Association of continuous BMI with health-related quality of life in the United States by age and sex.

OBJECTIVE: The objective of this study is to estimate health-related quality of life (HRQoL) by continuous BMI by age, sex, and demographic group in the United States. METHODS: We estimated HRQoL (overall and by domain) by continuous BMI using SF-6D (Short-Form Six-Dimension) data from 182,778 respondents ages 18 years and older from the repeated cross-sectional Medical Expenditure Panel Survey (MEPS) 2008 to 2016. We adjusted for BMI self-report bias and for potential confounding between BMI and HRQoL. RESULTS: We found an inverse J-shaped curve of HRQoL by BMI, with lower values for female individuals and the highest health utilities occurring at BMI of 20.4 kg/m2 (95% CI: 20.32-20.48) for female individuals and 26.5 kg/m2 (95% CI: 26.45-26.55) for male individuals. By BMI category, excess weight contributed to HRQoL loss of 0.0349 for obesity overall, rising to 0.0724 for class III obesity. By domain, pain was the largest cause of HRQoL loss for obesity (26%), followed by role limitations (22%). CONCLUSIONS: HRQoL is lower for people with excess body weight across a broad range of ages and BMI levels, especially at high levels of BMI, with pain being the largest driver of HRQoL loss. These findings highlight the importance of promoting a healthy weight for the entire population while also targeting efforts to prevent extreme weight gain over the life course.

Cancer incidence and survival for 11 cancers in the Commonwealth: a simulation-based modelling study.

BACKGROUND: The number of new cancer cases in Commonwealth countries rose by 35% between 2008 and 2018, but progress in cancer control has been slow in many low-income and lower-middle-income member states. We aimed to examine cancer outcomes and priority areas in the Commonwealth to provide insight and guidance on prioritisation of efforts to improve cancer survival and make the best use of scarce resources. METHODS: We adapted a previously developed microsimulation model of global cancer survival for 11 cancer sites (oesophagus, stomach, colon, rectum, anus, liver, pancreas, lung, breast, cervix uteri, and prostate). All 56 Commonwealth countries were included and classified based on the 2020 World Bank Income groups (low-income, lower-middle-income, upper-middle-income, and high-income countries) and Commonwealth geographical areas. We modelled the number of incident cancer cases in each Commonwealth country in 2020, based on age group-specific estimates of incidence rates from GLOBOCAN 2020. We simulated 5-year net survival for each patient, accounting for the stage at diagnosis (I-IV), availability of specific treatment and imaging modalities, and quality of care (based on residual differences in expected versus observed survival after accounting for the availability and effectiveness of treatment and imaging modalities). We also simulated counterfactual policy scenarios, in which we scaled up various aspects of cancer care to the mean level of high-income countries to estimate the comparative effectiveness of different policies. FINDINGS: Incident cancers in the Commonwealth accounted for an estimated 14·3% of global diagnosed cancer cases in 2020 among the 11 cancers modelled (1 610 000 Commonwealth cases [95% UI 1 556 000-1 674 000] of 11 227 000 global cases [11 069 000-11 406 000]) and are estimated to increase to 17·3% in 2050 due to population growth (3 330 000 [3 154 000-3 539 000] of 19 308 000 [18 706 000-19 911 000]). The 5-year net survival across 11 cancers combined in 2020 was 30·7% (95% UI 22·4-38·6) in Commonwealth countries, ranging from 4·1% (0·04-15·2) in low-income countries, 17·8% (3·7-30·9) in lower-middle-income countries, 33·1% (23·7-46·0) in upper-middle-income countries, to 59·0% (57·8-60·2) in high-income countries. Among single treatment policies, scaling up access to radiotherapy had the largest survival impact in low-income countries, surgery had the largest impact in lower-middle-income and upper-middle-income countries, and targeted therapy had the largest impact in high-income countries. By geographical area, improving radiotherapy availability was estimated to have the largest impact in Africa, surgery in Asia, targeted therapy in the Caribbean and the Americas and Europe, and quality of care in the Pacific Commonwealth countries. Comparing packages of scaling up the availability of all treatment modalities versus imaging modalities, expanding availability of imaging yielded the largest benefits in high-income countries, and in the Caribbean and the Americas, Europe, and the Pacific, whereas expanding treatment yielded larger benefits in all other income groups and geographical areas. INTERPRETATION: We found large variation in 5-year net survival, with a nearly 15-times difference in cancer survival by country income group within the Commonwealth. Efforts to improve the availability of treatment and imaging modalities and quality of care will be crucial to reduce these disparities, with specific priorities of scale-up policies varying by setting. The Commonwealth could leverage a broad range of knowledge and resources and have an important role in supporting member countries with setting-specific priorities to improve cancer outcomes. FUNDING: Harvard T H Chan School of Public Health.

Towards attainment of the 2030 goal for childhood cancer survival for the World Health Organization Global Initiative for Childhood Cancer: An ecological, cross-sectional study.

The World Health Organization (WHO) recently launched the Global Initiative for Childhood Cancer (GICC), with the goal of attaining at least 60% cancer survival for children worldwide by the year 2030. This study aims to describe the global patterns of childhood cancer survival in 2019 to help guide progress in attaining the GICC target goal. In this ecological, cross-sectional study, we used 5-year net childhood cancer survival (2015-2019) data from a prior micro-modeling study from 197 countries and territories. Descriptive statistics were used to analyze the patterns of overall childhood cancer survival and survival for each of the six cancer tracer diagnoses as proposed by the GICC. We used hot spot analysis to identify geographic clusters of high and low cancer survival. Most high-income countries reached at least 60% (92%, n = 59/64), net childhood cancer survival at baseline. No lower-middle-income or low-income country reached at least 60% overall cancer survival at baseline. The South-East Asia region had the highest proportion of countries that did not achieve at least 60% survival at baseline (100%, n = 10/10), followed by the African region (98%, n = 49/50). For each cancer tracer diagnosis, we found the highest number of countries that have achieved at least 60% survival was for Burkitt lymphoma (44%, n = 87/197) followed by acute lymphocytic leukemia (41%, n = 80/197).Hot spot analysis showed the highest overall survival was concentrated in North America and Europe, while the lowest survival was concentrated in Sub-Saharan Africa and South-East Asia.A majority of LMICs had not reached the WHO target goal of at least 60% survival from childhood cancer at baseline in 2019, with variable success for the six childhood cancer tracer diagnoses of the GICC. These findings provide baseline assessment of individual country performance to help achieve the GICC goal of 60% overall cancer survival globally by 2030.

Global maternal mortality projections by urban/rural location and education level: a simulation-based analysis.

Background: Maternal mortality remains a challenge in global health, with well-known disparities across countries. However, less is known about disparities in maternal health by subgroups within countries. The aim of this study is to estimate maternal health indicators for subgroups of women within each country. Methods: In this simulation-based analysis, we used the empirically calibrated Global Maternal Health (GMatH) microsimulation model to estimate a range of maternal health indicators by subgroup (urban/rural location and level of education) for 200 countries/territories from 1990 to 2050. Education levels were defined as low (less than primary), middle (less than secondary), and high (completed secondary or higher). The model simulates the reproductive lifecycle of each woman, accounting for individual-level factors such as family planning preferences, biological factors (e.g., anemia), and history of maternal complications, and how these factors vary by subgroup. We also estimated the impact of scaling up women's education on projected maternal health outcomes compared to clinical and health system-focused interventions. Findings: We find large subgroup differences in maternal health outcomes, with an estimated global maternal mortality ratio (MMR) in 2022 of 292 (95% UI 250-341) for rural women and 100 (95% UI 84-116) for urban women, and 536 (95% UI 450-594), 143 (95% UI 117-174), and 85 (95% UI 67-108) for low, middle, and high education levels, respectively. Ensuring all women complete secondary school is associated with a large impact on the projected global MMR in 2030 (97 [95% UI 76-120]) compared to current trends (167 [95% UI 142-188]), with especially large improvements in countries such as Afghanistan, Chad, Madagascar, Niger, and Yemen. Interpretation: Substantial subgroup disparities present a challenge for global maternal health and health equity. Outcomes are especially poor for rural women with low education, highlighting the need to ensure that policy interventions adequately address barriers to care in rural areas, and the importance of investing in social determinants of health, such as women's education, in addition to health system interventions to improve maternal health for all women. Funding: John D. and Catherine T. MacArthur Foundation, 10-97002-000-INP.

Cost-effectiveness of Improved WIC Food Package for Preventing Childhood Obesity.

BACKGROUND AND OBJECTIVES: The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) prevents food insecurity and supports nutrition for more than 3 million low-income young children. Our objectives were to determine the cost-effectiveness of changes to WIC's nutrition standards in 2009 for preventing obesity and to estimate impacts on socioeconomic and racial/ethnic inequities. METHODS: We conducted a cost-effectiveness analysis to estimate impacts from 2010 through 2019 of the 2009 WIC food package change on obesity risk for children aged 2 to 4 years participating in WIC. Microsimulation models estimated the cases of obesity prevented in 2019 and costs per quality-adjusted-life year gained. RESULTS: An estimated 14.0 million 2- to 4-year old US children (95% uncertainty interval (UI), 13.7-14.2 million) were reached by the updated WIC nutrition standards from 2010 through 2019. In 2019, an estimated 62 700 (95% UI, 53 900-71 100) cases of childhood obesity were prevented, entirely among children from households with low incomes, leading to improved health equity. The update was estimated to cost $10 600 per quality-adjusted-life year gained (95% UI, $9760-$11 700). If WIC had reached all eligible children, more than twice as many cases of childhood obesity would have been prevented. CONCLUSIONS: Updates to WIC's nutrition standards for young children in 2009 were estimated to be highly cost-effective for preventing childhood obesity and contributed to reducing socioeconomic and racial/ethnic inequities in obesity prevalence. Improving nutrition policies for young children can be a sound public health investment; future research should explore how to improve access to them.

Cost Effectiveness of Calorie Labeling at Large Fast-Food Chains Across the U.S.

INTRODUCTION: Calorie labeling of standard menu items has been implemented at large restaurant chains across the U.S. since 2018. The objective of this study was to evaluate the cost effectiveness of calorie labeling at large U.S. fast-food chains. METHODS: This study evaluated the national implementation of calorie labeling at large fast-food chains from a modified societal perspective and projected its cost effectiveness over a 10-year period (2018-2027) using the Childhood Obesity Intervention Cost-Effectiveness Study microsimulation model. Using evidence from over 67 million fast-food restaurant transactions between 2015 and 2019, the impact of calorie labeling on calorie consumption and obesity incidence was projected. Benefits were estimated across all racial, ethnic, and income groups. Analyses were performed in 2022. RESULTS: Calorie labeling is estimated to be cost saving; prevent 550,000 cases of obesity in 2027 alone (95% uncertainty interval=518,000; 586,000), including 41,500 (95% uncertainty interval=33,700; 50,800) cases of childhood obesity; and save $22.60 in healthcare costs for every $1 spent by society in implementation costs. Calorie labeling is also projected to prevent cases of obesity across all racial and ethnic groups (range between 126 and 185 cases per 100,000 people) and all income groups (range between 152 and 186 cases per 100,000 people). CONCLUSIONS: Calorie labeling at large fast-food chains is estimated to be a cost-saving intervention to improve long-term population health. Calorie labeling is a low-cost intervention that is already implemented across the U.S. in large chain restaurants.

A Sugar-Sweetened Beverage Excise Tax in California: Projected Benefits for Population Obesity and Health Equity.

INTRODUCTION: Amid the successes of local sugar-sweetened beverage (SSB) taxes, interest in state-wide policies has grown. This study evaluated the cost effectiveness of a hypothetical 2-cent-per-ounce excise tax in California and its implications for population health and health equity. METHODS: Using the Childhood Obesity Intervention Cost-Effectiveness Study microsimulation model, tax impacts on health, health equity, and cost effectiveness over 10 years in California were projected, both overall and stratified by race/ethnicity and income. Expanding on previous models, differences in the effect of intake of SSBs on weight by BMI category were incorporated. Costing was performed in 2020, and analyses were conducted in 2021-2022. RESULTS: The tax is projected to save $4.55 billion in healthcare costs, prevent 266,000 obesity cases in 2032, and gain 114,000 quality-adjusted life years. Cost-effectiveness metrics, including cost/quality-adjusted life year gained, were cost saving. Spending on SSBs was projected to decrease by $33 per adult and $26 per child overall in the first year. Reductions in obesity prevalence for Black and Hispanic Californians were 1.8 times larger than for White Californians, and reductions for adults with lowest incomes (<130% Federal Poverty Level) were 1.4 times the reduction among those with highest incomes (>350% Federal Poverty Level). The tax is projected to save $112 in obesity-related healthcare costs per $1 invested. CONCLUSIONS: A state-wide SSB tax in California would be cost saving, lead to reductions in obesity and improvement in SSB-related health equity, and lead to overall improvements in population health. The policy would generate more than $1.6 billion in state tax revenue annually that can also be used to improve health equity.

Treat All versus targeted strategies to select HBV-infected people for antiviral therapy in The Gambia, west Africa: a cost-effectiveness analysis.

BACKGROUND: Global elimination of hepatitis B virus (HBV) requires expanded uptake of antiviral therapy, potentially by simplifying testing algorithms, especially in resource-limited countries. We evaluated the effectiveness, cost-effectiveness, and budget impact of three strategies that determine eligibility for anti-HBV treatment, as compared with the WHO 2015 treatment eligibility criteria, in The Gambia. METHODS: We developed a microsimulation model of natural history using data from the Prevention of Liver Fibrosis and Cancer in Africa programme (known as PROLIFICA) in The Gambia, for an HBV-infected cohort of individuals aged 20 years. The algorithms included in the model were a conventional strategy using the European Association for the Study of the Liver (EASL) 2017 criteria, a simplified algorithm using hepatitis B e antigen and alanine aminotransferase (the Treatment Eligibility in Africa for the Hepatitis B Virus [TREAT-B] score), a Treat All approach for all HBV-infected individuals, and the WHO 2015 criteria. Outcomes to measure effectiveness were disability-adjusted life years (DALYs) and years of life saved (YLS), which were used to calculate incremental cost-effectiveness ratios (ICERs) with the WHO 2015 criteria as the base-case scenario. Costs were assessed from a modified social perspective. A budget impact analysis was also done. We tested the robustness of results with a range of sensitiviy analyses including probabilistic sensitivity analysis. FINDINGS: Compared with the WHO criteria, TREAT-B resulted in 4877 DALYs averted and Treat All resulted in 9352 DALYs averted, whereas the EASL criteria led to an excess of 795 DALYs. TREAT-B was cost-saving, whereas the ICER for Treat All (US$2149 per DALY averted) was higher than the cost-effectiveness threshold for The Gambia (0·5 times the country's gross domestic product per capita: $352). These patterns did not change when YLS was the outcome. In a modelled cohort of 5000 adults (aged 20 years) with chronic HBV infection from The Gambia, the 5-year budget impact was $1·14 million for Treat All, $0·66 million for TREAT-B, $1·03 million for the WHO criteria, and $1·16 million for the EASL criteria. Probabilistic sensitivity analysis indicated that among the Treat All, EASL, and TREAT-B algorithms, Treat All would become the most preferred strategy only with a willingness-to-pay threshold exceeding approximately $72 000 per DALY averted or $110 000 per YLS. INTERPRETATION: Although the Treat All strategy might be the most effective, it is unlikely to be cost-effective in The Gambia. A simplified strategy such as TREAT-B might be a cost-saving alternative. FUNDING: UK Research and Innovation (Medical Research Council). TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Social media platforms generate billions of dollars in revenue from U.S. youth: Findings from a simulated revenue model.

Social media platforms are suspected to derive hefty profits from youth users who may be vulnerable to negative mental health outcomes, including depression, anxiety, and eating disorders. Platforms, however, are not required to make these data publicly available, which may limit the abilities of researchers and policymakers to adequately investigate and regulate platform practices. This study aimed to estimate the number of U.S.-based child (0-12 years old) and adolescent (13-17 years old) users and the annual advertising revenue generated from youth across six major platforms. Data were drawn from public survey and market research sources conducted in 2021 and 2022. A simulation analysis was conducted to derive estimates of the number of users and the annual advertising revenue per age group and overall (ages 0-17 years) for 2022. The findings reveal that, across six major social media platforms, the 2022 annual advertising revenue from youth users ages 0-17 years is nearly $11 billion. Approximately 30-40% of the advertising revenue generated from three social media platforms is attributable to young people. Our findings highlight the need for greater transparency from social media platforms as well as regulation of potentially harmful advertising practices that may exploit vulnerable child and adolescent social media users.

Effects of post-transfer annealing and substrate interactions on the photoluminescence of 2D/3D monolayer WS2/Ge heterostructures.

The ultraflat and dangling bond-free features of two-dimensional (2D) transition metal dichalcogenides (TMDs) endow them with great potential to be integrated with arbitrary three-dimensional (3D) substrates, forming mixed-dimensional 2D/3D heterostructures. As examples, 2D/3D heterostructures based on monolayer TMDs (e.g., WS2) and bulk germanium (Ge) have become emerging candidates for optoelectronic applications, such as ultrasensitive photodetectors that are capable of detecting broadband light from the mid-infrared (IR) to visible range. Currently, the study of WS2/Ge(100) heterostructures is in its infancy and it remains largely unexplored how sample preparation conditions and different substrates affect their photoluminescence (PL) and other optoelectronic properties. In this report, we investigated the PL quenching effect in monolayer WS2/Ge heterostructures prepared via a wet transfer process, and employed PL spectroscopy and atomic force microscopy (AFM) to demonstrate that post-transfer low-pressure annealing improves the interface quality and homogenizes the PL signal. We further studied and compared the temperature-dependent PL emissions of WS2/Ge with those of as-grown WS2 and WS2/graphene/Ge heterostructures. The results demonstrate that the integration of WS2 on Ge significantly quenches the PL intensity (from room temperature down to 80 K), and the PL quenching effect becomes even more prominent in WS2/graphene/Ge heterostructures, which is likely due to synergistic PL quenching effects induced by graphene and Ge. Density functional theory (DFT) and Heyd-Scuseria-Ernzerhof (HSE) hybrid functional calculations show that the interaction of WS2 and Ge is stronger than in adjacent layers of bulk WS2, thus changing the electronic band structure and making the direct band gap of monolayer WS2 less accessible. By understanding the impact of post-transfer annealing and substrate interactions on the optical properties of monolayer TMD/Ge heterostructures, this study contributes to the exploration of the processing-properties relationship and may guide the future design and fabrication of optoelectronic devices based on 2D/3D heterostructures of TMDs/Ge.

The societal costs and health impacts on obesity of BMI report cards in US schools.

OBJECTIVE: This study aimed to estimate the 10-year cost-effectiveness of school-based BMI report cards, a commonly implemented program for childhood obesity prevention in the US where student BMI is reported to parents/guardians by letter with nutrition and physical activity resources, for students in grades 3 to 7. METHODS: A microsimulation model, using data inputs from evidence reviews on health impacts and costs, estimated: how many students would be reached if the 15 states currently measuring student BMI (but not reporting to parents/guardians) implemented BMI report cards from 2023 to 2032; how many cases of childhood obesity would be prevented; expected changes in childhood obesity prevalence; and costs to society. RESULTS: BMI report cards were projected to reach 8.3 million children with overweight or obesity (95% uncertainty interval [UI]: 7.7-8.9 million) but were not projected to prevent any cases of childhood obesity or significantly decrease childhood obesity prevalence. Ten-year costs totaled $210 million (95% UI: $30.5-$408 million) or $3.33 per child per year with overweight or obesity (95% UI: $3.11-$3.68). CONCLUSIONS: School-based BMI report cards are not cost-effective childhood obesity interventions. Deimplementation should be considered to free up resources for implementing effective programs.

State-Specific Prevalence of Severe Obesity Among Adults in the US Using Bias Correction of Self-Reported Body Mass Index.

INTRODUCTION: Adults with severe obesity are at increased risk for poor metabolic health and may need more intensive clinical and community supports. The prevalence of severe obesity is underestimated from self-reported weight and height data. We examined severe obesity prevalence among US adults by sociodemographic characteristics and by state after adjusting for self-report bias. METHODS: Using a validated bias-correction method, we adjusted self-reported body mass index (BMI) data from the 2020 Behavioral Risk Factor Surveillance System (BRFSS) by using measured data from the National Health and Nutrition Examination Survey. We compared bias-corrected prevalence of severe obesity (BMI ≥40) with self-reported estimates by sociodemographic characteristics and state. RESULTS: Self-reported BRFSS data significantly underestimated the prevalence of severe obesity compared with bias-corrected estimates. In 2020, 8.8% of adults had severe obesity based on the bias-corrected estimates, whereas 5.3% of adults had severe obesity based on self-reported data. Women had a significantly higher prevalence of bias-corrected severe obesity (11.1%) than men (6.5%). State-level prevalence of bias-corrected severe obesity ranged from 5.5% (Massachusetts) to 13.2% (West Virginia). Based on bias-corrected estimates, 16 states had a prevalence of severe obesity greater than 10%, a level not seen in the self-reported estimates. CONCLUSION: Self-reported BRFSS data underestimated the overall prevalence of severe obesity by 40% (5.3% vs 8.8%). Accurate state-level estimates of severe obesity can help public health and health care decision makers prioritize and plan to implement effective prevention and treatment strategies for people who are at high risk for poor metabolic health.

Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons.

Aging and the age-associated decline of the proteome is determined in part through neuronal control of evolutionarily conserved transcriptional effectors, which safeguard homeostasis under fluctuating metabolic and stress conditions by regulating an expansive proteostatic network. We have discovered the Caenorhabditis elegans homeodomain-interacting protein kinase (HPK-1) acts as a key transcriptional effector to preserve neuronal integrity, function, and proteostasis during aging. Loss of hpk-1 results in drastic dysregulation in expression of neuronal genes, including genes associated with neuronal aging. During normal aging hpk-1 expression increases throughout the nervous system more broadly than any other kinase. Within the aging nervous system, hpk-1 induction overlaps with key longevity transcription factors, which suggests that hpk-1 expression mitigates natural age-associated physiological decline. Consistently, pan-neuronal overexpression of hpk-1 extends longevity, preserves proteostasis both within and outside of the nervous system, and improves stress resistance. Neuronal HPK-1 improves proteostasis through kinase activity. HPK-1 functions cell non-autonomously within serotonergic and γ-aminobutyric acid (GABA)ergic neurons to improve proteostasis in distal tissues by specifically regulating distinct components of the proteostatic network. Increased serotonergic HPK-1 enhances the heat shock response and survival to acute stress. In contrast, GABAergic HPK-1 induces basal autophagy and extends longevity, which requires mxl-2 (MLX), hlh-30 (TFEB), and daf-16 (FOXO). Our work establishes hpk-1 as a key neuronal transcriptional regulator critical for preservation of neuronal function during aging. Further, these data provide novel insight as to how the nervous system partitions acute and chronic adaptive response pathways to delay aging by maintaining organismal homeostasis.

Proteins are essential for nearly every cellular process to sustain a healthy organism. A complex network of pathways and signalling molecules regulates the proteins so that they work correctly in a process known as proteostasis. As the body ages, this network can become damaged, which leads to the production of faulty proteins. Many proteins end up being misfolded ­ in other words, they are misshapen on the molecular level, which can be toxic for the cell. A build-up of such misfolded proteins is implicated in several neurological conditions, including Alzheimer's, Parkinson's and Huntington's disease. Cells have various ways to detect and respond to internal stressors, such as tissue or organ damage. For example, specific proteins in the nervous system can raise a 'central' alert when damage is detected, which then primes and coordinates the body's systems to respond in the peripheral cells and tissues. But exactly how this happens is still unclear. To find out more about the central coordination of stress responses, Lazaro-Pena et al. studied one such sensor protein, called HPK-1, in the roundworm C. elegans. They first overexpressed the protein in various tissues. This revealed that only when HPK-1 was overactive in nerve tissue, it protected proteins and prolonged the lifespan of the worms. An increased amount of HPK-1 improved the health span of the worms and older worms also moved better. However, genetically manipulated worms lacking HPK-1 in their nerve cells showed a faster decline in nervous system health as they aged, which could be reversed once HPK-1 was activated again. Lazaro-Pena et al. then measured the amount of HPK-1 in worms at different stages of their life. This showed that as the worms aged, the amount of HPK-1 increased in the nerve cells. The nerve cells in which HPK-1 levels increased overlapped with an increased expression of proteins associated with longevity. Moreover, when HPK-1 was overexpressed, it stimulated the release of other cell signals, which then triggered protective responses to prevent the misfolding and aggregation of proteins and to help degrade damaged proteins. This study shows for the first time that HPK-1 appears to play a protective role during normal ageing and that it may act as a key switch to stimulate other protective mechanisms. These findings may give rise to new insights into how the nervous system can coordinate many different stress responses, and ultimately delay ageing throughout the whole body.

Machine Learning-Aided Band Gap Engineering of BaZrS3 Chalcogenide Perovskite.

The non-toxic and stable chalcogenide perovskite BaZrS3 fulfills many key optoelectronic properties for a high-efficiency photovoltaic material. It has been shown to possess a direct band gap with a large absorption coefficient and good carrier mobility values. With a reported band gap of 1.7-1.8 eV, BaZrS3 is a good candidate for tandem solar cell materials; however, its band gap is significantly larger than the optimal value for a high-efficiency single-junction solar cell (∼1.3 eV, Shockley-Queisser limit)─thus doping is required to lower the band gap. By combining first-principles calculations and machine learning algorithms, we are able to identify and predict the best dopants for the BaZrS3 perovskites for potential future photovoltaic devices with a band gap within the Shockley-Queisser limit. It is found that the Ca dopant at the Ba site or Ti dopant at the Zr site is the best candidate dopant. Based on this information, we report for the first time partial doping at the Ba site in BaZrS3 with Ca (i.e., Ba1-xCaxZrS3) and compare its photoluminescence with Ti-doped perovskites [i.e., Ba(Zr1-xTix)S3]. Synthesized (Ba,Ca)ZrS3 perovskites show a reduction in the band gap from ∼1.75 to ∼1.26 eV with <2 atom % Ca doping. Our results indicate that for the purpose of band gap tuning for photovoltaic applications, Ca-doping at the Ba-site is superior to Ti-doping at the Zr-site reported previously.

Simulation-based estimates and projections of global, regional and country-level maternal mortality by cause, 1990-2050.

Maternal mortality is a major global health challenge. Although progress has been made globally in reducing maternal deaths, measurement remains challenging given the many causes and frequent underreporting of maternal deaths. We developed the Global Maternal Health microsimulation model for women in 200 countries and territories, accounting for individual fertility preferences and clinical histories. Demographic, epidemiologic, clinical and health system data were synthesized from multiple sources, including the medical literature, Civil Registration Vital Statistics systems and Demographic and Health Survey data. We calibrated the model to empirical data from 1990 to 2015 and assessed the predictive accuracy of our model using indicators from 2016 to 2020. We projected maternal health indicators from 1990 to 2050 for each country and estimate that between 1990 and 2020 annual global maternal deaths declined by over 40% from 587,500 (95% uncertainty intervals (UI) 520,600-714,000) to 337,600 (95% UI 307,900-364,100), and are projected to decrease to 327,400 (95% UI 287,800-360,700) in 2030 and 320,200 (95% UI 267,100-374,600) in 2050. The global maternal mortality ratio is projected to decline to 167 (95% UI 142-188) in 2030, with 58 countries above 140, suggesting that on current trends, maternal mortality Sustainable Development Goal targets are unlikely to be met. Building on the development of our structural model, future research can identify context-specific policy interventions that could allow countries to accelerate reductions in maternal deaths.

A simulation-based comparative effectiveness analysis of policies to improve global maternal health outcomes.

The Sustainable Development Goals include a target to reduce the global maternal mortality ratio (MMR) to less than 70 maternal deaths per 100,000 live births by 2030, with no individual country exceeding 140. However, on current trends the goals are unlikely to be met. We used the empirically calibrated Global Maternal Health microsimulation model, which simulates individual women in 200 countries and territories to evaluate the impact of different interventions and strategies from 2022 to 2030. Although individual interventions yielded fairly small reductions in maternal mortality, integrated strategies were more effective. A strategy to simultaneously increase facility births, improve the availability of clinical services and quality of care at facilities, and improve linkages to care would yield a projected global MMR of 72 (95% uncertainty interval (UI) = 58-87) in 2030. A comprehensive strategy adding family planning and community-based interventions would have an even larger impact, with a projected MMR of 58 (95% UI = 46-70). Although integrated strategies consisting of multiple interventions will probably be needed to achieve substantial reductions in maternal mortality, the relative priority of different interventions varies by setting. Our regional and country-level estimates can help guide priority setting in specific contexts to accelerate improvements in maternal health.

Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons.

Aging and the age-associated decline of the proteome is determined in part through neuronal control of evolutionarily conserved transcriptional effectors, which safeguard homeostasis under fluctuating metabolic and stress conditions by regulating an expansive proteostatic network. We have discovered the Caenorhabditis elegans h omeodomain-interacting p rotein k inase (HPK-1) acts as a key transcriptional effector to preserve neuronal integrity, function, and proteostasis during aging. Loss of hpk-1 results in drastic dysregulation in expression of neuronal genes, including genes associated with neuronal aging. During normal aging hpk-1 expression increases throughout the nervous system more broadly than any other kinase. Within the aging nervous system, hpk-1 induction overlaps with key longevity transcription factors, which suggests hpk-1 expression mitigates natural age-associated physiological decline. Consistently, pan-neuronal overexpression of hpk-1 extends longevity, preserves proteostasis both within and outside of the nervous system, and improves stress resistance. Neuronal HPK-1 improves proteostasis through kinase activity. HPK-1 functions cell non-autonomously within serotonergic and GABAergic neurons to improve proteostasis in distal tissues by specifically regulating distinct components of the proteostatic network. Increased serotonergic HPK-1 enhances the heat shock response and survival to acute stress. In contrast, GABAergic HPK-1 induces basal autophagy and extends longevity, which requires mxl-2 (MLX), hlh-30 (TFEB), and daf-16 (FOXO). Our work establishes hpk-1 as a key neuronal transcriptional regulator critical for preservation of neuronal function during aging. Further, these data provide novel insight as to how the nervous system partitions acute and chronic adaptive response pathways to delay aging by maintaining organismal homeostasis.

Estimating the total incidence of type 1 diabetes in children and adolescents aged 0-19 years from 1990 to 2050: a global simulation-based analysis.

BACKGROUND: Previous studies of type 1 diabetes in childhood and adolescence have found large variations in reported incidence around the world. However, it is unclear whether these reported incidence levels are impacted by differences in country health systems and possible underdiagnosis and if so, to what degree. The aim of this study was to estimate both the total and diagnosed incidence of type 1 diabetes globally and to project childhood type 1 diabetes incidence indicators from 1990 to 2050 for each country. METHODS: We developed the type 1 diabetes global microsimulation model to simulate the natural history and diagnosis of type 1 diabetes for children and adolescents (aged 0-19 years) in 200 countries and territories, accounting for variability in underlying incidence and health system performance. The model follows an open population of children and adolescents in monthly intervals and simulates type 1 diabetes incidence and progression, as well as health system factors which influence diagnosis. We calibrated the model to published data on type 1 diabetes incidence, autoantibody profiles, and proportion of cases diagnosed with diabetic ketoacidosis from 1990 to 2020 and assessed the predictive accuracy using a randomly sampled test set of data withheld from calibration. FINDINGS: We estimate that in 2021 there were 355 900 (95% UI 334 200-377 300) total new cases of type 1 diabetes globally among children and adolescents, of which 56% (200 400 cases, 95% UI 180 600-219 500) were diagnosed. Estimated underdiagnosis varies substantially by region, with over 95% of new cases diagnosed in Australia and New Zealand, western and northern Europe, and North America, but less than 35% of new cases diagnosed in west Africa, south and southeastern Asia, and Melanesia. The total number of incident childhood cases of type 1 diabetes is projected to increase to 476 700 (95% UI 449 500-504 300) in 2050. INTERPRETATION: Our research indicates that the total global incidence of childhood and adolescent type 1 diabetes is larger than previously estimated, with nearly one-in-two children currently undiagnosed. Policymakers should plan for adequate diagnostic and medical capacity to improve timely type 1 diabetes detection and treatment, particularly as incidence is projected to increase worldwide, with highest numbers of new cases in Africa. FUNDING: Novo Nordisk.

Cost-Effectiveness of 5 Public Health Approaches to Prevent Eating Disorders.

INTRODUCTION: Eating disorders cause suffering and a high risk of death. Accelerating the translation of research into implementation will require intervention cost-effectiveness estimates. The objective of this study was to estimate the cost-effectiveness of 5 public health approaches to preventing eating disorders among adolescents and young adults. METHODS: Using data from 2001 to 2017, the authors developed a microsimulation model of a closed cohort starting at the age of 10 years and ending at 40 years. In 2021, an analysis was conducted of 5 primary and secondary prevention strategies for eating disorders: school-based screening, primary care‒based screening, school-based universal prevention, excise tax on over-the-counter diet pills, and restriction on youth purchase of over-the-counter diet pills. The authors estimated the reduction in years lived with eating disorders and the increase in quality-adjusted life-years. Intervention costs and net monetary benefit were estimated using a threshold of $100,000/quality-adjusted life year. RESULTS: All the 5 interventions were estimated to be cost-saving compared with the current practice. Discounted per person cost savings (over the 30-year analytic time horizon) ranged from $63 (clinic screening) to $1,102 (school-based universal prevention). Excluding caregiver costs for binge eating disorder and otherwise specified feeding and eating disorders substantially reduced cost savings (e.g., from $1,102 to $149 for the school-based intervention). CONCLUSIONS: A range of public health strategies to reduce the societal burden of eating disorders are likely cost saving. Universal prevention interventions that promote healthy nutrition, physical activity, and media use behaviors without introducing weight stigma may prevent additional negative health outcomes, such as excess weight gain.