Prevalence of multiple non-communicable diseases risk factors among adolescents in 140 countries:A population-based study

BACKGROUND: Modifiable non-communicable disease (NCD) risk factors are becoming increasingly common among adolescents, with clustering of these risk factors in individuals of particular concern. The aim of this study was to assess global status of clustering of common modifiable NCD risk factors among adolescents. METHODS: We used latest available data from nationally representative survey for 140 countries, namely the Global School-based Student Health Survey, the Health Behaviour in School-Aged Children and the longitudinal study of Australian Children. Weighted mean estimates of prevalence with corresponding 95% confidence intervals of nine NCD risk factors - physical inactivity, sedentary behaviour, insufficient fruits and vegetable consumption, carbonated soft drink consumption, fast food consumption, tobacco use, alcohol consumption and overweight/obesity - were calculated by country, region and sex. FINDINGS: Over 487,565 adolescents, aged 11–17 years, were included in this study. According to trend analysis, prevalence of four or more NCD risk factors increased gradually over time. Prevalence of four or more NCD risk factors was 14.8% in 2003–2007 and increased to 44% in 2013–2017, an approximately three-fold increase (44.0%). Similar trends were also observed for three and two risk factors. Large variation between countries in the prevalence of adolescents with four or more risk factors was found in all regions. The country level range was higher in the South-East Asia Region (minimum Sri Lanka = 8%, maximum Myanmar = 84%) than Western Pacific Region (minimum China = 3%, maximum Niue = 72%), European Region (minimum Sweden = 13.9%, maximum Ireland = 66.0%), African Region (minimum Senegal = 0.8%, maximum Uganda = 82.1%) and Eastern Mediterranean Region (minimum Libya = 0.2%, maximum Lebanon = 80.2%). Insufficient vegetable consumption, insufficient fruit consumption and physically inactivity were three of the four most prevalent risk factors in all regions. INTERPRETATION: Our results suggest a high prevalence of four or more NCD risk factors in adolescents globally, although variation was found between countries. Results from our study indicate that efforts to reduce adolescent NCD risk factors and the associated health burden need to be improved. These findings can assist policy makers to target the rollout of country- specific interventions. FUNDING: None

Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS

Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, 2 cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, “S-XL6,” was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S-XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S-XL6 (up to 24°C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of-enzymatic function. We show that S-XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1G93A by S-XL6 that increases SOD1G93A’s in vivo half-life; and that S-XL6 crosses the blood–brain barrier. S-XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS

Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS.

Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, 2 cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, "S-XL6," was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S-XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S-XL6 (up to 24°C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of-enzymatic function. We show that S-XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1G93A by S-XL6 that increases SOD1G93A's in vivo half-life; and that S-XL6 crosses the blood-brain barrier. S-XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS