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Jonathan C Roberts,1 Annette von Drygalski,2 Jenny Y Zhou,2 George M Rodgers,3 Kristin Ansteatt,1 Michael D Tarantino1 1Bleeding & Clotting Disorders Institute, University of Illinois College of Medicine – Peoria, Peoria, IL, USA; 2Hemophilia and Thrombosis Treatment Center, University of California at San Diego, San Diego, CA, USA; 3Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USACorrespondence: Michael D Tarantino, The Bleeding and Clotting Disorders Institute, University of Illinois College of Medicine – Peoria, 427 West Northmoor Road, Peoria, IL, 61614, USA, Tel +1 309-692-5337, Email mtarantino@ilbcdi.orgAbstract: Hereditary antithrombin deficiency (ATD) is a rare autosomal dominant condition (estimated prevalence 1:500– 1:5000). Most ATD patients have AT activity levels 40– 60% of normal. We present treatments for venous thromboembolism (VTE) in five cases of hereditary ATD. Four patients had a family history of ATD, and one had a de novo mutation. The majority of patients had a VTE while on prophylactic anticoagulation. AT concentrate augmentation was added in these cases to treat the VTE and for prophylaxis against further episodes. Two patients had significant bleeding events, one had permanent physical sequelae. Two of the patients were pregnant. VTE is a common cause of morbidity and mortality during pregnancy. Although low molecular weight heparins are the drugs of choice during pregnancy, this treatment was inadequate in one patient (developed VTE on therapy). These cases emphasize the need to screen for ATD in young patients (< 55 years) presenting with VTE. AT augmentation therapy may be necessary in patients inadequately treated with conventional anticoagulants. Careful monitoring and individualized care are needed in ATD patients, especially those with demonstrated bleeding tendencies.Keywords: clotting disorders, venous thromboembolism, anticoagulation, bleeding tendencies

Accurately predicting the responses of organisms to novel or changing environments requires the development of ecologically-appropriate experimental methodology and process-based models. For ectotherms, thermal performance curves (TPCs) have provided a useful framework to describe how organismal performance is dependent on temperature. However, this approach often lacks a mechanistic underpinning, which limits our ability to use TPCs predictively. Furthermore, thermal dependence varies across traits, and performance is also limited by additional abiotic factors, such as oxygen availability. We test a central prediction of our recent Hierarchical Mechanisms of Thermal Limitation (HMTL) Hypothesis which proposes that natural hypoxia exposure will reduce maximal performance and cause the TPC for whole-organism performance to become more symmetrical. We quantified TPCs for two traits often used as fitness proxies, sprint speed and aerobic scope, in lizards under conditions of normoxia and high-elevation hypoxia. In line with the predictions of HMTL, anaerobically fuelled sprint speed was unaffected by acute hypoxia while the TPC for aerobic scope became shorter and more symmetrical. This change in TPC shape resulted from both the maximum aerobic scope and the optimal temperature for aerobic scope being reduced in hypoxia as predicted. Following these results, we present a mathematical framework, which we call Temperature–Oxygen Performance Surfaces, to quantify the interactive effects of temperature and oxygen on whole-organism performance in line with the HMTL hypothesis. This framework is transferrable across traits and levels of organization to allow predictions for how ectotherms will respond to novel combinations of temperature and other abiotic factors, providing a useful tool in a time of rapidly changing environmental conditions.

