Nonlinear Association Research Articles

Association of diabetic retinopathy with plasma atherosclerotic index, visceral obesity index, and lipid accumulation products: NHANES 2005–2008

BackgroundAbdominal obesity, a significant risk factor for the progression of diabetic retinopathy (DR), may lead to improved visual outcomes through early assessment. This study aims to evaluate any potential associations between DR and novel lipid metabolism markers, including the Atherogenic Index of Plasma (AIP), Visceral Adiposity Index (VAI), and Lipid Accumulation Product (LAP).MethodsThis study aimed to elucidate the association between various lipid markers and DR by screening the National Health and Nutrition Examination Survey (NHANES) database in the United States from 2005 to 2008. To examine the correlation, multifactor logistic regression analysis, subgroup analysis, threshold effect analysis, interaction test, and smooth curve fitting were used.ResultsAmong the 2591 participants included, the incidence of DR was 13.6% and the mean age was 59.55 ± 12.26 years. After adjusting for important confounding covariates, logistic regression studies suggested a possible positive association between LAP, VAI, AIP, and DR occurrence (odds ratio [OR] = 1.004; 95% confidence interval [CI]: 1.002, 1.006; P < 0.0001; [OR] = 1.090; 95% [CI]: 1.037, 1.146; P = 0.0007; [OR] = 1.802; 95% [CI]: 1.240, 2.618; P = 0.0020). The nonlinear association between LAP and DR was further illustrated using an S-shaped curve by smoothing curve fitting, with the inflection point of the curve located at 63.4. Subgroup analyses and interaction tests were performed with full variable adjustment (P > 0.05 for all interactions).ConclusionStudies have shown that elevated levels of LAP, VAI, and AIP increase the likelihood of DR, suggesting that they have the potential to be predictive markers of DR, emphasizing their potential utility in risk assessment and prevention strategies, and advocating for early intervention to mitigate the likelihood of DR.

Investigating nonlinear associations between neutrophil percentage to albumin ratio and cardiovascular disease: a nationally representative cross-sectional study

While the negative consequences of particular illnesses have been associated with the neutrophil percentage to albumin ratio (NPAR), its association with cardiovascular disease (CVD) is still lacking in the broader public. This study examines the relationship between NPAR and CVD prevalence using information from the National Health and Nutrition Examination Survey (NHANES), with particular attention to potential nonlinear associations. This analysis included 26,225 adults from NHANES 2011–2020. We investigated the association between NPAR levels and CVD using weighted generalized linear models, subgroup analysis, threshold effects, receiver operating characteristic (ROC) curves, and sensitivity analysis. Restricted cubic splines were used to assess potential nonlinearity in the NPAR-CVD association. Elevated NPAR levels were significantly associated with increased CVD prevalence (P < 0.001). In model 3, individuals in the highest NPAR quartile had a 46% greater CVD prevalence compared to those in the lowest quartile [OR: 1.46 (1.16, 1.83), P = 0.002], a finding consistent across unweighted logistic regression models. This association remained unchanged by various factors (P > 0.05). While restricted cubic spline analysis indicated potential nonlinearity, it did not significantly improve model fit over the linear model (P > 0.05). This study identifies a significant association between NPAR and CVD prevalence among the broader populace, suggesting the potential influence of inflammation on cardiovascular disease.

Ultra-processed foods and the incidence of pre-diabetes and type 2 diabetes among Iranian adults: the Tehran lipid and glucose study

BackgroundNo study has investigated the association between ultra-processed food (UPF) and pre-diabetes development. Furthermore, prior investigations on the association between UPF and the risk of type 2 diabetes (T2D) were primarily conducted in Europe and America, and studies in other regions are lacking. We investigated the association between ultra-processed foods and the risk of pre-diabetes and T2D in a cohort of Iranians.MethodsThis prospective study, with a sample size of 1954 for pre-diabetes and 2457 for T2D, was conducted among adults’ participants (aged ≥ 18 years) from the Tehran Lipid and Glucose Study (TLGS). We defined UPF intake using NOVA calcification as a proportion of total energy, and calculated its average intake during the follow-ups. The hazard ratios (HR) and 95% confidence intervals (95% CI) for pre-diabetes/T2D across tertiles of total UPF and per 10% of its increment were examined using Cox proportional hazards models. We also investigated the possibility of non-linear association using a restricted cubic spline regression.ResultsWe identified 766 and 256 cases of pre-diabetes and T2D, respectively, during a median follow-up of 7 years for pre-diabetes and 8.6 years for T2D. In the multivariable adjusted model, a 10% increase in total UPF intake was associated with a 12% higher risk of pre-diabetes (HR = 1.12; 95% 1.02, 1.23). The incidence of pre-diabetes was also higher in those in tertile 3 than those in tertile 1 (HR = 1.28; 95% CI = 1.07, 1.52). Following additional adjustment for diet quality, the results remained unchanged. Spline regression demonstrated a J-shaped association between UPF and the risk of pre-diabetes; the risk of pre-diabetes did not increase until UPF consumption exceeded about 24% of total energy intake. Of the individual UPF, hydrogenated fat/mayonnaise/ margarine group was related to an increased risk of pre-diabetes. The total UPF and its individual items were not associated with T2D.ConclusionsThis study found a positive, non-linear relationship between total UPF and the risk of pre-diabetes in Iranian adults. Our data could not show any significant association between UPF and T2D risk.

Association of uric acid and fructose levels in polycystic ovary syndrome.

Is there a relationship between serum uric acid and fructose levels in polycystic ovary syndrome (PCOS)? Elevated serum uric acid levels in women with PCOS positively correlate with serum fructose levels, and elevated serum fructose levels are an independent risk factor for hyperuricemia in women with PCOS. Our previous study suggested a link between elevated serum fructose levels and PCOS. Fructose is unique as it generates uric acid during metabolism, and high uric acid levels are associated with metabolic disorders and an increased risk of anovulation. However, the relationship between serum uric acid and fructose levels in women with PCOS remains unclear. In a case-control study of 774 women (482 controls and 292 patients with PCOS) between May and October 2020 at the Shengjing Hospital of China Medical University, the relationship between uric acid and fructose levels in women with PCOS was examined. Participants were divided into subgroups based on various factors, including BMI, insulin resistance, dyslipidemia, metabolic syndrome, and hyperuricemia. Serum uric acid concentrations were measured using enzymatic assays, and serum fructose levels were determined using a fluorescent enzyme immunoassay. Dietary fructose data were collected through a validated food-frequency questionnaire of 81 food items. We applied restricted cubic splines to a flexibly model and visualized the linear/nonlinear relationships between serum uric acid and fructose levels in PCOS. Multivariate logistic analysis was executed to assess the association between serum fructose levels and hyperuricemia in PCOS. Human granulosa cell and oocyte mRNA profile sequencing data were downloaded for mapping uric acid and fructose metabolism genes in PCOS. Further downstream analyses, including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analysis, and protein-protein interactions were then carried out on the differentially expressed genes (DEGs). The correlation between uric acid and fructose metabolism genes was calculated using the Pearson correlation coefficient. The GeneCards database was used to identify DEGs related to uric acid and fructose metabolism in PCOS, and then several DEGs were confirmed by quantitative real-time PCR. Both serum fructose and uric acid levels were significantly increased in women with PCOS compared with the control women (P < 0.001), and there was no statistically significant difference in dietary fructose intake between PCOS and controls, regardless of metabolic status. There was a positive linear correlation between serum uric acid and fructose levels in women with PCOS (Poverall < 0.001, Pnon-linear = 0.30). In contrast, no correlation was found in control women (Poverall = 0.712, Pnon-linear = 0.43). Additionally, a non-linear association was observed in the obese subgroup of patients with PCOS (Poverall < 0.001, Pnon-linear = 0.02). Serum uric acid levels were linearly and positively associated with serum fructose levels in patients with PCOS with insulin resistance, dyslipidemia, and metabolic syndrome. Furthermore, even after adjusting for confounding factors, elevated serum fructose levels were an independent risk factor for hyperuricemia in patients with PCOS (P = 0.001; OR, 1.380; 95% CI, 1.207-1.577). There were 28 uric acid and 25 fructose metabolism genes which showed a significant correlation in PCOS. Seven upregulated genes (CAT, CRP, CCL2, TNF, MMP9, GCG, and APOB) related to uric acid and fructose metabolism in PCOS ovarian granulosa cells were ultimately successfully validated using quantitative real-time PCR. Due to limited conditions, more possible covariates (such as smoking and ethnicity) were not included, and the underlying molecular mechanism between fructose and uric acid levels in women with PCOS remains to be further investigated. The results of this study and our previous research indicate that the high uric acid status of PCOS may be mediated by fructose metabolism disorders, highlighting the importance of analyzing fructose metabolism, and especially its metabolic byproduct uric acid, during the clinical diagnosis of PCOS. These results suggest the adverse effects of high uric acid in PCOS, and the importance of taking early interventions regarding uric acid levels to reduce the occurrence and development of further clinical signs, such as metabolic disorders in women with PCOS. This work was supported by: the National Natural Science Foundation of China (No. 82371647, No. 82071607, and No. 32100691); LiaoNing Revitalization Talents Program (No. XLYC1907071); Fok Ying Tung Education Foundation (No. 151039); and Outstanding Scientific Fund of Shengjing Hospital (No. 202003). No competing interests were declared. N/A.

