The Role of Medications in Predicting Activity Restriction Due to a Fear of Falling

Objectives: To examine the role of medication use and other factors in predicting activity restriction due to a fear of falling (AR/FF). Methods: Older adults were assessed twice with the interRAI Community Health Assessment and the Berg Balance Scale (BBS). The main outcome was limiting going outdoors due to an AR/FF. Medications were recorded by trained assessors. Results: Participants (n=441) had a mean age of 80.3 (sd=7.1) years, most were aged 65+ (96.8%) and 29.3% reported activity restriction. Taking nervous system active or cardiovascular medications was associated with AR/FF. In a multivariate model, the main predictors were having 3+ comorbid health conditions, lower (i.e., worse) scores on the BBS, having difficulty with climbing stairs, and having a visual impairment. Discussion: Modifiable risk factors, related to functional impairments, such as difficulties with balance and vision, appear to be more important predictors than medications

New Insights into the Pathogenesis of Ovarian Cancer: Oxidative Stress

Ovarian cancer is the leading cause of death from gynecologic malignancies yet the underlying pathophysiology is not clearly established. Epithelial ovarian cancer (EOC) has long been considered a heterogeneous disease with respect to histopathology, molecular biology, and clinical outcome. Treatment of ovarian cancer includes a combination of cytoreductive surgery and combination chemotherapy, with platinums and taxanes. Despite initial success, over 75% of patients with advanced disease will relapse around 18 months and the overall 5-year survival is approximately 50%. Cancer cells are known to be under intrinsic oxidative stress, which alters their metabolic activity and reduces apoptosis. Epithelial ovarian cancer has been shown to manifest a persistent pro-oxidant state as evident by the upregulation of several key oxidant enzymes in EOC tissues and cells. In the light of our scientific research and the most recent experimental and clinical observations, this chapter provides the reader with up to date most relevant findings on the role of oxidative stress in the pathogenesis and prognosis of ovarian cancer, as well as a novel mechanism of apoptosis/survival in EOC cells

Plant-Derived Polyphenols Modulate Human Dendritic Cell Metabolism and Immune Function via AMPK-Dependent Induction of Heme Oxygenase-1

Polyphenols are important immunonutrients which have been investigated in the context of inflammatory and autoimmune disease due to their significant immunosuppressive properties. However, the mechanism of action of many polyphenols is unclear, particularly in human immune cells. The emerging field of immunometabolism has highlighted the significance of metabolic function in the regulation of immune cell activity, yet the effects of polyphenols on immune cell metabolic signaling and function has not been explored. We have investigated the effects of two plant-derived polyphenols, carnosol and curcumin, on the metabolism of primary human dendritic cells (DC). We report that human DC display an increase in glycolysis and spare respiratory capacity in response to LPS stimulation, which was attenuated by both carnosol and curcumin treatment. The regulation of DC metabolism by these polyphenols appeared to be mediated by their activation of the cellular energy sensor, AMP-activated Protein Kinase (AMPK), which resulted in the inhibition of mTOR signaling in LPS-stimulated DC. Previously we have reported that both carnosol and curcumin can regulate the maturation and function of human DC through upregulation of the immunomodulatory enzyme, Heme Oxygenase-1 (HO-1). Here we also demonstrate that the induction of HO-1 by polyphenols in human DC is dependent on their activation of AMPK. Moreover, pharmacological inhibition of AMPK was found to reverse the observed reduction of DC maturation by carnosol and curcumin. This study therefore describes a novel relationship between metabolic signaling via AMPK and HO-1 induction by carnosol and curcumin in human DC, and characterizes the effects of these polyphenols on DC immunometabolism for the first time. These results expand our understanding of the mechanism of action of carnosol and curcumin in human immune cells, and suggest that polyphenol supplementation may be useful to regulate the metabolism and function of immune cells in inflammatory and metabolic disease

Applicant Reactions to the AAMC Standardized Video Interview During the 2018 Application Cycle

PURPOSE: This study examined applicant reactions to the Association of American Medical Colleges (AAMC) Standardized Video Interview (SVI) during its first year of operational use in emergency medicine (EM) residency program selection in order to identify strategies to improve applicants\u27 SVI experience and attitudes. METHOD: Individuals who self-classified as EM applicants applying in the Electronic Residency Application Service 2018 cycle and completed the SVI in summer 2017 were invited to participate in two surveys. Survey 1, which focused on procedural issues, was administered immediately after SVI completion. Survey 2, which focused on applicants\u27 SVI experience, was administered in fall 2017, after SVI scores were released. RESULTS: The response rates for surveys 1 and 2 were 82.3% (2,906/3,532) and 58.7% (2,074/3,532), respectively. Applicant reactions varied by aspect of the SVI studied and their SVI total scores. Most applicants were satisfied with most procedural aspects of the SVI, but most applicants were not satisfied with the SVI overall or with their total SVI scores. About 20-30% of applicants had neutral opinions about most aspects of the SVI. Negative reactions to the SVI were stronger for applicants who scored lower on the SVI. CONCLUSIONS: Applicants had generally negative reactions to the SVI. Most were skeptical of its ability to assess the target competencies and its potential to add value to the selection process. Applicant acceptance and appreciation of the SVI will be critical to the SVI\u27s acceptance by the graduate medical education community

The AAMC Standardized Video Interview: Reactions and Use by Residency Programs During the 2018 Application Cycle

PURPOSE: To evaluate how emergency medicine (EM) residency programs perceived and used Association of American Medical Colleges (AAMC) SVI total scores and videos during the Electronic Residency Application Service (ERAS) 2018 cycle. METHOD: Study 1 (November 2017) used a program director survey to evaluate user reactions to the SVI following the first year of operational use. Study 2 (January 2018) analyzed program usage of SVI video responses using data collected through the AAMC Program Director\u27s Workstation. RESULTS: Results from the survey (125/175 programs, 71% response rate) and video usage analysis suggested programs viewed videos out of curiosity and to understand the range of SVI total scores. Programs were more likely to view videos for attendees of U.S. MD-granting medical schools and applicants with higher United States Medical Licensing Examination Step 1 scores, but there were no differences by gender or race/ethnicity. More than half of programs that did not use SVI total scores in their selection processes were unsure of how to incorporate them (36/58, 62%) and wanted additional research on utility (33/58, 57%). More than half of programs indicated being at least somewhat likely to use SVI total scores (55/97; 57%) and videos (52/99; 53%) in the future. CONCLUSIONS: Program reactions on the utility and ease of use of SVI total scores were mixed. Survey results indicate programs used the SVI cautiously in their selection processes, consistent with AAMC recommendations. Future surveys of SVI users will help the AAMC gauge improvements in user acceptance and familiarity with the SVI

Undifferentiated round cell sarcoma with BCOR internal tandem duplications (ITD) or YWHAE fusions:a clinicopathologic and molecular study

Until recently, undifferentiated round cell sarcomas (URCS) in infants have been considered a wastebasket diagnosis, composed of various pathologic entities and lacking consistent genetic alterations. The recent identification of recurrent BCOR internal tandem duplications (ITD) and less common alternative YWHAE\u2013NUTM2B/E fusions in half of infantile URCS and the majority of so-called primitive myxoid mesenchymal tumors of infancy (PMMTI) suggests a common pathogenesis with clear cell sarcoma of the kidney which also harbors the same genetic alterations. These tumors also share a similar morphology and immunoprofile, including positivity for BCOR, cyclin D1, and SATB2. In this study, we investigate the largest cohort to date of genetically confirmed URCS and PMMTI with BCOR ITD or YWHAE fusions to better define their morphologic spectrum and clinical behavior. Twenty-eight cases harbored BCOR ITD and five YWHAE fusions, occurring in 29 infants and 4 children, 19 males and 14 females. Microscopically, 20 were classified as URCS and 13 as PMMTI. Follow-up was available in 25 patients, with 14 (56%) succumbing to their diseases at a mean duration of 18-months follow-up (range: 2\u201362). Six patients remained with no evidence of disease at a mean follow-up of 63 months (range: 4\u2013192), four patients were still alive with disease (mean follow-up: 46 months, range: 4\u2013120), and one died of other causes. Local recurrence and distant metastasis were each observed in 11/25 (44%) of the patients. The overall survival was 42% at 3 years and 34% at 5 years (median survival: 26 months). There was no statistically significant survival difference between cases diagnosed as URCS and PMMTI and between those with BCOR ITD and YWHAE fusions

Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids

Hepatic gluconeogenesis from amino acids contributes significantly to diabetic hyperglycemia, but the molecular mechanisms involved are incompletely understood. Alanine transaminases (ALT1 and ALT2) catalyze the interconversion of alanine and pyruvate, which is required for gluconeogenesis from alanine. We find that ALT2 is overexpressed in the liver of diet-induced obese and db/db mice and that the expression of the gene encoding ALT2 (GPT2) is downregulated following bariatric surgery in people with obesity. The increased hepatic expression of Gpt2 in db/db liver is mediated by activating transcription factor 4, an endoplasmic reticulum stress-activated transcription factor. Hepatocyte-specific knockout of Gpt2 attenuates incorporation o

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function

Evolutionary consequences of feedbacks between within-host competition and disease control

Lay Summary: Competition often occurs among diverse parasites within a single host, but control efforts could change its strength. We examined how the interplay between competition and control could shape the evolution of parasite traits like drug resistance and disease severity

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio