Long-Term Health Effects of Work Trajectories Among Middle-Aged and Older Adults: The Mediating Role of Work, Material, and Social Environments

Using data from 14 waves (2003–2016) of the Korean Labor and Income Panel Study (KLIPS) (N = 1,627 individuals aged 45–64; 22778 observations), in this study, we conducted sequence analysis and a multi-categorical variable mediation analysis (1) to examine to what extent long-term work histories exhibit varying degrees of de-standardization and precariousness using sequence analysis (2) to explore the potential mediating effects of work, material, and social environments in the association between multiple work sequences and self-rated health. We found the coexistence of a relatively stable long-term employment pattern and a high prevalence of precariousness. The health and economic risks of precarious work fall disproportionately on older workers. Future researchers should continue to analyze whether the COVID-19 pandemic will lead to long-term changes in the workforce to improve our understanding of and response to working in later life and its health effects

MEKK2 mediates aberrant ERK activation in neurofibromatosis type I

Neurofibromatosis type I (NF1) is characterized by prominent skeletal manifestations caused by NF1 loss. While inhibitors of the ERK activating kinases MEK1/2 are promising as a means to treat NF1, the broad blockade of the ERK pathway produced by this strategy is potentially associated with therapy limiting toxicities. Here, we have sought targets offering a more narrow inhibition of ERK activation downstream of NF1 loss in the skeleton, finding that MEKK2 is a novel component of a noncanonical ERK pathway in osteoblasts that mediates aberrant ERK activation after NF1 loss. Accordingly, despite mice with conditional deletion of Nf1 in mature osteoblasts (Nf1(fl/fl);Dmp1-Cre) and Mekk2(-/-) each displaying skeletal defects, Nf1(fl/fl);Mekk2(-/-);Dmp1-Cre mice show an amelioration of NF1-associated phenotypes. We also provide proof-of-principle that FDA-approved inhibitors with activity against MEKK2 can ameliorate NF1 skeletal pathology. Thus, MEKK2 functions as a MAP3K in the ERK pathway in osteoblasts, offering a potential new therapeutic strategy for the treatment of NF1

Thrombosis patterns and clinical outcome of COVID-19 vaccine-induced immune thrombotic thrombocytopenia: A Systematic Review and Meta-Analysis

Objectives- To meta-analyze the clinical manifestations, diagnosis, treatment, and mortality of vaccine-induced immune thrombotic thrombocytopaenia (VITT) after adenoviral vector vaccination. Methods- Eighteen studies of VITT after ChAdOx1 nCoV-19 or Ad26.COV2.S vaccine administration were reviewed from PubMed, Scopus, Embase, and Web of Science. The meta-analysis estimated the summary effects and between-study heterogeneity regarding the incidence, manifestations, sites of thrombosis, diagnostic findings, and clinical outcomes. Results- The incidence of total venous thrombosis after ChAdOx1 nCoV-19 was 28 (95% CI 12-52, I2=100%) per 100,000 doses administered. Of 664 patients in quantitative analysis (10 studies), the mean age of VITT patients was 45.6 years (95% CI 43.8-47.4, I2=57%), with a female predominance (70%). Cerebral venous thrombosis (CVT), deep vein thrombosis (DVT)/pulmonary thromboembolism (PE), and splanchnic vein thrombosis occurred in 54%, 36%, 19% of VITT patients, respectively. The pooled incidence rate of cerebral venous thrombosis after ChAdOx1 nCoV-19 (23 per 100,000 person-years) was higher than the pre-pandemic rate (0.9 per 100,000 person-years). Intracranial haemorrhage and extracranial thrombosis accompanied 47% and 33% of all CVT patients, respectively. The antiplatelet factor 4 (anti-PF4) antibody positivity rate was 91% (95% CI 88-94, I2=0%) and the overall mortality was 32% (95% CI 24-41, I2=69%), and no significant difference was observed between heparin- and non-heparin-based anticoagulation treatments (risk ratio 0.84, 95% CI 0.47-1.50, I2=0%). Conclusions- VITT patients after SARS-CoV-2 vaccination most frequently presented with CVT following DVT/PE and splanchnic vein thrombosis, and about one-third of patients had a fatal outcome. This meta-analysis should provide a better understanding of VITT and assist clinicians in identifying VITT early to improve outcomes and optimize management

Predictive biomarkers for 5-fluorouracil and oxaliplatin-based chemotherapy in gastric cancers via profiling of patient-derived xenografts.

Gastric cancer (GC) is commonly treated by chemotherapy using 5-fluorouracil (5-FU) derivatives and platinum combination, but predictive biomarker remains lacking. We develop patient-derived xenografts (PDXs) from 31 GC patients and treat with a combination of 5-FU and oxaliplatin, to determine biomarkers associated with responsiveness. When the PDXs are defined as either responders or non-responders according to tumor volume change after treatment, the responsiveness of PDXs is significantly consistent with the respective clinical outcomes of the patients. An integrative genomic and transcriptomic analysis of PDXs reveals that pathways associated with cell-to-cell and cell-to-extracellular matrix interactions enriched among the non-responders in both cancer cells and the tumor microenvironment (TME). We develop a 30-gene prediction model to determine the responsiveness to 5-FU and oxaliplatin-based chemotherapy and confirm the significant poor survival outcomes among cases classified as non-responder-like in three independent GC cohorts. Our study may inform clinical decision-making when designing treatment strategies

Population health outcomes in South Korea 1990-2019, and projections up to 2040: a systematic analysis for the Global Burden of Disease Study 2019

