Does diet mediate associations of volume and bouts of sedentary time with cardiometabolic health indicators in adolescents?

Objective: Examine the mediating role of diet in the relationship between volume and duration of sedentary time with cardiometabolic health in adolescents. Methods: Adolescents (12-19 years) participating in the 2003/04 and 2005/06 U.S. National Health and Nutrition Examination Survey (NHANES) were examined. Cardiometabolic health indicators were body mass index z-scores (zBMI) (n 5 1,797) and metabolic syndrome (MetS) (n 5 812). An ActiGraph hip-worn accelerometer was used to derive total sedentary time and usual sedentary bout duration. Dietary intake was assessed using two 24-hour dietary recalls. Mediation analyses were conducted to examine five dietary mediators [total energy intake, discretionary foods, sugar-sweetened beverages (SSB), fruits and vegetables, and dietary quality] of the relationship between total sedentary time and usual sedentary bout duration with zBMI and MetS. Results: Total sedentary time was inversely associated with zBMI (b 5 21.33; 95% CI 22.53 to 20.13) but attenuated after adjusting for moderate-to-vigorous physical activity. No significant associations were observed between usual sedentary bout duration with zBMI or either sedentary measure with MetS. None of the five dietary variables mediated any of the relationships examined. Conclusions: Further studies are needed to explore associations of specific time periods (e.g., after school) and bout durations with both cardiometabolic health indicators and dietary behaviors

Mediating effects of dietary intake on associations of TV viewing, body mass index and metabolic syndrome in adolescents

Objective Evidence suggests that TV viewing is associated with body mass index (BMI) and metabolic syndrome (MetS) in adolescents. However, it is unclear whether dietary intake mediates these relationships. Methods A cross‐sectional analysis was conducted in adolescents (12–19 years) participating in the 2003–2006 United States National Health and Nutrition Examination Survey. BMI z scores (zBMI) (n  = 3,161) and MetS (n  = 1,379) were calculated using age‐ and sex‐specific criteria for adolescents. TV viewing (h/day) was measured via a self‐reported questionnaire, and dietary intake was assessed using two 24‐h recalls. Using the MacKinnon method, a series of mediation analyses were conducted examining five dietary mediators (total energy intake, fruit and vegetable intake, discretionary snacks, sugar‐sweetened beverages and diet quality) of the relationships between TV viewing and zBMI and MetS. Results Small positive relationships were observed between TV viewing and zBMI (β = 0.99, p  < 0.001) and TV viewing and MetS (OR = 1.18, p  = 0.046). No dietary element appeared to mediate the relationship between TV viewing and zBMI. However, sugar‐sweetened beverage consumption and fruit and vegetable intake partially mediated the relationship between TV viewing and MetS, explaining 8.7% and 4.1% of the relationship, respectively. Conclusions These findings highlight the complexity of the relationships between TV viewing, dietary intake and cardiometabolic health outcomes, and that TV viewing should remain a target for interventions

Empirical ways to identify novel Bedaquiline resistance mutations in AtpE.

Clinical resistance against Bedaquiline, the first new anti-tuberculosis compound with a novel mechanism of action in over 40 years, has already been detected in Mycobacterium tuberculosis. As a new drug, however, there is currently insufficient clinical data to facilitate reliable and timely identification of genomic determinants of resistance. Here we investigate the structural basis for M. tuberculosis associated bedaquiline resistance in the drug target, AtpE. Together with the 9 previously identified resistance-associated variants in AtpE, 54 non-resistance-associated mutations were identified through comparisons of bedaquiline susceptibility across 23 different mycobacterial species. Computational analysis of the structural and functional consequences of these variants revealed that resistance associated variants were mainly localized at the drug binding site, disrupting key interactions with bedaquiline leading to reduced binding affinity. This was used to train a supervised predictive algorithm, which accurately identified likely resistance mutations (93.3% accuracy). Application of this model to circulating variants present in the Asia-Pacific region suggests that current circulating variants are likely to be susceptible to bedaquiline. We have made this model freely available through a user-friendly web interface called SUSPECT-BDQ, StrUctural Susceptibility PrEdiCTion for bedaquiline (http://biosig.unimelb.edu.au/suspect_bdq/). This tool could be useful for the rapid characterization of novel clinical variants, to help guide the effective use of bedaquiline, and to minimize the spread of clinical resistance.M.K was funded by the Melbourne Research Scholarship. D.B.A was funded by a Newton Fund RCUK-CONFAP Grant awarded by The Medical Research Council (MRC) and Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) (MR/M026302/1), the Jack Brockhoff Foundation (JBF 4186, 2016), and a C. J. Martin Research Fellowship from the National Health and Medical Research Council (NHMRC) of Australia (APP1072476). The Vietnam genomic dataset was funded by a NHMRC Australia grant (APP1056689) to SJD and KEH. Supported in part by the Victorian Government's OIS Program

Engineering enzymes with non-canonical active site functionality

The combination of computational enzyme design and laboratory evolution provides an attractive platform for the creation of protein catalysts with new function. To date, designed mechanisms have relied upon Nature’s alphabet of 20 genetically encoded amino acids, which greatly restricts the range of functionality which can be installed into enzyme active sites. Here, we have exploited engineered components of the cellular translation machinery to create a protein catalyst which operates via a non-canonical catalytic nucleophile. We have subsequently shown that powerful laboratory evolution protocols can be readily adapted to allow optimization of enzymes containing non-canonical active site functionality. Crystal structures obtained along the evolutionary trajectory highlight the origins of improved activity. Thus our approach merges beneficial features of organo- and biocatalysis, by combining the intrinsic reactivities and greater versatility of small molecule catalysts with the rate enhancements, reaction selectivities and evolvability of proteins. Please click Additional Files below to see the full abstract

Glucose-6-phosphate dehydrogenase (G6PD) mutations and haemoglobinuria syndrome in the Vietnamese population

<p>Abstract</p> <p>Background</p> <p>In Vietnam the blackwater fever syndrome (BWF) has been associated with malaria infection, quinine ingestion and G6PD deficiency. The G6PD variants within the Vietnamese Kinh contributing to the disease risk in this population, and more generally to haemoglobinuria, are currently unknown.</p> <p>Method</p> <p>Eighty-two haemoglobinuria patients and 524 healthy controls were screened for G6PD deficiency using either the methylene blue reduction test, the G-6-PDH kit or the micro-methaemoglobin reduction test. The G6PD gene variants were screened using SSCP combined with DNA sequencing in 82 patients with haemoglobinuria, and in 59 healthy controls found to be G6PD deficient.</p> <p>Results</p> <p>This study confirmed that G6PD deficiency is strongly associated with haemoglobinuria (OR = 15, 95% CI [7.7 to 28.9], P < 0.0001). Six <it>G6PD </it>variants were identified in the Vietnamese population, of which two are novel (Vietnam1 [Glu³Lys] and Vietnam2 [Phe⁶⁶Cys]). G6PD Viangchan [Val²⁹¹Met], common throughout south-east Asia, accounted for 77% of the variants detected and was significantly associated with haemoglobinuria within G6PD-deficient ethnic Kinh Vietnamese (OR = 5.8 95% CI [114-55.4], P = 0.022).</p> <p>Conclusion</p> <p>The primary frequency of several <it>G6PD </it>mutations, including novel mutations, in the Vietnamese Kinh population are reported and the contribution of <it>G6PD </it>mutations to the development of haemoglobinuria are investigated.</p

An artificial therapist (manage your life online) to support the mental health of youth: Co-design and case series

Background: The prevalence of child and adolescent mental health issues is increasing faster than the number of services available, leading to a shortfall. Mental health chatbots are a highly scalable method to address this gap. Manage Your Life Online (MYLO) is an artificially intelligent chatbot that emulates the method of levels therapy. Method of levels is a therapy that uses curious questioning to support the sustained awareness and exploration of current problems. Objective: This study aimed to assess the feasibility and acceptability of a co-designed interface for MYLO in young people aged 16 to 24 years with mental health problems. Methods: An iterative co-design phase occurred over 4 months, in which feedback was elicited from a group of young people (n=7) with lived experiences of mental health issues. This resulted in the development of a progressive web application version of MYLO that could be used on mobile phones. We conducted a case series to assess the feasibility and acceptability of MYLO in 13 young people over 2 weeks. During this time, the participants tested MYLO and completed surveys including clinical outcomes and acceptability measures. We then conducted focus groups and interviews and used thematic analysis to obtain feedback on MYLO and identify recommendations for further improvements. Results: Most participants were positive about their experience of using MYLO and would recommend MYLO to others. The participants enjoyed the simplicity of the interface, found it easy to use, and rated it as acceptable using the System Usability Scale. Inspection of the use data found evidence that MYLO can learn and adapt its questioning in response to user input. We found a large effect size for the decrease in participants’ problem-related distress and a medium effect size for the increase in their self-reported tendency to resolve goal conflicts (the proposed mechanism of change) in the testing phase. Some patients also experienced a reliable change in their clinical outcome measures over the 2 weeks. Conclusions: We established the feasibility and acceptability of MYLO. The initial outcomes suggest that MYLO has the potential to support the mental health of young people and help them resolve their own problems. We aim to establish whether the use of MYLO leads to a meaningful reduction in participants’ symptoms of depression and anxiety and whether these are maintained over time by conducting a randomized controlled evaluation trial