Adjustment For BMI Research Articles

Prognostic Value of PCSK9 Levels in Premenopausal Women at Risk of Breast Cancer-Evidence from a 17-Year Follow-Up Study.

The involvement of cholesterol in cancer development remains a topic of debate, and its association with breast cancer has yet to be consistently demonstrated. Considering that circulating cholesterol levels depend on several concomitant processes, we tested the liability of plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of cholesterol levels, as a prognostic biomarker in the context of breast neoplastic events. Within a prospective randomized breast cancer prevention trial we measured baseline plasma levels of PCSK9. A total of 235 at-risk premenopausal women were randomized and followed up for 17 years. Participants enrolled in this placebo-controlled, phase II, double-blind trial were randomly assigned to receive either tamoxifen 5 mg/d or fenretinide 200 mg/d, both agents, or placebo for 2 years. The associations with breast cancer events were evaluated through competing risk and Cox regression survival models, adjusted for randomization strata (5-year Gail risk ≥ 1.3% vs. intraepithelial neoplasia or small invasive breast cancer of favorable prognosis), age, and treatment allocation. PCSK9 associations with biomarkers linked to breast cancer risk were assessed on blood samples collected at baseline. The plasmatic PCSK9 median and interquartile range were 207 ng/mL and 170-252 ng/mL, respectively. Over a median follow-up period of 17 years and 89 breast neoplastic events, disease-free survival curves showed a hazard ratio of 1.002 (95% CI: 0.999-1.005, p = 0.22) for women with PCSK9 plasma levels ≥ 207 ng/mL compared to women with levels below 207 ng/mL. No differences between randomization strata were observed. We found a negative correlation between PCSK9 and estradiol (r = -0.305), maintained even after partial adjustment for BMI and age (r = -0.287). Cholesterol (r = 0.266), LDL-C (r = 0.207), non-HDL-C (r = 0.246), remnant cholesterol (r = 0.233), and triglycerides (r = 0.233) also correlated with PCSK9. In premenopausal women at risk of early-stage breast cancer, PCSK9 did not appear to have a role as a prognostic biomarker of breast neoplastic events. Larger studies are warranted investigating patients in different settings.

Associations between change in BMI and the risk of hypertension and dyslipidaemia in people receiving integrase strand-transfer inhibitors, tenofovir alafenamide, or both compared with other contemporary antiretroviral regimens: a multicentre, prospective observational study from the RESPOND consortium cohorts.

Integrase strand-transfer inhibitors (INSTIs) and tenofovir alafenamide have been associated with weight gain in several clinical trials and observational cohorts. However, whether weight gain associated with INSTIs and tenofovir alafenamide confers a higher risk of weight-related clinical events is unclear. We aimed to assess whether changes in BMI differentially increase hypertension or dyslipidaemia risk in people with HIV receiving INSTIs, tenofovir alafenamide, or both versus other contemporary regimens. This multicentre, prospective observational study analysed prospective data from RESPOND, an international consortium of HIV cohorts for which recruitment began in 2017 and is still ongoing from HIV clinics and hospitals in 37 European countries and Australia. Participants were eligible if they were aged 18 years or older, receiving INSTI-containing antiretroviral therapy (ART) regimens or a contemporary non-INSTI, did not have hypertension or dyslipidaemia at baseline, and had baseline and at least two follow-up BMI, lipid, and blood pressure measurements. We excluded participants without baseline CD4 or HIV RNA results and those receiving non-ART medications associated with weight changes, including antipsychotics and mood stabilisers, corticosteroids, insulin, and insulin secretagogues. They were followed up from baseline until the earliest hypertension or dyslipidaemia event, their last visit, or Dec 31, 2021, whichever was earlier. The primary outcomes were incidence of hypertension and dyslipidaemia, for which we used multivariable Poisson regression adjusted for time-updated BMI to determine unadjusted and adjusted incidence rate ratios (IRRs) of hypertension and dyslipidaemia in people receiving INSTIs, tenofovir alafenamide, or both, and tested for interaction between time-updated ART regimen and BMI. Of the 35 941 RESPOND participants, 9704 (7327 [75·5 %] male and 2377 [24·5%] female) were included in the hypertension analysis and 5231 (3796 [72·6%] male and 1435 [27·4%] female) were included in the dyslipidaemia analysis. In the univariable model, hypertension was more common in individuals receiving an INSTI with tenofovir alafenamide (IRR 1·70, 95% CI 1·54-1·88) or an INSTI without tenofovir alafenamide (1·41, 1·30-1·53) compared with those receiving neither INSTIs nor tenofovir alafenamide. Adjustment for time-updated BMI and confounders attenuated risk in participants receiving an INSTI with (IRR 1·48, 1·31-1·68) or without (1·25, 1·13-1·39) tenofovir alafenamide. Similarly, dyslipidaemia was more common in participants using tenofovir alafenamide with an INSTI (IRR 1·24, 1·10-1·40) and tenofovir alafenamide alone (1·22, 1·03-1·44) than in participants using neither INSTI nor tenofovir alafenamide. Adjustment for BMI and confounders attenuated the risk in participants receiving tenofovir alafenamide with an INSTI (adjusted IRR 1·21, 1·07-1·37), whereas the risk in those receiving tenofovir alafenamide alone became non-significant (1·15, 0·96-1·38). The associations between increasing BMI and risk of hypertension and dyslipidaemia did not differ between participants receiving different ART regimens (pinteraction=0·46 for hypertension; pinteraction=0·31 for dyslipidaemia). Although residual confounding cannot be entirely excluded, the use of INSTIs was associated with incident hypertension, and the use of tenofovir alafenamide was associated with dyslipidaemia, with the latter association partly mediated by weight gain. These results reiterate the need for hypertension and dyslipidaemia screening in people with HIV. The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The Brighton HIV Cohort, The National Croatian HIV Cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort, The University of Cologne HIV Cohort, Merck Life Sciences, ViiV Healthcare, and Gilead Sciences.

