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A number of epidemiological and genetic studies have attempted to determine whether levels of circulating lipids are associated with risks of various cancers, including breast cancer (BC). However, it remains unclear whether a causal relationship exists between lipids and BC. If alteration of lipid levels also reduced risk of BC, this could present a target for disease prevention. This study aimed to assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein, HDL; low-density lipoprotein, LDL; triglycerides, TGs) with risk for BC using Mendelian randomization (MR). Data from genome-wide association studies in up to 215,551 participants from the Million Veteran Program (MVP) were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on BC risk was evaluated using genetic data from the BCAC (Breast Cancer Association Consortium) based on 122,977 BC cases and 105,974 controls. Using MR, we observed that a 1-standard-deviation genetically determined increase in HDL levels is associated with an increased risk for all BCs (HDL: OR [odds ratio] = 1.08, 95% confidence interval [CI] = 1.04-1.13, P < 0.001). Multivariable MR analysis, which adjusted for the effects of LDL, TGs, body mass index (BMI), and age at menarche, corroborated this observation for HDL (OR = 1.06, 95% CI = 1.03-1.10, P = 4.9 × 10-4) and also found a relationship between LDL and BC risk (OR = 1.03, 95% CI = 1.01-1.07, P = 0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor (ER) status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for BCs (OR = 1.11, 95% CI = 1.06-1.16, P = 1.5 × 10-6), including locus-specific associations at ABCA1 (ATP Binding Cassette Subfamily A Member 1), APOE-APOC1-APOC4-APOC2 (Apolipoproteins E, C1, C4, and C2), and CETP (Cholesteryl Ester Transfer Protein). In addition, we found evidence that genetic variation at the ABO locus is associated with both lipid levels and BC. Through multiple statistical approaches, we minimized and tested for the confounding effects of pleiotropy and population stratification on our analysis; however, the possible existence of residual pleiotropy and stratification remains a limitation of this study. We observed that genetically elevated plasma HDL and LDL levels appear to be associated with increased BC risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal of developing potential therapeutic strategies aimed at altering the cholesterol-mediated effect on BC risk.

Background Critically ill adults typically develop hypocholesterolemia, associated with poor outcome. Whether similar alterations occur in critically ill children is less clear. Methods In secondary analyses of the PEPaNIC RCT (n = 1440), we first documented the time course of plasma cholesterol and triglyceride concentrations, and the effect of randomization to early-parenteral-nutrition (early-PN) or late-PN hereon, for 96 matched critically ill children staying ≥ 5 days in PICU. Second, for 1165 children with available admission plasma samples, lipid profiles were determined and their independent associations with outcome (time to live PICU discharge, new infection and 90-day mortality) were assessed with Multivariable Cox proportional hazard and logistic regression, adjusting for baseline risk factors. Results Plasma HDL-cholesterol, LDL-cholesterol, total-cholesterol and triglycerides were low throughout the 5 PICU days, with only HDL-cholesterol further decreasing over time ( P  < 0.0001) and without effect of randomization to early-PN or late-PN, and with admission values lower in infants than older children and in patients with infection ( P  < 0.05). Lower admission HDL- and total-cholesterol concentrations were independently associated with a lower likelihood of an earlier live PICU discharge ( P  < 0.001) and with a higher risk of 90-day mortality ( P  ≤ 0.01), whereas higher plasma triglycerides were independently associated with higher risk of 90-day mortality ( P  = 0.004). Low admission plasma HDL-cholesterol was independently associated with a higher risk of acquiring a new infection ( P  = 0.05). Conclusion Critically ill children presented with low circulating levels of lipids. Low plasma cholesterol concentrations were associated with poor outcomes, most robustly for HDL-cholesterol. Whether these associations are causal or casual requires further investigation.

Background Hypocholesterolemia hallmarks critical illness though the underlying pathophysiology is incompletely understood. As low circulating cholesterol levels could partly be due to an increased conversion to cortisol/corticosterone, we hypothesized that glucocorticoid treatment, via reduced de novo adrenal cortisol/corticosterone synthesis, might improve cholesterol availability and as such affect adrenal gland and skeletal muscle function. Methods In a matched set of prolonged critically ill patients (n = 324) included in the EPaNIC RCT, a secondary analysis was performed to assess the association between glucocorticoid treatment and plasma cholesterol from ICU admission to day five. Next, in a mouse model of cecal ligation and puncture-induced sepsis, septic mice were randomized to receive either hydrocortisone (1.2 mg/day) (n = 17) or placebo (n = 15) for 5 days, as compared with healthy mice (n = 18). Plasma corticosterone, cholesterol, and adrenocortical and myofiber cholesterol were quantified. Adrenal structure and steroidogenic capacity were evaluated. Muscle force and markers of atrophy, fibrosis and regeneration were quantified. In a consecutive mouse study with identical design (n = 24), whole body composition was assessed by EchoMRI to investigate impact on lean mass, fat mass, total and free water. Results In human patients, glucocorticoid treatment was associated with higher plasma HDL- and LDL-cholesterol from respectively ICU day two and day three, up to day five ( P  < 0.05). Plasma corticosterone was no longer elevated in hydrocortisone-treated septic mice compared to placebo, whereas the sepsis-induced reduction in plasma HDL- and LDL-cholesterol and in adrenocortical cholesterol was attenuated ( P  < 0.05), but without improving the adrenocortical ACTH-induced CORT response and with increased adrenocortical inflammation and apoptosis ( P  < 0.05). Total body mass was further decreased in hydrocortisone-treated septic mice ( P  < 0.01) compared to placebo, with no additional effect on muscle mass, force or myofiber size. The sepsis-induced rise in markers of muscle atrophy and fibrosis was unaffected by hydrocortisone treatment, whereas markers of muscle regeneration were suppressed compared to placebo ( P  < 0.05). An increased loss of lean body mass and total and free water was observed in hydrocortisone-treated septic mice compared to placebo ( P  < 0.05). Conclusions Glucocorticoid treatment partially attenuated critical illness-induced hypocholesterolemia, but at a cost of impaired adrenal function, suppressed muscle regeneration and exacerbated loss of body mass. Graphical abstract

Human milk lipids provide the infant with energy and essential vitamins, polyunsaturated fatty acids, and bioactive components. Adding complex lipids and milk fat globule membranes to vegetable oil-based infant formula has the potential to enhance infant development and reduce infections. Cholesterol provision with breastfeeding modulates infant sterol metabolism and may induce long-term benefits. Some 98–99% of milk lipids are comprised by triacylglycerols, whose properties depend on incorporated fatty acids. Attention has been devoted to the roles of the longchain polyunsaturated fatty acids docosahexaenoic (DHA) and arachidonic (ARA) acids. Recent studies on gene-diet interaction (Mendelian randomization) show that breastfeeding providing DHA and ARA improves cognitive development and reduces asthma risk at school age particularly in those children with a genetically determined lower activity of DHA and ARA synthesis. It appears prudent to follow the biological model of human milk in the design of infant formula as far as feasible, unless conclusive evidence for the suitability and safety of other choices is available. The recent European Union legislative stipulation of a high formula DHA content without required ARA deviates from this concept, and such a novel formula composition has not been adequately evaluated. Great future opportunities arise with significant methodological progress for example in lipidomic analyses and their bioinformatic evaluation, which should enhance understanding of the biology of human milk lipids. Such knowledge might lead to improved dietary advice to lactating mothers as well as to further opportunities to enhance infant formula composition.

IntroductionBlood-based sample collection is a challenge, and dried blood spots (DBS) represent an attractive alternative. However, for DBSs to be an alternative to venous blood it is important that these samples are able to deliver comparable associations with clinical outcomes. To explore this we looked to see if lipid profile data could be used to predict the concentration of triglyceride, HDL, LDL and total cholesterol in DBSs using markers identified in plasma.ObjectivesTo determine if DBSs can be used as an alternative to venous blood in both research and clinical settings, and to determine if machine learning could predict ‘clinical lipid’ concentration from lipid profile data.MethodsLipid profiles were generated from plasma (n = 777) and DBS (n = 835) samples. Random forest was applied to identify and validate panels of lipid markers in plasma, which were translated into the DBS cohort to provide robust measures of the four ‘clinical lipids’.ResultsIn plasma samples panels of lipid markers were identified that could predict the concentration of the ‘clinical lipids’ with correlations between estimated and measured triglyceride, HDL, LDL and total cholesterol of 0.920, 0.743, 0.580 and 0.424 respectively. When translated into DBS samples, correlations of 0.836, 0.591, 0.561 and 0.569 were achieved for triglyceride, HDL, LDL and total cholesterol.ConclusionDBSs represent an alternative to venous blood, however further work is required to improve the combined lipidomics and machine learning approach to develop it for use in health monitoring.

Dyslipidemia is a leading risk factor for atherosclerotic cardiovascular disease. There are few published epidemiological data regarding dyslipidemia in Africa. We determined full lipid and apolipoprotein profiles and investigated factors associated with lipid levels in urban and rural populations of north-western Tanzania and southern Uganda. We conducted a cross-sectional survey of randomly-selected, community-dwelling adults (≥18yrs) including five strata per country: one municipality, two district towns and two rural areas. Participants were interviewed and examined using the World Health Organization STEPwise survey questionnaire. Serum levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and apolipoproteins were measured. Factors associated with mean lipid levels were assessed by multivariable linear regression. Framingham 10-year cardiovascular risk scores were calculated with and without lipids. One-third of adults in the study population had dyslipidemia. Low high-density lipoprotein cholesterol affected 32-45% of rural adults. High total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B were found in <15% of adult population in all strata, but were more common in urban adults. Factors independently associated with higher mean low-density lipoprotein cholesterol and apolipoprotein B were female gender, older age, higher education, higher income, obesity, and hypertension. Framingham cardiovascular risk scores with and without lipids yielded similar results and 90% of study subjects in all strata were classified as \"low risk\". Among older adults (>55 years), 30% were classified as \"high\" or \"very high\" risk. Dyslipidemias are common among adults in north-western Tanzania and southern Uganda affecting one third of adult population. Overall, cardiovascular risk scores are low but high risk scores are common with older adults. Health services designed and equipped to diagnose and treat dyslipidemia are urgently needed.

Vegetable lipid emulsions (LE) contain non-declared phytosterols (PS). We aimed to determine PS content depending on the brand and LE batch, and in adult hospitalised patients treated with parenteral nutrition (PN), to establish the association between plasma and administered PS. Part I was the LE study: totals and fractions of PS in three to four non-consecutive batches from six LE were analysed. Part II was the patient study: patients with at least 7 previous days of PN with 0·8 g/kg per d of an olive/soyabean (O/S) LE were randomised (day 0) 1:1 to O/S or 100 % fish oil (FO) at a dose of 0·4 g/kg per d for 7 d (day 7). Plasma PS, its fractions, total cholesterol on days 0 and 7, their clearance and their association with PS administered by LE were studied. In part I, LE study: differences were found in the total PS, their fractions and cholesterol among different LE brands and batches. Exclusive soyabean LE had the highest content of PS (422·36 ( sd 130·46) μg/ml). In part II, patient study: nineteen patients were included. In the O/S group, PS levels were maintained (1·11 ( sd 6·98) μg/ml) from day 0 to 7, while in the FO group, significant decreases were seen in total PS (−6·21 ( sd 4·73) μg/ml) and their fractions, except for campesterol and stigmasterol. Plasma PS on day 7 were significantly associated with PS administered ( R 2 0·443). PS content in different LE brands had great variability. PS administered during PN resulted in accumulation and could be prevented with the exclusive administration of FO LE.

Background One of the important problems for mothers after the birth of a premature infant is a decrease in milk production. This study aimed to investigate the effect of foot reflexology on the volume and composition of breast milk in mothers of premature infants hospitalized in the neonatal intensive care unit. Methods This randomized clinical trial was conducted on 76 primiparous mothers whose premature infants up to 34 weeks were hospitalized in the neonatal intensive care unit of Ayatollah Rouhani Hospital from February 2023 to November 2023. Mothers in the intervention group received foot reflexology for 20 min on both feet (ten minutes per foot) for seven consecutive days every morning. On the first and seventh days of the study, both groups were compared in terms of milk volume (ml), triglycerides, cholesterol, albumin, total protein, and calcium (mg/dl). Results The mean difference in breast milk characteristics before and after the intervention in the control and intervention groups were as follows: in terms of breast milk volume 12.43 and 23.51 ml, triglyceride 418.37 and 406.21, cholesterol 5.48 and 3.67, albumin 1.02 and 0.35, total protein 1.89 and 4.59, calcium was -3.54 and -1.83 mg/dL; the net difference in breast milk volume in the intervention group compared to the control group increased, which was not statistically significant but was significant in terms of value. No significant difference was observed in other components of breast milk. Conclusion In this single-center study, foot reflexology massage showed a trend towards increasing the volume of breast milk, total protein and calcium, although it was not statistically significant. Therefore, it needs further investigation. Trial registration IRCT, IRCT20221220056872N1. Registered 22 January 2023- prospective registered, https://irct.behdasht.gov.ir/trial/67512 .

To evaluate the effects of supervised exercise training (SET) on cardiometabolic risk, cardiorespiratory fitness and oxidative stress status in 2 diabetes mellitus (T2DM), twenty male subjects with T2DM were randomly assigned to an intervention group, which performed SET in a hospital-based setting and to a control group. SET consisted of a 12-month supervised aerobic, resistance and flexibility training. A reference group of ten healthy male subjects was also recruited for baseline evaluation only. Participants underwent medical examination, biochemical analyses and cardiopulmonary exercise testing. Oxidative stress markers (1-palmitoyl-2-[5-oxovaleroyl]-sn-glycero-3-phosphorylcholine [POVPC]; 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine [PGPC]) were measured in plasma and in peripheral blood mononuclear cells. All investigations were carried out at baseline and after 12 months. SET yielded a significant modification (p < 0.05) in the following parameters: V'O 2max (+14.4%), gas exchange threshold (+23.4%), waist circumference (−1.4%), total cholesterol (−14.6%), LDL cholesterol (−20.2%), fasting insulinemia (−48.5%), HOMA-IR (−52.5%), plasma POVPC (−27.9%) and PGPC (−31.6%). After 12 months, the control group presented a V'O 2max and a gas exchange threshold significantly lower than the intervention group. Plasma POVC and PGPC were significantly different from healthy subjects before the intervention, but not after. In conclusion, SET was effective in improving cardiorespiratory fitness, cardiometabolic risk and oxidative stress status in T2DM.

Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients. This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and ISRCTN54137607. 4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0·85 mmol/L (SE 0·02; with about two-thirds compliance) during a median follow-up of 4·9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11·3%] simvastatin plus ezetimibe vs 619 [13·4%] placebo; rate ratio [RR] 0·83, 95% CI 0·74–0·94; log-rank p=0·0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4·6%] vs 230 [5·0%]; RR 0·92, 95% CI 0·76–1·11; p=0·37) and there were significant reductions in non-haemorrhagic stroke (131 [2·8%] vs 174 [3·8%]; RR 0·75, 95% CI 0·60–0·94; p=0·01) and arterial revascularisation procedures (284 [6·1%] vs 352 [7·6%]; RR 0·79, 95% CI 0·68–0·93; p=0·0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10 000 patients per year of treatment with this combination (9 [0·2%] vs 5 [0·1%]). There was no evidence of excess risks of hepatitis (21 [0·5%] vs 18 [0·4%]), gallstones (106 [2·3%] vs 106 [2·3%]), or cancer (438 [9·4%] vs 439 [9·5%], p=0·89) and there was no significant excess of death from any non-vascular cause (668 [14·4%] vs 612 [13·2%], p=0·13). Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease. Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council.