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Abstract Genome-wide Illumina InfiniumMethylation 450 K DNA methylation analysis was performed on blood samples from clinical atherosclerosis patients (n = 8) and healthy donors (n = 8) in the LVAD study (NCT02174133, NCT01799005). Multiple differentially methylated regions (DMR) could be identified in atherosclerosis patients, related to epigenetic control of cell adhesion, chemotaxis, cytoskeletal reorganisations, cell proliferation, cell death, estrogen receptor pathways and phagocytic immune responses. Furthermore, a subset of 34 DMRs related to impaired oxidative stress, DNA repair, and inflammatory pathways could be replicated in an independent cohort study of donor-matched healthy and atherosclerotic human aorta tissue (n = 15) and human carotid plaque samples (n = 19). Upon integrated network analysis, BRCA1 and CRISP2 DMRs were identified as most central disease-associated DNA methylation biomarkers. Differentially methylated BRCA1 and CRISP2 regions were verified by MassARRAY Epityper and pyrosequencing assays and could be further replicated in blood, aorta tissue and carotid plaque material of atherosclerosis patients. Moreover, methylation changes at BRCA1 and CRISP2 specific CpG sites were consistently associated with subclinical atherosclerosis measures (coronary calcium score and carotid intima media thickness) in an independent sample cohort of middle-aged men with subclinical cardiovascular disease in the Aragon Workers’ Health Study (n = 24). Altogether, BRCA1 and CRISP2 DMRs hold promise as novel blood surrogate markers for early risk stratification and CVD prevention.

The Seventh Annual Deep Brain Stimulation (DBS) Think Tank held on September 8th of 2019 addressed the most current: (1) use and utility of complex neurophysiological signals for development of adaptive neurostimulation to improve clinical outcomes; (2) Advancements in recent neuromodulation techniques to treat neuropsychiatric disorders; (3) New developments in optogenetics and DBS; (4) The use of augmented Virtual reality (VR) and neuromodulation; (5) commercially available technologies; and (6) ethical issues arising in and from research and use of DBS. These advances serve as both “markers of progress” and challenges and opportunities for ongoing address, engagement, and deliberation as we move to improve the functional capabilities and translational value of DBS. It is in this light that these proceedings are presented to inform the field and initiate ongoing discourse. As consistent with the intent, and spirit of this, and prior DBS Think Tanks, the overarching goal is to continue to develop multidisciplinary collaborations to rapidly advance the field and ultimately improve patient outcomes.

In May 2016, the remote-controlled Automated Filtration System for Marine Microbes (AUTOFIM) was implemented in parallel to the Long Term Ecological Research (LTER) observatory Helgoland Roads in the German Bight. We collected samples for characterization of dynamics within the eukaryotic microbial communities at the end of a phytoplankton bloom via 18S meta-barcoding. Understanding consequences of environmental change for key marine ecosystem processes, such as phytoplankton bloom dynamics requires information on biodiversity and species occurrences with adequate temporal and taxonomic resolution via time series observations. Sampling automation and molecular high throughput methods can serve these needs by improving the resolution of current conventional marine time series observations. A technical evaluation based on an investigation of eukaryotic microbes using the partial 18S rRNA gene suggests that automated filtration with the AUTOFIM device and preservation of the plankton samples leads to highly similar 18S community profiles, compared to manual filtration and snap freezing. The molecular data were correlated with conventional microscopic counts. Overall, we observed substantial change in the eukaryotic microbial community structure during the observation period. A simultaneous decline of diatom and ciliate sequences succeeded a peak of Miracula helgolandica, suggesting a potential impact of these oomycete parasites on diatom bloom dynamics and phenology in the North Sea. As oomycetes are not routinely counted at Helgoland Roads LTER, our findings illustrate the benefits of combining automated filtration with metabarcodingto augment classical time series observations, particularly for taxa currently neglected due to methodological constraints.

Background The Acute Care Surgery (ACS) model developed during the last decade fuses critical care, trauma, and emergency general surgery. ACS teams commonly perform laparoscopic cholecystectomy (LC) for acute biliary disease. This study reviewed LCs performed by an ACS service focusing on risk factors for complications in the emergent setting.Methods All patients who underwent LC on an ACS service during a 26-month period were identified. Demographic, perioperative, and complication data were collected and analyzed with Fisher’s exact test, χ2 test, and Mann-Whitney U Test.Results During the study period, 547 patients (70.2% female, mean age 46.1±18.1, mean body mass index 32.4±7.8 kg/m2) had LC performed for various acute indications. Mean surgery time was 77.9±50.2 minutes, and 5.7% of cases were performed “after hours.” Rate of conversion to open procedure was 6%. Complications seen included minor bile leaks (3.8%), infection (3.8%), retained gallstones (1.1%), organ injury (1.1%), major duct injury (0.9%), and postoperative bleeding (0.9%). Statistical analysis demonstrated significant relationships between conversion, length of surgery, age, gender, and intraoperative cholangiogram with various complications. No significant relationships were detected between complications and BMI, pregnancy, attending experience, and time of operation.Discussion Although several statistically significant relationships were identified between several risk factors and complications, these findings have limited clinical significance. Factors including attending years in practice and time of the operation were not associated with increased complications. ACS services are capable of performing a high volume of LCs for emergent indications with low complication and conversion rates.­Level of evidence:IV

The OceanGliders program started in 2016 to support active coordination and enhancement of global glider activity. OceanGliders contributes to the international efforts of the Global Ocean Observation System (GOOS) for Climate, Ocean Health, and Operational Services. It brings together marine scientists and engineers operating gliders around the world: (1) to observe the long-term physical, biogeochemical, and biological ocean processes and phenomena that are relevant for societal applications; and, (2) to contribute to the GOOS through real-time and delayed mode data dissemination. The OceanGliders program is distributed across national and regional observing systems and significantly contributes to integrated, multi-scale and multi-platform sampling strategies. OceanGliders shares best practices, requirements, and scientific knowledge needed for glider operations, data collection and analysis. It also monitors global glider activity and supports the dissemination of glider data through regional and global databases, in real-time and delayed modes, facilitating data access to the wider community. OceanGliders currently supports national, regional and global initiatives to maintain and expand the capabilities and application of gliders to meet key global challenges such as improved measurement of ocean boundary currents, water transformation and storm forecast.

Background Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a less-invasive technique for aortic occlusion (AO). Commonly performed in the emergency department (ED), the role of intraoperative placement is less defined. We hypothesized that operating room (OR) placement is associated with increased in-hospital mortality.Methods The American Association for the Surgery of Trauma AORTA registry was used to identify patients undergoing REBOA. Injury characteristics and outcomes data were compared between OR and ED groups. The primary outcome was in-hospital mortality; secondary outcomes included total AO time, transfusion requirements, and acute kidney injury.Results Location and timing of catheter insertion were available for 305 of 321 (95%) subjects. 58 patients underwent REBOA in the OR (19%). There were no differences with respect to sex, admission lactate, and Injury Severity Score. The OR group was younger (33 years vs. 41 years, p=0.01) and with more penetrating injuries (36% vs. 15%, p

Subarachnoid hemorrhage (SAH) results frequently from traumatic brain injury (TBI). The standard management for these patients includes brief admission by the acute care surgery (trauma) service with neurological checks, neurosurgical consultation and repeat head CT within 24 hours to identify any progression or resolution. Recent studies have questioned the need for repeat CT imaging and specialty consultation in mild TBI. We reviewed patients with mild TBI specifically with isolated SAH to determine progression of the pathology and need for neurosurgical involvement. All patients with SAH secondary to mild TBI (Glasgow Coma Score (GCS) of 13–15) who presented over a 5-year period (January 2010 to December 2014) to a level I trauma center were identified from the trauma registry. Demographic data, initial CT findings, neurosurgical consultation, follow-up CT findings, Injury Severity Score (ISS), admission GCS and length of stay (LOS) were all obtained from the patient’s charts. Patients with other traumatic brain lesions on the initial CT were excluded. There were 299 patients (male, 48.5%), mean age 60.9 and mean ISS 8. Average time between the first and second CT was 11.3 hours. In all, 267 (89.2%) patients had either no change or an improvement/resolution on follow-up CT scan. Only 26 patients (8.7%) had either worsening or new findings on CT. Eight patients did not have a second scan completed (2.6%). All patients had neurosurgical consultation. Patients with mild TBI with isolated SAH generally have low morbidity, short LOS and negligible mortality. Less than 10% of this population had worsening of their head injury on repeat CT scanning. Given the low acuity of these patients with SAH and tendency towards resolution without intervention, acute care surgeons can manage this specific group of patients with TBI without routine neurosurgical consultation. Repeat CT scanning continues to have utility as it may identify new lesions, deterioration or need for further management.

Abstract We propose that tongue protrusive strength and tone may be related to upper airway patency, and when protrusive strength is reduced, individuals are at higher risk of developing sleep apnea, or speech/swallow disorders. The goal of the current study was to determine normative values of maximum tongue protrusion force (MTPF) in healthy young adults, using a unique newly developed device. We hypothesized that MTPF would be greater in males than in females. One hundred and one healthy young adults (mean age: 22.99 years; male: 23, female: 78) participated in this study. The subjects pushed their tongue forward against the device’s piston (protrusion) as hard as possible for 2–5 sec and MTPF was recorded in Newtons (N). A minimum of 5 MTPF measurements were obtained with 1–2 min rest between measurements. The average MTPF for all subjects was 15.4 N (SD: ±3.8), with a range of 8–29. The male average MTPF was higher than female (17.8 N, SD: ±3.7 vs. 14.7 N, SD: ±3.5; P = 0.001). There was no significant difference for age between males and females; males had significantly greater height and weight. The results demonstrate our novel device can effectively measure tongue protrusive force in healthy young adults. This study provides normative values for MTPF, and identified significant tongue protrusion strength differences between males and females.

Control of negative emotions (e.g., anger and fear) by political cues perpetuate intractable conflict by mobilizing public support for aggressive actions. Halperin et al. (2013) found that reappraisal – an adaptive form of emotion regulation – decreased negative emotions triggered by anger-inducing information related to the Israeli–Palestinian conflict, and increased support for conciliatory statements. We tested these effects in the context of the conflict between the Colombian government and the Fuerzas Armadas Revolucionarias de Colombia-Ejército del Pueblo (FARC-EP). Reappraisal training reduced negative emotions produced by a presentation that illustrated FARC’s violent actions, and increased support for conciliatory statements (with overall moderate effect magnitudes). We also found that negative emotions mediated the effects of reappraisal on the support for aggressive and conciliatory statements. These findings indicate a high degree of generality of the phenomena, especially considering the differences between the Israeli–Palestinian conflict and the Colombian conflict. Our findings also show promise for replicating these effects on other types of intergroup conflicts and guiding effective public policy.

Pelagic chlorophyll-a concentrations are key for evaluation of the environmental status and productivity of marine systems, and data can be provided by in situ measurements, remote sensing and modelling. However, modelling chlorophyll-a is not trivial due to its nonlinear dynamics and complexity. In this study, chlorophyll-a concentrations for the Helgoland Roads time series were modeled using a number of measured water and environmental parameters. We chose three common machine learning algorithms from the literature: the support vector machine regressor, neural networks multi-layer perceptron regressor and random forest regressor. Results showed that the support vector machine regressor slightly outperformed other models. The evaluation with a test dataset and verification with an independent validation dataset for chlorophyll-a concentrations showed a good generalization capacity, evaluated by the root mean squared errors of less than 1 µg L−1. Feature selection and engineering are important and improved the models significantly, as measured in performance, improving the adjusted R2 by a minimum of 48%. We tested SARIMA in comparison and found that the univariate nature of SARIMA does not allow for better results than the machine learning models. Additionally, the computer processing time needed was much higher (prohibitive) for SARIMA.

The objective or aim of this review was to determine a relation between the level of realized physical activity and the reduction of the risk of death in hypertensive patients. A search was conducted for the identification of the documents from this review that included epidemiological cohort studies, relevant publications were identified in the biomedical databases PubMed and Cochrane Collaboration, the search strategy follows the recommendations of PRISMA. The results showed that an association exists between the level of physical activity and the risk of death in patients with hypertension. There was a diminution of death that ranges between 17-67 % in the hypertensive ones that do high physical activity levels. The results support the theory that regular physical activity is associated with a reduction in the rates of mortality in hypertensive patients and it is suggested that this protective effect can be of great benefit in a lower incidence of disease and cardiovascular death. In addition it is noted that the studies that consider ages of 40 to 80 years, the reduction of relative risk was 28-67%. Thus it is suggested that physical activity is likely to generate higher profits in the older age groups.

El artículo analiza el trato eufemístico y metodológico que a través de la historia se le ha dado a la pobreza y la exclusión social en el mundo, particularmente en Colombia, concibiéndola como un fenómeno coyuntural y metodológico, y encubriendo sus verdaderas causas estructurales. Igualmente, se hace una crítica a las políticas de desarrollo impulsadas por organismos multilaterales y por el Gobierno colombiano, se resalta que no han tenido una continuidad y que, por el contrario, obedecen a fenómenos coyunturales. La investigación se fun - damenta en la teoría de los sistemas examinando la mutación estadística de los pobres con el nuevo calificativo de clase vulnerable . Los resultados evidencian una descontextualización de la miseria y un trato eufemístico que con guarismos, y benevolencia solapada de principialismo bioético, frustran el presente, y con proyecciones inalcanzables condenan el futuro de un alto porcentaje de la población.

Abstract Background The rapid adoption of next-generation sequencing provides an efficient system for detecting somatic alterations in neoplasms. The detection of such alterations requires a matched non-neoplastic sample for adequate filtering of non-somatic events such as germline polymorphisms. Non-neoplastic tissue adjacent to the excised neoplasm is often used for this purpose as it is simultaneously collected and generally contains the same tissue type as the neoplasm. Following NGS analysis, we and others have frequently observed low-level somatic mutations in these non-neoplastic tissues, which may impose additional challenges to somatic mutation detection as it complicates germline variant filtering. Methods We hypothesized that the low-level somatic mutation observed in non-neoplastic tissues may be entirely or partially caused by inadvertent contamination by neoplastic cells during the surgical pathology gross assessment or tissue procurement process. To test this hypothesis, we applied a systematic protocol designed to collect multiple grossly non-neoplastic tissues using different methods surrounding each single neoplasm. The procedure was applied in two breast cancer lumpectomy specimens. In each case, all samples were first sequenced by whole-exome sequencing to identify somatic mutations in the neoplasm and determine their presence in the adjacent non-neoplastic tissues. We then generated ultra-deep coverage using targeted sequencing to assess the levels of contamination in non-neoplastic tissue samples collected under different conditions. Results Contamination levels in non-neoplastic tissues ranged up to 3.5 and 20.9 % respectively in the two cases tested, with consistent pattern correlated with the manner of grossing and procurement. By carefully controlling the conditions of various steps during this process, we were able to eliminate any detectable contamination in both patients. Conclusion The results demonstrated that the process of tissue procurement contributes to the level of contamination in non-neoplastic tissue, and contamination can be reduced to below detectable levels by using a carefully designed collection method. A standard protocol dedicated for acquiring adjacent non-neoplastic tissue that minimizes neoplasm contamination should be implemented for all somatic mutation detection studies.

El artículo analiza la crisis del sistema de salud colombiano sometido al modelo de economía de mercado con regulación estatal a partir de la Ley 100 de 1993. Su interés se centra en reflexionar sobre la concepción que el modelo da al gasto en salud como una inversión sometida a las fuerzas del mercado y consecuencialmente, con una tasa de rentabilidad esperada. Mediante el análisis de estadísticas oficiales y de encuestas de satisfacción de los usuarios se devela la crisis estructural que padece la prestación del servicio de salud pública como un sistema, involucrando variables económicas, políticas y sociales. La interdisciplinariedad del abordaje temático del estudio permite profundizar en el análisis desde la reflexión de los valores morales y éticos que debe acompañar la asistencia sanitaria, al igual que la visión económica de su administración. Bioética, salud y economía constituyen descriptores fácticos de un sistema en crisis estructural que alimenta la patología social de la pobreza.

This article focuses on the development of an engaging library orientation module for UC San Diego First Year Experience (FYE) courses. The library module included a brief in-class presentation about research concepts and library services, an online interactive library scavenger hunt given as an in-class activity, and a homework assignment where students created public service announcements highlighting their favorite library space or resource. Over 400 FYE students completed the library module, and many indicated a marked increase in comfort using the library by the end of the module. Recommended practices are included for those wishing to create a similar module.

Orientation: A need exists to investigate leader behaviour necessary to curb the corruption that has infected and weakened South Africa’s moral fibre. Such leader behaviour would need to be underpinned by a set of universal moral values. Research purpose: The purpose of this study was to develop a new measure, the principled leadership scale (PLS), by integrating the value-based behaviours inherent in transformational, servant, authentic and ethical leadership. Motivation for the study: Leader behaviour intrinsic to value-based leadership was found to be closely aligned with universal moral values. Because the study found a considerable overlap between the behaviours mentioned in the value-based leadership theories, it sought to integrate these behaviours under one construct and to develop a reliable and valid scale to assess this construct. Research approach/design and method: Data from the quantitative study were analysed by means of item analysis, exploratory and confirmatory bi-factor analysis conducted via structural equation modelling. Main findings: The confirmatory bi-factor solution corroborated a strong general principled leadership factor and four moderately weak group factors. The statistical analyses provided good fit of the PLS measurement model with the empirical data. Practical and managerial implications: The study found acceptable measurement properties of the PLS that may be used for applications, such as the selecting, training and developing of ethical leadership in organisations. Contribution/value-add: The study adds value in that it is the first to integrate the four value-based leadership theories under one construct and to develop a potential psychometrically sound instrument to measure principled leadership.

The pedagogical effectiveness of active learning methods within university teaching, such as simulations, has been widely acknowledged. There is some evidence that simulations are effective tools at engaging students in the classroom. Yet, empirical evidence of actual impacts on learning are not as well-documented as they could be. Importantly however, little work has been done to see their contribution and impact as an outreach and recruitment tool to bring new students into the social sciences discipline. This article builds on the assumption that simulations can prove effective when used as university outreach tools to enhance interest in pursuing higher education study. We argue that EU-related simulations engaging students in secondary education stimulate their interest in studying European politics and, more generally, international relations at university level. The article relies on data collected through pre- and post-simulation questionnaires completed by the pupils who participated in simulations that took place in six secondary schools between 2016 and 2017. The empirical investigation reveals three key effects of those simulations. First, the simulations enhanced the participants’ interest in pursuing university degrees associated with European Union (EU) politics. Second, the simulations increased the participants’ self-assessed knowledge of EU politics. Third, the simulations consolidated the participants’ perceived importance of understanding how the EU works. Overall, these findings back our claim that EU-related simulations may be used as outreach tools to boost interest in pursuing EU-related subjects in higher education. In the context of the ongoing Brexit process, such a boost is desirable as the understanding of EU politics will continue to be relevant for the future generations of British students.

Burkholderia pseudomallei causes melioidosis, a common source of pneumonia and sepsis in Southeast Asia and Northern Australia that results in high mortality rates. A caprine melioidosis model of aerosol infection that leads to a systemic infection has the potential to characterize the humoral immune response. This could help identify immunogenic proteins for new diagnostics and vaccine candidates. Outbred goats may more accurately mimic human infection, in contrast to the inbred mouse models used to date. B. pseudomallei infection was delivered as an intratracheal aerosol. Antigenic protein profiling was generated from the infecting strain MSHR511. Humoral immune responses were analyzed by ELISA and western blot, and the antigenic proteins were identified by mass spectrometry. Throughout the course of the infection the assay results demonstrated a much greater humoral response with IgG antibodies, in both breadth and quantity, compared to IgM antibodies. Pre-infection sera showed multiple immunogenic proteins already reactive for IgG (7-20) and IgM (0-12) in most of the goats despite no previous exposure to B. pseudomallei. After infection, the number of IgG reactive proteins showed a marked increase as the disease progressed. Early stage infection (day 7) showed immune reaction to chaperone proteins (GroEL, EF-Tu, and DnaK). These three proteins were detected in all serum samples after infection, with GroEL immunogenically dominant. Seven common reactive antigens were selected for further analysis using ELISA. The heat shock protein GroEL1 elicited the strongest goat antibody immune response compared to the other six antigens. Most of the six antigens showed the peak IgM reactivity at day 14, whereas the IgG reactivity increased further as the disease progressed. An overall MSHR511 proteomic comparison between the goat model and human sera showed that many immune reactive proteins are common between humans and goats with melioidosis.

Herpes simplex virus type 1 and type 2 (HSV-1 & HSV-2) are one of the leading causes of ulcer and blister lesions worldwide. These infections are latent with recurrences but many people may have a seropositive antibody yet remain asymptomatic. Although HSV presenting with hypertrophic lesions have been reported in the literature at urogenital, lung, and conjunctival sites, we describe a case of a mass lesion in the nasal cavity of a 46 year-old female with a history of human immunodeficiency virus (HIV). The patient presented initially with nasal congestion and subsequently developed facial edema. The mass lesion regressed after one month of treatment with valacyclovir. Keywords: Nasal hypertrophic lesion, Nasal pseudotumor, Herpes simplex virus, Human immunodeficiency virus

Although a critical tradition has existed in the social work profession since its inception more than a century ago, a distinct and internally diverse critical social work canon emerged only in the 1960s and 1970s. Substantial structural changes over the past four decades, including the rise of globalisation and market driven approaches to the management of human services, already threaten the continuation of critical practice traditions in social work. Indeed, some critical social workers have declared the halcyon days of activist practice have now passed. The paper reviews contemporary contests from within the critical tradition to the core assumptions of critical practice theory. These challenges arise from practice, from critical analyses of the changing environment of public administration and from postmodern analyses. It is argued that these contests provide sites for the reinvention of critical practice theory towards more collaborative and open ended approaches to activism in social work. By recognising the challenges from within, critical social workers can strengthen and diversify their capacity to forge critical approaches relevant to social work in the 21st century.

Anxiety is an important comorbidity in chronic obstructive pulmonary disease (COPD). We investigated if cognitive behavioural therapy (CBT), delivered by respiratory nurses, reduced symptoms of anxiety and was cost-effective. Patients with COPD and anxiety were randomised to CBT or self-help leaflets. Anxiety, depression and quality of life were measured at baseline, 3, 6 and 12 months. A cost-effectiveness analysis was conducted from a National Health Service hospital perspective and quality-adjusted life-years estimated using the EuroQol-5D questionnaire. In total, 279 patients were recruited. Group mean change from baseline to 3 months in the Hospital Anxiety and Depression Anxiety Subscale was 3.4 (95% CI 2.62–4.17, p

The responsibility for producing safe and competent health care professionals rests with educators who periodically evaluate and modify curricula to meet program outcomes (Atcherson, Zraick & Hadden, 2017; Coleman, Peterson-Perry, & Bumsted, 2016; Kennard, 2016; Mosley & Taylor, 2017; Toronto & Weatherford, 2015). The association between client safety and effective communication is increasingly recognized in research (Wolf & Bailey, 2009). Communication strategies used to help clients understand and follow health teachings are fundamental to health literacy (HL) education (Agency for Healthcare Research and Quality, 2017). Recently, more health professions educators are integrating necessary HL concepts and evaluating the effectiveness of curricular efforts (Massey et al., 2017). Despite increasing integration of HL concepts into the curricula, teaching strategies and evaluation efforts vary greatly, in part due to the heterogeneity encompassed by the term “health professions education.” In the United States, the education continuum spans from the undergraduate (2-year and 4-year college degrees and pre-professional education; Campus Explorer, 2018) to the postgraduate or professional degrees of medicine, pharmacy, dentistry, and others. Because we teach in a 4-year nursing program, we use the term “undergraduate” to describe students who have not yet completed their baccalaureate degrees.

La mayor exigencia de los clientes en el cumplimiento de las especificaciones de los productos ha implicado que las industrias aumenten esfuerzos en el análisis y control de las características del producto a lo largo de su producción. El control estadístico multivariado es una herramienta que permite evaluar el cumplimiento de las especificaciones de un producto cuando para determinar su conformidad este tiene dos o más características relacionadas. El objetivo de este artículo consiste en la aplicación del control estadístico multivariado para medir la capacidad del proceso de fabricación de resortes de compresión en acero inoxidable, teniendo en cuenta que este producto es conforme si se cumplen en simultáneo diferentes características. En este estudio se realizó la carta de control multivariada para determinar los parámetros del proceso y luego se calculó el índice de capacidad multivariado para revisar cumplimiento. Los resultados permitieron evidenciar que el proceso en la fase inicial estaba en control y era capaz de cumplir las especificaciones, pero luego en la segunda fase se encontró un proceso con alta variabilidad y poca capacidad de cumplimiento.

Using a mobile device, the user could access the map application anywhere you go. The study was developed to determine the best path from one location to another using GPS Satellite. It has three features: Searching, Detecting, and Logbook. The user can input the starting location and destination anywhere on land through searching using the Shortest Path Algorithm. Based on the inputted location given by the user, the list of available routes will be determined which enables the user to select one from a set of possible routes. Afterward, the application will detect which path that the user will take to reach their destination applicable anywhere in the world through GPS satellite. It identifies the current location of the person and once the user moves from his current location to another location, the GPS will update every 20 seconds so that all possible routes with the number of kilometers will give the user to choose the shortest route. After the completion of the Google Map application, it was found out that this application can be used worldwide. It can detect routes anywhere in the world by using arrays (from JSON) as data provided from the satellite as long as travel is on land.

Objective: To describe the clinical and sociodemographic characteristics of geriatric patients who were treated at a university hospital in southern Colombia. Methods: A database of trauma patients over 65 admitted between June 2014 and December 2015 was constructed. Univariate analysis was performed. Measures of central tendency and dispersion for continuous variables were calculated. >Results: A total of 760 patients were analyzed, the median age was 74 years (65–98). The median injury severity score was 9 (4–25) the 71.97% were men, and overall mortality was 25.39%. The 92.10% was blunt trauma, and the main mechanism of injury was falls. >Conclusions: Trauma in the elderly is a common condition with high risk of mortality. It is important to know the frequency of these injuries to provide the best possible handling. In our hospital we found that geriatric trauma is a common disease, the main cause is falls without embargos traffic accidents are common in this population.

A National Immunization Program Review (NIP Review) is a comprehensive external assessment of the performance of a country's immunization programme. The number of recommended special-topic NIP assessments, such as those for vaccine introduction or vaccine management, has increased. These assessments often have substantial overlap with NIP reviews, raising concern about duplication. Innovative technical and management approaches, including integrating several assessments into one, were applied in the United Republic of Tanzania's 2015 NIP Review. These approaches and processes were documented and a post-Review survey and group discussion. The Tanzania Review found that integrating assessments so they can be conducted at one time was feasible and efficient. There are concrete approaches for successfully managing a Review that can be shared and practiced including having a well-planned desk review and nominating topic-leads. The use of tablets for data entry has the potential to improve Review data quality and timely analysis; however, careful team training is needed. A key area to improve was to better coordinate and link findings from the national-level and field teams.

An introduction to the new special section of the journal, Teaching, Learning and the Profession that outlines the five articles and encourages future submissions.

Background: Oral vancomycin is a first line treatment for an initial episode of Clostridioides difficile infection. However, the comparative efficacy of different dosing regimens is lacking evidence in the current literature. Methods: We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. from inception to May 2019. Only articles published in English are reviewed. This meta-analysis compares the effects of low dose oral vancomycin (Clostridioides difficile infection. Results: One randomized controlled trial and two retrospective cohort studies are included. A total of 137 patients are identified, 53 of which were treated with low dose oral vancomycin (39%) and 84 with high dose oral vancomycin (61%). There is no significant reduction in recurrence rates with high dose vancomycin compared to low dose vancomycin for treating initial episodes of non-fulminant Clostridioides difficile infection ((odds ratio (OR) 2.058, 95%, confidence interval (CI): 0.653 to 6.489). Conclusions: Based on limited data in the literature, low dose vancomycin is no different than high dose vancomycin for treatment of an initial episode of Clostridioides difficile infection in terms of recurrence rate. Additional large clinical trials comparing the different dosages of vancomycin in initial Clostridioides difficile infection are warranted.

The presence of Candida albicans in the biofilm underlying the dental prosthesis is related to denture stomatitis (DS), an inflammatory reaction of the oral mucosa. The oral epithelium, a component of the innate immune response, has the ability to react to fungal invasion. In this study, we evaluated the in vitro effect of viable C. albicans on the apoptosis, nitric oxide (NO) production, and β-defensin 2 (hBD-2) expression and production of human palate epithelial cells (HPECs). We further determined whether or not these effects were correlated with fungal invasion of epithelial cells. Interaction between HPEC primary culture and C. albicans was obtained through either direct or indirect cell−cell contact with a supernatant from a hyphal fungus. We found that the hyphae supernatants were sufficient to induce slight HPEC apoptosis, which occurred prior to the activation of the specific mechanisms of epithelial defense. The epithelial defense responses were found to occur via NO and antimicrobial peptide hBD-2 production only during direct contact between C. albicans and HPECs and coincided with the fungus’s intraepithelial invasion. However, although the hBD-2 levels remained constant in the HPEC supernatants over time, the NO release and hBD-2 gene expression were reduced at a later time (10 h), indicating that the epithelial defense capacity against the fungal invasion was not maintained in later phases. This aspect of the immune response was associated with increased epithelial invasion and apoptosis maintenance.

Global transcriptome studies can help pinpoint key cellular pathways exploited by viruses to replicate and cause pathogenesis. Previous data showed that laboratory-adapted HIV-1 triggers significant gene expression changes in CD4+ T cell lines and mitogen-activated CD4+ T cells from peripheral blood. However, HIV-1 primarily targets mucosal compartments during acute infection in vivo. Moreover, early HIV-1 infection causes extensive depletion of CD4+ T cells in the gastrointestinal tract that herald persistent inflammation due to the translocation of enteric microbes to the systemic circulation. Here, we profiled the transcriptome of primary intestinal CD4+ T cells infected ex vivo with transmitted/founder (TF) HIV-1. Infections were performed in the presence or absence of Prevotella stercorea, a gut microbe enriched in the mucosa of HIV-1-infected individuals that enhanced both TF HIV-1 replication and CD4+ T cell death ex vivo. In the absence of bacteria, HIV-1 triggered a cellular shutdown response involving the downregulation of HIV-1 reactome genes, while perturbing genes linked to OX40, PPAR and FOXO3 signaling. However, in the presence of bacteria, HIV-1 did not perturb these gene sets or pathways. Instead, HIV-1 enhanced granzyme expression and Th17 cell function, inhibited G1/S cell cycle checkpoint genes and triggered downstream cell death pathways in microbe-exposed gut CD4+ T cells. To gain insights on these differential effects, we profiled the gene expression landscape of HIV-1-uninfected gut CD4+ T cells exposed to bacteria. Microbial exposure upregulated genes involved in cellular proliferation, MAPK activation, Th17 cell differentiation and type I interferon signaling. Our findings reveal that microbial exposure influenced how HIV-1 altered the gut CD4+ T cell transcriptome, with potential consequences for HIV-1 susceptibility, cell survival and inflammation. The HIV-1- and microbe-altered pathways unraveled here may serve as a molecular blueprint to gain basic insights in mucosal HIV-1 pathogenesis.

O câncer de colo uterino é mundialmente o quarto tipo de câncer entre as mulheres, e a neoplasia intraepitelial cervical (NIC) é a lesão precursora deste tipo de câncer, sendo importante a análise de fatores que estariam relacionados à persistência ou recorrência deste tipo de lesão. O presente estudo realizou o levantamento das biópsias excisionais da zona de transformação do colo uterino realizadas no Hospital Universitário da Universidade Federal de Juiz de Fora, no período de 2009 a 2012, a fim de se analisar o grau histológico das lesões (neoplasia intraepitelial cervical grau I, II ou III) e status da margem destas, correlacionando estes dados à possível detecção de doença recorrente ou persistente. Trata-se de um estudo retrospectivo que analisou resultados histopatológicos de material da excisão da zona de transformação (EZT) do colo uterino de pacientes com diagnóstico de neoplasia intraepitelial cervical grau I, II ou III, realizados entre os anos de 2009 a 2012, levando-se em consideração tipo de lesão diagnosticada neste exame, status da margem, presença de substituição glandular e ocorrência de doença persistente/recorrente, esta última avaliada através de exames citológicos e histopatológicos feitos até 24 meses após a excisão da zona de transformação. A média de idade das pacientes foi de 32 anos. Verificou-se que a maior parte das pacientes que tiveram margem comprometida apresentou NICIII como lesão ao diagnóstico da EZT. Assim, nesta análise, o tipo de lesão ao diagnóstico da biópsia excisional (EZT) interfere em se ter a margem comprometida ou não. A maioria das pacientes (63%) não apresentou recidiva e não teve margem comprometida (76%) e entre as pacientes que recidivaram (36%), grande parte também não possuía margem comprometida (70,7%), o que chama atenção para o fato de que mesmo pacientes com margens livres de lesão devem realizar seguimento adequado.

El artículo analiza el trato eufemístico y metodológico que a través de la historia se le ha dado a la pobreza y la exclusión social en el mundo, particularmente en Colombia, concibiéndola como un fenómeno coyuntural y metodológico, y encubriendo sus verdaderas causas estructurales. Igualmente, se hace una crítica a las políticas de desarrollo impulsadas por organismos multilaterales y por el Gobierno colombiano, se resalta que no han tenido una continuidad y que, por el contrario, obedecen a fenómenos coyunturales. La investigación se fun- damenta en la teoría de los sistemas examinando la mutación estadística de los pobres con el nuevo calificativo de clase vulnerable. Los resultados evidencian una descontextualización de la miseria y un trato eufemístico que con guarismos, y benevolencia solapada de principialismo bioético, frustran el presente, y con proyecciones inalcanzables condenan el futuro de un alto porcentaje de la población.

This research aimed to understand the social representations of the resolution of conflict in the household by mothers and daughters. The sample was constituted by four single mothers and four adolescents. On the other hand, qualitative techniques were applied in order to provide the desired information. In analyzing the results, it was found that after breaking up with the couple, mothers began to play new roles. One of them was the struggling mother, characterized by assuming financial responsibility for her family. Besides, daughters assumed the role of daughter in charge of home because of the conflicts that have taken place at home. It must be taken into account that instrumental or hostile aggression emerge to solve conflict to fulfill the role. Through this study, it was intended to understand the whole conflict and its importance for the family dynamics. So, it would be possible to establish intervention strategies which fit the population needs.

Zoanthids of the genus Palythoa are distributed worldwide in shallow waters around coral reefs. Like all cnidarians, they possess nematocysts that contain a large diversity of toxins that paralyze their prey. This work was aimed at isolating and functionally characterizing a cnidarian neurotoxic phospholipase named A2-PLTX-Pcb1a for the first time. This phospholipase was isolated from the venomous extract of the zoanthid Palythoa caribaeorum. This enzyme, which is Ca2+-dependent, is a 149 amino acid residue protein. The analysis of the A2-PLTX-Pcb1a sequence showed neurotoxic domain similitude with other neurotoxic sPLA2´s, but a different catalytic histidine domain. This is remarkable, since A2-PLTX-Pcb1a displays properties like those of other known PLA2 enzymes.

Antecedentes: El trigo (Triticum aestivum) es un alimento con alto valor nutricional ampliamente disponible en diferentes alimentos procesados. La prevalencia de la alergia al trigo es de 0.4-1.3 % en niños y de 0.2-0.9 % en adultos en estudios de Europa y Estados Unidos. En Colombia, la frecuencia de sensibilización a las harinas en pacientes con sospecha de alergia es de 4.7 %. Objetivo: Describir un caso de alergia al trigo de inicio en la adultez en Medellín, Colombia. Reporte de caso: Hombre de 71 años quien fue remitido por cuadro clínico de 30 años de evolución de múltiples episodios consistente en erupciones generalizadas producidas entre 15 y 20 minutos después del consumo de pan, galletas y pastas, no asociadas con síntomas respiratorios o gastrointestinales. Como antecedentes de importancia presentaba síntomas similares con la ingesta de aspirina, dipirona y diclofenaco. Toleraba 1 g de acetaminofén. Al paciente se le hizo historia clínica detallada que fue compatible con alergia al trigo; posteriormente se le realizó pruebas séricas y cutáneas de alimentos con resultado positivo. Se le indicó al paciente la restricción estricta del consumo de productos con trigo. Conclusiones: La presencia de esta alergia no es comúnmente reportada y la resolución no siempre sigue el curso natural de la enfermedad, lo cual puede estar relacionado con la edad de inicio de los síntomas y porque los valores de IgE específica no muestran un buen desempeño diagnóstico.

Apart from conventional understandings of its utilitarian function as spatial labels (often eponymous in character), toponymy is seldom appreciated as palimpsest or for the layers of meaning it assumes, conveyed in place-name etymologies and local knowledge associated with the named places. Over the years, a growing body of literature has emerged on the use of toponymy in several research fields: the range spans from linguistic investigations into place-names and naming practices to the use of place-names in tracking environmental change, locating places of archaeological interest and understanding the knowledge possessed by local communities about the natural environment. The latter focus describes place-names research with Tl’azt’en Nation, the Dakelh-speaking people whose territory lies in the Stuart-Trembleur watershed of central British Columbia, Canada. From the perspective that indigenous place-names communicate knowledge about the natural world, indigenous language and(oral) history, this paper will draw upon examples of Dakelh place-names to put forth the argument that toponymy should be considered in curriculum not only as a means to educate about local geography and history, but to instill awareness and appreciation of, as in the case of indigenous place-names, other epistemologies or non-western ways of understanding the world.

The Council acknowledges specific comments from: The American Academy of Allergy, Asthma and Immunology (AAAAI) (Amal H Assa'ad); The American College of Allergy, Asthma and Immunology (ACAAI) (Mark Dykewicz, D. Betty Lew, Bryan L. Martin); The Argentine Association of Allergy and Immunology (Ledit RF Ardusso); The Argentine Society of Allergy and Immunopathology (Estrella Asayag); The Australasian Society of Clinical Immunology and Allergy (ASCIA) (Jill Smith); The British Society for Allergy and Clinical Immunology (Stephen Durham); The Brazilian Society of Allergy and Immunopathology (Nelson Rosario); The Bulgarian Society of Allergology (Vasil Dimitrov); The Canadian Society of Allergy and Clinical Immunology (CSACI) (Richard Warrington); The Chilean Society of Allergy and Immunology (Jessica Salinas); The Chinese Society of Allergology (Zhang Hongyu, Yin Jia); The Czech Society of Allergology and Clinical Immunology (Jiri Litzman); The Danish Society of Allergology (Lone Winther, Peter Plaschke); The Egyptian Society of Allergy and Clinical Immunology (Kamal Maurice Hanna); The Egyptian Society of Pediatric Allergy and Immunology (Yehia El-Gamal); The German Society for Allergy and Clinical Immunology (Thilo Jakob, Claus Bachert, Bernhard Przybilla); The Hungarian Society of Allergology and Clinical Immunology (Kristof Nekam); The Icelandic Society of Allergy and Clinical Immunology (Björn R. Lúðvíksson); The Italian Association of Territorial and Hospital Allergists (Riccardo Asero); The Italian Society of Allergy and Clinical Immunology (Luigi Fontana); The Japanese Society of Allergology (Sankei Nishima); The Korean Academy of Asthma Allergy and Clinical Immunology (Joon Sung Lee, Hae-Sim Park); The Latvian Association of Allergists (Ieva Cirule); The Lebanese Society of Allergy & Immunology (Fares Zaitoun); The Mongolian Society of Allergology (S. Munkhbayarlakh); The Allergy and Clinical Immunology Society (Singapore) (Chng Hiok Hee); The Allergy Society of South Africa (Sharon Kling); The Spanish Society of Allergy and Clinical Immunology (Tomás Chivato); The Swiss Society for Allergology and Immunology (SSAI-SGAI) (Beat A. Imhof, Andreas Bircher); The Allergy and Immunology Society of Thailand (Pakit Vichyanond); The Turkish National Society of Allergy and Clinical Immunology (Omer Kalayci); and The Venezuelan Society of Allergy, Asthma and Immunology (Luis F Sarmiento). Keywords: Undergraduate Medical Education, Training and Competencies in Allergy

The Canadian North Helicobacter pylori (CANHelp) working group is a team composed of investigators, health officials and community leaders from Alberta and the Northwest Territories. The group’s initial goals are to investigate the impact of H pylori infection on Canada’s Arctic communities; subsequent goals include identifying treatment strategies that are effective in this region and developing recommendations for health policy aimed at management of H pylori infection. The team’s investigations have begun with the Aklavik H pylori Project in the Aboriginal community of Aklavik, Northwest Territories.

Remineralisation and transformation of dissolved organic matter (DOM) by marine microbes shape the DOM composition and thus, have large impact on global carbon and nutrient cycling. However, information on bacterioplankton-DOM interactions on a molecular level is limited. We examined the variation of bacterial community composition at Helgoland Roads (North Sea) in relation to variation of molecular DOM composition and various environmental parameters on short-time scales. Surface water samples were taken daily over a period of twenty days. Bacterial community and molecular DOM composition were assessed via 16S rRNA gene tag sequencing and ultrahigh resolution Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR-MS), respectively. Environmental conditions were driven by a coastal water influx during the first half of the sampling period and the onset of a summer phytoplankton bloom towards the end of the sampling period. These phenomena led to a distinct grouping of bacterial communities and DOM composition which was particularly influenced by total dissolved nitrogen concentration, temperature and salinity, as revealed by distance-based linear regression analyses. Bacterioplankton-DOM interaction was demonstrated in strong correlations between specific bacterial taxa and particular DOM molecules, thus, suggesting potential specialization on particular substrates. We propose that a combination of high resolution techniques, as used in this study, may provide substantial information on substrate generalists and specialists and thus, contribute to prediction of bacterial community composition variation.

Two studies investigated the role of group allegiances in contributing to the failure of institutions to appropriately respond to allegations of child sexual abuse. In Study 1, 601 participants read a news article detailing an allegation of child sexual abuse against a Catholic Priest. Catholics were more protective of the accused-and more skeptical of the accuser-than other participants, an effect that was particularly pronounced among strongly identified Catholics. In Study 2 (N = 404), the tendency for Catholics to be more protective of the accused and more skeptical of the accuser than non-Catholics was replicated. Moreover, these effects held independently of the objective likelihood that the accused was guilty. Overall, the data show that group loyalties provide a psychological motivation to disbelieve child abuse allegations. Furthermore, the people for whom this motivation is strongest are also the people who are most likely to be responsible for receiving and investigating allegations: highly identified ingroup members. The findings highlight the psychological mechanisms that may limit the ability of senior Church figures to conduct impartial investigations into allegations of child abuse within the Church.

INTRODUCTION:Congenital myopathies (CM) often affect contractile proteins of the sarcomere, which could render patients susceptible to exercise-induced muscle damage. We investigated if exercise is safe and beneficial in patients with CM. METHODS:Patients exercised on a stationary bike for 30 minutes, three times weekly, for 10 weeks at 70% of their maximal oxygen uptake (VO2max). Creatine kinase (CK) was monitored as a marker of muscle damage. VO2max, functional tests, and questionnaires evaluated efficacy. RESULTS:Sixteen patients with CM were included in a controlled study. VO2max increased by 14% (range, 6-25%; 95% CI 7-20; p < 0.001) in the seven patients who completed training, and tended to decrease in a non-intervention group (n = 7; change -3.5%; range, -11-3%, p = 0.083). CK levels were normal and remained stable during training. Baseline Fatigue Severity Scale scores were high, 4.9 (SE 1.9), and tended to decrease (to 4.4 (SE 1.7); p = 0.08) with training. Nine patients dropped out of the training program. Fatigue was the major single reason. CONCLUSIONS:Ten weeks of endurance training is safe and improves fitness in patients with congenital myopathies. The training did not cause sarcomeric injury, even though sarcomeric function is affected by the genetic abnormalities in most patients with CM. Severe fatigue, which characterizes patients with CM, is a limiting factor for initiating training in CM, but tends to improve in those who train. TRIAL REGISTRATION:The Regional Committee on Health Research Ethics of the Capital Region of Denmark H-2-2013-066 and ClinicalTrials.gov H2-2013-066.

Algae are at the base of the aquatic food chain, producing the food resources that fish are adapted to consume. Previous studies have proven that the inclusion of small amounts (

Mycobacterium avium complex (MAC) infections rarely affect the pleura, accounting for 5–15% of pulmonary MAC. We report a case of MAC pleural effusion in an otherwise immunocompetent young patient. A 37-year-old healthy female with no past medical history was admitted to the hospital with two weeks of right sided pleuritic chest pain, productive cough, and fever. She was febrile, tachycardic, and tachypneic with signs of right sided pleural effusion which were confirmed by chest X-ray and chest CT. Thoracentesis revealed lymphocytic predominant exudative fluid. The patient underwent pleural biopsy, bronchoscopy with bronchoalveolar lavage, and video assisted thoracoscopic surgery (VATS), all of which failed to identify the causative organism. Six weeks later, MAC was identified in the pleural fluid and pleural biopsy by DNA hybridization and culture. The patient was started on clarithromycin, ethambutol, and rifampin. After six months of treatment, she was asymptomatic with complete radiological resolution of the effusion. The presence of lymphocytic effusion should raise the suspicion for both tuberculous and nontuberculous mycobacterial disease. Pleural biopsy must be considered to make the diagnosis. Clinicians must maintain a high index of suspicion of MAC infection in an otherwise immunocompetent patient presenting with a unilateral lymphocytic exudative effusion.

An introduction to the new special section of the journal, Teaching, Learning and the Profession that outlines the five articles and encourages future submissions.

Two human deaths caused by Australian bat lyssavirus (ABL) infection have been reported since 1996. Information was obtained from 205 persons (mostly adults from south Brisbane and the South Coast of Queensland), who reported potential ABL exposure to the Brisbane Southside Public Health Unit from November 1,1996, to January 31, 1999. Volunteer animal handlers accounted for 39% of potential exposures, their family members for 12%, professional animal handlers for 14%, community members who intentionally handled bats for 31%, and community members with contacts initiated by bats for 4%. The prevalence of Lyssavirus detected by fluorescent antibody test in 366 sick, injured, or orphaned bats from the area was 6%. Sequelae of exposure, including the requirement for expensive postexposure prophylaxis, may be reduced by educating bat handlers and the public of the risks involved in handling Australian bats.

Glucocorticoids (GCs) selectively trigger cell death in the multiple myeloma cell line MM1S which express NR3C1/Glucocorticoid Receptor (GR) protein, but fail to kill MM1R cells which lack GR protein. Given recent demonstrations of altered microRNA profiles in a diverse range of haematological malignancies and drug resistance, we characterized GC inducible mRNA and microRNA transcription profiles in GC sensitive MM1S as compared to GC resistant MM1R cells. Transcriptome analysis revealed that GCs regulate expression of multiple genes involved in cell cycle control, cell organization, cell death and immunological disease in MM1S cells, which remain unaffected in MM1R cells. With respect to microRNAs, mir-150-5p was identified as the most time persistent GC regulated microRNA, out of 5 QPCR validated microRNAs (mir-26b, mir-125a-5p, mir-146-5p, mir-150-5p, and mir-184), which are GC inducible in MM1S but not in MM1R cells. Functional studies further revealed that ectopic transfection of a synthetic mir-150-5p mimics GR dependent gene expression changes involved in cell death and cell proliferation pathways. Remarkably, despite the gene expression changes observed, overexpression of mir-150-5p in absence of GCs did not trigger significant cytotoxicity in MM1S or MM1R cells. This suggests the requirement of additional steps in GC induced cell death, which can not be mimicked by mir-150-5p overexpression alone. Interestingly, a combination of mir-150-5p transfection with low doses GC in MM1S cells was found to sensitize therapy response, whereas opposite effects could be observed with a mir-150-5p specific antagomir. Although mir-150-5p overexpression did not substantially change GR expression levels, it was found that mir-150-5p evokes GR specific effects through indirect mRNA regulation of GR interacting transcription factors and hormone receptors, GR chaperones, as well as various effectors of unfolded protein stress and chemokine signalling. Altogether GC-inducible mir-150-5p adds another level of regulation to GC specific therapeutic responses in multiple myeloma.

BackgroundIn a recent intervention study, the daily supplementation with 200 mg monomeric and oligomeric flavanols (MOF) from grape seeds for 8 weeks revealed a vascular health benefit in male smokers. The objective of the present study was to determine the impact of MOF consumption on the gene expression profile of leukocytes and to assess changes in DNA methylation.Methodology/principal findingsGene expression profiles were determined using whole genome microarrays (Agilent) and DNA methylation was assessed using HumanMethylation450 BeadChips (Illumina). MOF significantly modulated the expression of 864 genes. The majority of the affected genes are involved in chemotaxis, cell adhesion, cell infiltration or cytoskeleton organisation, suggesting lower immune cell adhesion to endothelial cells. This was corroborated by in vitro experiments showing that MOF exposure of monocytes attenuates their adhesion to TNF-α-stimulated endothelial cells. Nuclear factor kappa B (NF-κB) reporter gene assays confirmed that MOF decrease the activity of NF-κB. Strong inter-individual variability in the leukocytes' DNA methylation was observed. As a consequence, on group level, changes due to MOF supplementation could not be found.ConclusionOur study revealed that an 8 week daily supplementation with 200 mg MOF modulates the expression of genes associated with cardiovascular disease pathways without major changes of their DNA methylation state. However, strong inter-individual variation in leukocyte DNA methylation may obscure the subtle epigenetic response to dietary flavanols. Despite the lack of significant changes in DNA methylation, the modulation of gene expression appears to contribute to the observed vascular health effect of MOF in humans.

Withaferin A (WA) isolated from Withania somnifera (Ashwagandha) has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to different concentrations of WA which can be detected systemically in in vivo experiments. Whereas WA treatment demonstrated attenuation of multiple cancer hallmarks, the withanolide analogue Withanone (WN) did not exert any of the described effects at comparable concentrations. Pathway enrichment analysis revealed that WA targets specific cancer processes related to cell death, cell cycle and proliferation, which could be functionally validated by flow cytometry and real-time cell proliferation assays. WA also strongly decreased MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This was further supported by decreased gene expression of extracellular matrix-degrading proteases (uPA, PLAT, ADAM8), cell adhesion molecules (integrins, laminins), pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R) and concomitant increased expression of the validated breast cancer metastasis suppressor gene (BRMS1). In line with the transcriptional changes, nanomolar concentrations of WA significantly decreased protein levels and corresponding activity of uPA in MDA-MB-231 cell supernatant, further supporting its anti-metastatic properties. Finally, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking into account that sub-cytotoxic concentrations of WA target multiple metastatic effectors in therapy-resistant triple negative breast cancer, WA-based therapeutic strategies targeting the uPA pathway hold promise for further (pre)clinical development to defeat aggressive metastatic breast cancer.