Background: The recently published “Life’s Essential 8” (LE8) by the American Heart Association has overcome some limitations in evaluating cardiovascular health (CVH) in the previous “Life’s Simple 7.” Objective: We aimed to examine the secular trends in CVH, as assessed by the LE8, in US adults from 2005 to 2018. Methods: Using cross-sectional data from the National Health and Nutrition Examination Survey between 2005-2006 and 2017-2018, we calculated the age-standardized mean scores of overall CVH and each of the LE8 components, where a higher score (range 0-100 points) means a better health status. A total of 21,667 adults aged 20-79 years were included in this analysis. Results: The overall CVH did not significantly change between 2005-2006 and 2017-2018 (65.5, 95% CI 63.9-67.1 to 65.0, 95% CI 62.8-67.1; P=.82). The individual metrics did not significantly change for diet (41.0, 95% CI 38.0-43.9 to 41.5, 95% CI 36.5-46.6; P=.94), physical activity (57.5, 95% CI 53.0-61.9 to 53.0, 95% CI 48.7-57.3; P=.26), and blood pressure (68.4, 95% CI 65.2-71.5 to 68.6, 95% CI 65.3-71.9, P=.35), improved for nicotine exposure (64.7, 95% CI 61.1-68.4 to 71.9, 95% CI 67.7-76.2; P<.001), sleep health (83.7, 95% CI 81.6-85.7 to 84.1, 95% CI 81.2-87.1; P=.006), and blood lipids (61.6, 95% CI 59.1-64.0 to 67.0, 95% CI 63.5-70.4; P<.001), and worsened for BMI (63.4, 95% CI 59.7-67.1 to 56.2, 95% CI 52.5-59.9; P<.001) and blood glucose (83.9, 95% CI 82.4-85.4 to 77.4, 95% CI 74.5-80.3; P<.001). Conclusions: According to the LE8, the overall CVH did not change among US adults from 2005 to 2018, as well as 3 components (diet, physical activity, and blood pressure). Other metrics such as nicotine exposure, blood lipids, and sleep health improved, while BMI and blood glucose deteriorated over time.

Although observational studies have suggested associations between circulating antioxidants and many mental disorders, causal inferences have not been confirmed. Mendelian randomization (MR) analyses were conducted using summary-level statistics from genome-wide association studies (GWASs) to explore whether genetically determined absolute circulating antioxidants (i.e., ascorbate, retinol, β-carotene, and lycopene) and metabolites (i.e., α- and γ-tocopherol, ascorbate, and retinol) were causally associated with the risk of six major mental disorders, including anxiety disorders (AD), major depressive disorder (MDD), bipolar disorder (BIP), schizophrenia (SCZ), post-traumatic stress disorder (PTSD), and obsessive–compulsive disorder (OCD). MR analyses were performed per specific-outcome databases, including the largest GWAS published to date (from 9725 for OCD to 413,466 for BIP participants), UK Biobank (over 370,000 participants), and FinnGen (over 270,000 participants), followed by meta-analyses. We found no significant evidence that genetically determined diet-derived circulating antioxidants were significantly causally associated with the risk of the six above-mentioned major mental disorders. For absolute antioxidant levels, the odds ratios (ORs) ranged from 0.91 (95% CI, 0.67–1.23) for the effect of β-carotene on OCD to 1.18 (95% CI, 0.90–1.54) for the effect of ascorbate on OCD. Similarly, for antioxidant metabolites, ORs ranged from 0.87 (95% CI, 0.55–1.38) for the effect of ascorbate on MDD to 1.08 (95% CI, 0.88–1.33) for the effect of ascorbate on OCD. Our study does not support significant causal associations of genetically determined diet-derived circulating antioxidants with the risk of major mental disorders.

Background/Objectives: Research on the safety and efficacy of high-dose folinic acid in Chinese children with autism spectrum disorder (ASD) is limited, and the impact of folate metabolism gene polymorphisms on its efficacy remains unclear. This trial aimed to evaluate the safety and efficacy of high-dose folinic acid intervention in Chinese children with ASD and explore the association between folate metabolism gene polymorphisms and efficacy. Methods: A 12-week randomized clinical trial was conducted, including 80 eligible children with ASD, randomly assigned to an intervention group (n = 50) or a control group (n = 30). The intervention group was administered folinic acid (2 mg/kg/day, max 50 mg/day) in two divided doses. Efficacy was measured using the Psycho-Educational Profile, Third Edition (PEP-3) at baseline and 12 weeks by two trained professionals blind to the group assignments. Methylenetetrahydrofolate reductase (MTHFR C677T, MTHFR A1298C), methionine synthase (MTR A2756G), and methionine synthase reductase (MTRR A66G) were genotyped by the gold standard methods in the intervention group. Results: 49 participants in the intervention group and 27 in the control group completed this trial. Both groups showed improvements from baseline to 12 weeks across most outcome measures. The intervention group demonstrated significantly greater improvements in social reciprocity compared to the control group. Children with MTHFR A1298C or MTRR A66G mutations demonstrated greater improvements in various developmental domains than wild type. Folinic acid may be more effective in certain genotype combinations, such as MTHFR C677T and A1298C. No significant adverse effects were observed during the intervention. Conclusions: High-dose folinic acid may be a promising intervention for children with ASD, and its efficacy is associated with folate metabolism gene polymorphisms. High-dose folinic acid intervention may promote better neurodevelopmental outcomes by alleviating folate metabolism abnormalities caused by single or combined mutations in folate metabolism genes.

The global aging population raises concerns about heart failure (HF), yet its association with accelerated biological age (BA) remains inadequately understood. We aimed to examine the longitudinal association between BA acceleration and incident HF risk, assess its modifying effect on genetic susceptibility, and how much BA acceleration mediates the impact of modifiable health behaviors on incident HF. We analyzed 274,608 UK Biobank participants without HF at baseline. Two BA accelerations (Biological Age Acceleration [BioAgeAccel] and Phenotypic Age Acceleration [PhenoAgeAccel]) were calculated by regressing clinical biomarker‐based BA on chronological age, with higher values indicating accelerated aging. Health behavior scores were computed based on diet, physical activity, tobacco/nicotine, sleep, and BMI. Genetic risk scores (GRS) were calculated by 12 HF‐associated loci. During a median follow‐up of 13.5 years, 8915 HF cases were documented. Each standard deviation increase in BioAgeAccel and PhenoAgeAccel was associated with an increased incident HF risk, yielding HRs of 1.45 (95% CI, 1.42–1.48) and 1.42 (95% CI, 1.40–1.45), respectively. Participants with high GRS and highest quartile of BioAgeAccel had an HR of 2.69 (95% CI, 2.42–2.99), and for PhenoAgeAccel, an HR of 2.83 (95% CI, 2.52–3.18), compared to those with low GRS, and lowest quartile. Additive interactions were observed between GRS and BA accelerations. Health behaviors reduced HF risk, with 21.1% (95% CI, 19.5%–22.8%) mediated by decreased BioAgeAccel and 20.9% (95% CI, 19.5%–22.6%) by decreased PhenoAgeAccel. Accelerated BA is associated with an increased incident HF risk, with an additive effect when combined with genetic susceptibility. Maintaining health behaviors may help mitigate BA aging and reduce HF risk.

