The alpha-1A adrenergic receptor regulates mitochondrial oxidative metabolism in the mouse heart.

AIMS: The sympathetic nervous system regulates numerous critical aspects of mitochondrial function in the heart through activation of adrenergic receptors (ARs) on cardiomyocytes. Mounting evidence suggests that α1-ARs, particularly the α1A subtype, are cardioprotective and may mitigate the deleterious effects of chronic ß-AR activation by shared ligands. The mechanisms underlying these adaptive effects remain unclear. Here, we tested the hypothesis that α1A-ARs adaptively regulate cardiomyocyte oxidative metabolism in both the uninjured and infarcted heart. METHODS: We used high resolution respirometry, fatty acid oxidation (FAO) enzyme assays, substrate-specific electron transport chain (ETC) enzyme assays, transmission electron microscopy (TEM) and proteomics to characterize mitochondrial function comprehensively in the uninjured hearts of wild type and α1A-AR knockout mice and defined the effects of chronic ß-AR activation and myocardial infarction on selected mitochondrial functions. RESULTS: We found that isolated cardiac mitochondria from α1A-KO mice had deficits in fatty acid-dependent respiration, FAO, and ETC enzyme activity. TEM revealed abnormalities of mitochondrial morphology characteristic of these functional deficits. The selective α1A-AR agonist A61603 enhanced fatty-acid dependent respiration, fatty acid oxidation, and ETC enzyme activity in isolated cardiac mitochondria. The ß-AR agonist isoproterenol enhanced oxidative stress in vitro and this adverse effect was mitigated by A61603. A61603 enhanced ETC Complex I activity and protected contractile function following myocardial infarction. CONCLUSIONS: Collectively, these novel findings position α1A-ARs as critical regulators of cardiomyocyte metabolism in the basal state and suggest that metabolic mechanisms may underlie the protective effects of α1A-AR activation in the failing heart.

Vulnerability of Eastern Tropical Pacific chondrichthyan fish to climate change.

Climate change is an environmental emergency threatening species and ecosystems globally. Oceans have absorbed about 90% of anthropogenic heat and 20%-30% of the carbon emissions, resulting in ocean warming, acidification, deoxygenation, changes in ocean stratification and nutrient availability, and more severe extreme events. Given predictions of further changes, there is a critical need to understand how marine species will be affected. Here, we used an integrated risk assessment framework to evaluate the vulnerability of 132 chondrichthyans in the Eastern Tropical Pacific (ETP) to the impacts of climate change. Taking a precautionary view, we found that almost a quarter (23%) of the ETP chondrichthyan species evaluated were highly vulnerable to climate change, and much of the rest (76%) were moderately vulnerable. Most of the highly vulnerable species are batoids (77%), and a large proportion (90%) are coastal or pelagic species that use coastal habitats as nurseries. Six species of batoids were highly vulnerable in all three components of the assessment (exposure, sensitivity and adaptive capacity). This assessment indicates that coastal species, particularly those relying on inshore nursery areas are the most vulnerable to climate change. Ocean warming, in combination with acidification and potential deoxygenation, will likely have widespread effects on ETP chondrichthyan species, but coastal species may also contend with changes in freshwater inputs, salinity, and sea level rise. This climate-related vulnerability is compounded by other anthropogenic factors, such as overfishing and habitat degradation already occurring in the region. Mitigating the impacts of climate change on ETP chondrichthyans involves a range of approaches that include addressing habitat degradation, sustainability of exploitation, and species-specific actions may be required for species at higher risk. The assessment also highlighted the need to further understand climate change's impacts on key ETP habitats and processes and identified knowledge gaps on ETP chondrichthyan species.

El cambio climático es una emergencia medioambiental que amenaza a especies y ecosistemas en todo el mundo. Los océanos han absorbido alrededor del 90% del calor antropogénico y entre el 20% y el 30% de las emisiones de carbono, lo que ha provocado su calentamiento, acidificación, desoxigenación, cambios en la estratificación de los océanos y en la disponibilidad de nutrientes, así como fenómenos extremos más pronunciados. Dadas las predicciones de cambios, hay una importante necesidad de entender cómo las especies marinas se verán afectadas. En este estudio utilizamos una Evaluación Integrada de Riesgos para evaluar la vulnerabilidad de 132 condrictios del Pacífico Tropical Oriental (PTO) a los impactos del cambio climático. Adoptando un enfoque preventivo, estimamos que la vulnerabilidad general al cambio climático es Alta para casi una cuarta parte (23%) de las especies de condrictios del PTO evaluadas y Moderada para gran parte del resto (76%). La mayoría de las especies altamente vulnerables son batoideos (77%), y una gran proporción de éstas (90%) son especies costeras o especies pelágicas que utilizan los hábitats costeros como áreas de crianza. Seis especies de batoideos tuvieron una vulnerabilidad Alta en los tres componentes de la evaluación. Esta evaluación indica que las especies costeras, en particular las que dependen de áreas de crianza costeras, son las más vulnerables al cambio climático. Es probable que el calentamiento de los océanos, junto con la acidificación y la posible desoxigenación, tenga efectos generalizados sobre las especies de condrictios del PTO, pero las especies costeras se verán también afectadas por los cambios en los aportes de agua dulce, la salinidad y el aumento del nivel del mar. Esta vulnerabilidad relacionada con el clima se ve agravada por otros factores antropogénicos que ya se están produciendo en la región, como la sobrepesca y la degradación del hábitat. La mitigación de los impactos del cambio climático sobre los condrictios del PTO implica medidas que incluyan abordar la degradación del hábitat y la sostenibilidad de la explotación pesquera, y acciones para las especies de mayor riesgo son necesarias. Esta evaluación también destaca la necesidad de comprender mejor los impactos del cambio climático en los hábitats y procesos clave del PTO y las lagunas de conocimiento identificadas en relación con las especies de condrictios del PTO.

An open repository of real-time COVID-19 indicators.

The COVID-19 pandemic presented enormous data challenges in the United States. Policy makers, epidemiological modelers, and health researchers all require up-to-date data on the pandemic and relevant public behavior, ideally at fine spatial and temporal resolution. The COVIDcast API is our attempt to fill this need: Operational since April 2020, it provides open access to both traditional public health surveillance signals (cases, deaths, and hospitalizations) and many auxiliary indicators of COVID-19 activity, such as signals extracted from deidentified medical claims data, massive online surveys, cell phone mobility data, and internet search trends. These are available at a fine geographic resolution (mostly at the county level) and are updated daily. The COVIDcast API also tracks all revisions to historical data, allowing modelers to account for the frequent revisions and backfill that are common for many public health data sources. All of the data are available in a common format through the API and accompanying R and Python software packages. This paper describes the data sources and signals, and provides examples demonstrating that the auxiliary signals in the COVIDcast API present information relevant to tracking COVID activity, augmenting traditional public health reporting and empowering research and decision-making.

The role of biologics in pediatric food allergy and eosinophilic gastrointestinal disorders.

Continuing insight into the molecular mechanisms of atopic disorders has enabled the development of biologics to precisely target these diseases. Food allergy (FA) and eosinophilic gastrointestinal disorders (EGIDs) are driven by similar inflammatory molecular mechanisms and exist along the same atopic disease spectrum. Therefore, many of the same biologics are being investigated to target key drivers of mechanisms shared across the disease states. The enormous potential of biologics for the treatment of FA and EGIDs is highlighted by the significant increases in the number of ongoing clinical trials (more than 30) evaluating their use in these disease states, as well as by the recent US Food and Drug Administration approval of dupilumab for the treatment of eosinophilic esophagitis. Here we discuss past and current research into the use of biologics in FA and EGIDs and their potential role in improving treatment options in the future, with the need to have biologics widely clinically available.

Status of Southeast Asia's marine sharks and rays.

In Southeast Asia, elasmobranchs are particularly threatened. We synthesized knowledge from the peer-reviewed and gray literature on elasmobranchs in the region, including their fisheries, status, trade, biology, and management. We found that 59% of assessed species are threatened with extinction and 72.5% are in decline; rays were more threatened than sharks. Research and conservation is complicated by the socioeconomic contexts of the countries, geopolitical issues in the South China Sea, and the overcapacity and multispecies nature of fisheries that incidentally capture elasmobranchs. The general paucity of data, funds, personnel, and enforcement hinders management. Reduced capacity in the general fishery sector and marine protected areas of sufficient size (for elasmobranchs and local enforcement capabilities) are among recommendations to strengthen conservation.

En el sureste de Asia, los elasmobranquios se encuentran particularmente amenazados. Sintetizamos el conocimiento a partir de la literatura gris y revisada por pares sobre los elasmobranquios en la región, incluidos sus pesquerías, estado, mercado, biología y manejo. Nuestra evaluación incluyó x especies de tiburones y y especies de rayas. Descubrimos que el 59% de las especies evaluadas están bajo amenaza de extinción y 72.5% están en declive; de estas, las rayas estuvieron más amenazadas que los tiburones. La investigación y la conservación son complicadas debido al contexto socioeconómico de los países, los temas geopolíticos en el Mar del Sur de China y la sobrecapacidad y naturaleza multiespecie de las pesquerías que capturan accidentalmente a los elasmobranquios. La escasez general de datos, financiamiento, personal y aplicación limita el manejo. La capacidad reducida en el sector generalizado de la pesquería y las áreas marinas protegidas de tamaño suficiente (para los elasmobranquios y las capacidades de aplicación local) se encuentran entre las recomendaciones para fortalecer la conservación.

Conceptual frameworks and key questions for assessing the contribution of marine protected areas to shark and ray conservation.

Marine protected areas (MPAs) are key tools in addressing the global decline of sharks and rays, and marine parks and shark sanctuaries of various configurations have been established to conserve shark populations. However, assessments of their efficacy are compromised by inconsistent terminology, lack of standardized approaches to assess how MPAs contribute to shark and ray conservation, and ambiguity about how to integrate movement data in assessment processes. We devised a conceptual framework to standardize key terms (e.g., protection, contribution, potential impact, risk, threat) and used the concept of portfolio risk to identify key attributes of sharks and rays (assets), the threats they face (portfolio risk), and the specific role of MPAs in risk mitigation (insurance). Movement data can be integrated into the process by informing risk exposure and mitigation through MPAs. The framework is operationalized by posing 8 key questions that prompt practitioners to consider the assessment scope, MPA type and purpose, range of existing and potential threats, species biology and ecology, and management and operational contexts. Ultimately, MPA contributions to shark and ray conservation differ according to a complex set of human and natural factors and interactions that should be carefully considered in MPA design, implementation, and evaluation.

Marcos conceptuales y preguntas clave para evaluar la contribución de las áreas marinas protegidas a la conservación de tiburones y rayas Resumen Las áreas marinas protegidas (AMP) son herramientas importantes para manejar la declinación mundial de tiburones y rayas, por lo que se han establecido parques marinos y santuarios de diversas configuraciones para conservar las poblaciones de tiburones. Sin embargo, el análisis de su eficiencia está compuesto por una terminología inconstante, la falta de estrategias estandarizadas para evaluar cómo las AMP contribuyen a la conservación de tiburones y rayas, y una ambigüedad sobre cómo integrar la información sobre movimientos en los procesos de evaluación. Diseñamos un marco conceptual para estandarizar los términos más importantes (p. ej.: protección, contribución, impacto potencial, amenaza, riesgo) y usamos el concepto de riesgo de portafolio para identificar los atributos clave de los tiburones y las rayas (activos), las amenazas que enfrentan (riesgo de portafolio) y el papel específico que juegan las AMP en la mitigación del riesgo (seguro). La información sobre los movimientos puede integrarse al proceso al guiar la exposición y mitigación del riesgo con las AMP. El marco conceptual es operado con el planteamiento de ocho preguntas clave que invitan a los practicantes a considerar el enfoque de la evaluación, el tipo de AMP y su propósito, gama de amenazas existentes y potenciales, la biología y ecología de las especies, y los contextos operativos y de manejo. Finalmente, las contribuciones que tienen las AMP a la conservación de los tiburones y las rayas difieren de acuerdo con un conjunto complejo de factores naturales y humanos e interacciones que deberían considerarse cuidadosamente en el diseño, implementación y evaluación de la AMP.

Recent Mechanistic Studies in Allergic Diseases.

Allergic diseases, such as food allergies, asthma, and allergic rhinitis, continue to present a significant challenge for a broad cross-section of the population, despite recent advancements in their treatment and prevention [...].

Elemental analysis of vertebrae discerns diadromous movements of threatened non-marine elasmobranchs.