Identifying clusters of patient comorbidities associated with obstructive sleep apnea using electronic health records.

The objectives of this study were to understand the relative comorbidity burden of obstructive sleep apnea (OSA), determine whether these relationships were modified by sex or age, and identify patient subtypes defined by common comorbidities. Cases with OSA and noncases (controls) were defined using a validated electronic health record (EHR)-based phenotype and matched for age, sex, and time period of follow-up in the EHR. We compared prevalence of the 20 most common comorbidities between matched cases and controls using conditional logistic regression with and without controlling for body mass index. Latent class analysis was used to identify subtypes of OSA cases defined by combinations of these comorbidities. In total, 60,586 OSA cases were matched to 60,586 controls (from 1,226,755 total controls). Patients with OSA were more likely to have each of the 20 most common comorbidities compared with controls, with odds ratios ranging from 3.1 to 30.8 in the full matched set and 1.3 to 10.2 after body mass index adjustment. Associations between OSA and these comorbidities were generally stronger in females and patients with younger age at diagnosis. We identified 5 distinct subgroups based on EHR-defined comorbidities: High Comorbidity Burden, Low Comorbidity Burden, Cardiovascular Comorbidities, Inflammatory Conditions and Less Obesity, and Inflammatory Conditions and Obesity. Our study demonstrates the power of leveraging the EHR to understand the relative health burden of OSA, as well as heterogeneity in these relationships based on age and sex. In addition to enrichment for comorbidities, we identified 5 novel OSA subtypes defined by combinations of comorbidities in the EHR, which may be informative for understanding disease outcomes and improving prevention and clinical care. Overall, this study adds more evidence that OSA is heterogeneous and requires personalized management. Te TT, Keenan BT, Veatch OJ, Boland MR, Hubbard RA, Pack AI. Identifying clusters of patient comorbidities associated with obstructive sleep apnea using electronic health records. J Clin Sleep Med. 2024;20(4):521-533.

The Association of Iron Intake and Hypertension, Does Iron Intake Decrease Blood Pressure?

Previous studies reported that iron may have an indispensable role in the risk of hypertension (HTN). However, the result of the studies on the relationship between iron and risk of HTN is inconsistent. This study aimed to assess the association between the association of dietary iron intake and HTN in the Iranian population. This case-control study was conducted on 4184 people aged 35 to 70, including 1239 people with HTN and 2945 people with normal blood pressure (BP) in Sabzevar, Iran. Dietary intake was assessed using a food frequency questionnaire (FFQ). The Nutritionist IV software was used in terms of the assessment of dietary intake of iron. An inverse association was found between iron intake and HTN (OR = 0.97, CI 95%: 0.94-0.99, P = 0.04). The association remained significant after adjustment for age, gender, smoking, drinking alcohol, calorie intake, and BMI (OR = 0.94, CI 95%: 0.89-0.98, P = 0.01). As a conclusion, iron intake was inversely associated with HTN. Further longitudinal studies on the effect of iron intake on BP are required to confirm this finding.

Association of adrenal steroids with metabolomic profiles in patients with primary and endocrine hypertension.

Endocrine hypertension (EHT) due to pheochromocytoma/paraganglioma (PPGL), Cushing's syndrome (CS), or primary aldosteronism (PA) is linked to a variety of metabolic alterations and comorbidities. Accordingly, patients with EHT and primary hypertension (PHT) are characterized by distinct metabolic profiles. However, it remains unclear whether the metabolomic differences relate solely to the disease-defining hormonal parameters. Therefore, our objective was to study the association of disease defining hormonal excess and concomitant adrenal steroids with metabolomic alterations in patients with EHT. Retrospective European multicenter study of 263 patients (mean age 49 years, 50% females; 58 PHT, 69 PPGL, 37 CS, 99 PA) in whom targeted metabolomic and adrenal steroid profiling was available. The association of 13 adrenal steroids with differences in 79 metabolites between PPGL, CS, PA and PHT was examined after correction for age, sex, BMI, and presence of diabetes mellitus. After adjustment for BMI and diabetes mellitus significant association between adrenal steroids and metabolites - 18 in PPGL, 15 in CS, and 23 in PA - were revealed. In PPGL, the majority of metabolite associations were linked to catecholamine excess, whereas in PA, only one metabolite was associated with aldosterone. In contrast, cortisone (16 metabolites), cortisol (6 metabolites), and DHEA (8 metabolites) had the highest number of associated metabolites in PA. In CS, 18-hydroxycortisol significantly influenced 5 metabolites, cortisol affected 4, and cortisone, 11-deoxycortisol, and DHEA each were linked to 3 metabolites. Our study indicates cortisol, cortisone, and catecholamine excess are significantly associated with metabolomic variances in EHT versus PHT patients. Notably, catecholamine excess is key to PPGL's metabolomic changes, whereas in PA, other non-defining adrenal steroids mainly account for metabolomic differences. In CS, cortisol, alongside other non-defining adrenal hormones, contributes to these differences, suggesting that metabolic disorders and cardiovascular morbidity in these conditions could also be affected by various adrenal steroids.

Abstract 3432: Blood metabolomic profile of glioma risk: A pooled, multi-cohort analysis in COMETS

Abstract Although gliomas are relatively rare, they are among the most lethal malignancies. Yet, with the exception of ionizing radiation and family history, their etiologic factors remain largely unknown. We conducted an untargeted metabolomics investigation pooling nested case-control studies from 9 prospective cohorts (median age 63 years, 59% women) in the Consortium of Metabolomics Studies (COMETS). One cancer-free control was individually matched to each of the 803 glioma cases based on age, sex, self-identified race/ethnicity, and blood collection date. Using an ultrahigh-performance LC-MS/MS platform (Metabolon, Inc.), we identified 874 known metabolites in pre-diagnostic serum or plasma, and logistic regression models conditioned on the matching factors) estimated odds ratios (ORs) and 95% confidence intervals for the associations between 1-SD increases in circulating metabolites and glioma risk (Bonferroni corrected significance threshold P=5.7 × 10−5). A total of 58 metabolites were associated with glioma (P<0.05), with the top three being 3-methylglutarylcarnitine (OR=1.19; P=0.001), cholate (OR=0.85; P=0.001) and a sphingomyelin (SM) (d18:2/21:0, d16:2/23:0, OR=1.19; P=0.002). Analysis restricted to cases diagnosed >5 years after blood collection showed 51 metabolites associated with risk (P<0.05), including SM d18:2/23:1 (OR=1.32; P=5.2 × 10−5), and two other SMs (d18:2/21:0, d16:2/23:0 and d17:1/24:1(15Z)) (ORs=1.27 and 1.26, respectively; P<5.6 × 10−4). Our findings were not materially altered with further adjustment for smoking, BMI, height and diabetes. Analysis restricted to high-grade glioma cases (n=595) showed similar associations, whereas low-grade glioma (n=207) showed fewer metabolites related to risk (top signals of sphingosine, sphinganine and L-glutamic acid, each inversely associated). We did, however, observe that the 2-hydroxyglutarate/alpha-ketoglutarate ratio was significantly associated with low-grade disease (OR=2.9; P=0.0008), which was most pronounced among cases diagnosed >10 years following blood collection (OR=9.99; P=0.003). Glioblastoma (n=485) showed similar positive risk estimates including for 3-methylglutarylcarnitine which achieved Bonferroni significance (OR=1.35; P=3 × 10−5) and several SMs. In contrast, the top metabolite for astrocytoma risk (n=88) was tyrosine (OR=0.55; P=0.002). Gene-set and principal components analyses confirmed that the sub-pathways of SM, dihydro-SM, fatty acid, and dihydroceramide metabolism were significantly associated with overall glioma risk, and dihydro-SM, dihydroceramide, SM, lactosylceramide, glutathione, and purine metabolism were associated with high-grade glioma (all P values <0.05). These novel findings regarding altered metabolic pathways/dysregulation occurring years before glioma diagnoses may be related to etiologic factors or subclinical disease. Citation Format: Jiaqi Huang, Bin Zhao, Stephanie J. Weinstein, Marian L. Neuhouser, Steve C. Moore, Heather Eliassen, David J. Cote, Loic Le Marchand, Lorelei Mucci, Ying Yang, Victoria Stevens, Wei Zheng, Xiao-Ou Shu, Demetrius Albanes. Blood metabolomic profile of glioma risk: A pooled, multi-cohort analysis in COMETS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3432.

Abstract 6293: Influence of prescription opioids and recreational cannabis use on efficacy outcomes and adverse events related to immune checkpoint inhibitors

Abstract Introduction: Opioids and cannabis possess immunomodulatory properties. However, the effect of opioid receptor activity on immune function is complicated, facilitated by several mechanisms and can lead to enhancement or inhibition. Similarly, the relation between cannabinoid ligands of diverse types and endocannabinoid receptors on various immune cells is complex. We hereby delineate the effect of prescription opioids and recreational cannabis use on immune-related adverse events (IRAEs) during immune checkpoint inhibitor (ICI) therapy in various cancers, as well as efficacy outcomes in advanced non-small cell lung cancer (aNSCLC). Methods: This is a retrospective cohort study of adult patients with advanced cancers who received ICI with or without chemotherapy for at least two months at an urban safety net hospital from January 2016 to June 2022. All patients, as well as a subset of patients with aNSCLC, were divided into two arms based on whether they were prescribed opioids during ICI therapy or not (OP vs. NO). Similarly, they were grouped based on whether they reported recreational cannabis use during ICI therapy (since initiation of therapy) or not (CA vs. NC). Incidence of IRAEs, median overall survival (mOS) and median progression-free survival (mPFS) calculated per RECIST 1.1 were the outcome variables. Multivariate logistic regression and alternative log-rank test were utilized for analysis with adjustments for demographics, insurance status, BMI, ECOG, PD-L1, TMB, smoking and concurrent chemotherapy. Results: 230 patients received ICI-based therapy; 47% were female, 34% were African American and 6.5% were Hispanic. There was no significant difference in the incidence of IRAEs between OP (n=144) and NO (n=86; p=0.225). However, CA (n=44) had higher IRAEs than NC (n=186) with an odds ratio estimate of 2.023 (X2=4.18, CI 1.03-3.97, p=0.04). Among 110 patients with aNSCLC, 46% were female. Patients with aNSCLC in the OP arm (n=69) had no significant difference in mOS (HR=1.34, CI 0.8-2.25, p=0.26) or mPFS (HR=1.21, CI 0.69-2.1, p=0.51) compared to patients in the NO arm (n=51). Similarly, the two arms CA (n=21) and NC (n=89) had no difference in mOS (HR:0.96, CI 0.5-1.83, p=0.89) or mPFS (HR:1.18, CI 0.61-2.29, p=0.63) for aNSCLC. Conclusion: Recreational cannabis use during ICI therapy increased the incidence of IRAEs. Prescription opioids and recreational cannabis use did not significantly affect survival outcomes for ICI in aNSCLC. Prescription opioid use also did not significantly influence the occurrence of IRAEs. This study suggests that recreational cannabis may need to be used with caution in this patient population due to its influence on IRAEs. On the other hand, opioids appear to be a safe option for pain management in these patients. Larger studies are warranted to shed more insight into the effect of these substances on ICI therapy. Citation Format: Himil Mahadevia, Benjamin Eidenschink, An-Lin Cheng, Atharva Desai, Stephanie Harry, Lara Kujtan. Influence of prescription opioids and recreational cannabis use on efficacy outcomes and adverse events related to immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6293.

Plasma Ceramides and Other Sphingolipids in Relation to Incident Prediabetes in a Longitudinal Biracial Cohort.

Sphingolipids are linked to the pathogenesis of type 2 diabetes (T2D). To test the hypothesis that plasma sphingolipid profiles predict incident prediabetes. A case-control study nested in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study, a 5-year follow-up study. Academic health center. Normoglycemic adults enrolled in the POP-ABC study. Assessments included OGTT, insulin sensitivity and insulin secretion. Participants with incident prediabetes were matched in age, sex, and ethnicity with non-progressors. We assayed 58 sphingolipid species (ceramides, monohexosyl ceramides, sphingomyelins, and sphingosine) using LC/tandem mass spectrometry in baseline plasma levels from participants and determined association with prediabetes risk. The primary outcome was progression from normoglycemia to prediabetes, defined as impaired fasting glucose or impaired glucose tolerance. The mean age of participants (N = 140; 50% Black, 50% female) was 48.1 ± 8.69 y, BMI 30.1 ± 5.78 kg/m2, fasting plasma glucose (FPG) 92.7 ± 5.84 mg/dl, and two-hour plasma glucose (2hrPG) 121 ± 23.3 mg/dl. Of the 58 sphingolipid species assayed, higher ratios of sphingomyelin C26:0/C26:1 (OR 2.73 [95% CI 1.172-4.408], P = 0.015) and ceramide C18:0/C18:1 (OR 1.236 [95% CI 1.042-1.466], P = 0.015) in baseline plasma specimens were significantly associated with progression to prediabetes during the 5-year follow-up period, after adjustments for age, race, sex, BMI, FPG, 2hPG, insulin sensitivity, and insulin secretion. We conclude that the saturated-to-monounsaturated ratios of long-chain ceramide C18:0/C18:1 and very-long-chain sphingomyelin C26:0/C26:1 are potential biomarkers of prediabetes risk among individuals with parental history of T2D.

Mendelian randomization study on insulin resistance and risk of hypertension and cardiovascular disease

Observational studies have suggested that insulin resistance (IR) is associated with hypertension and various cardiovascular diseases. However, the presence of a causal relationship between IR and cardiovascular disease remains unclear. Here, we applied Mendelian randomization (MR) approaches to address the causal association between genetically determined IR and the risk of cardiovascular diseases. Our primary genetic instruments comprised 53 SNPs associated with IR phenotype from a GWAS of up to 188,577 participants. Genetic association estimates for hypertension and venous thromboembolism (VTE) were extracted from UK Biobank, estimates for atrial fibrillation (AF) were extracted from the hitherto largest GWAS meta-analysis on AF, estimates for heart failure were extracted from HERMES Consortium, estimates for peripheral artery disease (PAD) and aortic aneurysm were extracted from the FinnGen Study. The main analyses were performed using the random-effects inverse-variance weighted approach, and complemented by sensitivity analyses and multivariable MR analyses. Corresponding to 55% higher fasting insulin adjusted for body mass index, 0.46 mmol/L lower high-density lipoprotein cholesterol and 0.89 mmol/L higher triglyceride, one standard deviation change in genetically predicted IR was associated with increased risk of hypertension (odds ratio (OR) 1.06, 95% CI 1.04–1.08; P = 1.91 × 10–11) and PAD (OR 1.90, 95% CI 1.43–2.54; P = 1.19 × 10–5). Suggestive evidence was obtained for an association between IR and heart failure (OR per SD change in IR: 1.19, 95% CI 1.01–1.41, P = 0.041). There was no MR evidence for an association between genetically predicted IR and atrial fibrillation, VTE, and aortic aneurysm. Results were widely consistent across all sensitivity analyses. In multivariable MR, the association between IR and PAD was attenuated after adjustment for lipids (P = 0.347) or BMI (P = 0.163). Our findings support that genetically determined IR increases the risk of hypertension and PAD.