Orthopaedic surgery has the lowest proportion of women surgeons in practice of any specialty in the United States. Preliminary studies suggest that patients who are treated by physicians of the same race, ethnicity, cultural background, or gender feel more comfortable with their care and may have better outcomes. Therefore, understanding the discrepancies in the diversity of the orthopaedic surgeon workforce is crucial to addressing system-wide healthcare inequities.(1) Does a difference exist in gender representation among practicing orthopaedic surgeons across geographic distributions and years in practice? (2) Does a difference exist in gender representation among practicing orthopaedic surgeons with regard to rural-urban setting, group practice size, and years in practice?Orthopaedic surgeons serving Medicare patients in 2017 were identified in the Medicare Physician and Other Supplier Public Use File and Physician Compare national databases. This dataset encompasses more than 64% of practicing orthopaedic surgeons, providing a low proportion of missing data compared with other survey techniques. Group practice size, location, and Rural-urban Commuting Area scores were compared across physician gender and years in practice. Linear and logistic regressions modeled gender and outcomes relationships adjusted by years in practice. Least-square means estimates for outcomes were calculated by gender at the median years in practice (19 years) via regression models.According to the combined Medicare databases used, 5% (1019 of 19,221) of orthopaedic surgeons serving Medicare patients were women; this proportion increased with decreasing years in practice (R2 0.97; p0.001). Compared by region, the West region demonstrated the highest proportion of women orthopaedic surgeons overall (7% [259 of 3811]). The Midwest and South regions were below the national mean for proportions of women orthopaedic surgeons, both overall (5% [305 of 6666] and 5% [209 of 4146], respectively) and in the first 5 years of practice (9% [54 of 574] and 9% [74 of 817], respectively). Women worked in larger group practices than men (median [interquartile range] 118 physicians [20 to 636] versus median 56 [12 to 338]; p0.001, respectively). Both genders were more likely to practice in an urban setting, and when controlling for years in practice, there was no difference between men and women orthopaedic surgeons practicing in rural or urban settings (respectively, R2 = 0.0004 and 0.07; p = 0.89 and 0.09).Among orthopaedic surgeons, there is only one woman for every 20 men caring for Medicare patients in the United States. Although gender representation is increasing longitudinally for women, it trails behind other surgical subspecialties substantially. Longitudinal mentoring programs, among other evidenced initiatives, should focus on the more pronounced underrepresentation identified in Midwestern/Southern regions and smaller group practices. Gender-based equity, inclusion, and diversity efforts should focus on recruitment strategies, and further research is needed to study how inclusion and diversity efforts among orthopaedic surgeons improves patient-centered care.Level III, therapeutic study.

Cities are drivers of the global economy, containing products and industries that emit many chemicals. Here, we use the Multimedia Urban Model (MUM) to estimate atmospheric emissions and fate of organophosphate esters (OPEs) from 19 global mega or major cities, finding that they collectively emitted ~81,000 kg yr−1 of ∑10OPEs in 2018. Typically, polar “mobile” compounds tend to partition to and be advected by water, while non-polar “bioaccumulative” chemicals do not. Depending on the built environment and climate of the city considered, the same compound behaves like either a mobile or a bioaccumulative chemical. Cities with large impervious surface areas, such as Kolkata, mobilize even bioaccumulative contaminants to aquatic ecosystems. By contrast, cities with large areas of vegetation fix and transform contaminants, reducing loadings to aquatic ecosystems. Our results therefore suggest that urban design choices could support policies aimed at reducing chemical releases to the broader environment without increasing exposure for urban residents.

Background Hazard identification, risk assessment, regulatory, and policy activity are usually conducted on a chemical-by-chemical basis. Grouping chemicals into categories or classes is an underutilized approach that could make risk assessment and management of chemicals more efficient for regulators. Objective and methods While there are some available methods and regulatory frameworks that include the grouping of chemicals (e.g.,same molecular mechanism or similar chemical structure) there has not been a comprehensive evaluation of these different approaches nor a recommended course of action to better consider chemical classes in decision-making. This manuscript: 1) reviews current national and international approaches to grouping; 2) describes how groups could be defined based on the decision context (e.g., hazard/risk assessment, restrictions, prioritization, product development) and scientific considerations (e.g., intrinsic physical-chemical properties); 3) discusses advantages of developing a decision tree approach for grouping; 4) uses ortho-phthalates as a case study to identify and organize frameworks that could be used across agencies; and 5) discusses opportunities to advance the class concept within various regulatory decision-making scenarios. Results Structural similarity was the most common grouping approach for risk assessment among regulatory agencies (national and state level) and non-regulatory organizations, albeit with some variations in its definition. Toxicity to the same target organ or to the same biological function was also used in a few cases. The phthalates case study showed that a decision tree approach for grouping should include questions about uses regulated by other agencies to encourage more efficient, coherent, and protective chemical risk management. Discussion and conclusion Our evaluation of how classes of chemicals are defined and used identified commonalities and differences based on regulatory frameworks, risk assessments, and business strategies. We also identified that using a class-based approach could result in a more efficient process to reduce exposures to multiple hazardous chemicals and, ultimately, reduce health risks. We concluded that, in the absence of a prescribed method, a decision tree approach could facilitate the selection of chemicals belonging to a pre-defined class (e.g., chemicals with endocrine-disrupting activity; organohalogen flame retardants [OFR]) based on the decision-making context (e.g., regulatory risk management).

I. INTRODUCTION There is substantial evidence that married white men earn between 8% and 15% more than unmarried white men in the United States, even after controlling for education and informal job market experience (e.g., potential or actual experience). Cross-section analysis indicates that both the level and the growth rate of wages increase during marriage. These results suggest that men may become more productive after marriage, an effect often attributed to the increased specialization possible following the formation of a multiperson household. However, panel estimates indicate that much of the differential is explained by individual-specific fixed effects, which suggest that more productive men are more likely to marry. While these results and implications are well known, the precise nature of the implied productivity differentials has received little attention in the literature. Using the 1979 cohort of the National Longitudinal Survey of Youth (NLSY79), we investigate the structure or source of the observed differential. We do so by first extending the analysis to a sample of African American men in the United States. To our knowledge, ours is the first study to conduct a detailed analysis of the marital wage gap among African American men that is fully comparable to that already available for white men. This extension is informative because African American households are known to exhibit less specialization along gender lines and because marital patterns are quite different by race. Next, we explore formal job training as one avenue to productivity enhancement. We outline a simple story suggesting that married men may be more receptive to training opportunities than unmarried men and present some evidence suggesting that firms may be more willing to offer training to married as compared to unmarried men. Previous analysis has focused on labor market experience or years married as proxies for both informal and formal job training. We significantly improve upon this by using direct information on formal job training to see if wage changes at or following the time of marriage are driven by training-induced productivity differentials. Third, we explore the nature of the selection effect or the possibility that it is more productive men who marry. The NLSY79 has an extensive array of information on personal characteristics that might be associated with both marriage and earnings. If certain personal characteristics are associated with both marriage and earnings, but not typically included in wage analyses, then the marital controls in standard wage equations may simply be proxying for these characteristics. Controlling for such characteristics directly should identify the nature of the selection effect and reduce the significance of the marital indicators in cross-section estimates. The attributes we examine include cognitive skills, parental background, and personality traits. Our final contribution is to estimate panel models to eliminate all observable and unobservable individual-specific, time-invariant factors and to reconcile these results with those obtained from cross-section models. Specifically, we exploit the different identification conditions between panel and cross-section models, examining the role of respondents who are always married, never married, or always separated/divorced. Technically, such individuals contribute to the identification of the cross section but not the panel estimates of the marital wage differential. Thus, these individuals may explain the substantial differences often observed between panel and cross-section estimates of the white male marital wage differential. II. LITERATURE REVIEW Evidence of the marital wage differential for white men in the United States is extensive (see Ribar 2004, for a review). Some of this differential has been attributed to a selection effect, to the fact that men who marry earn more throughout their lives than men who do not marry. …

Bioretention cells can effectively infiltrate stormwater runoff and partly remove conventional water contaminants. A field tracer injection experiment in a conventionally designed bioretention cell was used to investigate the fate of benzotriazole, a model trace organic contaminant, during and between runoff events. Moderate (29%) benzotriazole load reductions were measured during the 6 h long injection experiment. The detection of 1-methyl benzotriazole, hydroxy benzotriazole, and methoxy benzotriazole provided in situ evidence of some rapid benzotriazole microbial transformation during the tracer test and more importantly between the events. The detection of benzotriazole alanine and benzotriazole acetyl alanine also showed fast benzotriazole phytotransformation to amino acid conjugates during the tracer test and suggests further transformation of phytotransformation products between events. These data provide conclusive full-scale evidence of benzotriazole microbial and phytotransformation in bioretention cells. Non-target chemical analysis revealed the presence of a diverse range of trace organic contaminants in urban runoff and exiting the bioretention cell, including pesticides and industrial, household, and pharmaceutical compounds. We have demonstrated the in situ potential of urban green infrastructure such as bioretention cells to eliminate polar trace organic contaminants from stormwater. However, targeted design and operation strategies, for example, hydraulic control and the use of soil amendments, should be incorporated for improved bioretention cell performance for such compounds.

Background The efficacy and safety of wilate (human von Willebrand factor/coagulation factor VIII) in patients with von Willebrand disease (VWD) has been demonstrated in clinical trials. Here, we present real-world data on the use of wilate for the routine care of patients with VWD. Objectives The objectives of this observational, prospective, phase 4 study were to evaluate the safety, tolerability, and effectiveness of wilate in on-demand treatment of bleeding episodes (BEs), long-term prophylaxis, and surgical prophylaxis among patients with any type of VWD. Methods Patients were enrolled at 31 study centers in 11 countries and followed for up to 2 years. Safety endpoints included adverse drug reactions (ADRs) and drug tolerability. Effectiveness was assessed using annualized bleeding rates (ABRs) during prophylaxis and predefined criteria for the treatment of BEs and surgical prophylaxis. Results A total of 111 patients (76 [68%] female) including 41 (37%) children were treated with wilate. Twenty-five patients received prophylaxis, 29 on-demand treatment, and 62 surgical prophylaxis. Tolerability was rated by patients as “excellent” for 96.2% of 6,497 infusions. No unexpected ADRs or thrombotic events were reported. Median ABR during prophylaxis was 1.9. Effectiveness was assessed as “excellent” or “good” by patients and investigators for 100% of BEs treated on-demand, 98% (patient rating) and 99% (investigator rating) of breakthrough BEs, and 99% of surgical procedures (investigator rating). Conclusion wilate was safe, well tolerated, and effective for the prevention and treatment of bleeding in pediatric and adult VWD patients in a real-world setting.

Iron plays an important role in mammalian physiological processes. It is a critical component for the function of many proteins, including enzymes that require heme and iron-sulfur clusters. However, excess iron is also detrimental because of its ability to catalyze the formation of reactive oxygen species. As a result, cellular and systemic iron levels are tightly regulated to prevent oxidative damage. Iron deficiency can lead to a number of pathological conditions, the most prominent being anemia. Iron deficiency should be corrected to improve adult patients’ symptoms and to facilitate normal growth during fetal development and childhood. However, inappropriate use of intravenous iron in chronic conditions, such as cancer and heart failure, in the absence of clear iron deficiency can lead to unwanted side effects. Thus, this form of therapy should be reserved for certain patients who cannot tolerate oral iron and need rapid iron replenishment. Here, we will review cellular and systemic iron homeostasis and will discuss complications of iron deficiency.

Alzheimer's disease (AD) is the leading cause of mortality, disability, and long-term care burden in the United States, with women comprising the majority of AD diagnoses. While AD-related dementia is associated with tau and amyloid beta accumulation, concurrent derangements in cerebral blood flow have been observed alongside these proteinopathies in humans and rodent models. The homeostatic production of nitric oxide synthases (NOS) becomes uncoupled in AD which leads to decreased NO-mediated vasodilation and oxidative stress via the production of peroxynitrite (ONOO-∙) superoxide species. Here, we investigate the role of the novel protein arginine methyltransferase 4 (PRMT4) enzyme function and its downstream product asymmetric dimethyl arginine (ADMA) as it relates to NOS dysregulation and cerebral blood flow in AD. ADMA (type-1 PRMT product) has been shown to bind NOS as a noncanonic ligand causing enzymatic dysfunction. Our results from RT-qPCR and protein analyses suggest that aged (9-12 months) female mice bearing tau- and amyloid beta-producing transgenic mutations (3xTg-AD) express higher levels of PRMT4 in the hippocampus when compared to age- and sex-matched C57BL6/J mice. In addition, we performed studies to quantify the expression and activity of different NOS isoforms. Furthermore, laser speckle contrast imaging analysis was indicative that 3xTg-AD mice have dysfunctional NOS activity, resulting in reduced production of NO metabolites, enhanced production of free-radical ONOO-, and decreased cerebral blood flow. Notably, the aforementioned phenomena can be reversed via pharmacologic PRMT4 inhibition. Together, these findings implicate the potential importance of PRMT4 signaling in the pathogenesis of Alzheimer's-related cerebrovascular derangement.

Background Acquired von Willebrand syndrome (AVWS) has been associated with monoclonal gammopathy of undetermined significance (MGUS), with limited data on its management. Methods We conducted a systematic literature search in Medline (Ovid), Embase, and Scopus up to September 11, 2019, for studies reporting on the management of AVWS associated with MGUS (AVWS‐MGUS). Data on patient characteristics, laboratory parameters at presentation, and clinical and laboratory outcomes were extracted. Objectives To describe the clinical presentation and outcomes of different therapeutic approaches. Results Seventy‐five studies were included in the final review, for a total of 137 patients. Most patients had von Willebrand factor ristocetin cofactor activity

Background:Recent physical activity research is limited by intention–behavior discordance and is beginning to recognize the importance of automatic processes in exercise. The purpose of the current study was to examine the role of multidimensional exercise self-efficacy (SE), explicit–implicit evaluative discrepancies (EIEDs) for health, and appearance on the intention–behavior gap in exercise.Methods:A total of 141 middle-aged inactive participants (mean age = 46.12 [8.17] y) completed measures of intentions, SE, and explicit and implicit evaluations of exercise outcomes. The participants were classified as inclined actors (n = 107) if they successfully started the exercise program and inclined abstainers (n = 35) if they were not successful.Results:The inclined actors and abstainers did not differ on intentions to exercise; however, the inclined actors had higher coping SE and lower EIEDs for health. In addition, the coping SE (Exp [β] = 1.03) and EIEDs for health (Exp [β] = −0.405) were significant predictors of being an inclined actor.Conclusions:The interaction between explicit and implicit processes in regard to health motives for exercise appears to influence the successful enactment of exercise from positive intentions. As most physical activity promotion strategies focus on health as a reason to be active, the role of implicit and explicit evaluations on behavioral decisions to exercise may inform future interventions.

The objectives of this study were firstly to determine the prevalence of overweight/obesity in adult persons with hemophilia in Utah, and to explore the association between age, disease severity and race with body mass index (BMI), and secondly to provide recent data on the prevalence of overweight/obesity in the hemophilia population via a review of the literature. We conducted a retrospective cross section study of adult persons with hemophilia who were seen at a Utah hemophilia treatment center from 1 January 2017 to 31 December 2019. The electronic database PubMed was searched for studies with observation periods from 1 January 2012 to 31 December 2019. The age-adjusted prevalence for overweight/obesity in the adult Utah hemophilia population was higher than the overall Utah population and the general US population. After adjusting for race and age, mild hemophilia was associated with a 7.7% higher BMI (95% confidence interval, 0.023-15.98%, P < 0.05). Review of the literature demonstrated high levels of overweight/obesity in hemophilia communities globally with considerable heterogeneity between studies. Despite increasing awareness, prevalence of overweight/obesity in the hemophilia population remains high in comparison with the general population. There is a critical need to address this issue acutely at hemophilia treatment centers due to the considerable burden of obesity.

Despite increasing use of targeted therapies to treat cancer, anemia remains a common complication of cancer therapy. Physician concerns about the safety of intravenous (IV) iron products and erythropoiesis-stimulating agents (ESAs) have resulted in many patients with cancer receiving no or suboptimal anemia therapy. In this article, we present 4 patient cases that illustrate both common and complex clinical scenarios. We first present a review of erythropoiesis and then describe our approach to cancer-associated anemia by identifying the contributing causes before selecting specific treatments. We summarize clinical trial data affirming the safety and efficacy of currently available IV iron products used to treat cancer-associated anemia and illustrate how we use commonly available laboratory tests to assess iron status during routine patient management. We compare adverse event rates associated with IV iron vs red cell transfusion and discuss using first-line IV iron monotherapy to treat anemic patients with cancer, which decreases the need for ESAs. A possible mechanism behind ESA-induced tumor progression is discussed. Finally, we review the potential of novel therapies such as ascorbic acid, prolyl hydroxylase inhibitors, activin traps, hepcidin, and bone morphogenetic protein antagonists in treating cancer-associated anemia.

Objective To present a topical review of minority stressors contributing to psychosocial and physical health disparities in transgender and gender expansive (TGE) adolescents. Methods We conducted a topical review of original research studies focused on distal stressors (e.g., discrimination; victimization; rejection; nonaffirmation), proximal stressors (e.g., expected rejection; identity concealment; internalized transphobia), and resilience factors (e.g., community connectedness; pride; parental support) and mental and physical health outcomes. Results Extant literature suggests that TGE adolescents experience a host of gender minority stressors and are at heightened risk for negative health outcomes; however, limited research has directly applied the gender minority stress framework to the experiences of TGE adolescents. Most research to date has focused on distal minority stressors and single path models to negative health outcomes, which do not account for the complex interplay between chronic minority stress, individual resilience factors, and health outcomes. Research examining proximal stressors and resilience factors is particularly scarce. Conclusions The gender minority stress model is a helpful framework for understanding how minority stressors contribute to health disparities and poor health outcomes among TGE adolescents. Future research should include multiple path models that examine relations between gender minority stressors, resilience factors, and health outcomes in large, nationally representative samples of TGE adolescents. Clinically, adaptations of evidence-based interventions to account for gender minority stressors may increase effectiveness of interventions for TGE adolescents and reduce health disparities in this population of vulnerable youth.

We provide a framework for extending equilibrium local molecular field (LMF) theory to a statistical ensemble evolving under a time-dependent applied field. In this context, the self-consistency of the original LMF equation is achieved dynamically, which provides an efficient method for computing the equilibrium LMF potential, in addition to providing the nonequilibrium generalization. As a concrete example, we investigate water confined between hydrophobic or charged walls, systems that are very sensitive to the treatment of long-ranged electrostatics. We then analyze confined water in the presence of a time-dependent applied electric field, generated by a sinusoidal or abrupt variation of the magnitudes of uniform charge densities on each wall. Very accurate results are found from the time-dependent LMF formalism even for strong static fields and for time-dependent systems that are driven far from equilibrium where linear response methods fail.

PFAS are persistent and toxic chemicals used in many commercial and industrial applications that are often added to consumer products, including those used by children and adolescents, to impart water and stain resistance. Since product labels rarely list chemical additives, including PFAS, we evaluated whether other information on product labels can be used by consumers to select products without PFAS. We selected 93 items marketed to or often used by children and adolescents across three product types (furnishings, apparel, bedding) and five labeling groups representing different combinations of water and/or stain resistance and "green" (including "nontoxic") assurances. We screened all products for total fluorine (F) and analyzed solvent extracts from a subset (

Bioretention cells are a stormwater management technology intended to reduce the quantity of water entering receiving bodies. They are also used to reduce contaminant releases, but their performance is unclear for hydrophilic persistent and mobile organic compounds (PMOCs). We developed a novel eight-compartment one-dimensional (1D) multimedia model of a bioretention cell ("Bioretention Blues") and applied it to a spike and recovery experiment conducted on a system near Toronto, Canada, involving PMOC benzotriazole and four organophosphate esters (OPEs). Compounds with (log

The progression of climate warming will expose ectotherms to transient heatwave events and temperatures above their tolerance range at increased frequencies. It is therefore pivotal that we understand species' physiological limits and the capacity for various controls to plastically alter these thresholds. Exercise training could have beneficial impacts on organismal heat tolerance through improvements in cardio-respiratory capacity, but this remains unexplored. Using juvenile Chinook salmon (Oncorhynchus tshawytscha), we tested the hypothesis that exercise training improves heat tolerance through enhancements in oxygen-carrying capacity. Fish were trained once daily at 60% of their maximum sustainable swim speed, U