Surrogate Marker Research Articles

Examination of Sex Differences in Energy Availability, Disordered Eating, and Compulsive Exercise Among Male and Female Adolescent Athletes.

The primary aim of this study was to examine sex differences in energy availability (EA) and its relationships with disordered eating, compulsive exercise, and body mass index (BMI) among adolescent athletes. Cross-sectional study. University hospital pediatric sports medicine center. Sixty-four participants (61% female) of ages 13 to 18 years, actively participating in at least 1 organized sport. Participant sex. Average 7-day EA (kcal/kg FFM/d; calculated using participant-recorded dietary intake and exercise expenditure from a wrist-worn heart rate/activity monitor), Eating Disorder Examination Questionnaire (EDE-Q) score (range 0-6), Compulsive Exercise Test (CET) score (range 0-25), and age- and sex-adjusted BMI percentile. There were no significant sex differences in EA (females: 40.37 ± 12.17 kcal/kg FFM/d; males: 35.99 ± 12.43 kcal/kg FFM/d; P = 0.29), EDE-Q (females: 0.68 ± 0.70; males: 0.68 ± 0.83; P = 0.99), or CET scores (females: 11.07 ± 0.44; males: 10.73 ± 0.63; P = 0.66). There were low and insignificant negative correlations between EA and EDE-Q and CET scores for female athletes (EDE-Q: r = -0.22, P = 0.18; CET: r = -0.21, P = 0.09) and male athletes (EDE-Q: r = -0.09, P = 0.66; CET: r = -0.35, P = 0.08). EA and BMI-for-age percentile were inversely correlated in both male (r = -0.451, P = 0.009) and female (r = -0.37, P = 0.02) participants. In our sample of adolescent athletes, lower EA occurred in the absence of notable disordered eating or compulsive exercise behaviors, suggesting unintentional underfueling (and/or underreporting of energy intake), without significant sex differences. Low BMI can be an imperfect surrogate marker for low EA. These findings inform risk factors and screening practices for low EA among adolescent athletes.

Association between triglyceride-glucose index and risk of kidney stone: a Chinese population-based case–control study

ObjectiveTo investigate the association between the triglyceride-glucose (TyG) index, a surrogate marker of insulin resistance and the risk of kidney stones (KSs) in a Chinese population.DesignCase–control study.SettingThree Physical Examination Centers...

Association between advanced fibrosis and epigenetic age acceleration among individuals with MASLD.

The biological process of aging plays an important role in the progress of liver fibrosis. However, epidemiological evidence about the associations between advanced fibrosis and epigenetic age acceleration (EAA) among individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) is limited. We utilized publicly available DNA methylation data (GSE180474) for our analysis. Five EAA measures were calculated in this study, including IEAA, PhenoAA, GrimAA, DunedinPACE, and DNAmTLAA. Separate linear regression models were conducted to explore the associations between different fibrosis grades and each measure of EAA. A total of 325 participants were included in this study, with a mean (± SD) age of 48.56 ± 11.50years. Of these participants, 64.6% with no fibrosis, 16.9% with bridging fibrosis, 11.1% with incomplete cirrhosis, and 7.4% with cirrhosis. After adjusting for demographics and medication status, MASLD individuals with advanced fibrosis were associated with a 5% increase in the pace of aging (DunedinPACE, β = 0.05, 95% CI: 0.03-0.07) and a 10% decrease in DNAmTLAA (β = -0.10, 95% CI: -0.13 to -0.07) compared those without fibrosis. Similarly, higher stages of fibrosis were associated with an increased pace of aging (DunedinPACE, β = 0.02, 95% CI: 0.01-0.03, Ptrend < 0.001) and decreased DNAmTLAA (β = -0.05, 95% CI: -0.07 to -0.04, Ptrend < 0.001). However, no significant association was found between advanced fibrosis and IEAA, PhenoAA, and GrimAA. Our findings suggest that advanced fibrosis was associated with an accelerated pace of aging, as measured by the third-generation EA measure DunedinPACE, and shorter telomere length, captured by DNAmTLAA, among individuals with MASLD. This finding has potential prognostic implications and suggests EAA may serve as a surrogate marker of therapeutic efficacy in MASLD.

Impact of personalized response-directed surgery and adjuvant therapy on survival after neoadjuvant immunotherapy in stage III melanoma: Comparison of 3-year data from PRADO and OpACIN-neo

BackgroundPathologic response following neoadjuvant immune checkpoint blockade (ICB) in stage III melanoma serves as a surrogate marker for long-term outcomes. This may support more personalized, response-directed treatment strategies. MethodsThe OpACIN-neo and PRADO trials were phase 2 studies evaluating neoadjuvant treatment with ipilimumab and nivolumab in stage III melanoma. In OpACIN-neo, all patients underwent therapeutic lymph node dissection (TLND) without subsequent adjuvant therapy. In contrast, PRADO explored a response- directed strategy, where patients achieving a major pathologic response (MPR) omitted TLND and adjuvant therapy, while those without a pathologic response (pNR) received TLND and adjuvant therapy. Here, we provide a descriptive post-hoc comparison of 3-year survival outcomes between the non-personalized approach in OpACIN-neo and the response-directed approach in PRADO. ResultsFor patients who achieved an MPR, the 3-year recurrence-free survival (RFS) was 93 % for those without TLND versus 96 % for those with TLND (log-rank p = 0.47), and distant metastasis-free survival (DMFS) was 98 % compared to 96 % (log-rank p = 0.49), respectively. For patients with pNR, 3-year RFS rates were 64 % for those receiving adjuvant systemic therapy and 35 % for patients without (log-rank p = 0.10). DMFS rates were 70 % versus 52 % (log-rank p = 0.24), respectively. ConclusionsThese data suggest that TLND and adjuvant therapy may be safely omitted in most patients achieving an MPR, while adjuvant systemic therapy following TLND appears to improve RFS and DMFS in patients with pNR. Although these results are hypothesis-generating and require further validation, they offer a potential foundation for developing personalized neoadjuvant immunotherapy approaches.

Multi-indication Evidence Synthesis in Oncology Health Technology Assessment: Meta-analysis Methods and Their Application to a Case Study of Bevacizumab

Background Multi-indication cancer drugs receive licensing extensions to include additional indications, as trial evidence on treatment effectiveness accumulates. We investigate how sharing information across indications can strengthen the inferences supporting health technology assessment (HTA). Methods We applied meta-analytic methods to randomized trial data on bevacizumab, to share information across oncology indications on the treatment effect on overall survival (OS) or progression-free survival (PFS) and on the surrogate relationship between effects on PFS and OS. Common or random indication-level parameters were used to facilitate information sharing, and the further flexibility of mixture models was also explored. Results Treatment effects on OS lacked precision when pooling data available at present day within each indication separately, particularly for indications with few trials. There was no suggestion of heterogeneity across indications. Sharing information across indications provided more precise estimates of treatment effects and surrogacy parameters, with the strength of sharing depending on the model. When a surrogate relationship was used to predict treatment effects on OS, uncertainty was reduced only when sharing effects on PFS in addition to surrogacy parameters. Corresponding analyses using the earlier, sparser (within and across indications) evidence available for particular HTAs showed that sharing on both surrogacy and PFS effects did not notably reduce uncertainty in OS predictions. Little heterogeneity across indications meant limited added value of the mixture models. Conclusions Meta-analysis methods can be usefully applied to share information on treatment effectiveness across indications in an HTA context, to increase the precision of target indication estimates. Sharing on surrogate relationships requires caution, as meaningful precision gains in predictions will likely require a substantial evidence base and clear support for surrogacy from other indications. Highlights We investigated how sharing information across indications can strengthen inferences on the effectiveness of multi-indication treatments in the context of health technology assessment (HTA). Multi-indication meta-analysis methods can provide more precise estimates of an effect on a final outcome or of the parameters describing the relationship between effects on a surrogate endpoint and a final outcome. Precision of the predicted effect on the final outcome based on an effect on the surrogate endpoint will depend on the precision of the effect on the surrogate endpoint and the strength of evidence of a surrogate relationship across indications. Multi-indication meta-analysis methods can be usefully applied to predict an effect on the final outcome, particularly where there is limited evidence in the indication of interest.

