Calibration of Multiple In Silico Tools for Predicting Pathogenicity of Mismatch Repair Gene Missense Substitutions

Classification of rare missense substitutions observed during genetic testing for patient management is a considerable problem in clinical genetics. The Bayesian integrated evaluation of unclassified variants is a solution originally developed for BRCA1/2. Here, we take a step toward an analogous system for the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) that confer colon cancer susceptibility in Lynch syndrome by calibrating in silico tools to estimate prior probabilities of pathogenicity for MMR gene missense substitutions. A qualitative five‐class classification system was developed and applied to 143 MMR missense variants. This identified 74 missense substitutions suitable for calibration. These substitutions were scored using six different in silico tools (Align‐Grantham Variation Grantham Deviation, multivariate analysis of protein polymorphisms [MAPP], MutPred, PolyPhen‐2.1, Sorting Intolerant From Tolerant, and Xvar), using curated MMR multiple sequence alignments where possible. The output from each tool was calibrated by regression against the classifications of the 74 missense substitutions; these calibrated outputs are interpretable as prior probabilities of pathogenicity. MAPP was the most accurate tool and MAPP + PolyPhen‐2.1 provided the best‐combined model (R² = 0.62 and area under receiver operating characteristic = 0.93). The MAPP + PolyPhen‐2.1 output is sufficiently predictive to feed as a continuous variable into the quantitative Bayesian integrated evaluation for clinical classification of MMR gene missense substitutions.     

National Athletic Trainers' Association Position Statement: Evaluation of Dietary Supplements for Performance Nutrition

Objectives

To help athletic trainers promote a “food-first” philosophy to support health and performance, understand federal and sport governing body rules and regulations regarding dietary supplements and banned substances, and become familiar with reliable resources for evaluating the safety, purity, and efficacy of dietary supplements.

Background

The dietary supplement industry is poorly regulated and takes in billions of dollars per year. Uneducated athletes need to gain a better understanding of the safety, eligibility, and efficacy concerns associated with choosing to take dietary supplements. The athletic trainer is a valuable athletic team member who can help in the educational process. In many cases, athletic trainers are asked to help evaluate the legality, safety, and efficacy of dietary supplements. For this position statement, our mission is to provide the athletic trainer with the necessary resources for these tasks.

Recommendations

Proper nutrition and changes in the athlete''s habitual diet should be considered first when improved performance is the goal. Athletes need to understand the level of regulation (or lack thereof) governing the dietary supplement industry at the international, federal, state, and individual sport-participation levels. Athletes should not assume a product is safe simply because it is marketed over the counter. All products athletes are considering using should be evaluated for purity (ie, truth in labeling), safety, and efficacy.Key Words: ergogenics, Dietary Supplement and Health Education Act, World Anti-Doping AgencyFoods and dietary supplements have been used to enhance health and athletic performance (ergogenics) since the early Olympic Games. Today, athletes at all levels of competition continually work to improve performance, and many consider the use of dietary supplements or engineered foods to gain an additional performance edge or health benefit. This may concern health care professionals because athletes may receive advice and feel pressure from many well-meaning supporters and advocates. However, athletes can be vulnerable to misinformation and risk in terms of the safety, legality, and efficacy of dietary supplements.Although determining overall rates of supplement use among athletes is difficult, estimates of use by collegiate, high school, and middle school athletes have been reported in the literature.^1–6 In a 2004 study by Burns et al,¹ 88% of the collegiate athletes surveyed used 1 or more nutritional supplements, yet the perceived efficacy of those supplements was only moderate. Athletic trainers (ATs) were their primary sources of nutrition information and were perceived to have significant nutrition knowledge. The 2012 “Substance Use” report compiled by the National Collegiate Athletic Association (NCAA) presented survey data from 20 474 US athletes and compared those data with 2005 outcomes.⁷ Although survey data are limited by the perceived anonymity of the results, they can be useful to better understand trends and potential risk factors.The overwhelming industry presence and advertising appeal likely has strong influence on athlete choices. According to the 2011 “Sports Nutrition and Weight Loss Report,”⁸ 9% annual sales growth and $22.7 billion in total sales were noted for sports nutrition and weight-loss products in 2010. Energy drinks and shots (small containers of concentrated product) were the primary product category ($12 million) and were purchased through mass channels. A December 2010 press release from the US Food and Drug Administration (FDA) regarding methylhexaneamine, which has been identified as the “new ephedra” (stimulant), anticipated continued reports of adverse events, failed drug tests, and product recalls. The release also cited consumer-trust issues in the supplement industry and the joining of forces by the FDA and major trade organizations to “clean up” the industry. Obviously, health care practitioners need to be aware of the trends in supplement use and the risks the supplements may carry for athletes'' health and sport eligibility.As health care professionals, ATs must be knowledgeable regarding basic nutrition and supplement use and must be able to educate their athletes regarding the efficacy, safety, and legal issues associated with the use of supplements. If they are not knowledgeable in these areas, ATs must be aware of resources for education and proper referral, so they can provide guidance for those within the athletic community. This position statement provides suggested resources to help ATs stay current in the ever-changing landscape of dietary supplements.To formalize the position statement objectives into recommendations, we used (where appropriate) evidence-based review and the Strength of Recommendation Taxonomy (SORT) criterion scale (9 and adopted by the National Athletic Trainers'' Association. Some of the educational materials regarding dietary supplements are found in federal law; these are noted in the recommendations.

