Exploring Mental Health and Academic Outcomes of Children Receiving Non-manualized, Transdiagnostic, Task-Shifted Mental Health Care From Their Teachers in a Low-and-Middle Income Country

A majority of children worldwide who face mental health difficulties, especially in low-and-middle income countries, remain undiagnosed and untreated. This deficit roots in part from a lack of trained professionals qualified to provide care. Task-shifting the provision of treatment to teachers, individuals with consistent access to children, can reduce the care gap. The current study investigated whether the implementation of a pilot trial of Tealeaf-Mansik Swastha (Teachers Leading the Frontlines—Mental Health; “Tealeaf”) was associated with improvements in child mental health and academic outcomes. Tealeaf is a transdiagnostic, non-manualized, task-shifting intervention in which teachers identify students in need of mental health care and then provide task-shifted care for them using an emerging, novel therapy modality, “education as mental health therapy” (Ed-MH). Pre-post standardized quantitative measures focused on child mental health status and academics. The measures were completed by multiple raters and compared to determine whether changes occurred. Results indicated that primary teacher raters observed significant improvements in child mental health symptoms overall, while secondary teacher raters and caregivers noted improvement for certain diagnostic categories. Caregivers observed on average a decreased impact of their children's mental health symptoms on their children's lives. Academically, math scores significantly improved while reading trended toward significance. Preliminary evidence overall supports the viability of Tealeaf and Ed-MH for positively impacting child mental health and academics. Future directions include the implementation of a formalized, randomized-controlled trial to strengthen preliminary outcomes

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

The burden of trisomy 21 disrupts the proteostasis network in Down syndrome

<div><p>Down syndrome (DS) is a genetic disorder caused by trisomy of chromosome 21. Abnormalities in chromosome number have the potential to lead to disruption of the proteostasis network (PN) and accumulation of misfolded proteins. DS individuals suffer from several comorbidities, and we hypothesized that disruption of proteostasis could contribute to the observed pathology and decreased cell viability in DS. Our results confirm the presence of a disrupted PN in DS, as several of its elements, including the unfolded protein response, chaperone system, and proteasomal degradation exhibited significant alterations compared to euploid controls in both cell and mouse models. Additionally, when cell models were treated with compounds that promote disrupted proteostasis, we observed diminished levels of cell viability in DS compared to controls. Collectively our findings provide a cellular-level characterization of PN dysfunction in DS and an improved understanding of the potential pathogenic mechanisms contributing to disrupted cellular physiology in DS. Lastly, this study highlights the future potential of designing therapeutic strategies that mitigate protein quality control dysfunction.</p></div

Impaired heat shock response in DS fibroblasts.

<p>Basal levels of most heat shock proteins (Hsp) investigated were not significantly different controls; however, Hsp27 was significantly decreased in DS cells (A). Stimulation of these cells for 2h with 40°C heat stress did not result in a significant increase in Hsp90 or 70 (B). These results indicate an abnormal HSF-1 response in DS fibroblasts. Graphs represent results of Western blotting experiments that were conducted in triplicate. Data is represented as the mean ± SEM (*P<0.05, ****P<0.0001).</p

Cell viability in DS cells is altered to a greater extent due to exposure to ER stressors compared to CTL.

<p>Cells were treated for 24h with Tm (A) or MB (B) and cell viability was assessed using a WST-1 assay. N = 3–4, * P<0.05; ** P<0.01; *** P<0.001.</p

A simplified schematic illustrating the three major functions of the proteostasis network (Blue), and the key modulators (Red), UPR and HSF-1.

<p>A simplified schematic illustrating the three major functions of the proteostasis network (Blue), and the key modulators (Red), UPR and HSF-1.</p

Phosphorylation of IRE1α does not differ greatly between cells from DS and euploid controls.

<p>Three pairs of DS and CTL LCL, as well as one pair of DS and CTL fibroblasts, were analyzed for basal levels of IRE1α phosphorylation (A). These data show that LCLs did not display a clear DS-mediated phenotype, while the fibroblasts showed a DS-mediated increase in phosphorylation (B). Inhibition of the IRE1α endonuclease domain with 4μ8c did not significantly decrease XBP1s abundance in DS fibroblasts (C). Western blots were conducted in triplicate and the images are representative of these replications.</p