Aims: Existing evidence on the association between combined lifestyle and depressive symptoms is limited to the general population and is lacking in individuals with subthreshold depression, a high-risk group for depressive disorders. Furthermore, it remains unclear whether an overall healthy lifestyle can mitigate the association between childhood trauma (CT) and depressive symptoms, even in the general population. We aimed to explore the associations of combined lifestyle, and its interaction with CT, with depressive symptoms and their subtypes (i.e. cognitive-affective and somatic symptoms) among adults with subthreshold depression. Methods: This dynamic cohort was initiated in Shenzhen, China in 2019, including adults aged 18–65 years with the Patient Health Questionnaire-9 (PHQ-9) score of ≥ 5 but not diagnosed with depressive disorders at baseline. CT (present or absent) was assessed with the Childhood Trauma Questionnaire-Short Form. Combined lifestyle, including no current drinking, no current smoking, regular physical exercise, optimal sleep duration and no obesity, was categorized into 0–2, 3 and 4–5 healthy lifestyles. Depressive symptoms were assessed using the PHQ-9 during follow-up. This cohort was followed every 6 months, and as of March 2023, had been followed for 3.5 years. Findings: This study included 2298 participants (mean [SD] age, 40.3 [11.1] years; 37.7% male). After fully adjusting for confounders, compared with 0–2 healthy lifestyles, 3 (β coefficient, −0.619 [95% CI, −0.943, −0.294]) and 4–5 (β coefficient, −0.986 [95% CI, −1.302, −0.671]) healthy lifestyles were associated with milder depressive symptoms during follow-up. There exists a significant synergistic interaction between a healthy lifestyle and the absence of CT. The CT-stratified analysis showed that compared with 0–2 healthy lifestyles, 3 healthy lifestyles were associated with milder depressive symptoms in participants with CT, but not in those without CT, and 4–5 healthy lifestyles were associated with milder depressive symptoms in both participants with and without CT, with a stronger association in those with CT. The lifestyle-stratified analysis showed that CT was associated with more severe depressive symptoms in participants with 0–2 healthy lifestyles, but not in those with 3 or 4–5 healthy lifestyles. Cognitive-affective and somatic symptoms showed similar results. Conclusions: In this 3.5-year longitudinal study of adults with subthreshold depression, an overall healthy lifestyle was associated with subsequent milder depressive symptoms and their subtypes, with a stronger association in adults with CT than those without CT. Moreover, an overall healthy lifestyle mitigated the association of CT with depressive symptoms and their subtypes.

Background: Unguided internet-based cognitive behavioral therapy (ICBT) has been proven effective for major depressive disorder (MDD). However, few studies have examined its cost-effectiveness in low-resource countries and under nonspecialist routine care. Objective: This study aimed to evaluate the short- and long-term cost utility of unguided ICBT compared to a waitlist control for persons with MDD from the perspectives of society and the health care system. Methods: This analysis was implemented alongside an 8-week 2-arm randomized controlled trial with a 12-month follow-up period conducted in Shenzhen, China. Outcomes including cost and health utility were collected at the pretreatment and posttreatment time points and 3, 6, and 12 months after the intervention. Direct medical costs and indirect costs were prospectively collected using the hospital information system and the Sheehan Disability Scale. Health outcomes were measured using the Chinese version of the Short-Form Six-Dimension health index. The primary outcome was incremental cost utility ratio (ICUR) expressed as the difference in costs between 2 therapies by the difference in quality-adjusted life years (QALYs). The seemingly unrelated regression model and the bootstrap method were performed to estimate adjusted ICURs. Cost-effectiveness planes and cost-effectiveness acceptability curves were used to demonstrate uncertainty. A series of scenario analyses were conducted to verify the robustness of base-case results. Results: In total, 244 participants with MDD were randomly allocated to the ICBT (n=122, 50%) or waitlist control (n=122, 50%) groups. At the pretreatment time point, no statistically significant difference was observed in direct medical cost (P=.41), indirect cost (P=.10), or health utility (P=.11) between the 2 groups. In the base-case analysis, the ICBT group reported higher direct medical costs and better quality of life but lower total costs at the posttreatment time point. The adjusted ICURs at the posttreatment time point were CN ¥–194,720.38 (US $–26,551.50; 95% CI CN ¥–198,766.78 to CN ¥–190,673.98 [US $–27,103.20 to US $–25,999.70]) and CN ¥49,700.33 (US $6776.99; 95% CI CN ¥46,626.34-CN ¥52,774.31 [US $6357.83-$7196.15]) per QALY from the societal and health care system perspectives, respectively, with a probability of unguided ICBT being cost-effective of 75.93% and 54.4%, respectively, if the willingness to pay was set at 1 time the per-capita gross domestic product. In the scenario analyses, the probabilities increased to 76.85% and 77.61%, respectively, indicating the potential of ICBT to be cost-effective over the long term. Conclusions: Unguided ICBT is a cost-effective treatment for MDD. This intervention not only helps patients with MDD improve clinically but also generates societal savings. These findings provide health economic evidence for a potential scalable MDD treatment method in low- and middle-income countries. Trial Registration: Chinese Clinical Trial Registry (ChiCTR) ChiCTR2100046425; https://tinyurl.com/bdcrj4zv