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Mental and substance use disorders are common and often persistent, with many emerging in early life. Compared to adult mental and substance use disorders, the global burden attributable to these disorders in children and youth has received relatively little attention. Data from the Global Burden of Disease Study 2010 was used to investigate the burden of mental and substance disorders in children and youth aged 0-24 years. Burden was estimated in terms of disability-adjusted life years (DALYs), derived from the sum of years lived with disability (YLDs) and years of life lost (YLLs). Globally, mental and substance use disorders are the leading cause of disability in children and youth, accounting for a quarter of all YLDs (54.2 million). In terms of DALYs, they ranked 6th with 55.5 million DALYs (5.7%) and rose to 5th when mortality burden of suicide was reattributed. While mental and substance use disorders were the leading cause of DALYs in high-income countries (HICs), they ranked 7th in low- and middle-income countries (LMICs) due to mortality attributable to infectious diseases. Mental and substance use disorders are significant contributors to disease burden in children and youth across the globe. As reproductive health and the management of infectious diseases improves in LMICs, the proportion of disease burden in children and youth attributable to mental and substance use disorders will increase, necessitating a realignment of health services in these countries.

Depression and anxiety (internalizing disorders) are the largest contributors to the non-fatal health burden among young people. This is the first meta-analysis to examine the joint efficacy of universal, selective, and indicated preventive interventions upon both depression and anxiety among children and adolescents (5–18 years) while accounting for their co-morbidity. We conducted a systematic review of reviews in Medline, PsycINFO and the Cochrane Library of Systematic Reviews, from 1980 to August 2014. Multivariate meta-analysis examined the efficacy of preventive interventions on depression and anxiety outcomes separately, and the joint efficacy on both disorders combined. Meta-regressions examined heterogeneity of effect according to a range of study variables. Outcomes were relative risks (RR) for disorder, and standardized mean differences (Cohen's d) for symptoms. One hundred and forty-six randomized controlled trials (46 072 participants) evaluated universal (children with no identified risk, n = 54) selective (population subgroups of children who have an increased risk of developing internalizing disorders due to shared risk factors, n = 45) and indicated prevention (children with minimal but detectable symptoms of an internalizing disorder, n = 47), mostly using psychological-only strategies (n = 105). Reductions in internalizing disorder onset occurred up to 9 months post-intervention, whether universal [RR 0.47, 95% confidence interval (CI) 0.37–0.60], selective (RR 0.61, 95% CI 0.43–0.85) or indicated (RR 0.48, 95% CI 0.29–0.78). Reductions in internalizing symptoms occurred up to 12 months post-intervention for universal prevention; however, reductions only occurred in the shorter term for selective and indicated prevention. Universal, selective and indicated prevention interventions are efficacious in reducing internalizing disorders and symptoms in the short term. They might be considered as repeated exposures in school settings across childhood and adolescence. (PROSPERO registration: CRD42014013990.)

A massively parallel large-eddy simulation (LES) code for planetary boundary layers (PBLs) that utilizes pseudospectral differencing in horizontal planes and solves an elliptic pressure equation is described. As an application, this code is used to examine the numerical convergence of the three-dimensional time-dependent simulations of a weakly sheared daytime convective PBL on meshes varying from 323 to 10243 grid points. Based on the variation of the second-order statistics, energy spectra, and entrainment statistics, LES solutions converge provided there is adequate separation between the energy-containing eddies and those near the filter cutoff scale. For the convective PBL studied, the majority of the low-order moment statistics (means, variances, and fluxes) become grid independent when the ratio zi/(CsΔf) > 310, where zi is the boundary layer height, Δf is the filter cutoff scale, and Cs is the Smagorinsky constant. In this regime, the spectra show clear Kolmogorov inertial subrange scaling. The bulk entrainment rate determined from the time variation of the boundary layer height we = dzi/dt is a sensitive measure of the LES solution convergence; we becomes grid independent when the vertical grid resolution is able to capture both the mean structure of the overlying inversion and the turbulence. For all mesh resolutions used, the vertical temperature flux profile varies linearly over the interior of the boundary layer and the minimum temperature flux is approximately −0.2 of the surface heat flux. Thus, these metrics are inadequate measures of solution convergence. The variation of the vertical velocity skewness and third-order moments expose the LES’s sensitivity to grid resolution.

Momentum and scalar transport in the marine atmospheric boundary layer (MABL) is driven by a turbulent mix of winds, buoyancy, and surface gravity waves. To investigate the interaction between these processes, a large-eddy simulation (LES) model is developed with the capability to impose a broadband spectrum of time-varying finite-amplitude surface waves at its lower boundary. The LES model adopts a Boussinesq flow model and integrates the governing equations on a time-varying, surface-fitted, nonorthogonal mesh using cell-centered variables with special attention paid to the solution of the pressure Poisson equation near the wavy boundary. Weakly unstable MABLs are simulated with geostrophic winds increasing from 5 to 25 m s−1 and wave age varying from swell-dominated to wind-wave equilibrium. The simulations illustrate cross-scale coupling as wave-impacted near-surface turbulence transitions into shear-convective rolls with increasing distance from the water. In a regime with swell, low winds, and weak heating, wave-induced vertical velocity and pressure signals are readily observed well above the standard reference height ζa = 10 m. At wind-wave equilibrium, the small-scale wave-induced signals are detectable only near the water surface. Below ζa, a nearly-constant-flux layer is observed where the momentum flux carried by turbulence, form stress, and subgrid-scale motions shifts with varying wave age and distance above the water. The spectral content of the surface form stress is wave-age dependent, especially at low wavenumbers. The LES wind profiles deviate from Monin–Obukhov similarity theory in nonequilibrium wind-wave conditions, and entrainment is greatly enhanced by shear-induced engulfment events.

Background Epithelial-to-mesenchymal transition (EMT) is a process linked to metastasis and drug resistance with non-coding RNAs (ncRNAs) playing pivotal roles. We previously showed that miR-100 and miR-125b, embedded within the third intron of the ncRNA host gene MIR100HG , confer resistance to cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in colorectal cancer (CRC). However, whether the MIR100HG transcript itself has a role in cetuximab resistance or EMT is unknown. Methods The correlation between MIR100HG and EMT was analyzed by curating public CRC data repositories. The biological roles of MIR100HG in EMT, metastasis and cetuximab resistance in CRC were determined both in vitro and in vivo. The expression patterns of MIR100HG, hnRNPA2B1 and TCF7L2 in CRC specimens from patients who progressed on cetuximab and patients with metastatic disease were analyzed by RNAscope and immunohistochemical staining. Results The expression of MIR100HG was strongly correlated with EMT markers and acted as a positive regulator of EMT. MIR100HG sustained cetuximab resistance and facilitated invasion and metastasis in CRC cells both in vitro and in vivo. hnRNPA2B1 was identified as a binding partner of MIR100HG. Mechanistically, MIR100HG maintained mRNA stability of TCF7L2, a major transcriptional coactivator of the Wnt/β-catenin signaling, by interacting with hnRNPA2B1. hnRNPA2B1 recognized the N6-methyladenosine (m 6 A) site of TCF7L2 mRNA in the presence of MIR100HG. TCF7L2, in turn, activated MIR100HG transcription, forming a feed forward regulatory loop. The MIR100HG/hnRNPA2B1/TCF7L2 axis was augmented in specimens from CRC patients who either developed local or distant metastasis or had disease progression that was associated with cetuximab resistance. Conclusions MIR100HG and hnRNPA2B1 interact to control the transcriptional activity of Wnt signaling in CRC via regulation of TCF7L2 mRNA stability. Our findings identified MIR100HG as a potent EMT inducer in CRC that may contribute to cetuximab resistance and metastasis by activation of a MIR100HG/hnRNPA2B1/TCF7L2 feedback loop.

Children and adolescents make up almost a quarter of the world's population with 85% living in low- and middle-income countries (LMICs). Globally, mental (and substance use) disorders are the leading cause of disability in young people; however, the representativeness or 'coverage' of the prevalence data is unknown. Coverage refers to the proportion of the target population (ages 5-17 years) represented by the available data. Prevalence data for conduct disorder (CD), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), eating disorders (EDs), depression, and anxiety disorders were sourced from systematic reviews conducted for the Global Burden of Disease Study 2010 (GBD 2010) and 2013 (GBD 2013). For each study, the location proportion was multiplied by the age proportion to give study coverage. Location proportion was calculated by dividing the total study location population by the total study location population. Age proportion was calculated by dividing the population of the country aged within the age range of the study sample by the population of the country aged within the age range of the study sample. If a study only sampled one sex, study coverage was halved. Coverage across studies was then summed for each country to give coverage by country. This method was repeated at the region and global level, and separately for GBD 2013 and GBD 2010. Mean global coverage of prevalence data for mental disorders in ages 5-17 years was 6.7% (CD: 5.0%, ADHD: 5.5%, ASDs: 16.1%, EDs: 4.4%, depression: 6.2%, anxiety: 3.2%). Of 187 countries, 124 had no data for any disorder. Many LMICs were poorly represented in the available prevalence data, for example, no region in sub-Saharan Africa had more than 2% coverage for any disorder. While coverage increased between GBD 2010 and GBD 2013, this differed greatly between disorders and few new countries provided data. The global coverage of prevalence data for mental disorders in children and adolescents is limited. Practical methodology must be developed and epidemiological surveys funded to provide representative prevalence estimates so as to inform appropriate resource allocation and support policies that address mental health needs of children and adolescents.

We compare the turbulence statistics of the canopy/roughness sublayer (RSL) and the inertial sublayer (ISL) above. In the RSL the turbulence is more coherent and more efficient at transporting momentum and scalars and in most ways resembles a turbulent mixing layer rather than a boundary layer. To understand these differences we analyse a large-eddy simulation of the flow above and within a vegetation canopy. The three-dimensional velocity and scalar structure of a characteristic eddy is educed by compositing, using local maxima of static pressure at the canopy top as a trigger. The characteristic eddy consists of an upstream head-down sweep-generating hairpin vortex superimposed on a downstream head-up ejection-generating hairpin. The conjunction of the sweep and ejection produces the pressure maximum between the hairpins, and this is also the location of a coherent scalar microfront. This eddy structure matches that observed in simulations of homogeneous-shear flows and channel flows by several workers and also fits with earlier field and wind-tunnel measurements in canopy flows. It is significantly different from the eddy structure educed over smooth walls by conditional sampling based only on ejections as a trigger. The characteristic eddy was also reconstructed by empirical orthogonal function (EOF) analysis, when only the dominant, sweep-generating head-down hairpin was recovered, prompting a re-evaluation of earlier results based on EOF analysis of wind-tunnel data. A phenomenological model is proposed to explain both the structure of the characteristic eddy and the key differences between turbulence in the canopy/RSL and the ISL above. This model suggests a new scaling length that can be used to collapse turbulence moments over vegetation canopies.

Momentum and scalar (heat and water vapor) transfer between a walnut canopy and the overlying atmosphere are investigated for two seasonal periods (before and after leaf-out), and for five thermal stability regimes (free and forced convection, near-neutral condition, transition to stable, and stable). Quadrant and octant analyses of momentum and scalar fluxes followed by space-time autocorrelations of observations from the Canopy Horizontal Array Turbulence Study's (CHATS) thirty meter tower help characterize the motions exchanging momentum, heat, and moisture between the canopy layers and aloft. During sufficiently windy conditions, i.e. in forced convection, near-neutral and transition to stable regimes, momentum and scalars are generally transported by sweep and ejection motions associated with the well-known canopy-top \"shear-driven\" coherent eddy structures. During extreme stability conditions (both unstable and stable), the role of these \"shear-driven\" structures in transporting scalars decreases, inducing notable dissimilarity between momentum and scalar transport. In unstable conditions, \"shear-driven\" coherent structures are progressively replaced by \"buo-yantly-driven\" structures, known as thermal plumes; which appear very efficient at transporting scalars, especially upward thermal plumes above the canopy. Within the canopy, downward thermal plumes become more efficient at transporting scalars than upward thermal plumes if scalar sources are located in the upper canopy. We explain these features by suggesting that: (i) downward plumes within the canopy correspond to large downward plumes coming from above, and (ii) upward plumes within the canopy are local small plumes induced by canopy heat sources where passive scalars are first injected if there sources are at the same location as heat sources. Above the canopy, these small upward thermal plumes aggregate to form larger scale upward thermal plumes. Furthermore, scalar quantities carried by downward plumes are not modified when penetrating the canopy and crossing upper scalar sources. Consequently, scalars appear to be preferentially injected into upward thermal plumes as opposed to in downward thermal plumes. In stable conditions, intermittent downward and upward motions probably related to elevated shear layers are responsible for canopy-top heat and water vapor transport through the initiation of turbulent instabilities, but this transport remains small. During the foliated period, lower-canopy heat and water vapor transport occurs through thermal plumes associated with a subcanopy unstable layer.

Young adults who are not in employment, education, or training (NEET) are at risk of long-term economic disadvantage and social exclusion. Knowledge about risk factors for being NEET largely comes from cross-sectional studies of vulnerable individuals. Using data collected over a 10-year period, we examined adolescent predictors of being NEET in young adulthood. We used data on 1938 participants from the Victorian Adolescent Health Cohort Study, a community-based longitudinal study of adolescents in Victoria, Australia. Associations between common mental disorders, disruptive behaviour, cannabis use and drinking behaviour in adolescence, and NEET status at two waves of follow-up in young adulthood (mean ages of 20.7 and 24.1 years) were investigated using logistic regression, with generalised estimating equations used to account for the repeated outcome measure. Overall, 8.5% of the participants were NEET at age 20.7 years and 8.2% at 24.1 years. After adjusting for potential confounders, we found evidence of increased risk of being NEET among frequent adolescent cannabis users [adjusted odds ratio (ORadj) = 1.74; 95% confidence interval (CI) 1.10-2.75] and those who reported repeated disruptive behaviours (ORadj = 1.71; 95% CI 1.15-2.55) or persistent common mental disorders in adolescence (ORadj = 1.60; 95% CI 1.07-2.40). Similar associations were present when participants with children were included in the same category as those in employment, education, or training. Young people with an early onset of mental health and behavioural problems are at risk of failing to make the transition from school to employment. This finding reinforces the importance of integrated employment and mental health support programmes.

Determining the mechanism of gene function is greatly enhanced using conditional mutagenesis. However, generating engineered conditional alleles is inefficient and has only been widely used in mice. Importantly, multiplex conditional mutagenesis requires extensive breeding. Here we demonstrate a system for one-generation multiplex conditional mutagenesis in zebrafish (Danio rerio) using transgenic expression of both cas9 and multiple single guide RNAs (sgRNAs). We describe five distinct zebrafish U6 promoters for sgRNA expression and demonstrate efficient multiplex biallelic inactivation of tyrosinase and insulin receptor a and b, resulting in defects in pigmentation and glucose homeostasis. Furthermore, we demonstrate temporal and tissue-specific mutagenesis using transgenic expression of Cas9. Heat-shock-inducible expression of cas9 allows temporal control of tyr mutagenesis. Liver-specific expression of cas9 disrupts insulin receptor a and b, causing fasting hypoglycemia and postprandial hyperglycemia. We also show that delivery of sgRNAs targeting ascl1a into the eye leads to impaired damage-induced photoreceptor regeneration. Our findings suggest that CRISPR/Cas9-based conditional mutagenesis in zebrafish is not only feasible but rapid and straightforward.