Influence of abdominal fat distribution and inflammatory status on post-operative prognosis in non-small cell lung cancer patients: a retrospective cohort study

PurposeTo evaluate the influence of visceral fat area (VFA), subcutaneous fat area (SFA), the systemic immune-inflammation index (SII) and total inflammation-based systemic index (AISI) on the postoperative prognosis of non-small cell lung cancers (NSCLC) patients.Methods266 NSCLC patients received surgery from two academic medical centers were included. To assess the effect of abdominal fat measured by computed tomography (CT) imaging and inflammatory indicators on patients’ overall survival (OS) and progression-free survival (PFS), Kaplan–Meier survival analysis and Cox proportional hazards models were used.ResultsKaplan–Meier analysis showed the OS and PFS of patients in high-VFA group was better than low-VFA group (p < 0.05). AISI and SII were shown to be risk factors for OS and PFS (p < 0.05) after additional adjustment for BMI (Cox regression model II). After further adjustment for VFA (Cox regression model III), low-SFA group had longer OS (p < 0.05). Among the four subgroups based on VFA (high/low) and SFA (high/low) (p < 0.05), the high-VFA & low-SFA group had the longest median OS (108 months; 95% CI 74–117 months) and PFS (85 months; 95% CI 65–117 months), as well as the lowest SII and AISI (p < 0.05). Low-SFA was a protective factor for OS with different VFA stratification (p < 0.05).ConclusionVFA, SFA, SII and AISI may be employed as significant prognostic markers of postoperative survival in NSCLC patients. Moreover, excessive SFA levels may encourage systemic inflammation decreasing the protective impact of VFA, which may help to provide targeted nutritional support and interventions for postoperative NSCLC patients with poor prognosis.

Associations between lifestyle, health, and clinical characteristics and circulating oxysterols and cholesterol precursors in women diagnosed with breast cancer: a cross-sectional study

Despite increasing evidence that cholesterol precursors and oxysterols, oxidized cholesterol metabolites, play a role in numerous pathological processes and diseases including breast cancer, little is known about correlates of these sterols in women with breast cancer. In this study, 2282 women with breast cancer and blood draw post diagnosis were included and cross-sectional associations between circulating levels of 15 sterols/oxysterols and (a) lifestyle, anthropometric, reproductive characteristics, (b) comorbidities and medication use, and (c) breast cancer tumor and treatment characteristics were calculated using generalized linear models. Obesity was strongly associated with circulating levels of 7-dehydrocholesterol (DC) (body mass index ≥ 30 vs. 18.5–24.9 kg/m2: 51.7% difference) and 7-ketocholesterol (KC) (40.0% difference). After adjustment for BMI, comorbidities such as cardiovascular disease were associated with higher levels of 7-DC (26.1% difference) and lower levels of desmosterol (− 16.4% difference). Breast cancer tumor characteristics including hormone receptor status, tumor stage, and endocrine therapy were associated with lanosterol, 24-DHLan, 7b-HC, and THC (e.g., THC; tumor stage IIIa vs. I: 36.9% difference). Weaker associations were observed for lifestyle characteristics and for any of the other oxysterols. The findings of this study suggest that cholesterol precursors are strongly associated with metabolic factors, while oxysterols are associated with breast cancer tumor characteristics, warranting further investigation into the role of cholesterol precursors and oxysterols in women with breast cancer and other populations.

Perinatal Outcomes in Early and Late Gestational Diabetes Mellitus After Treatment From 24-28 Weeks' Gestation: A TOBOGM Secondary Analysis.

In most gestational diabetes mellitus (GDM) studies, cohorts have included women combined into study populations without regard to whether hyperglycemia was present earlier in pregnancy. In this study we sought to compare perinatal outcomes between groups: women with early GDM (EGDM group: diagnosis before 20 weeks but no treatment until 24-28 weeks if GDM still present), with late GDM (LGDM group: present only at 24-28 weeks), and with normoglycemia at 24-28 weeks (control subjects). This is a secondary analysis of a randomized controlled treatment trial where we studied, among women with risk factors, early (<20 weeks' gestation) GDM defined according to World Health Organization 2013 criteria. Those receiving early treatment for GDM treatment were excluded. GDM was treated if present at 24-28 weeks. The primary outcome was a composite of birth before 37 weeks' gestation, birth weight ≥4,500 g, birth trauma, neonatal respiratory distress, phototherapy, stillbirth/neonatal death, and shoulder dystocia. Comparisons included adjustment for age, ethnicity, BMI, site, smoking, primigravity, and education. Women with EGDM (n = 254) and LGDM (n = 467) had shorter pregnancy duration than control subjects (n = 2,339). BMI was lowest with LGDM. The composite was increased with EGDM (odds ratio [OR] 1.59, 95% CI 1.18-2.12)) but not LGDM (OR 1.19, 95% CI 0.94-1.50). Induction of labor was higher in both GDM groups. In comparisons with control subjects there were higher birth centile, higher preterm birth rate, and higher rate of neonatal jaundice for the EGDM group (but not the LGDM group). The greatest need for insulin and/or metformin was with EGDM. Adverse perinatal outcomes were increased with EGDM despite treatment from 24-28 weeks' gestation, suggesting the need to initiate treatment early, and more aggressively, to reduce the effects of exposure to the more severe maternal hyperglycemia from early pregnancy.

Associations between Neck Circumference, Mid-Upper Arm Circumference, Wrist Circumference, and High Blood Pressure among Lithuanian Children and Adolescents: A Cross-Sectional Study.

(1) Background: High blood pressure (HBP) and obesity are significant and growing public health issues worldwide. Our study aimed to evaluate the associations of neck circumference (NC), mid-upper arm circumference (MUAC), and wrist circumference (WrC) with HBP among Lithuanian children and adolescents aged 7-17 years. (2) Methods: In this cross-sectional study, data on BP and anthropometric measurements were analysed in 3688 children and adolescents aged 7-17 years. Multivariate logistic regression analysis was used to estimate the associations between anthropometric indices and HBP. (3) Results: Overall, the prevalence rates of elevated BP and hypertension were 13.7% and 12.9%, respectively. After adjustment for age, BMI, and WC, statistically significant elevated aORs were observed for associations between greater NC, MUAC, WrC, and HBP in boys (aORs: 2.13, 2.46, and 2.48, respectively) and in girls (aORs: 2.01, 2.36, and 2.09, respectively). Moreover, per-unit increase in NC, MUAC, and WrC was also associated with greater odds of HBP in boys (aORs: 1.20, 1.21, and 1.37, respectively) and in girls (aORs: 1.10, 1.10, and 1.21, respectively). The analysed anthropometric indices presented higher area under the curve values for predicting HBP in boys than in girls. (4) Conclusions: This study suggests that higher NC, MUAC, and WrC are associated with increased odds of HBP in Lithuanian children and adolescents.

Preoperative proximal tibial bone density, bone microarchitecture, and bone turnover are not associated with postoperative tibial component migration in cemented and cementless medial unicompartmental knee replacements: secondary analyses from a randomized controlled trial.

Cementless arthroplasty fixation relies on early bone ingrowth and may be poor in patients with low proximal tibial bone density or abnormal bone turnover. We aimed first to describe the baseline bone properties in patients undergoing medial unicompartmental knee replacement (UKR), and second to investigate its association with cemented and cementless tibial component migration until 2 years. A subset investigation of 2 patient groups from a 3-armed randomized controlled trial was conducted. There were 26 cemented and 25 cementless medial UKRs with twin-pegged femoral components. Volumetric bone mineral density (vBMD) and microstructure of the excised medial tibial plateau were ascertained with µCT. Bone turnover was estimated using dynamic histomorphometry (eroded surface/bone surface = ES/BS, osteoid surface/bone surface = OS/BS, mineralizing surface/bone surface = MS/BS). Tibial component migration in 4 feature points was followed for 2 years with radiostereometry. At the 2-year follow-up, the cementless tibial components migrated 0.38 mm (95% confidence interval [CI] 0.14-0.62) total translation more than the cemented components at the posterior feature point. The greatest migration in the cementless group was subsidence at the posterior feature point of 0.66 mm (CI 0.48-0.84) until 6 weeks, and from 3 months the components were stable. Cemented tibial components subsided very little. Between 1- and 2-year follow-ups, no cementless but 4 cemented tibial components revealed continuous migration. OS/BS was half of the ES/BS. No µCT or histomorphometric parameters showed any clinically relevant correlation with tibial component migration at the posterior feature point for either cemented or cementless UKR at 6 weeks' or 2 years' follow-up after adjustment for age, BMI, and sex. Preoperative vBMD, bone turnover, and microstructure were not associated with postoperative tibial component migration of cemented and cementless medial UKR.

Serum uric acid did not affect embryonic and pregnancy outcomes in women without PCOS during IVF procedures.

Serum uric acid (UA) levels are associated with many systemic diseases. A previous study confirmed the association between high serum uric acid levels and poor prognosis of in vitro fertilization (IVF) treatment in polycystic ovary syndrome (PCOS) patients. This study aimed to explore the correlation between serum uric acid levels and reproductive outcomes in patients without PCOS. A retrospective study that included 1057 patients who underwent pre-implantation genetic testing for monogenic disorders (PGT-M) treatment from January 2013 to December 2020 was conducted. The study population was further divided into 3 groups according to serum UA levels: the ≤250 μmol/L group, the 251-360 μmol/L group, and the >360 μmol/L group. The controlled ovarian hyperstimulation (COH) treatment outcomes, embryonic treatment outcomes and pregnancy outcomes of the first frozen embryo transfer (FET) cycle were compared among groups. Multivariable linear regression and binary regression were applied to detect the association between IVF outcomes and serum uric acid levels. The number of retrieved oocytes, fertilization rate, viable embryo rate, blastocyst formation rate and euploid rate were not associated with serum uric acid levels. The mature oocyte rate was negatively correlated with serum uric acid levels. The pregnancy outcomes of the first FET cycle were also not associated with serum uric acid levels. After adjustment for BMI, the perinatal outcomes were not associated with serum uric acid levels. IVF treatment outcomes were not associated with serum uric acid levels in patients without PCOS.

Separating the effects of life course adiposity on diabetic nephropathy: a comprehensive multivariable Mendelian randomization study.

