Lipotoxicity, aging, and muscle contractility: does fiber type matter?

Sarcopenia is a universal characteristic of the aging process and is often accompanied by increases in whole-body adiposity. These changes in body composition have important clinical implications, given that loss of muscle and gain of fat mass are both significantly and independently associated with declining physical performance as well as an increased risk for disability, hospitalizations, and mortality in older individuals. This increased fat mass is not exclusively stored in adipose depots but may become deposited in non-adipose tissues, such as skeletal muscle, when the oxidative capacity of the adipose tissue itself is exceeded. The redistributed adipose tissue is thought to exert detrimental local effects on the muscle environment given the close proximity. Thus, sarcopenia observed with aging may be better defined in the context of loss of muscle quality rather than loss of muscle quantity per se. In this perspective, we briefly review the age-related physiological changes in cellularity, secretory profiles, and inflammatory status of adipose tissue which drive lipotoxicity (spillover) of skeletal muscle and then provide evidence of how this may affect specific fiber type contractility. We focus on biological contributors (cellular machinery) to contractility for which there is some evidence of vulnerability to lipid stress distinguishing between fiber types.Accepted manuscrip

Quantifying and Monitoring Overdiagnosis in Cancer Screening: A Systematic Review of Methods

Introduction: To reduce overdiagnosis, we need accurate methods to quantify and monitor this phenomenon over time. Aims: To systematically review the methods that have been used for measuring overdiagnosis from cancer screening; to evaluate the strengths and weaknesses of each method. Methods: We searched PUBMED, EMBASE, and the Cochrane Library for primary research studies of any design that quantified overdiagnosis from cancer screening. We abstracted relevant data and appraised study design and methods using established criteria. Results: 49 studies met inclusion criteria. We grouped studies into four methodologic categories and found strengths and weaknesses with all designs. (1) Follow-up of a well-designed RCT (n=1) is theoretically an ideal method but requires substantial time, may not be generalizable, and is not suitable for monitoring. (2) Pathologic/imaging studies (n=8) that draw conclusions about overdiagnosis by examining the range of biological or behavioral characteristics among cancers are simpler in design but assume that these characteristics are highly correlated with progression. (3) Modeling studies (n=19) can be done in a shorter time frame but require complex mathematical equations simulating the natural history of screen-detected cancer, which is the fundamental unknown question. (4) Ecologic studies (n=21) are limited by a lack of agreed-upon standards, by variable data quality, by inadequate follow-up time, and by the potential for population-level confounders. Some ecologic studies, however, have used excellent methods; several of these studies from different geographic areas may together provide the best overall estimate of overdiagnosis and are ideal for monitoring it over time. Conclusions: Well-conducted ecologic studies in multiple settings should be used for quantifying and monitoring overdiagnosis in cancer screening programs. To support this work, we need internationally agreed-upon standards for ecologic studies and a multi-national team of unbiased researchers to perform analysis.Master of Public Healt

Association Between Internet Use and Body Dissatisfaction Among Young Females: Cross-Sectional Analysis of the Canadian Community Health Survey

Background: Recent research suggests Internet exposure, including Facebook use, is positively correlated with body dissatisfaction, especially among girls and young women. Canada has one of the highest Internet access rates in the world, yet no previous study has examined this relationship using nationally representative data. Objective: Our objective was to evaluate the relationship between Internet use and body dissatisfaction among a national, population-based sample of Canadian females 12-29 years of age. Methods: We used cross-sectional data from the Canadian Community Health Survey 2011-2012. Body dissatisfaction was measured using a 5-point Likert scale and defined as “very dissatisfied/dissatisfied” with one’s body. The explanatory variable was time spent using the Internet per week in the past 3 months, ranging from none/<1 hour to >20 hours. We used multinomial logistic regression to investigate whether greater Internet use was associated with increasing odds of being very dissatisfied/dissatisfied, neutral, or satisfied with one’s body, using very satisfied as the referent. Probability survey sampling weights were applied to all analyses. Results: Of 2983 included participants, sampled to represent 940,786 young Canadian females, most were 20-29 years old (61.98%) and living in households with an annual income Can $80,000 or more (44.61%). The prevalence of body dissatisfaction was 14.70%, and 25- to 29-year-olds were more likely than 12- to 14-year-olds to be very dissatisfied or dissatisfied with their body (20.76% vs 6.34%). Few (5.01%) reported none/<1 hour of Internet use, over half (56.93%) reported 1-10 hours, and one-fifth (19.52%) reported spending >20 hours online per week. Adjusting for age and income, the odds of being very dissatisfied/dissatisfied, relative to very satisfied, were greater in the highest versus lowest Internet use group (adjusted odds ratio [AOR] 3.03, 95% CI 1.19-7.70). The AORs for this level of body dissatisfaction increased across increasing levels of Internet use, ranging from 0.88 (95% CI 0.35-2.21) to 3.03 (95% CI 1.19-7.70). Additionally, those who spent 11-14 hours online were more likely to be neutral (AOR 3.66, 95% CI 1.17-11.45) and those who spent 15-20 hours online were more likely to be neutral (AOR 4.36, 95% CI 1.18-16.13) or satisfied (AOR 2.82, 95% CI 1.14-7.01) with their bodies, relative to very satisfied, compared with those spending no time or <1 hour online. Conclusions: A substantial proportion of Canadian females 12-29 years of age spent large amounts of time (>20 hours) on the Internet each week, and body dissatisfaction was significantly more likely among this group. Those who spent 11-20 hours online were also more likely to be less satisfied with their bodies. Efforts are needed to support girls and young women to achieve and maintain a positive body image in today’s digital age

The Sewing Circle Model for Community Collaboration: A Multicultural Approach

Introduction Excerpt:The Cocke County Collaborative (a division of Community House Cooperative, Inc.) of Newport and Cocke County in East Tennessee developed a new model for collaboration. The model has drawn a host of interested people and organizations from across the country both in following the progress of the working model and partnering for community based projects..

A BIOMECHANICAL INVESTIGATION OF A SPANISH SQUAT: THE EFFECT OF TRUNK INCLINATION AND LOAD ON QUADRICEPS ACTIVITY AND PATELLAR TENDON FORCE

The Spanish squat targets the knee extensor muscles and has been suggested to be an appropriate rehabilitation exercise for patellar tendinopathy. This study provides novel empirical data on the effect of trunk inclination and load on quadricep muscle activity and patellar tendon load while performing the Spanish squat. The findings of this study informs on the progression and regression of the Spanish Squat and provides evidence to support the application of the Spanish squat in progressive tendon loading strategies in the treatment of PT

Critiquing Protein Family Classification Models Using Sufficient Input Subsets.

In many application domains, neural networks are highly accurate and have been deployed at large scale. However, users often do not have good tools for understanding how these models arrive at their predictions. This has hindered adoption in fields such as the life and medical sciences, where researchers require that models base their decisions on underlying biological phenomena rather than peculiarities of the dataset. We propose a set of methods for critiquing deep learning models and demonstrate their application for protein family classification, a task for which high-accuracy models have considerable potential impact. Our methods extend the Sufficient Input Subsets (SIS) technique, which we use to identify subsets of features in each protein sequence that are alone sufficient for classification. Our suite of tools analyzes these subsets to shed light on the decision-making criteria employed by models trained on this task. These tools show that while deep models may perform classification for biologically relevant reasons, their behavior varies considerably across the choice of network architecture and parameter initialization. While the techniques that we develop are specific to the protein sequence classification task, the approach taken generalizes to a broad set of scientific contexts in which model interpretability is essential

C/EBPβ-1 promotes transformation and chemoresistance in Ewing sarcoma cells.

CEBPB copy number gain in Ewing sarcoma was previously shown to be associated with worse clinical outcome compared to tumors with normal CEBPB copy number, although the mechanism was not characterized. We employed gene knockdown and rescue assays to explore the consequences of altered CEBPB gene expression in Ewing sarcoma cell lines. Knockdown of EWS-FLI1 expression led to a decrease in expression of all three C/EBPβ isoforms while re-expression of EWS-FLI1 rescued C/EBPβ expression. Overexpression of C/EBPβ-1, the largest of the three C/EBPβ isoforms, led to a significant increase in colony formation when cells were grown in soft agar compared to empty vector transduced cells. In addition, depletion of C/EBPβ decreased colony formation, and re-expression of either C/EBPβ-1 or C/EBPβ-2 rescued the phenotype. We identified the cancer stem cell marker ALDH1A1 as a target of C/EBPβ in Ewing sarcoma. Furthermore, increased expression of C/EBPβ led to resistance to chemotherapeutic agents. In summary, we have identified CEBPB as an oncogene in Ewing sarcoma. Overexpression of C/EBPβ-1 increases transformation, upregulates expression of the cancer stem cell marker ALDH1A1, and leads to chemoresistance

Quantifying and monitoring overdiagnosis in cancer screening: a systematic review of methods

Objective To determine the optimal method for quantifying and monitoring overdiagnosis in cancer screening over time.Design Systematic review of primary research studies of any design that quantified overdiagnosis from screening for nine types of cancer. We used explicit criteria to critically appraise individual studies and assess strength of the body of evidence for each study design (double blinded review), and assessed the potential for each study design to accurately quantify and monitor overdiagnosis over time.Data sources PubMed and Embase up to 28 February 2014; hand searching of systematic reviews.Eligibility criteria for selecting studies English language studies of any design that quantified overdiagnosis for any of nine common cancers (prostate, breast, lung, colorectal, melanoma, bladder, renal, thyroid, and uterine); excluded case series, case reports, and reviews that only reported results of other studies.Results 52 studies met the inclusion criteria. We grouped studies into four methodological categories: (1) follow-up of a well designed randomized controlled trial (n=3), which has low risk of bias but may not be generalizable and is not suitable for monitoring; (2) pathological or imaging studies (n=8), drawing conclusions about overdiagnosis by examining biological characteristics of cancers, a simple design limited by the uncertain assumption that the measured characteristics are highly correlated with disease progression; (3) modeling studies (n=21), which can be done in a shorter time frame but require complex mathematical equations simulating the natural course of screen detected cancer, the fundamental unknown question; and (4) ecological and cohort studies (n=20), which are suitable for monitoring over time but are limited by a lack of agreed standards, by variable data quality, by inadequate follow-up time, and by the potential for population level confounders. Some ecological and cohort studies, however, have addressed these potential weaknesses in reasonable ways.Conclusions Well conducted ecological and cohort studies in multiple settings are the most appropriate approach for quantifying and monitoring overdiagnosis in cancer screening programs. To support this work, we need internationally agreed standards for ecological and cohort studies and a multinational team of unbiased researchers to perform ongoing analysis

National drinking water targets – trends and factors associated with target-setting

We examine how national targets change with time and show that no consistent pattern exists across all countries examined for this article during the 1980–2013 period. Instead, countries fall into different trend types including constant, increasing, and decreasing national targets with time. We found that level of coverage is one likely factor in determining the national target of a country, where countries with low coverage levels set lower national targets compared to countries with high levels of coverage. In general, most countries set ambitious national targets that require the future rate of change to be more than 20% greater than the current rate. Setting ambitious targets is related to greater progress in increasing coverage, as long as the national target does not require countries to more than triple their current rate of change. Changes in national standards of safe water were shown to have occurred, where improved technology type was not used in national standards in 1994 but was present in 2011 and 2013. Comparison of national and international targets suggests that international targets may influence national targets, with approximately 70% of countries having national targets equal to, higher than, or converging towards international targets