labels describing the kinds of issues being discussed with respect to delta-8 THC. Results were then validated by human subject matter experts., Results: There were 41,191 delta-8 THC posts identified and 81 topics isolated, the most prevalent being (1) discussion of specific brands or products, (2) comparison of delta-8 THC to other hemp-derived cannabinoids, and (3) safety warnings. About 5% (n=1220) of posts from the resulting topics included content discussing health-related symptoms such as anxiety, sleep disturbance, and breathing problems. Until 2020, Reddit posts contained fewer than 10 mentions of delta-8-THC for every 100,000 cannabis posts annually. However, in 2020, these rates increased by 13 times the 2019 rate (to 99.2 mentions per 100,000 cannabis posts) and continued to increase into 2021 (349.5 mentions per 100,000 cannabis posts)., Conclusions: Our study provides insights into emerging public health concerns around delta-8 THC, a novel substance about which little is known. Furthermore, we demonstrate the use of transformer-based unsupervised learning approaches to derive intelligible topics from highly unstructured discussions of delta-8 THC, which may help improve the timeliness of identification of emerging health concerns related to new substances., (©Brandi Patrice Smith, Brooke Hoots, Lara DePadilla, Douglas R Roehler, Kristin M Holland, Daniel A Bowen, Steven A Sumner. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 21.12.2023.)

More than ever the welfare of horses in equestrian sport is in the spotlight. In response to this scrutiny, one peak body, the Federation Equestre Internationale (FEI) has created an Equine Ethics and Wellbeing Commission to protect their sport's longevity. However, for welfare-based strategies to be successful, the conceptualisation of horse welfare must align across various stakeholders, including the general public. The value-laden nature of welfare makes agreement on its definition, even among scientists, difficult. Given little is known about how equestrians conceptualise horse welfare, we interviewed 19 Australian amateur equestrians using a semi-structured format. Systems thinking and the Five Domains Model provided the theoretical framework and informed our methods. Using reflexive thematic analysis, three themes were identified: (1) good horse welfare is tangible; (2) owners misinterpret unwanted horse behaviour; and (3) equestrians publicly minimise horse welfare issues but are privately concerned. Our results highlight participants' conceptualisations of horse welfare do not align with the Five Domains Model; participants' ideal of prioritising horse welfare does not align with their practice; and there is inconsistency between what participants share publicly and what they think privately about horse welfare. These findings can inform the development of programmes to improve ridden horse welfare throughout the horse industry. As a starting point, programmes that provide a safe space for equestrians to explore their private horse welfare concerns, and programmes that build a partnership mindset to facilitate knowledge exchange between all stakeholders are needed., Competing Interests: None., (© The Author(s) 2023.)

During May 10-December 31, 2022, a total of 29,980 confirmed and probable † U.S. monkeypox (mpox) cases were reported to CDC, predominantly in cisgender adult men reporting recent same-gender sexual partners (1). Urban-rural differences in health (2) and diagnosis of HIV (3,4) and other sexually transmitted infections (5) are well documented nationally. This report describes urban-rural differences in mpox incidence (cases per 100,000 population) among persons aged 15-64 years, by gender and race and ethnicity. Urbanicity was assessed using the 2013 National Center for Health Statistics (NCHS) Urban-Rural Classification Scheme for Counties (2). Substantial differences in incidence by urbanicity, gender, and race and ethnicity were observed; most (71.0%) cases occurred in persons residing in large central urban areas. Among the cases in large central urban areas, most (95.7%) were in cisgender men. The overall incidence of mpox in the United States was 13.5 per 100,000 persons aged 15-64 years and peaked in August in both urban and rural areas. Among cisgender men, incidence in rural areas was approximately 4% that in large central urban areas (risk ratio [RR] = 0.04). Among cisgender women, incidence in rural areas was approximately 11% that in large central urban areas (RR = 0.11). In both urban and rural areas, incidence among non-Hispanic Black or African American (Black) and Hispanic or Latino (Hispanic) persons was consistently higher than that among non-Hispanic White (White) persons; RRs between Black and White persons were highest in rural areas. Support and maintenance of mpox surveillance and prevention efforts including vaccinations should focus on urban areas with the highest incidence of mpox during the 2022 outbreak; however, surveillance and prevention efforts should include all genders, persons of color, and persons residing in both urban and rural areas who are at increased risk for mpox., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Siobhán O’Connor reports patent applications for kits and methods for determining physiologic levels, ranges of hemoglobin, and disease state, unrelated to the current work. No other potential conflicts of interest were disclosed.

Background: Enhanced recovery programs (ERPs) improve outcomes, but over 20 % of patients fail ERP and the contribution of social vulnerability is unknown. This study aimed to characterize the association between social vulnerability and ERP adherence and failure., Methods: This was a retrospective cohort study of colorectal surgery patients between 2015 and 2020 utilizing ACS-NSQIP data. Patients who failed ERP (LOS > 6 days) were compared to patients not failing ERP. The CDC's social vulnerability index (SVI) was used to assess social vulnerability., Result: 273 of 1191 patients (22.9 %) failed ERP. SVI was a significant predictor of ERP failure (OR 4.6, 95 % CI 1.3-16.8) among those with >70 % ERP component adherence. SVI scores were significantly higher among patients non-adherent with 3 key ERP components: preoperative block (0.58 vs. 0.51, p < 0.01), early diet (0.57 vs. 0.52, p = 0.04) and early foley removal (0.55 vs. 0.50, p < 0.01)., Conclusions: Higher social vulnerability was associated with non-adherence to 3 key ERP components as well as ERP failure among those who were adherent with >70 % of ERP components. Social vulnerability needs to be recognized, addressed, and included in efforts to further improve ERPs., Key Message: Social vulnerability is associated with non-adherence to enhanced recovery components and ERP failure among those with high ERP adherence. Social vulnerability needs to be addressed in efforts to improve ERPs., Competing Interests: The authors have no additional conflict of interest to disclose other than the funding sources listed below., (© 2023 The Authors.)

Carbonate rocks provide unique and valuable sedimentary archives for secular changes in Earth's physical, chemical, and biological processes. However, reading the stratigraphic record produces overlapping, nonunique interpretations that stem from the difficulty in directly comparing competing biological, physical, or chemical mechanisms within a common quantitative framework. We built a mathematical model that decomposes these processes and casts the marine carbonate record in terms of energy fluxes across the sediment-water interface. Results showed that physical, chemical, and biological energy terms across the seafloor are subequal and that the energetic dominance of different processes varies both as a function of environment (e.g., onshore vs. offshore) as well as with time-varying changes in seawater chemistry and with evolutionary changes in animal abundance and behavior. We applied our model to observations from the end-Permian mass extinction-a massive upheaval in ocean chemistry and biology-revealing an energetic equivalence between two hypothesized drivers of changing carbonate environments: a reduction in physical bioturbation increased carbonate saturation states in the oceans. Early Triassic occurrences of 'anachronistic' carbonates-facies largely absent from marine environments after the Early Paleozoic-were likely driven more by reduction in animal biomass than by repeated perturbations to seawater chemistry. This analysis highlighted the importance of animals and their evolutionary history in physically shaping patterns in the sedimentary record via their impact on the energetics of marine environments.

Cholesterol has been implicated in the clinical progression of breast cancer, a disease that continues to be the most commonly diagnosed cancer in women. Previous work has identified the cholesterol metabolite 27-hydroxycholesterol (27HC) as a major mediator of the effects of cholesterol on breast tumor growth and progression. 27HC can act as an estrogen receptor (ER) modulator to promote the growth of ERα+ tumors, and as a liver X receptor (LXR) ligand in myeloid immune cells to establish an immune-suppressive program. In fact, the metastatic properties of 27HC require the presence of myeloid cells with neutrophils (polymorphonuclear neutrophils; PMNs) being essential for the increase in lung metastasis in murine models. In an effort to further elucidate the mechanisms by which 27HC alters breast cancer progression, we made the striking finding that 27HC promoted the secretion of extracellular vesicles (EVs), a diverse assortment of membrane bound particles that includes exosomes. The resulting EVs had a size distribution that was skewed slightly larger than EVs generated by treating cells with vehicle. The increase in EV secretion and size was consistent across 3 different subtypes: primary murine PMNs, RAW264.7 monocytic cells, and 4T1 murine mammary cancer cells. Label-free analysis of 27HC-EVs indicated that they had a different metabolite composition to those from vehicle-treated cells. Importantly, 27HC-EVs from primary PMNs promoted tumor growth and metastasis in 2 different syngeneic models, demonstrating the potential role of 27HC-induced EVs in the progression of breast cancer. EVs from PMNs were taken up by cancer cells, macrophages, and PMNs, but not T cells. Since EVs did not alter proliferation of cancer cells, it is likely that their protumor effects are mediated through interactions with myeloid cells. Interestingly, RNA-seq analysis of tumors from 27HC-EV-treated mice do not display significantly altered transcriptomes, suggesting that the effects of 27HC-EVs occur early on in tumor establishment and growth. Future work will be required to elucidate the mechanisms by which 27HC increases EV secretion, and how these EVs promote breast cancer progression. Collectively, however, our data indicate that EV secretion and content can be regulated by a cholesterol metabolite, which may have detrimental effects in terms of disease progression, important findings given the prevalence of both breast cancer and hypercholesterolemia., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Previously, quality of life (Qol) has been defined as an individual's evaluation of a satisfactory life as a whole (i.e. physically, mentally, psychologically, and socially). Only a few studies have examined the racial differences between QoL and risk factors associated with health, demographics, and lifestyle in midlife women. Thus, the purpose of our study was to determine racial differences in QoL in menopausal women due to lifestyle, demographic, and health related risk factors. A stratified ordinal logistic regression model was applied to self-reported questionnaire data from the Midlife Women's Health Study (MWHS) to determine risk factors associated with QoL differences between White and Black women during the menopausal transition. In multivariable models, our results showed Black women who had 3 or 4 comorbidities were about 4 times as likely to have higher QoL compared to women who had 0 to 2 comorbidities (95% CI: 1.65,10.78). However, the number of comorbidities was not significantly associated with QoL in White women in univariate or multiple regression. Further, body mass index and income were not significant factors in QoL in Black women but were in White women. Overall, our results illustrate that differences in health, demographic, and lifestyle factors are associated with QoL during menopause. Also, we suggest that future studies evaluate stratified models between racial groups to determine race-specific risk factors related to quality of life.

Screening agrochemicals and pharmaceuticals for potential liver toxicity is required for regulatory approval and is an expensive and time-consuming process. The identification and utilization of early exposure gene signatures and robust predictive models in regulatory toxicity testing has the potential to reduce time and costs substantially. In this study, comparative supervised machine learning approaches were applied to the rat liver TG-GATEs dataset to develop feature selection and predictive testing. We identified ten gene biomarkers using three different feature selection methods that predicted liver necrosis with high specificity and selectivity in an independent validation dataset from the Microarray Quality Control (MAQC)-II study. Nine of the ten genes that were selected with the supervised methods are involved in metabolism and detoxification (Car3, Crat, Cyp39a1, Dcd, Lbp, Scly, Slc23a1, and Tkfc) and transcriptional regulation (Ablim3). Several of these genes are also implicated in liver carcinogenesis, including Crat, Car3 and Slc23a1. Our biomarker gene signature provides high statistical accuracy and a manageable number of genes to study as indicators to potentially accelerate toxicity testing based on their ability to induce liver necrosis and, eventually, liver cancer.

The majority of breast cancer specific deaths in women with estrogen receptor positive (ER + ) tumors occur due to metastases that are resistant to therapy. There is a critical need for novel therapeutic approaches to achieve tumor regression and/or maintain therapy responsiveness in metastatic ER + tumors. The objective of this study was to elucidate the role of metabolic pathways that undermine therapy efficacy in ER + breast cancers. Our previous studies identified Exportin 1 (XPO1), a nuclear export protein, as an important player in endocrine resistance progression and showed that combining selinexor (SEL), an FDA-approved XPO1 antagonist, synergized with endocrine agents and provided sustained tumor regression. In the current study, using a combination of transcriptomics, metabolomics and metabolic flux experiments, we identified certain mitochondrial pathways to be upregulated during endocrine resistance. When endocrine resistant cells were treated with single agents in media conditions that mimic a nutrient deprived tumor microenvironment, their glutamine dependence for continuation of mitochondrial respiration increased. The effect of glutamine was dependent on conversion of the glutamine to glutamate, and generation of NAD + . PGC1α, a key regulator of metabolism, was the main driver of the rewired metabolic phenotype. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and our findings reveal a critical role that ERα-XPO1 crosstalk plays in reducing cancer recurrences. Combining SEL with current therapies used in clinical management of ER + metastatic breast cancer shows promise for treating and keeping these cancers responsive to therapies in already metastasized patients.

Millennia of human conflict with wildlife have built a culture of intolerance toward wildlife among some stakeholders. We explored 2 key obstacles to improved human-wildlife coexistence: coexistence inequality (how the costs and benefits of coexisting with wildlife are unequally shared) and intolerance. The costs of coexisting with wildlife are often disproportionately borne by the so-called global south and rural communities, and the benefits often flow to the global north and urban dwellers. Attitudes and behaviors toward wildlife (tolerance versus intolerance) vary with social and cultural norms. We suggest more empathetic advocacy is needed that, for example, promotes conservation while appropriately considering those who bear the costs of conflict with wildlife. To achieve more equitable cost-sharing, we suggest limiting the costs incurred by those most affected or by sharing those costs more widely. For example, we advocate for the development of improved wildlife compensation schemes, increasing the scale of rewilding efforts, and preventing wildlife-derived revenue leaching out of the local communities bearing the costs of coexistence., (© 2020 Society for Conservation Biology.)

Humans regularly enter into co-sleeping arrangements with human and non-human partners. Studies of adults who co-sleep report that co-sleeping can impact sleep quality, particularly for women. Although dog owners often choose to bedshare with their dogs, we know relatively little about the nature of these relationships, nor the extent to which co-sleeping might interfere with sleep quality or quantity. In an effort to rectify this, we selected a sample of 12 adult female human ( M = 50.8 years) and dog dyads, and monitored their activity using actigraphy. We collected movement data in one-minute epochs for each sleep period for an average of 10 nights per participant. This resulted in 124 nights of data, covering 54,533 observations ( M = 7.3 hours per night). In addition, we collected subjective sleep diary data from human participants. We found a significant positive relationship between human and dog movement over sleep periods, with dogs influencing human movement more than humans influenced dog movement. Dog movement accompanied approximately 50% of human movement observations, and dog movement tripled the likelihood of the human transitioning from a non-moving state to a moving state. Nevertheless, humans rarely reported that their dog disrupted their sleep. We encourage the continued exploration of human-animal co-sleeping in all its facets and provide recommendations for future research in this area., Competing Interests: The authors declare no conflict of interest.

The transcription factor FOXM1 is upregulated and overexpressed in aggressive, therapy-resistant forms of hormone receptor-positive and triple negative breast cancers, and is associated with less good patient survival. FOXM1 signaling is also a key driver in many other cancers. Here, we identify a new class of compounds effective in suppressing FOXM1 activity in breast cancers, and displaying good potency for antitumor efficacy. The compounds bind directly to FOXM1 and alter its proteolytic sensitivity, reduce the cellular level of FOXM1 protein by a proteasome- dependent process, and suppress breast cancer cell proliferation and cell cycle progression and increase apoptosis. RNA-seq and gene set enrichment analyses indicate that the compounds decrease expression of FOXM1-regulated genes and suppress gene ontologies under FOXM1 regulation. Several compounds have favorable pharmacokinetic properties and show good tumor suppression in preclinical breast tumor models. These compounds may be suitable for further clinical evaluation in targeting aggressive breast cancers driven by FOXM1., Competing Interests: Competing interestsJ.A.K., B.S.K., and S.H.K. are coinventors on a Provisional Application filed by the University of Illinois to cover the compounds described in this paper. The other authors declare no competing interests., (© The Author(s) 2019.)

Attending the veterinary clinic is an integral part of the physical welfare of every companion dog. However, some dogs experience their veterinary visits negatively, which poses a risk of injury to the veterinary staff, their guardian (owner) and themselves. It may also influence the regularity of non-urgent veterinary appointments. To date there have been conflicting reports relating to the proportion of dogs that show fear during their veterinary visits. In this study, we explored the risk factors associated with fear during veterinary examination and in novel situations (including first time at the veterinary clinic) from 26,555 responses in the Canine Behavioral Assessment and Research Questionnaire database. According to their guardians, 41% of companion dogs displayed mild to moderate fearful behaviour when examined by a veterinarian, and 14% exhibited severe or extreme fear. A similar trend was observed with dogs responding fearfully when in unfamiliar situations, including the dog's first time at the veterinary clinic. Chi-squared tests showed every bivariate relationship between fear and the environmental and demographic factors measured was significant (p < 0.05). The most important predictors of fear in a veterinary examination were, in order: the dog's breed group (27.1%), their history of roles or activities (16.7%), where they were sourced (15.2%), their weight (12%), the age of other dogs in the household (9.5%) and dog owner experience (6.3%). However, combined these risk factors only explain a total of 7% of variance of fear observed during veterinary examination. This suggests that fear exhibited during veterinary visits is common in dogs, but that the environment or human-animal interactions are likely to contribute more to prevalence and severity of this problem than the demographic factors measured here. We conclude by highlighting opportunities for future research aimed at facilitating less stressful veterinary visits for dogs and their guardians., Competing Interests: The authors have declared that no competing interests exist.

Obesity is a risk factor for postmenopausal estrogen receptor alpha (ERα)-positive (ER + ) breast cancer. Molecular mechanisms underlying factors from plasma that contribute to this risk and how these mechanisms affect ERα signaling have yet to be elucidated. To identify such mechanisms, we performed whole metabolite and protein profiling in plasma samples from women at high risk for breast cancer, which led us to focus on factors that were differentially present in plasma of obese versus nonobese postmenopausal women. These studies, combined with in vitro assays, identified free fatty acids (FFA) as circulating plasma factors that correlated with increased proliferation and aggressiveness in ER + breast cancer cells. FFAs activated both the ERα and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which targets ERα and mTOR signaling, was able to block changes induced by FFA and was more effective in the presence of FFA. Collectively, these data suggest a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ER + breast cancer in postmenopausal women. Furthermore, they provide a basis for preclinical and clinical trials where the impact of agents that target ERα and mTOR signaling cross-talk would be tested to prevent ER + breast cancers in obese postmenopausal women. SIGNIFICANCE: These findings show that obesity-associated changes in certain blood metabolites rewire metabolic programs in cancer cells, influence mammary epithelial cell tumorigenicity and aggressiveness, and increase breast cancer risk., (©2019 American Association for Cancer Research.)

The effects on dehydration and cognitive performance from heat and/or physical activity are well established in the laboratory, although have not yet been studied for personnel working in occupations such as wildland firefighting regularly exposed to these types of conditions. This study aimed to investigate the effects of temperature and dehydration on seventy-three volunteer firefighters (35.7 ± 13.7 years, mean ± standard deviation) during a simulation of wildfire suppression under either control or hot (18-20; or 33-35 °C) temperature conditions. Results showed cognitive performance on the psychomotor vigilance task declined when participants were dehydrated in the heat and Stroop task performance was impaired when dehydrated late in the afternoon. Firefighters may be at risk of deteriorations in simple cognitive functions in the heat whilst dehydrated, although may also experience impairments in complex cognitive functions if dehydrated late in the day, irrespective of the environmental temperature., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

A majority of breast cancer specific deaths in women with ERα (+) tumors occur due to metastases that are resistant to endocrine therapy. There is a critical need for novel therapeutic approaches to resensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and the nuclear transport protein XPO1 in overcoming endocrine resistance. Selinexor (SEL), an XPO1 antagonist, has been evaluated in multiple late stage clinical trials in patients with relapsed and /or refractory hematological and solid tumor malignancies. Our transcriptomics analysis showed that 4-Hydroxytamoxifen (4-OHT), SEL alone or their combination induced differential Akt signaling- and metabolism-associated gene expression profiles. Western blot analysis in endocrine resistant cell lines and xenograft models validated differential Akt phosphorylation. Using the Seahorse metabolic profiler, we showed that ERα-XPO1 targeting changed the metabolic phenotype of TAM-resistant breast cancer cells from an energetic to a quiescent profile. This finding demonstrated that combined targeting of XPO1 and ERα rewired the metabolic pathways and shut down both glycolytic and mitochondrial pathways that would eventually lead to autophagy. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and given the need for better strategies to improve therapy response in relapsed ERα (+) tumors, our findings show great promise for uncovering the role that ERα-XPO1 crosstalk plays in reducing cancer recurrences., Competing Interests: Z.M.-E. is a coinventor on several patents entitled “Novel Compounds Which Activate Estrogen Receptors and Compositions and Methods of Using the Same”. Z.M.-E. was a PI on an investigator-initiated grant from Pfizer, Corteva Agrisciences and Karyopharm Therapeutics.

Background: Grape phylloxera (Daktulosphaira vitifoliae Fitch) is a major insect pest that negatively impacts commercial grapevine performance worldwide. Consequently, the use of phylloxera resistant rootstocks is an essential component of vineyard management. However, the majority of commercially available rootstocks used in viticulture production provide limited levels of grape phylloxera resistance, in part due to the adaptation of phylloxera biotypes to different Vitis species. Therefore, there is pressing need to develop new rootstocks better adapted to specific grape growing regions with complete resistance to grape phylloxera biotypes., Results: Grapevine rootstock breeding material, including an accession of Vitis cinerea and V. aestivalis, DRX55 ([M. rotundifolia x V. vinifera] x open pollinated) and MS27-31 (M. rotundifolia specific hybrid), provided complete resistance to grape phylloxera in potted plant assays. To map the genetic factor(s) of grape phylloxera resistance, a F 1 V. cinerea x V. vinifera Riesling population was screened for resistance. Heritability analysis indicates that the V. cinerea accession contained a single allele referred as RESISTANCE TO DAKTULOSPHAIRA VITIFOLIAE 2 (RDV2) that confers grape phylloxera resistance. Using genetic maps constructed with pseudo-testcross markers for V. cinerea and Riesling, a single phylloxera resistance locus was identified in V. cinerea. After validating SNPs at the RDV2 locus, interval and linkage mapping showed that grape phylloxera resistance mapped to linkage group 14 at position 16.7 cM., Conclusion: The mapping of RDV2 and the validation of markers linked to grape phylloxera resistance provides the basis to breed new rootstocks via marker-assisted selection that improve vineyard performance.

The purpose of the present study was to examine regional differences in average self-reported BMI, obesity prevalence, and frequent exercise (FE) among members of Team Red, White, and Blue (Team RWB) - a military veteran service organization founded to increase physical activity in veterans. A total of 10,015 military veterans participated in a needs assessment conducted by Team RWB between December 2014 and August 2016. Multivariate regression analysis with bootstrapped coefficients revealed that: BMI was highest in the Midwest region ( M  = 28.282) of the United States, F (20, 9882)  = 105.560, p  < 0.001; obesity prevalence was highest in the Southcentral (32.300%) and Southeast (32.200%) regions, x 2 (9731)  = 10,850, p  < 0.001; and FE was most prevalent in the Mid-Atlantic region (67.3%), x 2 (9882)  = 11,291, p  < 0.001.The results of this study closely mirror results found in studies of the general population. A better understanding of the geographic distribution of these outcomes could guide the targeting of sub-populations for public health programs. In particular, Team Red, White & Blue community growth and other fitness based public health programs could be expanded to reach more veterans.

Residential characteristics in urban neighborhoods impact health and might be important factors contributing to health disparities, especially in the African American population. The purpose of this systematic review is to understand the relationship between urban neighborhood and residential factors and breast cancer incidence and prognosis in African American women. Using PubMed and Web of Science, the existing literature was reviewed. Observational, cross-sectional, cohort, and prospective studies until February 2017 were examined. Studies including populations of African American women, setting in "urban" areas, and a measure of a neighborhood or residential factor were reviewed. Four parameters related to neighborhood or residential factors were extracted including: neighborhood socioeconomic status (nSES), residential segregation, spatial access to mammography, and residential pollution. Our analysis showed that African American women living in low nSES have greater odds of late stage diagnosis and mortality. Furthermore, African American women living in segregated areas (higher percentage of Blacks) have higher odds of late stage diagnosis and mortality compared to White and Hispanic women living in less segregated areas (lower percentage of Blacks). Late stage diagnosis was also shown to be significantly higher in areas with poor mammography access and areas with higher Black residential segregation. Lastly, residential pollution did not affect breast cancer risk in African American women. Overall, this systematic review provides a qualitative synthesis of major neighborhood and residential factors on breast cancer outcomes in African American women.

Plant parasitic nematodes, including root knot nematode Meloidogyne species, cause extensive damage to agriculture and horticultural crops. As Vitis vinifera cultivars are susceptible to root knot nematode parasitism, rootstocks resistant to these soil pests provide a sustainable approach to maintain grapevine production. Currently, most of the commercially available root knot nematode resistant rootstocks are highly vigorous and take up excess potassium, which reduces wine quality. As a result, there is a pressing need to breed new root knot nematode resistant rootstocks, which have no impact on wine quality. To develop molecular markers that predict root knot nematode resistance for marker assisted breeding, a genetic approach was employed to identify a root knot nematode resistance locus in grapevine. To this end, a Meloidogyne javanica resistant Vitis cinerea accession was crossed to a susceptible Vitis vinifera cultivar Riesling and results from screening the F1 individuals support a model that root knot nematode resistance, is conferred by a single dominant allele, referred as MELOIDOGYNE JAVANICA RESISTANCE1 (MJR1). Further, MJR1 resistance appears to be mediated by a hypersensitive response that occurs in the root apical meristem. Single nucleotide polymorphisms (SNPs) were identified using genotyping-by-sequencing and results from association and genetic mapping identified the MJR1 locus, which is located on chromosome 18 in the Vitis cinerea accession. Validation of the SNPs linked to the MJR1 locus using a Sequenom MassARRAY platform found that only 50% could be validated. The validated SNPs that flank and co-segregate with the MJR1 locus can be used for marker-assisted selection for Meloidogyne javanica resistance in grapevine.

The bazedoxifene and conjugated estrogens (CE+BZA) combination has been shown to prevent visceral adiposity and weight gain after ovariectomy. However, its impact on the liver transcriptomes associated with prevention of hepatosteatosis is yet to be determined. In the present study, we use liver transcriptomics and plasma metabolomics analysis to characterize the effects of various estrogens on liver. The CE+BZA combination was very effective at preventing ovariectomy-induced weight gain in mice fed a high-fat diet (HFD). In CE+BZA treated animals, liver weight and hepatic lipid deposition were significantly lower than in Vehicle (Veh) treated animals. Additionally, CE+BZA induced unique liver transcriptome and plasma metabolome profiles compared to estradiol, conjugated estrogens alone, and bazedoxifene alone. Blood plasma metabolite analysis identified several metabolites similar to and distinct from other estrogen treatments. Integrated pathway analysis showed that gene networks that were associated with inflammation, reactive oxygen species pathway and lipid metabolism and their relevant metabolites were regulated significantly by CE+BZA treatment. Thus, long-term CE+BZA treatment modulated hepatic metabolic gene networks and their associated metabolites and improves hepatic health without stimulating the uterus.

Background: Admission hypocalcemia predicts both massive transfusion and mortality in severely injured patients. However, the effect of calcium derangements during resuscitation remains unexplored. We hypothesize that any hypocalcemia or hypercalcemia (either primary or from overcorrection) in the first 24 hours after severe injury is associated with increased mortality., Methods: All patients at our institution with massive transfusion protocol activation from January 2013 through December 2014 were identified. Patients transferred from another hospital, those not transfused, those with no ionized calcium (Ca) measured, and those who expired in the trauma bay were excluded. Hypocalcemia and hypercalcemia were defined as any level outside the normal range of Ca at our institution (1-1.25 mmol/L). Receiver operator curve analysis was also used to further examine significant thresholds for both hypocalcemia and hypercalcemia. Hospital mortality was compared between groups. Secondary outcomes included advanced cardiovascular life support, damage control surgery, ventilator days, and intensive care unit days., Results: The massive transfusion protocol was activated for 77 patients of whom 36 were excluded leaving 41 for analysis. Hypocalcemia occurred in 35 (85%) patients and hypercalcemia occurred in 9 (22%). Mortality was no different in hypocalcemia versus no hypocalcemia (29% vs 0%; P = .13) but was greater in hypercalcemia versus no hypercalcemia (78% vs 9%; P < .01). Receiver operator curve analysis identified inflection points in mortality outside a Ca range of 0.84 to 1.30 mmol/L. Using these extreme values, 15 (37%) had hypocalcemia with a 60% mortality (vs 4%; P < .01) and 9 (22%) had hypercalcemia with a 78% mortality (vs 9%; P < .01). Patients with extreme hypocalcemia and hypercalcemia also received more red blood cells, plasma, platelets, and calcium repletion., Conclusions: Hypocalcemia and hypercalcemia occur commonly during the initial resuscitation of severely injured patients. Mild hypocalcemia may be tolerable, but more extreme hypocalcemia and any hypercalcemia should be avoided. Further assessment to define best practice for calcium management during resuscitation is warranted.

Objective: Unicompartmental knee arthroplasty (UKA) revision is usually due to the degenerative degree of knee articular osteochondral tissue in the untreated compartment. However, it is difficult to simulate the biomechanical behavior on this tissue accurately. This study presents and validates a reliable system to predict which osteoarthritis (OA) patients may suffer revision as a result of biomechanical reasons after having UKA., Design: We collected all revision cases available (n = 11) and randomly selected 67 UKA cases to keep the revision prevalence of almost 14%. All these 78 cases have been followed at least 2 years. An elastic model is designed to characterize the biomechanical behavior of the articular osteochondral tissue for each patient. After calculated the force on the tissue, finite element method (FEM) is applied to calculating the strain of each tissue node. Kernel Ridge Regression (KRR) method is used to model the relationship between the strain information and the risk of revision. Therefore, the risk of UKA revision can be predicted by this integrated model., Results: Leave-one-out (LOO) cross-validation (CV) is implemented to assess the prediction accuracy. As a result, the mean prediction accuracy is 93.58% for all these cases, demonstrating the high value of this model as a decision-making assistant for surgical plaining of knee OA., Conclusions: The results of this study demonstrated that this integrated model can predict the risk of UKA revision with theoretically high accuracy. It combines bio-mechanical and statistical learning approach to create a surgical planning tool which may support clinical decision in the future., (Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Adequate sleep is fundamental to workplace performance. For volunteer firefighters who work in safety critical roles, poor performance at work can be life threatening. Extended shifts and sleeping conditions negatively impact sleep during multi-day fire suppression campaigns. Having sleep disordered breathing (SDB) could contribute further to sleep deficits. Our aim was to investigate whether those with suspected SDB slept and performed more poorly during a fire ground simulation involving sleep restriction. Participants, n = 20 participated in a 3-day-4-night fire ground simulation. Based on oximetry desaturation index data collected during their participation, participants were retrospectively allocated to either a SDB (n = 8) or a non-SDB group (n = 12). The simulation began with an 8 h Baseline sleep (BL) followed by two nights of restricted (4 h) sleep and an 8 h recovery sleep (R). All sleeps were recorded using a standard electroencephalography (EEG) montage as well as oxygen saturation. During the day, participants completed neurobehavioral (response time, lapses and subjective fatigue) tasks. Mixed effects ANOVA were used to compare differences in sleep and wake variables. Analyses revealed a main effect of group for Total sleep (TST), REM , wake after sleep onset (WASO) and Arousals/h with the SDB group obtaining less TST and REM and greater WASO and Arousals/h. The group × night interaction was significant for N3 with the SDB group obtaining 42 min less during BL. There was a significant main effect of day for RRT, lapses and subjective fatigue and a significant day × group interaction for RRT. Overall, the SDB group slept less, experienced more disturbed sleep and had poorer response time performance, which was exacerbated by the second night of sleep restriction. This could present a safety concern, particularly during longer campaigns and is worthy of further investigation. In addition, we would recommend promotion of awareness of SDB, its symptoms and potential impact among volunteers and relevant agencies.

Under controlled laboratory conditions, neurobehavioral assays such as the Psychomotor Vigilance Task (PVT) are sensitive to increasing levels of fatigue, and in general, tend to correlate with subjective ratings. However, laboratory studies specifically curtail physical activity, potentially limiting the applicability of such findings to field settings that involve physical work. In addition, laboratory studies typically involve healthy young male participants that are not always representative of a typical working population. In order to determine whether these findings extend to field-like conditions, we put 88 Australian volunteer firefighters through a multi-day firefighting simulation. Participants were required to perform real-world physical and cognitive tasks under conditions of elevated temperature and moderate sleep restriction. We aimed to examine changes in fatigue in an effort to determine the optimum objective and subjective measures. Objective and subjective tests were sensitive to fatigue outside laboratory conditions. The PVT was the most sensitive assay of objective fatigue, with the Samn-Perelli fatigue scale the most sensitive of the subjective measures. The Samn-Perilli fatigue scale correlated best with PVT performance, but explained a small amount of variance. Although the Samn-Perelli scale can be easily administered in the field, the wide range of individual variance limits its efficacy as a once-off assessment tool. Rather, fatigue measures should be applied as a component of a broader fatigue risk management system. Findings provide firefighting agencies, and other occupations involving physical work, guidance as to the most sensitive and specific measures for assessing fatigue in their personnel.

Therapeutic agents that block the calcitonin gene-related peptide (CGRP) signaling pathway are a highly anticipated and promising new drug class for migraine therapy, especially after reports that small-molecule CGRP-receptor antagonists are efficacious for both acute migraine treatment and migraine prevention. Using XenoMouse technology, we successfully generated AMG 334, a fully human monoclonal antibody against the CGRP receptor. Here we show that AMG 334 competes with [(125)I]-CGRP binding to the human CGRP receptor, with a Ki of 0.02 nM. AMG 334 fully inhibited CGRP-stimulated cAMP production with an IC50 of 2.3 nM in cell-based functional assays (human CGRP receptor) and was 5000-fold more selective for the CGRP receptor than other human calcitonin family receptors, including adrenomedullin, calcitonin, and amylin receptors. The potency of AMG 334 at the cynomolgus monkey (cyno) CGRP receptor was similar to that at the human receptor, with an IC50 of 5.7 nM, but its potency at dog, rabbit, and rat receptors was significantly reduced (>5000-fold). Therefore, in vivo target coverage of AMG 334 was assessed in cynos using the capsaicin-induced increase in dermal blood flow model. AMG 334 dose-dependently prevented capsaicin-induced increases in dermal blood flow on days 2 and 4 postdosing. These results indicate AMG 334 is a potent, selective, full antagonist of the CGRP receptor and show in vivo dose-dependent target coverage in cynos. AMG 334 is currently in clinical development for the prevention of migraine., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

Objective: Limited evidence exists to guide clinical management of acute finger ischemia (AFI). To further inform diagnostic evaluation and decision making, we evaluated anatomic findings, procedural management, and amputation-free survival in an institutional cohort of patients with AFI., Methods: Consecutive patients undergoing transfemoral upper extremity angiography for AFI were identified. Clinical, laboratory, and procedural data were collected retrospectively from medical records, and arteriograms were reviewed to characterize anatomic findings. Telephone interviews were used to determine long-term outcomes, and additional symptomatic assessments (Symptom Severity and Functional Status scale, the Cold Sensitivity Severity scale, and the McGill Pain Severity Scale) were available in a subgroup of patients. Outcomes included anatomic findings, use of thrombolysis, complications, and amputation-free survival. Descriptive statistics and survival analysis were used to evaluate results., Results: Thirty-five patients (54% women) were analyzed with a median follow-up of 13.7 months. Symptom duration at time of presentation ranged from 1 to 28 days, and seven patients had tissue loss or gangrene, or both. Mean age was 47.7 ± 12.2 years. Baseline characteristics included smoking in 22 (65%), connective tissue disorder in 11 (31%), and history of repetitive hand trauma in 10 (29%). The most frequent anatomic location of arterial pathology identified during angiography was distal to the wrist (n = 32), including eight ulnar/radial aneurysms; upper arm (n = 3) and forearm (n = 8) lesions were less common. Sixteen patients were treated with catheter-directed thrombolysis, of which eight (50%) had interval anatomic improvement on repeat angiography. Procedure-related adverse events associated with angiography included bleeding (n = 3) and pseudoaneurysm (n = 1). Eleven of 35 patients had subsequent surgical revascularization at a median of 15 days after angiography. Estimated (standard error) amputation-free survival was 0.88 (0.07) at 1 month and 0.84 (0.08) at 6 months among patients without tissue loss or gangrene. Estimated 60-day amputation-free survival was 0.84 (standard error, 0.08). Overall amputation-free survival was similar between patients managed with vs without thrombolysis (P = .61), but subgroup analysis of those patients without tissue loss or gangrene at the time of presentation revealed a trend toward improved amputation-free survival with use of thrombolysis, with 60-day amputation-free survival of 0.92 vs 0.75 (P = .12). Persistent late symptoms were present in 17 patients (48.6%) at the last follow-up and were generally characterized as mild by functional and pain scale assessments., Conclusions: Angiography performed for AFI frequently identifies distal occlusive disease, and catheter-directed thrombolysis may expand revascularization options in select patients., (Copyright © 2014 Society for Vascular Surgery. All rights reserved.)

The objective of this study was to develop prediction models for the serum IgG concentration in critically ill calves based on indirect assays and to assess if the predictive ability of the models could be improved by inclusion of age, clinical covariates, and/or laboratory covariates. Seventy-eight critically ill calves between 1 and 13 days old were selected from 1 farm. Statistical models to predict IgG concentration from the results of the radial immunodiffusion test, the gold standard, were built as a function of indirect assays of serum and plasma protein concentrations, zinc sulfate (ZnSO4) turbidity and transmittance, and serum γ-glutamyl transferase (GGT) activity. For each assay 4 models were built: without covariates, with age, with age and clinical covariates (infection and dehydration status), and with age and laboratory covariates (fibrinogen concentration and packed cell volume). For the protein models, dehydration status (clinical model) and fibrinogen concentration (laboratory model) were selected for inclusion owing to their statistical significance. These variables increased the coefficient of determination (R (2) ) of the models by ≥ 7% but did not significantly improve the sensitivity or specificity of the models to predict passive transfer with a cutoff IgG concentration of 1000 mg/dL. For the GGT assay, including age as a covariate increased the R (2) of the model by 3%. For the ZnSO4 turbidity test, none of the covariates were statistically significant. Overall, the R (2) of the models ranged from 34% to 62%. This study has provided insight into the importance of adjusting for covariates when using indirect assays to predict IgG concentration in critically ill calves. Results also indicate that ZnSO4 transmittance and turbidity assays could be used advantageously in a field setting.

Unicompartmental knee arthroplasty (UKA) allows replacement of a single compartment in patients with limited disease. However, UKA is technically challenging and relies on accurate component positioning and restoration of natural knee kinematics. This study examined the accuracy of dynamic, real-time ligament balancing using a robotic-assisted UKA system. Surgical data obtained from the computer system were prospectively collected from 51 patients (52 knees) undergoing robotic-assisted medial UKA by a single surgeon. Dynamic ligament balancing of the knee was obtained under valgus stress prior to component implantation and then compared to final ligament balance with the components in place. Ligament balancing was accurate up to 0.53 mm compared to the preoperative plan, with 83% of cases within 1 mm at 0°, 30°, 60°, 90°, and 110° of flexion. Ligamentous laxity of 1.31 ± 0.13 mm at 30° of flexion was corrected successfully to 0.78 ± 0.17 mm (P < 0.05). Robotic-assisted UKA allows accurate and precise reproduction of a surgical balance plan using dynamic, real-time soft-tissue balancing to help restore natural knee kinematics, potentially improving implant survival and functional outcomes.