Non-linear relationship between relative fat mass and diabetes risk in Japanese adults: a retrospective cohort study

Background: Relative fat mass (RFM) represents a newly developed sex-specific anthropometric formula to estimate total body fat percentage. Nonetheless, research examining the correlation between RFM and the risk of diabetes remains scarce. This research assessed the link between RFM and DM risk within the Japanese demographic. Methods: From 2004 to 2015, 15,462 Japanese individuals without diabetes underwent physical evaluations at Murakami Memorial Hospital. The relationship between RFM and the onset of diabetes was analyzed separately using Cox proportional-hazards regression models. This study employed Cox proportional hazards regression incorporating cubic spline functions and smooth curve fitting to detect non-linear associations between RFM and new cases of diabetes, categorized by sex. Sensitivity analyses were performed to confirm the robustness of the link between RFM and incident diabetes. Results: After controlling for confounding factors, a significant positive correlation between RFM and diabetes risk was found in women (HR: 1.13, 95%CI: 1.04–1.24, P = 0.0061), while the association in men was not statistically significant (HR: 1.05, 95%CI: 0.98–1.13, P = 0.1511). Additionally, a non-linear relationship between RFM and the incidence of diabetes was detected in both genders. The RFM threshold was identified at 39.23 for women and 23.08 for men. For women, HR was 1.11 (95%CI: 1.01–1.21) below the threshold and 1.39 (95%CI: 1.17–1.65) above it. In men, an RFM above 23.08 was positively related to diabetes risk (HR: 1.16, 95%CI: 1.06–1.28, P = 0.0012), whereas an RFM below this point did not show a significant association (HR: 0.98, 95%CI: 0.91–1.06, P = 0.5899). Conclusion: Our findings suggest a non-linear relationship and threshold effect between RFM and the risk of diabetes. These findings imply that maintaining RFM at lower levels may be beneficial in mitigating the onset of DM.

Nonlinear association of sex hormone-binding globulin levels and chronic kidney disease, an analysis based on the National Health and Nutrition Examination Survey (NHANES) 2013–2016

Studies on the relationship between serum sex hormone-binding globulin (SHBG) levels and chronic kidney disease (CKD) remain limited and inconclusive. Therefore, this study aims to evaluate the effects of SHBG on CKD in a nationally representative population. We included a total of 7713 adults from the National Health and Nutrition Examination Survey (NHANES) conducted between 2013 and 2016. Multivariate logistic regression models were utilized to evaluate the association between SHBG levels and CKD, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Additionally, we employed a restricted cubic-spline regression model to explore potential dose-response associations. Among the participants, 4030 (52.2%) were women, and CKD was observed in 13.50% (1043/7713). After adjusting for various variables, SHBG levels were found to be associated with the risk of CKD (OR: 1.24; 95% CI: 1.11–1.38), indicating a 24% higher risk of CKD for SHBG levels (log2-transformed). A comparison between the highest quartile (Q4) and the lowest quartile (Q1) of SHBG levels revealed an OR of 1.51 (95% CI: 1.17–1.95) for CKD prevalence. Notably, while the association between SHBG and the risk of CKD disappeared when SHBG levels were <46.1 nmol/l, it existed when SHBG levels exceeded 46.1 nmol/l. Taken together, these findings indicate nonlinear correlations between serum SHBG levels and CKD, with the inflection point occurring at approximately 46.1 nmol/l, which suggest that SHBG levels could serve as a useful marker for assessing CKD risk, with potential applications in early detection and management strategies.

The fetal origins of metabolic health: exploring the association between newborn biological age and metabolism hormones in childhood

BackgroundTelomere length (TL), mitochondrial DNA copy number (mtDNAcn), and DNA methylation age (DNAmAge) are common aging biomarkers. However, research on the associations between these three markers at birth and subsequent metabolic status was limited. This study aimed to evaluate the association between TL, mtDNAcn, and DNAmAge in newborns and the variation in metabolic hormones of children at 3 years old.MethodsThis research involved 895 mother–child pairs from a birth cohort in China, with TL and mtDNAcn measured using quantitative real-time PCR, DNA methylation (DNAm) assessed using Infinium MethylationEPIC Beadchip, and DNAm age (DNAmAge) determined using Horvath’s epigenetic clock. Insulin and leptin levels were measured via electrochemiluminescence assay. Multivariable adjusted linear regression and restricted cubic spline (RCS) analysis were utilized to examine the association between aging markers and metabolic hormones.ResultsThe linear regression analysis indicated the percentage change of metabolism hormones for per doubling of aging biomarkers alterations and found significant associations between DNAmAge and insulin levels (adjusted percent change (95% CI), − 13.22 (− 23.21 to − 1.94)), TL and leptin levels (adjusted percent change (95% CI), 15.32 (1.32 to 31.24)), and mtDNAcn and leptin levels (adjusted percent change (95% CI), − 14.13 (− 21.59 to − 5.95)). The RCS analysis revealed significant non-linear associations between TL (Ln transformed) and insulin (Ln transformed) (P = 0.024 for nonlinearity), as well as DNAmAge (Ln transformed) and leptin (Ln transformed) (P = 0.043 for nonlinearity). Specifically, for TL and insulin, a positive association was observed when TL (Ln transformed) was less than − 0.05, which transitioned to an inverse association when TL (Ln transformed) was greater than − 0.05. Regarding DNAmAge and leptin, there was a sharp decline when DNAmAge (Ln transformed) was less than − 1.35, followed by a plateau between − 1.35 and − 0.67 and then a further decline when DNAmAge (Ln transformed) was greater than − 0.67.ConclusionsIn this prospective birth cohort study, variation in metabolic hormones of children at 3 years old was associated with TL, mtDNAcn, and DNAmAge at birth. These findings suggested that TL, mtDNAcn, and DNAmAge might play a role in the biological programming of metabolic health from birth.

Sex-specific associations between levels of high-sensitivity C-reactive protein and severity of depression: retrospective cross-sectional analysis of inpatients in China.

We aimed to clarify the controversial relationship between levels of high-sensitivity C-reactive protein (hs-CRP) and severity of depression in men and women. Medical records were retrospectively analyzed for 1,236 inpatients at our medical center who were diagnosed with depression at discharge between January 2018 and August 2022. Depression severity was assessed during hospitalization using the 24-item Hamilton Depression Rating Scale. Potential associations between severity scores and hs-CRP levels were explored using multivariate linear regression as well as smooth curve fitting to detect non-linear patterns. In male patients, hs-CRP levels between 2.00mg/L and 10.00mg/L showed a non-linear association with depression severity overall (fully adjusted β = 1.69, 95% CI 0.65 to 2.72), as well as with severity of specific symptoms such as hopelessness, sluggishness, and cognitive disturbance. In female patients, hs-CRP levels showed a linear association with severity of cognitive disturbance (fully adjusted β = 0.07, 95% CI 0.01 to 0.12). These results remained significant after adjusting for age, body mass index, diabetes, hypertension, history of drinking, history of smoking, and estradiol levels. Levels of hs-CRP show sex-specific associations with depression severity, particularly levels between 2.00 and 10.00mg/L in men. These findings may help develop personalized anti-inflammatory treatments for depression, particularly for men with hs-CRP levels of 2.00-10.00mg/L.

Associations of Serum Testosterone and Sex Hormone-Binding Globulin with Incident Fractures in Middle-Aged to Older Men.

As men age, circulating testosterone (T) decreases, circulating sex-hormone binding globulin (SHBG) increases, and risk of fracture increases. It is unclear if circulating T, independently of comorbidities, is associated with fracture risk in men. To determine associations for T and SHBG with incident fractures in men. We utilized the large (n=205,973 participants, 11,088 any fracture cases, 1,680 hip fracture cases, 1,366 forearm fracture cases) and well-characterized UK Biobank cohort. Associations were modelled using Cox regressions, adjusting for multiple comorbidities/covariates, imputing for missing information, and assessing non-linearity using cubic splines. For T, not considering SHBG, there was a non-linear association with hip but not forearm fractures, with the lowest risk in the second quintile. However, in models adjusted for SHBG or using calculated free T, lower T was associated with higher risk for fractures at all evaluated bone sites. Lower SHBG was strongly associated with lower risk of hip and forearm fractures (Q1 vs Q5, hip 0.55, 0.47-0.65; forearm 0.62, 0.52-0.74). Low circulating SHBG is strongly associated with low risk of fracture at all evaluated bone sites, while the associations of circulating T with fracture risk are of lesser magnitude, non-linear, inconsistent among fracture site, and affected by adjustment for SHBG. These findings demonstrate that circulating SHBG, rather than T, is a major independent biomarker of fracture risk in men. Consequently, both total T and SHBG should be assessed when examining the relationship of endogenous T concentrations with fractures in middle-aged to older men.

Nucleated red blood cell distribution in critically ill patients with acute pancreatitis: a retrospective cohort study

ObjectivesThis study examined the potential association between nucleated red blood cell (NRBC) levels and mortality in critically ill patients with acute pancreatitis (AP) in the intensive care unit, due to limited existing research on this correlation.MethodsThis retrospective cohort study utilized data from the MIMIC-IV v2.0 and MIMIC-III v1.4 databases to investigate the potential relationship between NRBC levels and patient outcomes. The study employed restricted cubic splines (RCS) regression analysis to explore non-linear associations. The impact of NRBC on prognosis was assessed using a generalized linear model (GLM) with a logit link, adjusted for potential confounders. Furthermore, four machine learning models, including Gradient Boosting Classifier (GBC), Random Forest, Gaussian Naive Bayes, and Decision Tree Classifier model, were constructed using NRBC data to generate risk scores and evaluate the potential of NRBC in predicting patient prognosis.ResultsA total of 354 patients were enrolled in the study, with 162 (45.8%) individuals aged 60 years or older and 204 (57.6%) males. RCS regression analysis demonstrated a non-linear relationship between NRBC levels and 90-day mortality. Receiver Operating Characteristic (ROC) analysis identified a 1.7% NRBC cutoff to distinguish survivor from non-survivor patients for 90-day mortality, yielding an Area Under the Curve (AUC) of 0.599, with a sensitivity of 0.475 and specificity of 0.711. Elevated NRBC levels were associated with increased risks of 90-day mortality in both unadjusted and adjusted models (all Odds Ratios > 1, P < 0.05). Assessment of various machine learning models with nine variables, including NRBC, Sex, Age, Simplified Acute Physiology Score II, Acute Physiology Score III, Congestive Heart Failure, Vasopressin, Norepinephrine, and Mean Arterial Pressure, indicated that the GBC model displayed the highest predictive accuracy for 90-day mortality, with an AUC of 0.982 (95% CI 0.970–0.994). Post hoc power analysis showed a statistical power of 0.880 in the study.ConclusionsElevated levels of NRBC are linked to an increased mortality risk in critically ill patients with AP, suggesting its potential for predicting mortality.

Perceptual sensitivity to labeling stereotyped emotion expressions: Associations with age and subclinical psychopathology symptoms from childhood through early adulthood.

This study investigates (a) age-related differences in how the intensity of stereotyped facial expressions influence the emotion label children, adolescents, and adults assign to that face and (b) how this perceptual sensitivity relates to subclinical symptoms of psychopathology. In 2015-2016, 184 participants aged 4-25 years viewed posed stereotypes of angry, fearful, sad, and happy expressions morphed with neutral expressions at 10%-90% intensity. Thin plate regression smoothing splines were used to chart nonlinear associations between age and the perceptual threshold participants needed to assign the emotion label expected based on cultural consensus. Results suggest that sensitivity to labeling stereotypical happy faces as "happy" peaked by age 4. Sensitivity to perceiving stereotypical angry faces as "angry" increased from ages 4 to 7 and then plateaued. In contrast, sensitivity to perceiving stereotypical fearful and sad faces demonstrated protracted development, not reaching a plateau until ages 15 and 16, respectively. Reduction in selecting the "I don't know" response was the primary driver of these age-related changes. Stereotyped fear expressions required the highest intensity to be labeled as such and showed the most marked change in perceptual threshold across development. Interestingly, lower intensity morphs of stereotypical fear faces were frequently labeled "sad." Furthermore, perceiving lower intensity fear morphs was associated with fewer internalizing and externalizing symptoms in participants aged 7-19. This study describes the development of perceptual sensitivity to labeling stereotypical expressions of emotion according to cultural consensus and shows that how people perceive and categorize ambiguous facial expressions is associated with vulnerability to psychopathology. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

8377 Associations of Serum Testosterone and Sex Hormone-Binding Globulin with Incident Fractures in Middle-Aged to Older Men

Abstract Disclosure: L. Grahnemo: None. R.J. Marriott: None. K. Murray: None. L. Tyack: None. M. Nethander: None. A.M. Matsumoto: None. E.S. Orwoll: None. D. Vanderschueren: None. B.B. Yeap: None. C. Ohlsson: None. As men age, their circulating testosterone (T) decreases, circulating sex-hormone binding globulin (SHBG) increases, and risk of bone fracture increases. Unexpectedly, a recent large clinical trial reported that T treatment increased fracture risk in men. It is unclear if circulating T, independently of comorbidities, is associated with male fracture risk. We tested the hypothesis that serum T concentration is an independent risk predictor for incident bone fractures in men. We analyzed associations for T and SHBG with incident fractures in the large and well-characterized UK Biobank cohort (205,973 male participants median age 58 years, excluding men on androgen-related therapies). Baseline serum total T and SHBG were measured by immunoassay, and incident fractures documented over a median follow-up of 13.6 years (11,088 any fracture cases; 1,680 hip fracture cases; 1,366 forearm fracture cases). Associations of hormonal variables with fracture outcomes were modelled using Cox regression, adjusted for multiple comorbidities/covariates, with imputation for missing data, and non-linearity assessed using cubic splines. For total T, in multivariable models not including SHBG, there was a non-linear association with any fracture and hip fractures but not forearm fractures, with the lowest risk in the second quintile (Q2; hazard ratio (HR), 95% confidence intervals (CIs) Q2 vs Q5 any fracture 0.89, 0.84-0.94; hip fracture 0.76, 0.66-0.87; forearm fracture 0.97, 0.83-1.13). However, in multivariable models analyzing total T which were adjusted for SHBG, lower total T was associated with higher risk for fractures at all evaluated bone sites (HR, 95% CIs Q1 vs Q5 any fracture 1.24, 1.16-1.33; hip fracture 1.28, 1.08-1.51; forearm fracture 1.51, 1.25-1.82). Similar results were seen in multivariable models using calculated free T values. Lower SHBG concentration was associated with lower risk of any fracture, hip fractures, and forearm fractures, in multivariable models not including total T (HR, 95% CIs Q1 vs Q5, any fracture 0.71, 0.67-0.75; hip fracture 0.55, 0.47-0.65; forearm fracture 0.62, 0.52-0.74), with similar results following additional adjustment for total T. In conclusion, associations of total T concentrations with fracture risk without adjustment for SHBG are non-linear and inconsistent, whereas lower total T concentration, adjusted for SHBG, was independently associated with higher risks of any fracture, hip fractures, and forearm fractures. Lower circulating SHBG, without or with adjustment for total T, was strongly associated with lower risk of fractures at all three sites, consistent with SHBG being a major independent biomarker of fracture risk in men. When examining the relationship of endogenous T concentrations with health outcomes influenced by androgen-sensitive tissues in middle-aged to older men, both total T and SHBG concentrations should be assessed. Presentation: 6/2/2024