The Association Between Diabetic Nephropathy and Triglyceride/Glucose Index and Triglyceride/High-Density Lipoprotein Cholesterol Ratio in Patients with Type 2 Diabetes Mellitus.

Background: In this study, we aimed to investigate the relationship between diabetic nephropathy (DN) and triglyceride/glucose (TyG) index and triglyceride/high-density lipoprotein cholesterol ratio (Tg/HDL-C) as surrogate markers of insulin resistance. Method: Medical records of 15,378 individuals between February 2019 and May 2024 were examined. Serum glucose, Tg, HDL-C, HbA1c, estimated glomerular filtration rate (eGFR), and urine albumin/creatinine ratio (UACR) were evaluated and the TyG index and TG/HDL-C ratios were calculated for each individual. DN was defined as a UACR ≥ 30 mg/g and/or eGFR <60 mL/min/1.73 m2. Results: Of 10,714 patients, DN was detected in 3763 (35.1%). Females had 10% higher odds of developing DN compared to males. A TyG index at or above the determined cutoff point (9.58) indicated a risk of DN and the sensitivity and specificity values were 44.01% and 71.28%, respectively. The risk of DN was 1.95 times higher in individuals with a TyG index value of ≥9.58 compared to those with a TyG index <9.58. While the Tg/HDL ratio was significant in detecting DN in the univariate analysis (odds ratio (OR) 1.59; 95% confidence interval 1.46-1.73), this significance was not found in the multivariate analysis (OR 1.15; 95% confidence interval 0.94-1.40). Conclusions: A high TyG index is associated with DN in patients with type 2 diabetes and it might be a potential marker in predicting DN.

Identification of Functional Immune Biomarkers in Breast Cancer Patients.

Cancer immunotherapy has emerged as an effective, personalized treatment for certain patients, particularly for those with hematological malignancies. However, its efficacy in breast cancer has been marginal-perhaps due to cold, immune-excluded, or immune-desert tumors. Natural killer T (NKT) cells play a critical role in cancer immune surveillance and are reduced in cancer patients. Thus, we hypothesized that NKT cells could serve as a surrogate marker for immune function. In order to assess which breast cancer patients would likely benefit from immune cell-based therapies, we have developed a quantitative method to rapidly assess NKT function using stimulation with artificial antigen presenting cells followed by quantitative real-time PCR for IFN-γ. We observed a significant reduction in the percentage of circulating NKT cells in breast cancer patients, compared to healthy donors; however, the majority of patients had functional NKT cells. When we compared BC patients with highly functional NKT cells, as indicated by high IFN-γ induction, to those with little to no induction, following stimulation of NKT cells, there was no significant difference in NKT cell number between the groups, suggesting functional loss has more impact than physical loss of this subpopulation of T cells. In addition, we assessed the percentage of tumor-infiltrating lymphocytes and PD-L1 expression within the tumor microenvironment in the low and high responders. Further characterization of immune gene signatures in these groups identified a concomitant decrease in the induction of TNFα, LAG3, and LIGHT in the low responders. We next investigated the mechanisms by which breast cancers suppress NKT-mediated anti-tumor immune responses. We found that breast cancers secrete immunosuppressive lipids, and treatment with commonly prescribed medications that modulate lipid metabolism, can reduce tumor growth and restore NKT cell responses.

