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Measurement of low-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and lipoprotein(a) predicted the 30-year cardiovascular disease risk among women enrolled in the Women’s Health Study.

Abstract Context Elevated concentrations of branched-chain amino acids (BCAA) are strong predictors of type 2 diabetes mellitus (T2DM). Their association with cardiovascular disease (CVD) remains uncertain, particularly in youth. Objective We investigated the role of BCAA and aromatic amino acids (AAA) in obesity, their relationships with novel biomarkers of CVD, and response to a physical activity-based lifestyle intervention (PAL-I) in a randomized controlled study in youth with normal weight (NW) and obesity (OB). Methods Age (14-18 years) and Tanner stage (≥IV) matched youth (OB, n = 15 and NW, n = 6) were studied; the 15 participants with OB underwent a 3-month randomized controlled PAL-I. Circulating amino acid profile, glucose, insulin, lipids, adiponectin, retinol binding protein-4, fibrinogen, high-sensitivity C-reactive protein, interleukin-6, and 25-hydroxy vitamin-D, along with body composition, were measured at baseline and after PAL-I. Independent t tests, analysis of covariance, and mixed-effect models were used for analysis of the data. Results Compared with NW, the concentration of various amino acids, including BCAA and AAA, were altered in OB (P < 0.05). BCAA and AAA showed baseline correlations with body composition and novel biomarkers of CVD, particularly inflammatory factors (all P < 0.05). The PAL-I produced only negligible effects (P > 0.05) on BCAA and AAA. Glutamine, glycine, and aspartic acid decreased with PAL-I (all P < 0.05). Conclusion The novel finding of the BCAA–inflammation relationship, along with strong correlations with nontraditional biomarkers of CVD, may raise the prospect of BCAA as a biomarker of CVD and evoke a potential link between obesity, T2DM, and CVD.

This controlled, randomized, multicenter trial compared early initiation (<2 days) with late initiation (≥8 days) of parenteral nutrition in adults in the intensive care unit. Late initiation was associated with less morbidity and enhanced recovery. Critical illness induces anorexia and the inability to eat normally, predisposing patients to serious nutritional deficits, muscle wasting, weakness, and delayed recovery. Whether artificial nutritional support improves the outcome for critically ill patients is unclear. The administration route, the time until the initiation of artificial nutrition, the number of calories, and the type of nutrients may be important. 1 – 3 Enteral nutrition is associated with fewer complications than parenteral nutrition and is less expensive to administer. 4 – 6 However, the use of enteral nutrition alone often does not achieve caloric targets. 7 In addition, underfeeding is associated with weakness, infection, 8 an increased duration . . .

C-reactive protein (CRP) has been used as a biomarker of chronic low-grade inflammation in observational studies. We aimed to determine whether genetically determined CRP was associated with hundreds of human phenotypes to guide anti-inflammatory interventions. We used individual data from the UK Biobank to perform a phenome-wide two-stage least squares (2SLS) Mendelian randomization (MR) analysis for CRP with 879 diseases. Summary-level data from the FinnGen consortium were utilized to perform phenome-wide two-sample MR analysis on 821 phenotypes. Systematic two-sample MR methods included MR-IVW, MR-WME, MR-Mod, and MR-PRESSO as sensitivity analyses combined with multivariable MR to identify robust associations. Genetic correlation analysis was applied to identify shared genetic risks. We found genetically determined CRP was robustly associated with 15 diseases in the UK Biobank and 11 diseases in the FinnGen population ( < 0.05 for all MR analyses). CRP was positively associated with tongue cancer, bronchitis, hydronephrosis, and acute pancreatitis and negatively associated with colorectal cancer, colon cancer, cerebral ischemia, electrolyte imbalance, Parkinson's disease, epilepsy, anemia of chronic disease, encephalitis, psychophysical visual disturbances, and aseptic necrosis of bone in the UK Biobank. There were positive associations with impetigo, vascular dementia, bipolar disorders, hypercholesterolemia, vertigo, and neurological diseases, and negative correlations with degenerative macular diseases, metatarsalgia, interstitial lung disease, and idiopathic pulmonary fibrosis, and others. in the FinnGen population. The electrolyte imbalance and anemia of chronic disease in UK Biobank and hypercholesterolemia and neurological diseases in FinnGen pass the corrections. Neurological diseases and bipolar disorders also presented positive genetic correlations with CRP. We found no overlapping causal associations between the populations. Previous causal evidence also failed to support these associations (except for bipolar disorders). Genetically determined CRP was robustly associated with several diseases in the UK Biobank and the FinnGen population, but could not be replicated, suggesting heterogeneous and non-repeatable effects of CRP across populations. This implies that interventions at CRP are unlikely to result in decreased risk for most human diseases in the general population but may benefit specific high-risk populations. The limited causal evidence and potential double-sided effects remind us to be cautious about CRP interventions.

The immune response involved in each phase of type 2 diabetes (T2D) development might be different. We aimed to identify novel inflammatory markers that predict progression from normoglycemia to pre-diabetes, incident T2D and insulin therapy. We used plasma levels of 26 inflammatory markers in 971 subjects from the Rotterdam Study. Among them 17 are novel and 9 previously studied. Cox regression models were built to perform survival analysis. Main Outcome Measures: During a follow-up of up to 14.7 years (between April 1, 1997, and Jan 1, 2012) 139 cases of pre-diabetes, 110 cases of T2D and 26 cases of insulin initiation were identified. In age and sex adjusted Cox models, IL13 (HR = 0.78), EN-RAGE (1.30), CFH (1.24), IL18 (1.22) and CRP (1.32) were associated with incident pre-diabetes. IL13 (0.62), IL17 (0.75), EN-RAGE (1.25), complement 3 (1.44), IL18 (1.35), TNFRII (1.27), IL1ra (1.24) and CRP (1.64) were associated with incident T2D. In multivariate models, IL13 (0.77), EN-RAGE (1.23) and CRP (1.26) remained associated with pre-diabetes. IL13 (0.67), IL17 (0.76) and CRP (1.32) remained associated with T2D. IL13 (0.55) was the only marker associated with initiation of insulin therapy in diabetics. Various inflammatory markers are associated with progression from normoglycemia to pre-diabetes (IL13, EN-RAGE, CRP), T2D (IL13, IL17, CRP) or insulin therapy start (IL13). Among them, EN-RAGE is a novel inflammatory marker for pre-diabetes, IL 17 for incident T2D and IL 13 for pre-diabetes, incident T2D and insulin therapy start.

Stunting can afflict up to one-third of children in resource-constrained countries. We hypothesized that low-grade systemic inflammation (defined as elevations in serum C-reactive protein or alpha-1-acid glycoprotein) in infancy suppresses the growth hormone–insulin-like growth factor (IGF) axis and is associated with subsequent stunting. Blood samples of 590 children from periurban Dar es Salaam, Tanzania, were obtained at 6 weeks and 6 months of age as part of a randomized controlled trial. Primary outcomes were stunting, underweight, and wasting (defined as length-for-age, weight-for-age and weight-for-length z-scores < −2) between randomization and endline (18 months after randomization). Cox proportional hazards models were constructed to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of time to first stunting, underweight, and wasting as outcomes, with measures of systemic inflammation, insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) as exposures, adjusting for numerous demographic and clinical variables. The incidences of subsequent stunting, underweight, and wasting were 26%, 20%, and 18%, respectively. In multivariate analyses, systemic inflammation at 6 weeks of age was significantly associated with stunting (HR: 2.14, 95% CI: 1.23, 3.72; p = 0.002). Children with higher levels of IGF-1 at 6 weeks were less likely to become stunted (HR: 0.58, 95% CI: 0.37, 0.93; p for trend = 0.019); a similar trend was noted in children with higher levels of IGF-1 at 6 months of age (HR: 0.50, 95% CI: 0.22, 1.12; p for trend = 0.07). Systemic inflammation occurs as early as 6 weeks of age and is associated with the risk of future stunting among Tanzanian children.