Association between asthma and visceral adipose tissue in adults, a cross-sectional study from NHANES 2011-2018.

Asthma is a chronic inflammatory disease that affects millions of people worldwide. Obesity, particularly visceral adipose tissue (VAT), is known to secrete adipokines and pro-inflammatory factors, which are closely associated with various metabolic and cardiovascular diseases. Research indicates that these metabolic disturbances can exacerbate inflammatory conditions, contributing to both cardiovascular and respiratory diseases, including asthma. Despite these associations, studies on the specific relationship between VAT and asthma remain limited and warrant further investigation. Utilizing the NHANES database from 2011 to 2018, we included a total of 11,137 participants. Multivariable regression analysis was performed, stratifying subjects based on VAT levels and adjusting for various confounders. Subgroup interaction analysis and nonlinear analysis were conducted to explore potential effect modifiers and nonlinear associations. In this study, 11,137 participants were included, with 49.74% being female. Among the 509 asthma patients, 69.35% were female. The number of asthma patients among Non-Hispanic Whites was 212, representing 41.65% of the total, the highest proportion among the studied groups. The VAT for asthma patients was 529g, significantly higher than the 455g in the non-asthma group (P < 0.001). Multivariable regression analysis showed that for every 200g increase in VAT, the risk of asthma increased by 10.4% (P = 0.032), 20.8% (P < 0.001), and 20.3% (P = 0.004) across three models (unadjusted, adjusted for demographic factors, and fully adjusted). Subgroup analysis indicated a stronger association between VAT and asthma risk in females and individuals over 40 years old. Nonlinear analysis uncovers a J-shaped relationship between VAT and asthma, with the lowest risk observed at 464.57g (P < 0.001). The study findings suggest that increased VAT is associated with elevated asthma risk, particularly among females and older individuals. These results underscore the importance of considering VAT in asthma risk assessment and highlight potential targeted interventions to reduce asthma risk associated with excess visceral adiposity.

8648 Association of isoflavone intake and age at natural menopause

Abstract Disclosure: M. Mitsunami: None. E.R. Bertone-Johnson: None. A. Eliassen: None. J.E. Chavarro: None. Introduction: Isoflavones, a type of phytoestrogens found mainly in soy and legumes, are structurally similar to estrogens and are consumed at a relatively high rate by Asian populations with an average intake of approximately 15-40 mg/d for isoflavone. They have been reported to alleviate menopausal symptoms, such as hot flashes, suggesting that isoflavones may be biologically active in a low-estrogen environment. Previous studies have reported inconsistent associations between the intake of soy and isoflavones and age at natural menopause. Therefore, our aim was to test the hypothesis that higher isoflavone intake is related to higher age at natural menopause. Methods: We followed 85,810 premenopausal women (mean [SD], 36.5 [4.7] year) who completed a previously validated food frequency questionnaire, had not been diagnosed with cancer, and did not undergo any menopausal hormone therapy as of 1991. Diet was assessed every 4 years. Isoflavone intake was estimated from these reports. Participants self-reported their menopausal status and the type of menopause (natural, surgical, and radiation or chemotherapy) every 2 years. We used proportional hazard regression models with age in months to evaluate the relation of isoflavone intake with age at natural menopause where natural menopause was the study outcome and menopause due to surgery, radiation, or chemotherapy were censoring events. We used restricted cubic splines to assess the possibility of non-linear relations between isoflavone intake and age at menopause using the U.S. average isoflavone intake (0.8mg/d) as a reference while adjusting for potential confounders, including age at menarche, BMI, race/ethnicity, smoking status, physical activity, parity, breastfeeding, time to regular menstrual cycle, energy intake, and two dietary factors identified by principal component analysis. Results: Over 1,079,608 person-years, we observed 37,438 cases of natural menopause. Soy products contributed approximately half of isoflavone intake. There was a non-linear association between isoflavone intake and age at natural menopause (p&amp;lt;0.001). Women with isoflavone intakes below the U.S. national average were more likely to experience earlier onset menopause. Conversely, in women with intakes above the national average, the risk of menopause decreased with increasing isoflavone intakes, albeit plateauing at intakes of approximately 3-4mg/d (90-95th percentile of observed distribution). There was a suggestion of a positive association between isoflavone intake and earlier onset menopause for intakes above the 99th percentile of the observed distribution (∼14 mg/d). Conclusion: This study suggests a non-linear relation between isoflavone intake and age at natural menopause with a potential later onset of menopause at intake levels higher than typical in the US diet but lower than those typically observed in East Asia. Presentation: 6/2/2024

Environmental Quality, Extreme Heat, and Healthcare Expenditures

Although the effects of the environment on human health are well-established, the literature on the relationship between the quality of the environment and expenditures on healthcare is relatively sparse and disjointed. In this study, the Environmental Quality Index developed by the Environmental Protection Agency and heatwave days were compared against per capita Medicare spending at the county level. A general additive model with a Markov Random Field smoothing term was used for the analysis to ensure that spatial dependence did not undermine model results. The Environmental Quality Index was found to hold a statistically significant (p &lt; 0.05), multifaceted nonlinear association with spending, as was the average seasonal maximum heat index. The same was not true of heatwave days, however. In a secondary analysis on the individual domains of the index, the social and built environment components were significantly related to spending, but the air, water, and land domains were not. These results provide initial support for the simultaneous benefits of healthcare financing systems to mitigate some dimensions of poor environmental quality and consistently high air temperatures.

Impaired head circumference growth and behavioural problems in childhood: Longitudinal findings from the MINA-Brazil birth cohort.

Previous evidence on the relation between early head circumference (HC) growth and behavioural outcomes in preschoolers has been inconsistent. We aimed to investigate whether HC growth from birth to 5 years of age was related to internalising or externalising behavioural problems at 5 years of age in a sex-specific manner. Among 303 girls and 318 boys from the MINA-Brazil birth cohort, we examined the associations between changes in HC from birth to 5 years of age and internalising and externalising behaviour problem scores at 5 years according to the Strengths and Difficulties Questionnaire for parents. HC values were transformed into sex- and age-specific z-scores (HCZ) using World Health Organisation standards, and the differences between values at 5 years of age and birth were classified into quintiles. We estimated adjusted mean differences with 95% confidence intervals in behavioural problem scores between HCZ change quintiles using multivariable linear regression by sex. To examine nonlinear associations, we included cubic spline terms. Head circumference growth from birth to 5 years of age was inversely and nonlinearly associated with internalising problems in girls. Compared with girls at the lowest quintile of HC growth, those above had an adjusted 1.27 (95% confidence interval 0.28, 2.27) points lower mean internalising problems score. This association was mostly driven by HC growth during the first 2 years. We found no association between HC growth and externalising behaviour in either sex. Impaired HC growth was related to higher mean internalising problem scores at 5 years of age in girls but not in boys. HC growth was not associated with externalising problems.

Associations of arterial oxygen partial pressure with all‑cause mortality in critically ill ischemic stroke patients: a retrospective cohort study from MIMIC IV 2.2

BackgroundAs a supportive treatment, the effectiveness of oxygen therapy in ischemic stroke (IS) patients remains unclear. This study aimed to evaluate the relationships between arterial partial pressure of oxygen (PaO2) and both consciousness at discharge and all-cause mortality risk in ICU IS patients.MethodsBlood gas measurements for all patients diagnosed with IS were extracted from the MIMIC-IV database. Patients were classified into four groups based on their average PaO2 during the first ICU day: hypoxemia (PaO2 < 80 mmHg), normoxemia (PaO2 80–120 mmHg), mild hyperoxemia (PaO2 121–199 mmHg), and moderate/severe hyperoxemia (PaO2 ≥ 200 mmHg). The primary endpoint was 90-day all-cause mortality. Secondary outcomes included the level of consciousness at discharge, assessed by the Glasgow Coma Scale (GCS), and 30-day all-cause mortality. Multivariate Cox regression and Restricted cubic spline (RCS) analysis were used to investigate the relationship between mean PaO2 and mortality, and to assess the nonlinear association between exposure and outcomes.ResultsThis study included a total of 946 IS patients. The cumulative incidence of 30-day and 90-day all-cause mortality increased with decreasing PaO2 levels. RCS analysis revealed a nonlinear relationship between PaO2 and the risk of 30-day all-cause mortality (nonlinear P < 0.0001, overall P < 0.0001), as well as a nonlinear association between PaO2 and 90-day all-cause mortality (nonlinear P < 0.0001, overall P < 0.0001). The results remained consistent after excluding the small subset of patients who received reperfusion therapy. Sensitivity analysis indicated that the favorable impact on survival tends to increase with the extended duration of elevated PaO2.ConclusionsFor IS patients who do not receive reperfusion therapy or whose recanalization status is unknown, a lower PaO2 early during ICU admission is considered an independent risk factor for short-term and recent mortality. Adjusting respiratory parameters to maintain supraphysiological levels of PaO2 appears to be beneficial for survival, although this finding requires further validation through additional studies.Trial registrationNot applicable.

Unraveling nonlinear and spatial non-stationary effects of urban form on surface urban heat islands using explainable spatial machine learning

Under global warming, surface urban heat islands (SUHI) threaten human health and urban ecosystems. However, scant research focused on exploring the complex associations between urban form factors and SUHI at the county scale, compared with rich studies at the city scale. Therefore, this study simultaneously examined the nonlinear and spatial non-stationary association between SUHI and urban form factors (e.g., landscape structure, built environment, and industrial pattern) across 2321 Chinese counties. An explainable spatial machine learning method, combining the Geographically Weighted Regression, Random Forest, and Shapley Additive Explanation model, was employed to deal with nonlinearity, spatial non-stationary, and interpretability of modeling. The results indicate the remarkable spatial disparities in the relationship between urban form factors and SUHI. Landscape structure contributes the most in southern counties, while the built environment is more important in northeastern counties. The impact of building density and building height increases with the county size and becomes the main driver of urban heat in mega counties. Most urban form factors exhibit nonlinear impacts on SUHI. For example, urban contiguity significantly affects SUHI beyond a threshold of 0.93, while building density does so at 0.17. By comparison, the influence of shape complexity remains stable above a value of 7. Factors such as industrial density and diversity have a varied influence on SUHI between daytime and nighttime. The results of local explanations and nonlinear effects provide targeted regional mitigation strategies for urban heat.

Association between serum cotinine and total testosterone in adult males based on NHANES 2011–2016

The relationship between smoking and testosterone levels in adult males remains a topic of ongoing debate. Serum cotinine is considered a reliable marker of both smoking intensity and exposure to tobacco smoke. Therefore, we aim to examine the association between serum cotinine levels and total testosterone concentrations in adult males using data from the U.S. National Health and Nutrition Examination Survey (NHANES) database. Our study assessed the relationship between serum cotinine and total testosterone using weighted linear regression models and subgroup analysis. A fully adjusted model with smooth curve fitting was employed to investigate the potential nonlinear association between serum cotinine and total testosterone. Threshold effects were analyzed to identify the inflection point between serum cotinine and total testosterone. Indeed, a total of 7797 participants were included in our study. After adjusting for potential confounding variables, the findings indicate a positive association between serum cotinine levels and total testosterone levels (β: 0.05, 95%CI: 0.02, 0.09). Furthermore, applying smoothed curve fitting analysis and threshold effects, an inflection point was detected at a serum cotinine level of 487 ng/ml. Above this threshold, total testosterone levels declined with increasing serum cotinine levels. In conclusion, the findings of our study suggest a positive association between elevated serum cotinine levels and total testosterone levels in adult men. However, it is essential to note that this association may be reversed at excessively high serum cotinine concentrations.

Associations of Dietary Magnesium Intake with All-Cause and Cause-Specific Mortality Among Individuals with Gout and Hyperuricemia.

We aimed to evaluate the relationship of dietary magnesium intake with all-cause and cause-specific mortality among patients with gout and hyperuricemia (HUA). We analyzed data of 1171 gout patients and 6707 HUA patients from the National Health and Nutrition Examination Survey (NHANES) 2007-2018 and 2001-2018, respectively. Dietary intake data were obtained from 24-h dietary recall interviews. Mortality status was determined using the NHANES public-use linked mortality fill. We used Cox regression model and restricted cubic spline analysis to probe the association of dietary magnesium intake and mortality among gout and HUA patients. During 7081 person-years of follow-up, 257 deaths were documented in gout patients, among which 74 died from cardiovascular disease (CVD) and 48 died from cancer. For HUA patients followed up for 58,216 person-years, 1315 all-cause deaths occurred, including 411 CVD deaths and 224 cancer deaths. After multifactorial adjustments, higher dietary magnesium intake was associated with lower risk of all-cause mortality. Nonlinear negative associations were found between dietary magnesium intake and CVD mortality among gout and HUA patients, with inflection points of 152.5mg/day and 303mg/day, respectively, and cancer mortality among HUA patients, with the inflection point of 232mg/day. The results were robust in subgroup and sensitivity analyses. High dietary magnesium intake is linearly related to all-cause mortality, and nonlinearly associated with cause-specific mortality among gout and HUA patients.