Multiple surrogates in the meta-analytic setting for normally distributed endpoints

The identification of good surrogate endpoints is a challenging endeavour. This may, at least partially, be attributable to the fact that most researchers have focused on the identification of a single surrogate endpoint. It is thus implicitly assumed that the treatment effect on the true endpoint (T) can be accurately predicted based on the treatment effect on one surrogate endpoint (S) only. Given the complex nature of many diseases and the different therapeutic pathways in which a treatment can impact T, this assumption may be too optimistic. For example, in oncology, the effect of a treatment often depends on both the treatment’s efficacy and its toxicity. In the present paper, the meta-analytic framework of Buyse et al. (2000) is extended to the setting where multiple S are considered. To cope with potential model convergence issues that often arise in a meta-analytic framework, several simplified model fitting strategies are proposed. Further, simulation studies are conducted to evaluate the properties of the estimated surrogacy metrics, and the new methodology is applied on a case study in schizophrenia. An online Appendix that details how the analyses can be conducted in practice (using the R package Surrogate) is also provided.

Neurofilament light chain: a biomarker at the crossroads of clarity and confusion for gene-directed therapies.

Neurofilament light chain (NfL) is a promising biomarker for neurodegenerative diseases, measurable in both CSF and blood upon neuroaxonal damage. While CSF analysis was traditionally used, blood-based assays now offer a less invasive alternative. NfL levels correlate with disease severity and progression in conditions like Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and Huntington's disease. Clinical trials demonstrate its utility as a pharmacodynamic biomarker in MS and ALS. The FDA's approval of Tofersen for SOD1-ALS based on NfL reduction underscores its growing acceptance as surrogate marker. However, challenges remain in standardizing assays, interpreting clinical correlations, low specificity and understanding the dynamics between CSF and blood NfL levels. Addressing these issues is crucial for maximizing NfL's potential in neurodegenerative disease management.

A case series on endometrial cancer in multipara and their prognostication based on IHC markers

Endometrial carcinoma is one of the leading gynecological malignancies across the globe. With advent of molecular analysis, establishing an accurate treatment plan and improving patient outcome has become eminent. In resource limited settings like India, surrogate IHC markers like hormonal receptor expression are congruous substitutes that aid to accurately predict patient prognosis. In this case series, expression of hormonal receptors in multiparous women and it’s association with patient outcome seen as disease free survival at a span of 2 years was compared. This study opines inclusion of hormonal receptors in evaluation of endometrial carcinoma patients to accurately comment on patient outcome.

Detailed Lipid Profiles and Lipid-related Residual Risk after 12-week 10 mg Rosuvastatin Treatment for Acute Myocardial Infarction.

Objective We aimed to reveal detailed on-treatment lipid profiles, lipid-related surrogate markers, and factors predicting failure to achieve the guideline-recommended lipid management goal following guideline-recommended statin treatment in Japanese patients with acute myocardial infarction (AMI). Methods and Results Sixty AMI patients who underwent coronary intervention and had received rosuvastatin 10 mg/day since the start of their hospitalization were assessed for on-treatment lipid-related profiles, including high-sensitivity C-reactive protein, small dense low-density lipoprotein cholesterol (sd LDL-C), and lipoprotein (a), at the 12-week follow-up. Patients who failed to achieve the guideline-recommended lipid management at 12 weeks were defined as the "unachieved group." Univariate and multivariate logistic regression analyses were performed to evaluate the predictors of inclusion in the unachieved group after high-dose statin treatment. Despite the use of high-dose rosuvastatin, 61.7% of the enrolled AMI patients were included in the unachieved group. In addition, the unachieved group had higher sd LDL-C and lipoprotein (a) levels than the achieved group. Logistic regression analyses demonstrated that low baseline high-density lipoprotein cholesterol (HDL-C) levels and the absence of diabetes were predictors of inclusion in the unachieved group. Conclusion More than half of the Japanese AMI patients treated with rosuvastatin 10 mg/day did not achieve the guideline-recommended goal of lipid management and still had lipid-related residual risk at 12 weeks. Particular attention should be paid to patients with low baseline HDL-C levels and those without diabetes with regard to their on-treatment lipid profiles.

Cerebral Infarct Growth: Pathophysiology, Pragmatic Assessment, and Clinical Implications.

Cerebral ischemic injury occurs when blood flow drops below a critical level, resulting in an energy failure. The progressive transformation of hypoperfused viable tissue, the ischemic penumbra, into infarction is a mechanism shared by patients with ischemic stroke if timely reperfusion is not achieved. Yet, the pace at which this transformation occurs, known as the infarct growth rate (IGR), exhibits remarkable heterogeneity among patients, brain regions, and over time, reflecting differences in compensatory collateral flow and ischemic tolerance. We review (1) the pathophysiology of infarct growth, (2) the advantages and pitfalls of different approaches of IGR measurement, (3) research gaps for future studies, and (4) the clinical implications of stroke progressor phenotypes. The estimated average IGR in patients with acute large vessel occlusion stroke is 5.4 mL/h although there is wide variability based on ischemic stroke subtype, occlusion location, presence of collaterals, and patient baseline status. The IGR can be calculated using various pragmatic strategies, mostly either quantifying the extension of the infarct at a particular time and dividing this measure by the time that elapsed from symptom onset to imaging assessment or by using collateral blood flow status as a radiological surrogate marker. The IGR defines a spectrum of clinical stroke phenotypes, often dichotomized into fast and slow progressors. An IGR ≥10 mL/h and the perfusion metric hypoperfusion intensity ratio ≥0.5 are commonly used definitions of fast progressors. A nuanced understanding of the IGR and stroke progressor phenotypes could have clinical implications, including informing prognostication, acute decision-making in peripheral-to-comprehensive transfer patients eligible for thrombectomy, and selection for adjuvant neuroprotective agents.

Circulating levels of Low Density Granulocytes and cell-free DNA as predictors of cardiovascular disease and bone deterioration in SLE patients.

The present work evaluates the predictive value of low-density-granulocytes (LDG) for the development of cardiovascular disease (CVD) and/or bone deterioration (BD) in a six-year prospective study in Systemic Lupus Erythematosus (SLE). Considering the high SLE-LDG capacity to form Neutrophil Extracellular Traps (NETs), circulating levels of total cell-free DNA (cirDNA) and relative amounts of mitochondrial and nuclear DNA (mtDNA and nDNA, respectively) were tested as LDG-associated biomarkers to identify SLE patients at risk of CVD and BD. To this end, the frequency of total blood LDGs, as well as the CD16negCD14neg (nLDG) and CD16posCD14low (pLDG) subsets, was quantified by flow cytometry in 33 controls and 144 SLE patients. Total cirDNA and relative amounts of mitochondrial (mtDNA) and nuclear (nDNA) cell-free DNA were measured by fluorometry or qPCR in plasma from a subgroup of 117 patients and 23 controls at enrolment. Our findings showed increased blood levels of SLE-nLDGs at enrolment associated with prospective CVD development (pCVD) and the presence of BD, thus revealing LDG expansion as a predictor of both comorbidities in SLE progression. The amounts of the different types of circulating DNA analysed were increased in patients, especially those presenting traditional CV-risk factors or subclinical atheromatosis. Similar to nLDGs, the nDNA concentration could predict the development of pCVD in SLE, supporting the quantification of cirDNA levels as a surrogate marker of LDGs in clinical practice.

Association Between Zinc Status and Insulin Resistance/Sensitivity Check Indexes in Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is considered the most common metabolic disorder of the pregnancy period. It is characterized by pancreatic beta-cell dysfunction in the setting of chronic insulin resistance. Zinc is a nutrient involved in numerous metabolic processes and shows a relationship with glycometabolic disorders and GDM. The latest data have demonstrated the association of zinc with insulin sensitivity and resistance. The exact role of zinc in the connection with indexes of insulin resistance and insulin sensitivity is still not fully clarified. The aim of the study is to analyze the newly calculated indexes Glu/Zn, Ins/Zn, and HOMA-IR/Zn as surrogate markers to explore the correlation between serum zinc status and some indexes of insulin sensitivity and insulin resistance. The possible role of these indexes as markers of insulin resistance in pregnant women was analyzed too. An ROC analysis demonstrated that HOMA-IR/Zn with AUC 0.989, p < 0.001 (95% CI 0.967-1.000) and Ins/Zn with AUC 0.947, p < 0.001 (95% CI 0.889-1.000) in the GDM group, and only HOMA-IR/Zn index with AUC 0.953, p < 0.001 (95% CI 0.877-1.000) in healthy pregnant women, have good power as markers of insulin resistance in both groups. We speculate that these new ratios could be suitable for the assessment of pregnant women at high risk of insulin resistance development and, probably, for the evaluation of the specific pathophysiologic characteristics of women with GDM.