River sharks (Glyphis spp.) and some sawfishes (Pristidae) inhabit riverine environments, although their long-term habitat use patterns are poorly known. We investigated the diadromous movements of the northern river shark (Glyphis garricki), speartooth shark (Glyphis glyphis), narrow sawfish (Anoxypristis cuspidata), and largetooth sawfish (Pristis pristis) using in situ laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) on vertebrae to recover elemental ratios over each individual's lifetime. We also measured elemental ratios for the bull shark (Carcharhinus leucas) and a range of inshore and offshore stenohaline marine species to assist in interpretation of results. Barium (Ba) was found to be an effective indicator of freshwater use, whereas lithium (Li) and strontium (Sr) were effective indicators of marine water use. The relationships between Ba and Li and Ba and Sr were negatively correlated, whereas the relationship between Li and Sr was positively correlated. Both river shark species had elemental signatures indicative of prolonged use of upper-estuarine environments, whereas adults appear to mainly use lower-estuarine environments rather than marine environments. Decreases in Li:Ba and Sr:Ba at the end of the prenatal growth zone of P. pristis samples indicated that parturition likely occurs in fresh water. There was limited evidence of prolonged riverine habitat use for A. cuspidata. The results of this study support elemental-environment relationships observed in teleost otoliths and indicate that in situ LA-ICP-MS elemental characterization is applicable to a wide range of elasmobranch species as a discriminator for use and movement across salinity gradients. A greater understanding of processes that lead to element incorporation in vertebrae, and relative concentrations in vertebrae with respect to the ambient environment, will improve the applicability of elemental analysis to understand movements across the life history of elasmobranchs into the future.

Food allergy, mechanisms, diagnosis and treatment: Innovation through a multi-targeted approach.

The incidence of food allergy (FA) has continued to rise over the last several decades, posing significant burdens on health and quality of life. Significant strides into the advancement of FA diagnosis, prevention, and treatment have been made in recent years. In an effort to lower reliance on resource-intensive food challenges, the field has continued work toward the development of highly sensitive and specific assays capable of high-throughput analysis to assist in the diagnosis FA. In looking toward early infancy as a critical period in the development of allergy or acquisition of tolerance, evidence has increasingly suggested that early intervention via the early introduction of food allergens and maintenance of skin barrier function may decrease the risk of FA. As such, large-scale investigations are underway evaluating infant feeding and the impact of emollient and steroid use in infants with dry skin for the prevention of allergy. On the other end of the spectrum, the past few years have been witness to an explosive increase in clinical trials of novel and innovative therapeutic strategies aimed at the treatment of FA in those whom the disease has already manifested. A milestone in the field, 2020 marked the approval of the first drug, oral peanut allergen, for the indication of peanut allergy. With a foundation of promising data supporting the safety and efficacy of single- and multi-allergen oral immunotherapy, current efforts have turned toward the use of probiotics, biologic agents, and modified allergens to optimize and improve upon existing paradigms. Through these advancements, the field hopes to gain footing in the ongoing battle against FA.

Immunogenicity of SARS-CoV-2 Vaccine in Dialysis.

BACKGROUND: Patients receiving maintenance dialysis represent a high-risk, immune-compromised population with 15%-25% COVID-19 mortality rate who were unrepresented in clinical trials of mRNA vaccines. METHODS: All patients receiving maintenance dialysis who received two doses of SARS-CoV-2 mRNA vaccines with antibody test results drawn ≥14 days after the second dose, as documented in the electronic health record through March 18, 2021, were included. Response was on the basis of levels of Ig-G against the receptor binding domain of the S1 subunit of SARS-CoV-2 spike-antigen (seropositive ≥2 U/L) using an FDA-approved semiquantitative chemiluminescent assay (ADVIA Centaur XP/XPT COV2G). RESULTS: Among 186 patients on dialysis from 30 clinics in eight states tested 23±8 days after receiving two vaccine doses, there were 165 (88.7%) responders with 70% at maximum titer. There was no significant difference between BNT162b2/Pfizer (148 out of 168, 88.1%) and mRNA-1273/Moderna (17 out of 18, 94.4%), P=0.42. All 38 patients with COVID-19 history were responders, with 97% at maximum titer. Among patients without COVID-19, 127 out of 148 (85.8%) were responders, comparable between BNT162b2/Pfizer (113 out of 133) and mRNA-1273/Moderna (14 out of 15) vaccines (85.0% versus 93.3%, P=0.38). CONCLUSIONS: Most patients receiving maintenance dialysis responded after two doses of BNT162b2/Pfizer or mRNA-1273/Moderna vaccine, suggesting the short-term development of antispike antibody is good, giving hope that most of these patients who are vulnerable, once immunized, will be protected from COVID-19. Longer-term evaluation is needed to determine antibody titer durability and if booster dose(s) are warranted. Further research to evaluate the approach to patients without a serologic response is needed, including benefits of additional dose(s) or administration of alternate options.

School Risk and Protective Factors of Suicide: A Cultural Model of Suicide Risk and Protective Factors in Schools.

There are known cultural variations in correlates of and symptoms related to suicide-related thoughts and behaviors; however, the majority of research that informs suicide prevention in school systems has focused on research based on Euro-American/White students. By exploring school-related risk and protective factors in ethnic-racial minoritized students, we expand existing multicultural models of suicide prevention for school settings. Specifically, this systematic literature review identified 33 studies conducted with American Indian and Alaskan Native, Hispanic and Latinx, Black and African American, and Asian American and Pacific Islander students. Findings underscore the importance of building relationships with the school community and fostering a sense of safety for students, the need to approach school-based suicide prevention and intervention with cultural considerations, and the importance of connecting students and families with providers in culturally sensitive and informed ways. Taken together, schools need to build school-family-community partnerships that promote culturally sensitive approaches to suicide prevention.

Protein Composition Reflects Extracellular Vesicle Heterogeneity.

Extracellular vesicles (EVs) are membrane-enclosed particles that are released by virtually all cells from all living organisms. EVs shuttle biologically active cargo including protein, RNA, and DNA between cells. When shed by cancer cells, they function as potent intercellular messangers with important functional consequences. Cells produce a diverse spectrum of EVs, spanning from small vesicles of 40-150 nm in diameter, to large vesicles up to 10 µm in diameter. While this diversity was initially considered to be purely based on size, it is becoming evident that different classes of EVs, and different populations within one EV class may harbor distinct molecular cargo and play specific functions. Furthermore, there are considerable cell type-dependent differences in the cargo and function of shed EVs. This review focuses on the most recent proteomic studies that have attempted to capture the EV heterogeneity by directly comparing the protein composition of different EV classes and EV populations derived from the same cell source. Recent studies comparing protein composition of the same EV class(es) derived from different cell types are also summarized. Emerging approaches to study EV heterogeneity and their important implications for future studies are also discussed.

Biomechanical Comparison of the Reverse Hyperextension Machine and the Hyperextension Exercise.

Lawrence, MA, Chin, A, and Swanson, BT. Biomechanical comparison of the reverse hyperextension machine and the hyperextension exercise. J Strength Cond Res 33(8): 2053-2056, 2019-The purpose of this study was to compare activation of the erector spinae, gluteus maximus, and biceps femoris muscles, lower back extension moment, and lower extremity range of motion (ROM) between the reverse hyperextension (RHE) and hyperextension (HE) exercises. Motion and muscle activation of the trunk and lower extremity were measured while 20 recreationally active individuals performed 2 sets of 10 repetitions of each exercise. Equivalent loads were used for each exercise. Peak, average, and integrated muscle activity, low back moment, and ROM between the trunk and pelvis and the thigh and trunk were calculated. A Wilcoxon signed-rank test (p = 0.05) revealed significantly greater integrated activity of the biceps femoris and gluteus maximus during the HE exercise. The RHE exercise generated greater peak (+129%), integrated (+63%), and mean (+78%) low back moment as compared to the HE exercise. The RHE resulted in a significantly greater thigh to trunk ROM, 76.6 compared with 64.7. However, the RHE used less lumbar flexion, 20.4 compared with 31.1 for the HE. The RHE movement profile is preferable because it provides greater hip ROM with less angular stress and equivalent erector spinae activity.

Polarized Secretion of Extracellular Vesicles by Mammary Epithelia.

Extracellular vesicles (EVs) are secreted by many cell types and are increasingly investigated for their role in human diseases including cancer. Here we focus on the secretion and potential physiological function of non-pathological EVs secreted by polarized normal mammary epithelial cells. Using a transwell system to allow formation of epithelial polarity and EV collection from the apical versus basolateral compartments, we found that impaired secretion of EVs by knockdown of RAB27A or RAB27B suppressed the establishment of mammary epithelial polarity, and that addition of apical but not basolateral EVs suppressed epithelial polarity in a dose-dependent manner. This suggests that apical EV secretion contributes to epithelial polarity, and a possible mechanism is through removal of certain intracellular molecules. In contrast, basolateral but not apical EVs promoted migration of mammary epithelial cells in a motility assay. The protein contents of apical and basolateral EVs from MCF10A and primary human mammary epithelial cells were determined by mass spectrometry proteomic analysis, identifying apical-EV-enriched and basolateral-EV-enriched proteins that may contribute to different physiological functions. Most of these proteins differentially secreted by normal mammary epithelial cells through polarized EV release no longer showed polarized secretion in MCF10A-derived transformed epithelial cells. Our results suggest an essential role of EV secretion in normal mammary epithelial polarization and distinct protein contents and functions in apical versus basolateral EVs secreted by polarized mammary epithelia.

Regional and Temporal Variations in Comorbidity Among US Dialysis Patients: A Longitudinal Study of Medicare Claims Data.

Medicare claims data are commonly used to query comorbidities for case-mix adjustment in research of patients with end-stage renal disease (ESRD) in the United States. These adjustments may affect reimbursement and quality rating through comparative profiling and ranking of dialysis facilities. We studied regional and temporal variations in comorbidity from claims data in the United States Renal Data System. Patients with a previous 1-year Medicare history who initiated dialysis therapy between 2006 and 2009 were examined with a follow-up period until 2012. By linking pre- and post-ESRD Medicare claims with the Dartmouth Atlas, we carried out a longitudinal data analysis with multivariable adjustment to investigate regional and temporal variations in the Liu comorbidity index. We identified 23 336 incident hemodialysis patients who were covered by Medicare the year prior to dialysis initiation and had survived with complete 3 years of follow-up data. With the United States divided into 4 geographic regions, the Western region was found to have the lowest Liu index over all 3 follow-up years, compared with the respective years in the other regions (Midwest, Northeast, and South). In comparison with the first year, the Liu index dropped significantly during the second and third years of follow-up across all 4 regions. Significant regional and temporal variations observed in the comorbidity index cannot be explained by differences in reimbursement (average per state) or predialysis comorbidity. Based on our exploratory study, future studies should focus on identifying the factors and reasons for these variations which have the potential to affect health care policy and research.

Minimally Invasive Fibrin Sealant Application in Pilonidal Sinus: A Comparative Study.

The aim of this study was to compare the filling of the pilonidal sinus tract with fibrin sealant (FS) against tract excision and primary closure (PC) as the primary procedure. Details of all patients who underwent treatment for a symptomatic first episode of pilonidal sinus disease between January 2011 and December 2015 were prospectively recorded in a custom database. Patients underwent PC (n=17) or FS (n=17) according to patient preference. Prior surgical treatment and ongoing infection precluded entry. Patients were treated with antibiotics if presenting with infection. Outcomes measured were recurrence, further procedures, outpatient attendances and length of follow-up to resolution. 34 consecutive patients [FS vs. PC: male n=15 vs. 12 p=0.398; mean age 29 (SEM 12) vs. 30 (SEM 15) p=0.849] were included. Treated preoperative infections were similar FS (n=5) vs. PC (n=12) (p=0.038, chi-squared test). FS cohort had more sinuses FS median (range) 2 (1-4) vs. PC 1 (1-3) (p=0.046). Postoperative outcomes: recurrence rate FS (n=5) vs. PC (n=4) (p=0.629); infection rate FS (n=1) vs. PC (n=8) (p=0.045); total number of operations required FS 1 (1-2) vs. PC 1 (1-4) (p=0.19); total number of outpatient attendance FS 2 (1-7) vs. PC 3 (1-16) (p=0.629); follow-up FS 129 days ± 33 vs. PC 136 ± 51 (p=0.914). Fibrin sealant is not inferior to excision followed by primary closure.

Cancer-derived extracellular vesicles: the 'soil conditioner' in breast cancer metastasis?

It has been recognized that cancer-associated mortality is more often a result of the disrupted physiological functions in multiple organs following metastatic dissemination of cancer cells, rather than the presence and growth of the primary tumor. Despite advances in our understanding of the events leading to cancer initiation, growth, and acquisition of invasive properties, we are still unable to effectively treat metastatic disease. It is now being accepted that the secretion of extracellular vesicles, such as exosomes from cancer cells, has a profound impact on the initiation and propagation of metastatic breast cancer. These cancer-secreted vesicles differ from other means of cellular communication due to their capability of bulk delivery and organotropism. Here, we provide an overview of the role of extracellular vesicles in breast cancer metastasis and discuss key areas that may facilitate our understanding of metastatic breast cancer to guide our efforts towards providing better therapies.

Successful Hemodialysis Arteriovenous Fistula Creation in a Patient With Continuous-Flow Left Ventricular Assist Device Support.

Heart failure necessitating left ventricular assist device (LVAD) support can lead to kidney failure requiring dialysis. Some of these patients may require long-term hemodialysis (HD). Optimal vascular access for a patient on long-term HD therapy with an LVAD remains a complex issue. The majority of LVADs are of the continuous-flow type, and it has been theorized that native arteriovenous fistula maturation may be impaired in a setting of decreased pulsatile arterial flow. We describe a case of successful creation and use of an arteriovenous fistula in an HD-dependent patient with a continuous-flow LVAD.