Previous Mendelian randomization (MR) of obesity and diabetic nephropathy (DN) risk used small sample sizes or focused on a single adiposity metric. We explored the independent causal connection between obesity-related factors and DN risk using the most extensive GWAS summary data available, considering the distribution of adiposity across childhood and adulthood. To evaluate the overall effect of each obesity-related exposure on DN (Ncase = 3,676, Ncontrol = 283,456), a two-sample univariate MR (UVMR) analysis was performed. The independent causal influence of each obesity-related feature on DN was estimated using multivariable MR (MVMR) when accounting for confounding variables. It was also used to examine the independent effects of adult and pediatric obesity, adjusting for their interrelationships. We used data from genome-wide association studies, including overall general (body mass index, BMI) and abdominal obesity (waist-to-hip ratio with and without adjustment for BMI, i.e., WHR and WHRadjBMI), along with childhood obesity (childhood BMI). UVMR revealed a significant association between adult BMI (OR=1.24, 95%CI=1.03-1.49, P=2.06×10-2) and pediatric BMI (OR=1.97, 95%CI=1.59-2.45, P=8.55×10-10) with DN risk. At the same time, adult WHR showed a marginally significant increase in DN (OR =1.27, 95%CI = 1.01-1.60, P=3.80×10-2). However, the outcomes were adverse when the influence of BMI was taken out of the WHR (WHRadjBMI). After adjusting for childhood BMI, the causal effects of adult BMI and adult abdominal obesity (WHR) on DN were significantly attenuated and became nonsignificant in MVMR models. In contrast, childhood BMI had a constant and robust independent effect on DN risk(adjusted for adult BMI: IVW, OR=1.90, 95% CI=1.60-2.25, P=2.03×10-13; LASSO, OR=1.91, 95% CI=1.65-2.21, P=3.80×10-18; adjusted for adult WHR: IVW, OR=1.80, 95% CI=1.40-2.31, P=4.20×10-6; LASSO, OR=1.90, 95% CI=1.56-2.32, P=2.76×10-10). Our comprehensive analysis illustrated the hazard effect of obesity-related exposures for DN. In addition, we showed that childhood obesity plays a separate function in influencing the risk of DN and that the adverse effects of adult obesity (adult BMI and adult WHR) can be substantially attributed to it. Thus, several obesity-related traits deserve more attention and may become a new target for the prevention and treatment of DN and warrant further clinical investigation, especially in childhood obesity.

Fasting plasma metabolites reflecting meat consumption and their associations with incident type 2 diabetes in two Swedish cohorts

BackgroundConsumption of processed red meat has been associated with increased risk of developing type 2 diabetes (T2D), but challenges in dietary assessment call for objective intake biomarkers. ObjectivesThis study aimed to investigate metabolite biomarkers of meat intake and their associations with T2D risk. MethodsFasting plasma samples were collected from a case–control study nested within Västerbotten Intervention Program (VIP) (214 females and 189 males) who developed T2D after a median follow-up of 7 years. Panels of biomarker candidates reflecting the consumption of total, processed, and unprocessed red meat and poultry were selected from the untargeted metabolomics data collected on the controls. Observed associations were then replicated in Swedish Mammography clinical subcohort in Uppsala (SMCC) (n = 4457 females). Replicated metabolites were assessed for potential association with T2D risk using multivariable conditional logistic regression in the discovery and Cox regression in the replication cohorts. ResultsIn total, 15 metabolites were associated with ≥1 meat group in both cohorts. Acylcarnitines 8:1, 8:2, 10:3, reflecting higher processed meat intake [r > 0.22, false discovery rate (FDR) < 0.001 for VIP and r > 0.05; FDR < 0.001 for SMCC) were consistently associated with higher T2D risk in both data sets. Conversely, lysophosphatidylcholine 17:1 and phosphatidylcholine (PC) 15:0/18:2 were associated with lower processed meat intake (r < −0.12; FDR < 0.023, for VIP and r < −0.05; FDR < 0.001, for SMCC) and with lower T2D risk in both data sets, except for PC 15:0/18:2, which was significant only in the VIP cohort. All associations were attenuated after adjustment for BMI (kg/m2). ConclusionsConsistent associations of biomarker candidates involved in lipid metabolism between higher processed red meat intake with higher T2D risk and between those reflecting lower intake with the lower risk may suggest a relationship between processed meat intake and higher T2D risk. However, attenuated associations after adjusting for BMI indicates that such a relationship may at least partly be mediated or confounded by BMI.

Reference centiles of bone mineral density, and body composition of lower limbs in children and adolescents for Hologic DXA Discovery model A.

Background: Regional Dual-energy X-ray absorptiometry (DXA) assessments are useful for patients where whole body measurements are not feasible due to positioning difficulties because of anatomic anomalies (e.g. severe scoliosis) and artifacts due to neuroorthopedic hardware. Until now, there is a lack of reference centiles of bone mineral density and body composition of lower limbs for the DXA device Hologic Discovery model A densitometer. The study aimed to generate age-and sex specific reference centiles of bone mineral content (BMC), bone mineral density (BMD), lean body mass (LBM), and fat mass (FM) of the lower limbs of children and adolescents of Hologic DXA system (Discovery model A). Methodology: Data from children and adolescents aged 8-20 years of the National Health and Nutrition Examination Survey (NHANES) of the years 2015-2018 were used to create age-specific and sex-specific reference centiles. Study population was subdivided into three ethnic groups (non-Hispanic Black, non-Hispanic White and Mexican-American). The LMS method was used to calculate the reference centiles. Study population was adjusted concerning the BMI. Results: A total of DXA scans of 769 non-Hispanic Black children (386 females), 937 non-Hispanic White children (447 females) and 692 Mexican-American children (370 females) were used to calculate age-specific and sex-specific reference curves. 881 DXA scans had to be excluded because of extreme BMI values of the study population, leaving 513 non-Hispanic Black (205 females), 346 Mexican-American children (179 females), 658 Non-Hispanic White (282 females) for statistical analysis and creating age-and sex specific reference centiles after BMI adjustment. Conclusions: We presented pediatric reference centiles for regional bone mineral density, bone mineral content, lean body mass and fat mass of the lower limbs which were age-and sex-specific for three ethnic groups (Mexican-American, non-Hispanic Black and non-Hispanic-White). The reference centiles can be used for the Hologic DXA system Discovery model A with the software version 3.2.

P408 Complete endoscopic healing, the future therapeutic target in Crohn's disease? Results of a prospective multicenter study

Abstract Background The STRIDE II guidelines recognize endoscopic healing (EH), defined by an SES-CD score ≤2 or a CDEIS score &amp;lt;3, as one of the main therapeutic targets in Crohn's disease (CD). Nevertheless, complete endoscopic healing could reduce the risk of long-term complications in CD. The aim of this study was to assess the risk of long-term complications in CD according to the degree of endoscopic healing achieved. Methods We conducted a prospective multicenter study that included all patients with CD undergoing colonoscopy for EH assessment or dysplasia screening between September 2019 and September 2022 in one university hospital, one general hospital and one private center. Two groups were compared: patients with complete EH (CDEIS = 0) and those with partial EH (CDEIS &amp;lt;4). The primary endpoint was CD relapse, defined as the need for drug intensification and/or initiation of corticosteroid and/or CD-related hospitalization and/or development of a fistula (luminal or perianal) or abscess, and/or the need for bowel resection. Patients were followed up every 6 months for two years. Based on previously published data, 138 patients were expected to demonstrate a 13% difference with a two-sided alpha risk of 5% and a power of 80%. Results A total of 133 patients were included. The majority of patients were female (55%), non-smokers (63%), with a median disease duration of 10 (IQR, 4-19) years. Fifty-seven (43%) patients had ileocolonic location and 81 (61%) an inflammatory (B1) behavior. Patients had been on treatment for a median of 18.0 months (IQR 8.6-52) prior to colonoscopy, with no difference between the two groups. There was no significant difference between the two groups apart from BMI. Eighty-four (63%) patients had complete EH. After adjustment for BMI, the risk of relapse was significantly higher in the CDEIS&amp;gt;0 group (23% vs. 41%, HR = 2.05; IC95% = [1.09 - 3.87]; p=0.027). After a median follow-up of 23.3 months, the number of drug intensification, hospitalizations, use of corticosteroids, occurrence of abscess, fistula, or bowel resection in the CDEIS 0 and CDEIS &amp;gt; 0 and &amp;lt;4 groups were 20% and 35% (p=0.065), 2.4 and 16% (p=0.005), 2.4% and 10% (p=0.10), 3.6% and 18% (p=0.009), 7.1% and 18% (p=0.048), 7.1% and 18% (p=0.048) respectively. Conclusion This prospective multicenter study confirms that complete endoscopic healing is associated with better long-term outcomes than partial endoscopic healing in patients with CD, as well as fewer surgeries and hospitalizations and an overall decreased risk of treatment failure.

Causal association of rheumatoid arthritis with frailty and the mediation role of inflammatory cytokines: A Mendelian randomization study

BackgroundPrevious observational studies have suggested the association between rheumatoid arthritis (RA) and frailty. However, it remains obscure whether this association is causal. This study aims to investigate the causal association of RA with frailty and the mediation effect of inflammatory cytokines using Mendelian randomization (MR) design. MethodsSummary-level data for RA (N = 58,284), frailty index (FI) (N = 175,226), Fried frailty score (FFS) (N = 386,565), and 41 inflammatory cytokines (N = 8,293) were obtained from recent genome-wide association studies. Univariable and multivariable MR analyses were conducted to investigate and verify the causal association of RA with frailty. The potential mediation effects of inflammatory cytokines were estimated using two-step MR. ResultsUnivariable inverse variance weighted MR analysis suggested that genetically determined RA was associated with increased FI (beta=0.021; 95 % CI: 0.012, 0.03; p = 2.2 × 10−6) and FFS (beta=0.011; 95 %CI: 0.007, 0.015; p = 8.811 × 10−8). The consistent results were observed in multivariable MR analysis after adjustment for asthma, smoking, BMI, physical activity, telomere length, and depression. Mediation analysis showed evidence of an indirect effect of RA on FI through monokine induced by interferon-gamma (MIG) with a mediated proportion of 9.8 % (95 %CI: 4.76 %, 19.05 %), on FFS via MIG and stromal cell-derived factor-1 alpha with a mediated proportion of 9.6 % (95 %CI: 0 %, 18.18 %) and 8.44 % (95 %CI: 0 %, 18.18 %), respectively. ConclusionThis study provided credible evidence that genetically predicted RA was associated with a higher risk of frailty. Additionally, inflammatory cytokines were involved in the mechanism of RA-induced frailty.