Suggested guide to using lactate gap as a surrogate marker in the diagnosis of ethylene glycol overdose.

Ethylene glycol (EG) poisoning, if not diagnosed rapidly, can lead to poor patient outcomes. Gas Chromatography (GC) is primarily used for EG quantitation which is rarely available, and the turn-around time may be prolonged. Most lactate results from point-of care (POCT) methods are falsely elevated in EG poisoning compared with automated chemistry analyser results. In combination the lactate gap (POCT-Automated chemistry) can be used as surrogate marker in just about all laboratories to indicate likely EG toxicity and guide treatment. A male presented by ambulance to hospital with severe agitation requiring mechanical ventilation to facilitate ongoing management. Venous blood gas analysis confirmed a high anion gap metabolic acidosis (HAGMA) with an elevated lactate. The lactate and osmolarity measured in the laboratory showed a normal lactate and high osmolarity, giving a large osmolar gap. The patient was immediately commenced on renal replacement therapy for presumed EG poisoning to minimize kidney injury, and the treatment continued for 19 hours. A very high EG concentration was confirmed by GC the next day. An elevated lactate gap along with a HAGMA and osmolar gap can provide rapid surrogate laboratory data indicating EG poisoning enabling timely treatment and better patient outcomes.

Development of clinical questions and outcomes on Clinical Practice Guideline of Fire Needling Therapy for Herpes Zosters

To develop the clinical questions and outcomes of Clinical Practice Guideline of Fire Needling Therapy for Herpes Zosters based on Norms of Formulation and Evaluation for the Clinical Guideline on Acupuncture and Moxibustion released by World Federation of Acupuncture and Moxibustion Societies. Combined the investigation with expert consultation and consensus method, and taken clinicians (members) of Chinese Association of Acupuncture and Moxibustion as the subjects, the clinical questions concerned were collected and the two-round consultation was conducted among expert group by letter. In the first round questionnaire, using the voting method, the relevant clinical questions in intervention measures were collected; and in the second round, with the Delphi method adopted, the importance of clinical questions and outcomes in the investigation was scored. A total of 200 structured clinical questions proposed by 153 clinicians and the clinical experience with 13 kinds of combined therapies involved and fire needling as the key measure were collected. The authority coefficient (Cr) of the Delphi questionnaire was >0.70, and the coefficient of variation for the importance scores of alternative clinical questions and outcomes was 0.06-0.26 and 0.12-0.47, respectively. The top 10 clinical questions and 12 outcomes (6 outcomes referred to the patients either in the acute stage or the post-neuralgia stage) were included, with the importance score of clinical questions>4, the importance score of outcomes>6, and the coefficient of variation ≤0.25. The clinical questions and outcomes of Clinical Practice Guideline of Fire Needling Therapy for Herpes Zosters are formulated, which provides the research basis for the recommendation development of the guideline.

Do sociodemographic and health predictors affect the non-insulin-based insulin resistance index? A cross-sectional study.

Insulin resistance (IR) is considered a risk factor for cardiovascular diseases (CVD). Therefore, early diagnosis of IR is clinically significant for primary and secondary CVD prevention initiatives. In addition, non-insulin metabolic indices may be useful for diagnosing IR. The first objective was to estimate the triglyceride and glucose (TyG) index and the metabolic score for insulin resistance (METS-IR) index values in a local community with high social deprivation and increased cardiovascular risk according to the Systematic Coronary Risk Evaluation scale. The second objective was to identify significant sociodemographic and health predictors for the TyG index and METS-IR index. This cross-sectional study was conducted in the local community of Janów district in eastern Poland and consisted of 2 stages. The 1st stage involved basic research (n = 4,040), while the 2nd stage involved enhanced diagnostics (n = 2,657). Data from the 2nd stage was used for the analyses. Anthropometric and physiological measurements were taken, blood was drawn for laboratory tests, selected sociodemographic and health variables were evaluated, and the TyG index and METS-IR index were calculated. The mean TyG index score in the study group was 8.65 (±0.58), and the mean METS-IR index score was 41.45 (±9.02). Both indices were significantly associated with age, male sex, smoking, and systolic blood pressure (SBP) in a multivariable model. In addition, alcohol consumption and body mass index (BMI) were significantly correlated with the TyG index, whereas education was significantly associated with the METS-IR index. Our results show the association between IR and sociodemographic and health variables in a group with a high social deprivation rate and increased cardiovascular risk. Early detection of cardiometabolic risk is important for both primary and secondary CVD prevention. In primary healthcare, this can be accomplished through surrogate markers of IR.

Abstract 4138332: Lipoprotein (a), Triglyceride-Glucose Index and Incident Atherosclerotic Cardiovascular Disease (ASCVD): Analysis of the UK Biobank

Background: The triglyceride-glucose index (TyG), an inexpensive novel surrogate marker for insulin resistance, and lipoprotein (a) [Lp(a)] are both risk factors for atherosclerotic cardiovascular disease (ASCVD). However, it is uncertain whether TyG modifies the relationship of Lp(a) with incident ASCVD. Objective: To investigate the relationship of Lp(a) and TyG with the risk of incident ASCVD. Methods: We included UK Biobank participants without ASCVD at enrollment. Baseline TyG was calculated as ln[fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2]. We classified TyG values as high (≥75th percentile) or low (&lt;75th percentile), and Lp(a) levels, in nmol/L, as &lt;125 or ≥125. Participants were then stratified into four groups: Group-1: Low TyG with Lp(a), &lt;125, Group-2: Low TyG with Lp(a) ≥125, Group-3: High TyG with Lp(a) &lt;125, and Group-4: High TyG with Lp(a) ≥125. We used multivariable Cox regression to estimate the risk of ASCVD (a composite of peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, and cardiovascular mortality) of TyG and Lp(a) adjusted for the other, and in the four combination groups. Results: Eligible participants (N=254,377) had a mean (SD) age of 56.0 (8.1) years, and 53.2% were female. The median follow-up was 14.6 years. In separate models additionally adjusted for cardiovascular risk factors (see Figure legend), the hazard ratio (HR [95% CI]) for ASCVD was 1.18(1.13–1.23) for Lp(a) ≥125 nmol/L (vs. &lt;125 nmol/L), adjusted for TyG, and 1.09(1.05–1.13) for high TyG (vs. low), adjusted for Lp(a). A statistically significant interaction between TyG and Lp(a) was observed in the fully adjusted model (p &lt;0.001). Compared to Group-1 (low TyG with Lp(a) &lt;125nmol/L), the adjusted HR (95% CI) of incident ASCVD in Group-2, -3 and -4 were: 1.07(1.04–1.13), 1.15 (1.09–1.21) and 1.34(1.25–1.44), respectively (Figure). Conclusions: These findings demonstrate that TyG and Lp(a) are associated with incident ASCVD risk independently of each other. Moreover, TyG modified the effect of Lp(a) on ASCVD, suggesting that insulin resistance may amplify the atherogenic, inflammatory, and/or thrombotic effects of Lp(a), thereby further increasing ASCVD risk.

Abstract 4141457: Forms of Childhood Maltreatment and Subclinical Cardiovascular Disease Risk in Black men and women

Background: Exposure to specific forms of childhood maltreatment have been associated with cardiovascular disease (CVD) risk factors and CVD events in adulthood. Heterogenous experiences of childhood maltreatment across race and sex exist, yet there is little evidence regarding these relationships and CVD risk in Black populations. Aims: To investigate the association between various forms of childhood maltreatment (emotional, general, physical, and sexual abuse) and surrogate markers of vascular dysfunction and test whether sex modify these associations. Methods: Forms of childhood maltreatment and indices of vascular function were assessed in a cohort of healthy Black adults without known CVD (n=404) from a large metropolitan southeastern city. Childhood maltreatment was assessed using the Early Trauma Inventory short form (ETISR-SF) consisting of physical, sexual, emotional, and general domains. A trauma severity index score was calculated by summing the indexes for each of the four domains. Higher scores are indicative of higher traumatic life events before age 18 years. Outcomes of central augmentation index (cAIx) corrected for a heart rate of 75 bpm and carotid femoral pulse wave velocity (CfPWV) were measured as indices of wave reflections and arterial stiffness using applanation tonometry (Sphygmocor Inc.), and central pulse pressure (CPP) was calculated as the difference between the aortic systolic and diastolic blood pressures. Associations between each domain and outcomes were assessed using multivariate-adjusted and sex-stratified linear regression models. Results: Mean age of the cohort was 53 + 10.3 years, 61% women. Exposure to emotional [ b = -1.5%, 95%CI: -2.7,-0.3] and physical abuse [ b = -1.3%, 95%CI: -2.5,-0.2] was associated with cAIx overall but not CPP or CfPWV after adjusting for sociodemographic, clinical factors, health behaviors, and depressive symptoms. Significant emotional abuseXsex ( P= 0.014) and physical abuseXsex ( P=&lt; 0.001) interactions were identified for cAIx. Among women, physical abuse was associated with higher cAIx [ b =1.5%, 95%CI: 0.6, 2.4] and among men emotional [ b =-1.6%, 95%CI: -3.2, -0.0] and physical [ b =-1.7%, 95%CI: -3.1, -0.3] abuse was associated with lower cAIx. Conclusions: Exposure to emotional and physical abuse as children was associated with vascular dysfunction; moreover, exposure to physical abuse among women and not men have adverse clinical implications for CVD risk and prospects for enhanced preventive care.

Association of phenylalanine and tyrosine metabolism with mortality and response to nutritional support among patients at nutritional risk: a secondary analysis of the randomized clinical trial EFFORT.

Elevated phenylalanine serum level is a surrogate marker of whole-body proteolysis and has been associated with increased mortality in critically ill patients. Tyrosine is a metabolite of phenylalanine and serves as a precursor of thyroid hormones and catecholamines with important functions in the oxidative stress response among others. Herein, we examined the prognostic significance of phenylalanine, tyrosine, as well as its metabolites nitrotyrosine, L-3,4-dihydroxyphenylalanine (DOPA), and dopamine regarding clinical outcomes and response to nutritional therapy in patients at nutritional risk. This is a secondary analysis of the Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), a randomized controlled trial investigating individualized nutritional support compared to standard care in patients at risk of malnutrition. The primary outcome was 30-day all-cause mortality. We analyzed data of 238 patients and found a significant association between low plasma levels of phenylalanine [adjusted HR 2.27 (95% CI 1.29 to 3.00)] and tyrosine [adjusted HR 1.91 (95% CI 1.11 to 3.28)] with increased 30-day mortality. This association persisted over a longer period, extending to 5 years. Additionally, trends indicated elevated mortality rates among patients with low nitrotyrosine and high DOPA and dopamine levels. Patients with high tyrosine levels showed a more pronounced response to nutritional support compared to patients with low tyrosine levels (HR 0.45 versus 1.46, p for interaction = 0.02). In medical inpatients at nutritional risk, low phenylalanine and tyrosine levels were associated with increased short-and long-term mortality and patients with high tyrosine levels showed a more pronounced response to nutritional support. Further research is warranted to gain a deeper understanding of phenylalanine and tyrosine pathways, their association with clinical outcomes in patients at nutritional risk, as well as their response to nutritional therapy. www.clinicaltrials.gov, identifier NCT02517476.