BACKGROUND: South Korea has one of the longest operating universal health coverage (UHC) systems. A comprehensive analysis of long-term trajectories of morbidity and mortality in the South Korean population after the inception of UHC is needed to inform health-care policy and practice. METHODS: We used data from the Global Burden of Disease Study (GBD) 2019 to present estimates of cause-specific mortality, incidence, prevalence, years of life lost (YLLs), years of life lived with disability, and disability-adjusted life-years (DALYs) in South Korea from 1990 to 2019. We also examined forecasted estimates of YLLs up to 2040 to investigate likely future changes in disease burden. Finally, we evaluated GBD estimates from seven comparator countries to place disease burden in South Korea within a broader context. FINDINGS: Age-standardised DALYs related to non-communicable diseases (NCDs) decreased by 43·6% (95% uncertainty interval [UI] 39·4-47·9) and mortality by 58·8% (55·9-60·5) from 1990 to 2019. In 2019, the ratio of male to female age-standardised rates of YLLs in South Korea was higher than the global average for 75·9% (22 of 29 diseases) of leading causes, indicating a disproportional disease burden on males in South Korea. Among risk factors, tobacco use accounted for the highest number of 2019 deaths (44 470 [95% UI 37 432-53 989]) in males and high systolic blood pressure for the highest number (21 014 [15 553-26 723]) in females. Among the top ten leading causes of YLLs forecast in South Korea in 2040, nine were NCDs, for both males and females. INTERPRETATION: Our report shows a positive landscape of population health outcomes in South Korea following the establishment of UHC. However, due in part to the effects of population ageing driving up medical expenditures for NCDs, financial pressures and sustainability challenges associated with UHC are pressing concerns. Policy makers should work to tackle population ageing and allocate resources efficiently by prioritising interventions that address the leading causes of death and disability identified in this study. FUNDING: Bill & Melinda Gates Foundation

Global burden of primary liver cancer and its association with underlying aetiologies, sociodemographic status, and sex differences from 1990–2019: A DALY-based analysis of the Global Burden of Disease 2019 study

Background/Aims Global distribution of dominant liver cancer aetiologies has significantly changed over the past decades. This study analyzed the updated temporal trends of liver cancer aetiologies and sociodemographic status in 204 countries and territories from 1990 to 2019. Methods The Global Burden of Disease 2019 report was used for statistical analysis. In addition, we performed stratification analysis to five quintiles using sociodemographic index and 21 geographic regions. Results The crude numbers of liver cancer disease-adjusted life years (DALYs) and deaths significantly increased during the study period (DALYs; 11,278,630 in 1990 and 12,528,422 in 2019, deaths; 365,215 in 1990 and 484,577 in 2019). However, the Age-standardized DALY and mortality rates decreased. Hepatitis B virus (HBV) remains the leading cause of liver cancer DALYs and mortality, followed by hepatitis C virus (HCV), alcohol consumption, and non-alcoholic steatohepatitis/non-alcoholic fatty liver disease (NASH/NAFLD). Although Age-standardized DALY and mortality rates of liver cancer due to HBV and HCV have decreased, the rates due to alcohol consumption and NASH/NAFLD have increased. In 2019, the population of the East Asia region had the highest Age-standardized DALY and mortality rates, followed by high-income Asia-Pacific and Central Asia populations. Although East Asia and high-income Asia-Pacific regions showed a decrease during the study period, Age-standardized DALY rates increased in Central Asia. High-income North American and Australasian populations also showed a significant increase in Age-standardized DALY. Conclusions Liver cancer remains an ongoing global threat. The burden of liver cancer associated with alcohol consumption and NASH/NAFLD is markedly increasing and projected to continuously increase

A large‐scale meta‐analytic atlas of mental health problems prevalence during the COVID‐19 early pandemic

The COVID-19 pandemic and related restrictions can impact mental health. In order to quantify the mental health burden of COVID-19 pandemic, we conducted a systematic review and meta- analysis, searching World Health Organization COVID-19/PsycInfo/PubMed databases (09/29/2020), including observational studies reporting on mental health outcomes in any population affected by COVID-19. Primary outcomes were the prevalence of anxiety, depression, stress, sleep problems, post-traumatic symptoms. Sensitivity analyses were conducted on severe mental health problems, in high-quality studies, and in representative samples. Subgroup analyses were conducted stratified by age, sex, country income level, and COVID-19 infection status. One-hundred-seventy-three studies from February-July 2020 were included (n=502,261, median sample=948, age=34.4 years, females=63%). Ninety-one percent were cross-sectional studies, and 18.5%/57.2% were of high/moderate quality. Highest prevalence emerged for post-traumatic symptoms in COVID-19 infected people (94%), followed by behavioural problems in those with prior mental disorders (77%), fear in healthcare workers (71%), anxiety in caregivers/family members of people with COVID-19 (42%), general health/social contact/passive coping style in the general population (38%), depression in those with prior somatic disorders (37%), and fear in other-than-healthcare workers (29%). Females and people with COVID-19 infection had higher rates of almost all outcomes; college students/young adults of anxiety, depression, sleep problems, suicidal ideation; adults of fear and post-traumatic symptoms. Anxiety, depression, and post- traumatic symptoms were more prevalent in low-/middle-income countries, sleep problems in high-income countries. The COVID-19 pandemic adversely impacts mental health in unique manners across population subgroups. Our results inform tailored preventive strategies and interventions to mitigate current, future, and transgenerational adverse mental health of the COVID-19 pandemic

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. Methods: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. Interpretation: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic