External validation of a prediction model for estimating fat mass in children and adolescents in 19 countries: individual participant data meta-analysis.

OBJECTIVE: To evaluate the performance of a UK based prediction model for estimating fat-free mass (and indirectly fat mass) in children and adolescents in non-UK settings. DESIGN: Individual participant data meta-analysis. SETTING: 19 countries. PARTICIPANTS: 5693 children and adolescents (49.7% boys) aged 4 to 15 years with complete data on the predictors included in the UK based model (weight, height, age, sex, and ethnicity) and on the independently assessed outcome measure (fat-free mass determined by deuterium dilution assessment). MAIN OUTCOME MEASURES: The outcome of the UK based prediction model was natural log transformed fat-free mass (lnFFM). Predictive performance statistics of R2, calibration slope, calibration-in-the-large, and root mean square error were assessed in each of the 19 countries and then pooled through random effects meta-analysis. Calibration plots were also derived for each country, including flexible calibration curves. RESULTS: The model showed good predictive ability in non-UK populations of children and adolescents, providing R2 values of >75% in all countries and >90% in 11 of the 19 countries, and with good calibration (ie, agreement) of observed and predicted values. Root mean square error values (on fat-free mass scale) were <4 kg in 17 of the 19 settings. Pooled values (95% confidence intervals) of R2, calibration slope, and calibration-in-the-large were 88.7% (85.9% to 91.4%), 0.98 (0.97 to 1.00), and 0.01 (-0.02 to 0.04), respectively. Heterogeneity was evident in the R2 and calibration-in-the-large values across settings, but not in the calibration slope. Model performance did not vary markedly between boys and girls, age, ethnicity, and national income groups. To further improve the accuracy of the predictions, the model equation was recalibrated for the intercept in each setting so that country specific equations are available for future use. CONCLUSION: The UK based prediction model, which is based on readily available measures, provides predictions of childhood fat-free mass, and hence fat mass, in a range of non-UK settings that explain a large proportion of the variability in observed fat-free mass, and exhibit good calibration performance, especially after recalibration of the intercept for each population. The model demonstrates good generalisability in both low-middle income and high income populations of healthy children and adolescents aged 4-15 years.

Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice.

Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression.

Age- and stress-associated C. elegans granulins impair lysosomal function and induce a compensatory HLH-30/TFEB transcriptional response.

The progressive failure of protein homeostasis is a hallmark of aging and a common feature in neurodegenerative disease. As the enzymes executing the final stages of autophagy, lysosomal proteases are key contributors to the maintenance of protein homeostasis with age. We previously reported that expression of granulin peptides, the cleavage products of the neurodegenerative disease protein progranulin, enhance the accumulation and toxicity of TAR DNA binding protein 43 (TDP-43) in Caenorhabditis elegans (C. elegans). In this study we show that C. elegans granulins are produced in an age- and stress-dependent manner. Granulins localize to the endolysosomal compartment where they impair lysosomal protease expression and activity. Consequently, protein homeostasis is disrupted, promoting the nuclear translocation of the lysosomal transcription factor HLH-30/TFEB, and prompting cells to activate a compensatory transcriptional program. The three C. elegans granulin peptides exhibited distinct but overlapping functional effects in our assays, which may be due to amino acid composition that results in distinct electrostatic and hydrophobicity profiles. Our results support a model in which granulin production modulates a critical transition between the normal, physiological regulation of protease activity and the impairment of lysosomal function that can occur with age and disease.

Humans against Obesity: Who Will Win?

The global obesity epidemic continues its relentless advance, currently affecting >2 billion people. This paper explores alternative ways to assess the potential disease impact of the epidemic, which is currently based almost exclusively on body mass index (BMI) data. It also argues in favor of concerted efforts to modify the built ecosystem that is driving the obesity epidemic. Most of the epidemiologic data on obesity are based on BMI (in kg/m2) and use the ranges of 18.5-24.9 for normality, 25-29.9 for overweight, and ≥30 for obesity. But the gap between the median of the "normal" BMI distribution (∼22) and the current population BMI of, for example, the United States (27.7) has become so wide that it is unlikely that we will be able to close that gap in the near future. Furthermore, the correlation between BMI and disease risk is not linear. Over 60% of the global disease burden of obesity affects individuals with a BMI ≥30, who comprise only ∼10% of the global population of overweight/obese persons. Furthermore, BMI accounts for only ∼17% of the risk of insulin resistance and subsequent type 2 diabetes in the BMI ≥25 population. Epigenetics, specifically DNA methylation, appears to play a far more important role than BMI in determining the risk of obesity's comorbidities, such as diabetes. Similarly, socioeconomic status carries a higher risk than BMI level for the development of obesity-related noncommunicable diseases. Finally, the built environment that sustains our species' lifestyle is a major driver of the obesity epidemic. Modifying that ecosystem will require no less than a social movement, one able to promote and sustain the necessary coordinated action of virtually all sectors of society.

Novel public-private partnerships to address the double burden of malnutrition.

Public-private partnerships are an effective way to address the global double burden of malnutrition. While public-private partnerships operate in multiple forms, their leadership usually falls to governments, public health agencies, or nongovernmental organizations, with the private sector taking a subordinate role. The rapid ascent of social media and mass communications worldwide has provided a disruptive technology for new nutrition intervention programs. A new model, provisionally called private-public engagement, takes advantage of social media, mass media, and integrated social marketing to reach parents, families, and communities directly. These new private-public engagement initiatives need to be managed in ways suggested for public-private partnerships by the World Health Organization, especially if the private sector is in the lead. Once the rationale for engagement is defined, there is a need to mobilize resources, establish in-country partnerships and codes of conduct, and provide a plan for monitoring, evaluation, and accountability. Provided here is an example consistent with the private-public engagement approach, ie, the United for Healthier Kids program, which has been aimed at families with children aged less than 12 years. Materials to inspire behavioral change and promote healthier diets and lifestyle were disseminated in a number of countries through both digital and physical channels, often in partnership with local or regional governments. A description of this program, along with strategies to promote transparency and communication among stakeholders, serves to provide guidance for the development of future effective private-public engagements.

The Outcome of the Cryptococcus neoformans-Macrophage Interaction Depends on Phagolysosomal Membrane Integrity.

Cryptococcus neoformans is a fungal pathogen with worldwide distribution. C. neoformans resides within mature phagolysosomes where it often evades killing and replicates. C. neoformans induces phagolysosomal membrane permeabilization (PMP), but the mechanism for this phenomenon and its consequences for macrophage viability are unknown. In this study, we used flow cytometry methodology in combination with cell viability markers and LysoTracker to measure PMP in J774.16 and murine bone marrow-derived macrophages infected with C. neoformans Our results showed that cells manifesting PMP were positive for apoptotic markers, indicating an association between PMP and apoptosis. We investigated the role of phospholipase B1 in C. neoformans induction of PMP. Macrophages infected with a C. neoformans Δplb1 mutant had reduced PMP compared with those infected with wild-type and phospholipase B1-complemented strains, suggesting a mechanism of action for this virulence factor. Capsular enlargement inside macrophages was identified as an additional likely mechanism for phagolysosomal membrane damage. Macrophages undergoing apoptosis did not maintain an acidic phagolysosomal pH. Induction of PMP with ciprofloxacin enhanced macrophages to trigger lytic exocytosis whereas nonlytic exocytosis was common in those without PMP. Our results suggest that modulation of PMP is a critical event in determining the outcome of C. neoformans-macrophage interaction.

Interplay of pathogenic forms of human tau with different autophagic pathways.

Loss of neuronal proteostasis, a common feature of the aging brain, is accelerated in neurodegenerative disorders, including different types of tauopathies. Aberrant turnover of tau, a microtubule-stabilizing protein, contributes to its accumulation and subsequent toxicity in tauopathy patients' brains. A direct toxic effect of pathogenic forms of tau on the proteolytic systems that normally contribute to their turnover has been proposed. In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone-mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this age-related disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk-associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway. We also found defective autophagic degradation of tau when using mutations that mimic common posttranslational modifications in tau or known to promote its aggregation. Interestingly, although most mutations markedly reduced degradation of tau through autophagy, the step of this process preferentially affected varies depending on the type of tau mutation. Overall, our studies unveil a complex interplay between the multiple modifications of tau and selective forms of autophagy that may determine its physiological degradation and its faulty clearance in the disease context.

Research capacity for childhood obesity prevention in Latin America: an area for growth.

BACKGROUND: The rise of childhood obesity in Latin America calls for research capacity to understand, monitor and implement strategies, policies and programmes to address it. OBJECTIVE: The objective of the study was to assess current research capacity in Latin America related to childhood obesity, nutrition and physical activity. METHODS: We conducted a search of peer-reviewed articles on childhood obesity in Latin America with at least one Latin American author from 2010 to May 2015. We coded 484 published articles for author affiliation, study subjects' nationality, research topic and study design and extracted a series of networks per research topic, study design and collaborating country for each of the countries. RESULTS: Obesity is the most frequently explored topic. Nutrition and obesity are somewhat better developed compared with physical activity and sedentary behaviour. There are numerous observational and cross-sectional studies, indicating either a lack of capacity required for more complex research or the extent of the problem and associated factors is still unknown. The low number of intervention studies and the near absence of policy articles suggest a void in research capacity. CONCLUSION: For childhood obesity, there is a clear need to build research capacity that documents the current state of the problem and design evidence-based prevention and intervention efforts.

OPREVENT2: Design of a multi-institutional intervention for obesity control and prevention for American Indian adults.

BACKGROUND: Obesity and other nutrition-related chronic disease rates are high in American Indian (AI) populations, and an urgent need exists to identify evidence-based strategies for prevention and treatment. Multi-level, multi-component (MLMC) interventions are needed, but there are significant knowledge gaps on how to deliver these types of interventions in low-income rural AI communities. METHODS: OPREVENT2 is a MLMC intervention targeting AI adults living in six rural reservations in New Mexico and Wisconsin. Aiming to prevent and reduce obesity in adults by working at multiple levels of the food and physical activity (PA) environments, OPREVENT2 focuses on evidence-based strategies known to increase access to, demand for, and consumption of healthier foods and beverages, and increase worksite and home-based opportunities for PA. OPREVENT2 works to create systems-level change by partnering with tribal stakeholders, multiple levels of the food and PA environment (food stores, worksites, schools), and the social environment (children as change agents, families, social media). Extensive evaluation will be conducted at each level of the intervention to assess effectiveness via process and impact measures. DISCUSSION: Novel aspects of OPREVENT2 include: active engagement with stakeholders at many levels (policy, institutional, and at multiple levels of the food and PA system); use of community-based strategies to engage policymakers and other key stakeholders (community workshops, action committees); emphasis on both the built environment (intervening with retail food sources) and the social environment. This paper describes the design of the intervention and the evaluation plan of the OPREVENT2. TRIAL REGISTRATION: Clinical Trial Registration: NCT02803853 (June 10, 2016).

Heritability of Children's Dietary Intakes: A Population-Based Twin Study in China.

BACKGROUND: Despite evidence for some genetic control of dietary intake in adults, there is little evidence of how genetic factors influence children's dietary patterns. OBJECTIVE: To estimate heritability of dietary intake in twin children from China and test if genetic effects on dietary intakes vary by the children's socio-economic status (SES). METHODS: A sample of 622 twins (162 monozygotic and 149 dizygotic pairs; 298 boys and 324 girls aged 7-15 years) was recruited in South China. Dietary intakes were assessed using a validated 145-item semi-quantitative food frequency questionnaire. Pooled and sex-specific dietary patterns were identified using factor analysis. Heritability was estimated using structural equation models. RESULTS: Heritable components differed by gender and for nutrients and food groups; and estimated heritability of dietary patterns was generally greater in girls than boys. In boys, estimated heritabilities ranged from 18.8% (zinc) to 58.4% (fat) for nutrients; and for food group, 1.1% (Western fast foods) to 65.8% (soft drinks). In girls, these estimates ranged from 5.1% (total energy) to 38.7% (percentage of energy from fat) for nutrients, and 12.6% (eggs) to 94.6% (Western fast foods) for food groups. Factor analysis identified five food patterns: vegetables and fruits, fried and fast foods, beverages, snacks and meats. Maternal education and family income were positively associated with higher heritabilities for intake of meat, fried, and fast food. CONCLUSIONS: Genetic influence on dietary intakes differed by gender, nutrients, food groups, and dietary patterns among Chinese twins. Parental SES characteristics modified the estimated genetic influence.

A randomized trial on the effects of 2010 Dietary Guidelines for Americans and Korean diet patterns on cardiovascular risk factors in overweight and obese adults.

BACKGROUND: Dietary patterns that are considered healthy (eg, the Dietary Approaches to Stop Hypertension diet and Mediterranean diet) may be more successful in reducing typical cardiovascular disease risks compared to dietary patterns considered unhealthy (eg, energy-dense diets such as the typical American diet). OBJECTIVE: This study assessed the effects of a Korean diet, the 2010 Dietary Guidelines for Americans (DGA), and a typical American diet on cardiometabolic risk factors, including lipid levels and blood pressure, in overweight, non-Asian individuals in the United States with elevated low-density lipoprotein cholesterol. DESIGN/INTERVENTION: The study was a three-period crossover, controlled-feeding study from January 2012 to May 2012. Thirty-one subjects were randomly allocated to one of six possible sequential orders for consuming the three diets for 4 weeks, each separated by a 10-day break. Data analysis included 27 subjects on the Korean diet periods and 29 in the DGA and typical American diet periods. Subjects remained weight stable. MAIN OUTCOME MEASURES: Lipid profile, blood pressure, insulin, glucose, and 24-hour urinary sodium were determined at baseline and at the end of each diet period. STATISTICAL ANALYSES PERFORMED: The additive main effects multiplicative interactions model was used to test for a subject by diet interaction. Differences among diets were determined using a mixed-models procedure (PROC MIXED) with random intercept for each subject. RESULTS: Total cholesterol and low-density lipoprotein cholesterol significantly decreased on Korean (P<0.0001 and P<0.01, respectively) and DGA (P<0.01 and P<0.05, respectively) diets, but not on the typical American diet. Although an unfavorable outcome, high-density lipoprotein cholesterol significantly decreased on all three diets (Korean: P<0.0001; DGA: P<0.0001; typical American: P<0.05). No diet had a significant effect on serum triglycerides, but a slight increase in triglycerides in the Korean and decrease in the DGA resulted in a significant difference between these two diets (P<0.01). All three diets caused modest decreases in systolic and diastolic blood pressure, which reached statistical significance for DGA only (P<0.05 and P<0.01, respectively). No diet had significant effect on fasting insulin, whereas fasting glucose decreased significantly on the Korean (P<0.01) and typical American (P<0.05) diets only. Urinary sodium output decreased significantly on DGA (P<0.0001). CONCLUSIONS: After a 4-week feeding period, Korean and DGA diet patterns resulted in positive changes in cardiovascular disease risk factors.

Early Obesity Prevention: A Randomized Trial of a Practice-Based Intervention in 0-24-Month Infants.

OBJECTIVE: A pediatric office-based intervention was implemented following a randomized, controlled design, aimed at improving child feeding practices and growth patterns and ultimately reducing risk for overweight and obesity later in life. METHODS: Four clinics (232 infants) were randomized to control or intervention (I), the latter delivered by health care provider at each of 7-9 well-baby visits over 2 years, using a previously developed program (Growing Leaps and Bounds) that included verbal, visual, and text advice and information for parents. RESULTS: The I group offered significantly less soda (p = 0.006), sweetened tea (p = 0.01), punch (p = 0.02) and/or cow's milk (p = 0.001) to infants and delayed the introduction of drink/food other than breast milk (p < 0.05). Parents in the I group had a higher perceived parental monitoring (p = 0.05) and restriction (p = 0.01) on infant feeding. While the I group exhibited at baseline more adverse socioeconomic indicators than the control group, growth trajectory or body size indices did not significantly differ between groups. CONCLUSIONS: Education provided by health care providers in addition to follow-up monthly phone calls may help modify parental behaviors related to child feeding and increase parental sense of responsibility toward child eating behaviors.

Validation of a BMI cut-off point to predict an adverse cardiometabolic profile with adiposity measurements by dual-energy X-ray absorptiometry in Guatemalan children.

OBJECTIVE: To identify a body fat percentage (%BF) threshold related to an adverse cardiometabolic profile and its surrogate BMI cut-off point. DESIGN: Cross-sectional study. SETTING: Two public schools in poor urban areas on the outskirts of Guatemala City. SUBJECTS: A convenience sample of ninety-three healthy, prepubertal, Ladino children (aged 7-12 years). RESULTS: Spearman correlations of cardiometabolic parameters were higher with %BF than with BMI-for-age Z-score. BMI-for-age Z-score and %BF were highly correlated (r=0·84). The %BF threshold that maximized sensitivity and specificity for predicting an adverse cardiometabolic profile (elevated homeostasis model assessment-insulin resistance index and/or total cholesterol:HDL-cholesterol ratio) according to receiver operating characteristic curve analysis was 36 %. The BMI-for-age Z-score cut-off point that maximized the prediction of BF ≥ 36 % by the same procedure was 1·5. The area under the curve (AUC) for %BF and for BMI data showed excellent accuracy to predict an adverse cardiometabolic profile (AUC 0·93 (sd 0·04)) and excess adiposity (AUC 0·95 (sd 0·02)). CONCLUSIONS: Since BMI standards have limitations in screening for adiposity, specific cut-off points based on ethnic-/sex- and age-specific %BF thresholds are needed to better predict an adverse cardiometabolic profile.

Formative research to develop a community-based intervention for chronic disease prevention in Guatemalan school-age children.

BACKGROUND: Noncommunicable diseases (NCD) are the most common causes of morbidity and mortality worldwide, even in low- and middle-income countries (LMIC). Recent trends in health promotion emphasize community-based interventions as an important strategy for improving health outcomes. The aim of this study was to conduct formative research regarding the perceptions of NCD risk factors, their influencing factors, and community resources available to aid the development and implementation of a community-based intervention with school-age children. METHODS: Focus group discussions (n = 18), home visits (n = 30), and individual semi-structured interviews (n = 26) were conducted in three urban communities in Guatemala with school-age children (10-12 years of age), teachers, parents, and local community members (i.e., school principals, school food kiosk vendors, religious leaders, authority representatives). All focus groups and interviews were transcribed verbatim for thematic analysis. RESULTS: Children, parents, and teachers have general knowledge about modifiable risk factors. Adults worried more about tobacco use, as compared to unhealthy diet and physical inactivity in children. Participants identified features at the intrapersonal (e.g., negative emotional state), interpersonal (e.g., peers as role models), and organizational and community levels (e.g., high levels of crime) that influence these risk factors in children. School committees, religious leaders, and government programs and activities were among the positive community resources identified. CONCLUSIONS: These findings should help researchers in Guatemala and similar LMIC to develop community-based interventions for NCD prevention in school-age children that are effective, feasible, and culturally acceptable.

Assessing dietary intake among infants and toddlers 0-24 months of age in Baltimore, Maryland, USA.

OBJECTIVE: To characterize food and nutrient intake and develop a population-specific food list to be used as a comprehensive dietary assessment tool for Baltimore infants and toddlers aged 0-24 months. The data were used to inform the Growing Leaps and Bounds (GLB) program, which promotes early obesity prevention among Baltimore infants and toddlers. RESEARCH METHODS & PROCEDURES: A cross-sectional dietary survey using 24-hour recalls among randomly selected primary caregivers of infants and toddlers was conducted. RESULTS: Data were collected from 84 children, (response rate 61%) 45 boys; 39 girls. Mean daily energy intakes were 677 kcal, 988 kcal, and 1,123 kcal for children 0-6 months, 7-12 months and 13-24 months, respectively. Infants 0-6 months had higher percentage of energy from fat (48%) than infants 7-12 months (34%) and 13-24 months (31%). Mean daily intakes for all nutrients among 0-12 months old were ≥ Dietary Reference Intakes (DRI), while toddlers 13-24 months had inadequate vitamins A, D, and E intake. Breastfeeding occurred in 33% of infants and toddlers 0 to 6 months, while less than 3% of those aged 7 to 24 months were breastfed. A 104-item food list with eight food and drink categories was developed. CONCLUSIONS: Infants were formula fed with a higher frequency than they were breastfed. The consumption of high-sugar and high-fat foods (e.g. sweetened drinks, French fries) increased with each age group, which can increase the risk of childhood obesity.

Population-wide weight loss and regain in relation to diabetes burden and cardiovascular mortality in Cuba 1980-2010: repeated cross sectional surveys and ecological comparison of secular trends.

OBJECTIVE: To evaluate the associations between population-wide loss and gain in weight with diabetes prevalence, incidence, and mortality, as well as cardiovascular and cancer mortality trends, in Cuba over a 30 year interval. DESIGN: Repeated cross sectional surveys and ecological comparison of secular trends. SETTING: Cuba and the province of Cienfuegos, from 1980 to 2010. PARTICIPANTS: Measurements in Cienfuegos included a representative sample of 1657, 1351, 1667, and 1492 adults in 1991, 1995, 2001, and 2010, respectively. National surveys included a representative sample of 14 304, 22 851, and 8031 participants in 1995, 2001, and 2010, respectively. MAIN OUTCOME MEASURES: Changes in smoking, daily energy intake, physical activity, and body weight were tracked from 1980 to 2010 using national and regional surveys. Data for diabetes prevalence and incidence were obtained from national population based registries. Mortality trends were modelled using national vital statistics. RESULTS: Rapid declines in diabetes and heart disease accompanied an average population-wide loss of 5.5 kg in weight, driven by an economic crisis in the mid-1990s. A rebound in population weight followed in 1995 (33.5% prevalence of overweight and obesity) and exceeded pre-crisis levels by 2010 (52.9% prevalence). The population-wide increase in weight was immediately followed by a 116% increase in diabetes prevalence and 140% increase in diabetes incidence. Six years into the weight rebound phase, diabetes mortality increased by 49% (from 9.3 deaths per 10 000 people in 2002 to 13.9 deaths per 10 000 people in 2010). A deceleration in the rate of decline in mortality from coronary heart disease was also observed. CONCLUSIONS: In relation to the Cuban experience in 1980-2010, there is an association at the population level between weight reduction and death from diabetes and cardiovascular disease; the opposite effect on the diabetes and cardiovascular burden was seen on population-wide weight gain.