Table. Strength of Recommendation Taxonomy (SORT)^a

A combined clinical,neuropsychological, and neuroanatomical study of adults with high functioning autism

Introduction. Three hypotheses concerning associations between neuroanatomical abnormalities, neuropsychological impairments, and the behavioural manifestations of autism were investigated. The primary hypothesis was that the social interaction impairments diagnostic of autism are associated with deficits of socioemotional perception and abnormalities of the amygdala. One subsidiary hypothesis was that the learning and language impairments that occur in less able individuals with autism are associated with impaired memory, and with abnormalities of hippocampal regions. A second subsidiary hypothesis was that the repetitive behaviour diagnostic of autism is associated with executive deficits and with abnormalities of the prefrontal cortex. Associations between the neuroanatomical regions investigated were also examined.Methods. Ten adult males with high functioning autism (HFA) were compared with 10 healthy controls matched for age, sex, verbal and nonverbal ability. Hypothesis-driven structural MRI and neuropsychological tests were used to collect neuroanatomical and neuropsychological data on all subjects. A version of the Wing Autism Diagnostic Interview Checklist was used to collect clinical data on the HFA subjects.Results. Strong convergent evidence in support of the amygdala hypothesis was obtained, and preliminary support for the hippocampal/parahippocampal hypothesis. No clear evidence was obtained in support of the prefrontal hypothesis. Patterns of associations amongst volume measures within and between medial temporal and prefrontal regions suggest stronger within-region and weaker between-region associations in the HFA group compared with controls.Conclusions. These findings are discussed in terms of a model of autism in which selective abnormalities of the amygdala and hippocampus (in all cases) and of the parahippocampal gyrus (in lower functioning cases) are implicated, and in which a disruption of coordinated limbic and prefrontal activity may be critical.     

A randomized trial of Chinese herbal medicines for the treatment of symptomatic hepatitis C

BACKGROUND: Many patients with the hepatitis C virus (HCV) cannot be successfully treated with interferon-based regimens. Chinese herbal medicines have been widely prescribed for HCV in Asia, and many infected patients in the United States have used these agents. However, data to support the efficacy of these medications are limited and, to our knowledge, no published trials have been conducted in a US population. METHODS: In a double-blinded design, 45 patients with HCV and fatigue were randomized to receive a combination of Chinese herbal medications or a matched placebo for 12 weeks. The main outcome measures were changes in health-related quality of life using the role physical and vitality scale scores from the validated Hepatitis Quality of Life Questionnaire and alanine aminotransferase levels. In addition, other Hepatitis Quality of Life Questionnaire variables, HCV load, and adverse effects were monitored. RESULTS: In patients with HCV, the herbal medications had no effect on any quality-of-life variables, as measured by the Hepatitis Quality of Life Questionnaire. In addition, no significant changes in alanine aminotransferase or serum HCV RNA levels were noted. No significant adverse effects were observed. CONCLUSIONS: In this study, a regimen of Chinese herbal medicines did not improve quality of life, liver chemistry results, or viral load in a cohort of patients with HCV. Patients and practitioners should remain cautious about the use of herbal medicines for HCV, because studies have not shown a clear benefit of these agents.     

Securing sustainable funding for viral hepatitis elimination plans

The majority of people infected with chronic hepatitis C virus (HCV) in the European Union (EU) remain undiagnosed and untreated. During recent years, immigration to EU has further increased HCV prevalence. It has been estimated that, out of the 4.2 million adults affected by HCV infection in the 31 EU/ European Economic Area (EEA) countries, as many as 580 000 are migrants. Additionally, HCV is highly prevalent and under addressed in Eastern Europe. In 2013, the introduction of highly effective treatments for HCV with direct‐acting antivirals created an unprecedented opportunity to cure almost all patients, reduce HCV transmission and eliminate the disease. However, in many settings, HCV elimination poses a serious challenge for countries’ health spending. On 6 June 2018, the Hepatitis B and C Public Policy Association held the 2nd EU HCV Policy summit. It was emphasized that key stakeholders should work collaboratively since only a few countries in the EU are on track to achieve HCV elimination by 2030. In particular, more effort is needed for universal screening. The micro‐elimination approach in specific populations is less complex and less costly than country‐wide elimination programmes and is an important first step in many settings. Preliminary data suggest that implementation of the World Health Organization (WHO) Global Health Sector Strategy on Viral Hepatitis can be cost saving. However, innovative financing mechanisms are needed to raise funds upfront for scaling up screening, treatment and harm reduction interventions that can lead to HCV elimination by 2030, the stated goal of the WHO.