Despite suggestive observational epidemiology and laboratory studies, there is limited experimental evidence regarding the effect of organic diet on human health. A cluster-randomized 40-day-organic (vs. 40-day-conventional) crossover trial was conducted among children (11-12 years old) from six schools in Cyprus. One restaurant provided all organic meals, and adherence to the organic diet intervention was measured by parent-provided diet questionnaire/diary data. Biomarkers of pyrethroid and neonicotinoid pesticide exposures were measured using tandem mass spectrometry, and oxidative stress/inflammation (OSI) biomarkers using immunoassays or spectrophotometry. Associations were assessed using mixed-effect regression models including interactions of treatment with time. Seventy-two percent of neonicotinoid biomarkers were non-detectable and modeled as binary (whether detectable). In post-hoc analysis, we considered the outcome of age-and-sex-standardized BMI. Multiple comparisons were handled using Benjamini-Hochberg correction for 58 regression parameters. Outcome data were available for 149 children. Children had lower pesticide exposures during the organic period (pyrethroid geometric mean ratio, GMR = 0.297; [95% confidence interval (95% CI): 0.237, 0.373], Q-value<0.05); odds for detection of neonicotinoids (OR = 0.651; [95% CI: 0.463, 0.917), Q-value<0.05); and decreased OSI biomarker 8-OHdG (GMR = 0.888; [95% CI: 0.808, 0.976], Q-value<0.05). An initial increase was followed by a countervailing decrease over time in the organic period for OSI biomarkers 8-iso-PGF2a and MDA. BMI z-scores were lower at the end of the organic period (β = -0.131; [95% CI: 0.179, -0.920], Q-value<0.05). Energy intake during the conventional period was reported to be higher than the recommended reference levels. The organic diet intervention reduced children's exposure to pyrethroid and neonicotinoid pesticides and, over time lowered biomarkers of oxidative stress/inflammation (8-iso-PGF2a, 8-OHdG and MDA). The several-week organic diet intervention also reduced children's age-and-sex-standardized BMI z-scores, but causal inferences regarding organic diet's physiological benefits are limited by the confounding of the organic diet intervention with caloric intake reduction and possible lifestyle changes during the trial. Trial registration: This trial is registered with ClinicalTrials.gov, number: NCT02998203.

Iron supplementation may have adverse health effects in infants, probably through manipulation of the gut microbiome. Previous research in low-resource settings have focused primarily on anemic infants. This was a double blind, randomized, controlled trial of home fortification comparing multiple micronutrient powder (MNP) with and without iron. Six-month-old, non- or mildly anemic, predominantly-breastfed Kenyan infants in a rural malaria-endemic area were randomized to consume: (1) MNP containing 12.5 mg iron (MNP+Fe, n = 13); (2) MNP containing no iron (MNP−Fe, n = 13); or (3) Placebo (CONTROL, n = 7), from 6–9 months of age. Fecal microbiota were profiled by high-throughput bacterial 16S rRNA gene sequencing. Markers of inflammation in serum and stool samples were also measured. At baseline, the most abundant phylum was Proteobacteria (37.6% of rRNA sequences). The proteobacterial genus Escherichia was the most abundant genus across all phyla (30.1% of sequences). At the end of the intervention, the relative abundance of Escherichia significantly decreased in MNP−Fe (−16.05 ± 6.9%, p = 0.05) and CONTROL (−19.75 ± 4.5%, p = 0.01), but not in the MNP+Fe group (−6.23 ± 9%, p = 0.41). The second most abundant genus at baseline was Bifidobacterium (17.3%), the relative abundance of which significantly decreased in MNP+Fe (−6.38 ± 2.5%, p = 0.02) and CONTROL (−8.05 ± 1.46%, p = 0.01), but not in MNP-Fe (−4.27 ± 5%, p = 0.4445). Clostridium increased in MNP-Fe only (1.9 ± 0.5%, p = 0.02). No significant differences were observed in inflammation markers, except for IL-8, which decreased in CONTROL. MNP fortification over three months in non- or mildly anemic Kenyan infants can potentially alter the gut microbiome. Consistent with previous research, addition of iron to the MNP may adversely affect the colonization of potential beneficial microbes and attenuate the decrease of potential pathogens.

Background Icosapent ethyl (IPE) is a high-purity prescription form of eicosapentaenoic acid ethyl ester approved by the US Food and Drug Administration as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia. In addition to TG-lowering effects, IPE also reduces non-high-density lipoprotein cholesterol and apolipoprotein B levels without significantly increasing low-density lipoprotein cholesterol (LDL-C) in patients with very high TG levels ≥500 mg/dL (MARINE study) and in patients with well-controlled LDL-C and residually high TG levels 200–500 mg/dL (ANCHOR study). This analysis examined the effect of IPE on inflammatory markers in patients from MARINE and ANCHOR. Methods MARINE ( N  = 229) and ANCHOR ( N  = 702) were Phase III, double-blind studies that randomized hypertriglyceridemic patients to IPE 4 g/day, 2 g/day, or placebo. This analysis assessed the median placebo-adjusted percentage change from baseline in markers representing various stages of atherosclerotic inflammation such as intercellular adhesion molecule-1 (ICAM-1), oxidized low-density lipoprotein (Ox-LDL), lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP). Results Compared to placebo, IPE 4 g/day significantly decreased Ox-LDL (13 %, p  < 0.0001, ANCHOR), Lp-PLA 2 (14 %, p  < 0.001, MARINE; 19 %, p  < 0.0001, ANCHOR), and hsCRP levels (36 %, p  < 0.01, MARINE; 22 %, p  < 0.001, ANCHOR), but did not significantly change ICAM-1 and IL-6 levels. In the MARINE study, IPE 2 g/day did not significantly change ICAM-1, Ox-LDL, Lp-PLA 2 , IL-6, or hsCRP levels. Also, compared to placebo in the ANCHOR study, IPE 2 g/day significantly decreased Lp-PLA 2 levels (8 %, p  < 0.0001), but did not significantly change levels of other assessed inflammatory markers. Conclusion Compared to placebo, in hypertriglyceridemic patients, IPE 4 g/day significantly decreased Ox-LDL, Lp-PLA 2 , and hsCRP levels.

The diagnosis and treatment of iron deficiency is a primary public health goal. This study aimed to make an inventory of the use of biomarkers to assess the iron supply in patients given iron replacement therapy. A retrospective longitudinal real-world study of a cohort of patients receiving iron replacement therapy was conducted using data from healthcare coverage databases between January 2006 and December 2015 in France. The frequency of oral or intravenous iron treatment episodes preceded and/or followed by a biological assessment of iron deficiency was described. We then differentiate patients with or without chronic inflammatory diseases, which could impact the prescription. The evolution between 2006 and 2015 was also studied. The 96,724 patients received an average of 4.9 administrations of iron per patient, corresponding to 1.7 treatment episodes. In one-third of treatment episodes (34.6%), patients had a pre-treatment biological assessment, 15.5% a post-treatment assessment, and 7.3% both. The post-treatment measure of iron supply markers (i.e., Ferritin and transferrin saturation) was more frequent in patients suffering from chronic inflammatory diseases than in those without underlying chronic condition (22.6% to 41.0% vs. 3.1%; p < 0.0001). Serum ferritin was measured 30 times more than transferrin saturation measurements. The use of both tests increased steadily during the study period, although remaining low. Despite the recommendations, biological assessments of iron status are seldom prescribed and/or performed in the context of a pre- or post-treatment assessment, although more frequently realized in patients with chronic inflammatory diseases.