Abstract Background Consumption of low-calorie sweeteners (LCSs) has increased markedly during the past several decades, yet the prevalence of LCS consumption in recent years is currently unknown. ...Objective The aim of this study was to describe LCS consumption in the United States and to characterize consumption by sociodemographic subgroups, source, frequency, eating occasion, and location. Design Cross-sectional study using National Health and Nutrition Examination Survey data from 2009 to 2012. The prevalence of LCS consumption was assessed using two 24-hour dietary recalls, while the frequency (number of times per day), occasion (meal vs snack vs alone), and location of LCS consumption (at home vs away from home) was assessed using data from the one, in-person, 24-hour dietary recall. Participants National Health and Nutrition Examination Survey participants (2 years old or older) either in 2009-2010 (n=9,047) or in 2011-2012 (n=7,939). After excluding participants with implausible energy intake (n=44), the final sample size was 16,942. Main outcome measures The primary outcome was the proportion of individuals consuming one or more foods, beverages, or packets containing LCSs during at least one of their two dietary recalls. Statistical analyses performed Data were weighted to provide national estimates and Stata frequency procedures for complex survey design were used for all analyses. Results Our findings were that 25.1% of children and 41.4% adults reported consuming LCSs. Most LCS consumers reported use once daily (80% of children, 56% of adults) and frequency of consumption increased with body weight in adults. LCS consumption was higher in females compared with males among adults, and in obese individuals, compared with overweight and normal-weight individuals. Individuals of non-Hispanic white race/ethnicity also had higher prevalence of consumption compared with non-Hispanic blacks and Hispanics and those in the highest tertile of income had higher LCS consumption compared with individuals of middle or low income across LCS product categories in adults, and for LCS beverages and LCS foods in children. Most LCS consumers reported consuming LCS with meals (64% of adults, 62% of children) and the majority of LCS consumption occurred at home (71% and 72% among adults and children, respectively). Conclusions LCS consumption is highly prevalent in the United States, among both children and adults. Well-controlled, prospective trials are required to understand the health impact of this widespread LCS exposure.
To illustrate the difficulties in optimal growth monitoring of children with severe obesity or underweight by using the Centers for Disease Control and Prevention (CDC) 2000 age- and sex-specific BMI ...percentile growth charts. We also aimed to examine the utility of a new modified CDC BMI
score chart to monitor growth in children with normal and extreme BMI percentiles by using real-life clinical scenarios.
Modified BMI
score charts were created by using the 2000 CDC algorithm. Three cases of children with extreme BMI values and abnormal growth patterns were plotted by using the standard CDC 2000 clinical growth chart, the modified BMI
score chart, and the CDC BMI percentile chart, modified to include the percentage of the 95th percentile (%BMI
) curves.
Children with severe obesity could not be plotted on the standard CDC BMI percentile chart because their BMI points lay above the chart cutoff. Children with a low BMI (<3%) were also difficult to track on the standard BMI percentile chart. The addition of the %BMI
scale to the standard BMI percentile chart allowed tracking of severely obese children; however, it did not address severely underweight children and required a change of units within the chart when transitioning from normal to obese BMIs. The modified BMI
score chart allowed uniform tracking.
The modified CDC
score chart is suitable for growth tracking of children with normal and extreme growth patterns; the measures correlate well with the %BMI
and the chart can be incorporated easily into existing electronic health record systems for clinical use.
The risk of early-onset type 2 diabetes associated with the severity of obesity in youth is not well understood. This study aims to determine metabolic alterations and type 2 diabetes risk among ...American Indian children who are obese or severely obese.
Incidence rates of diabetes before 20 years (youth-onset) and 45 years were computed in 2728 children who were from 5 to <10 years and 4317 adolescents who were from 10 to <18 years without diabetes examined between 1965 and 2007. Obesity was defined as age-sex-adjusted body mass index (BMI) ≥95th percentile, and its severity was quantified as the percentage of the 95th percentile (%BMI
).
In the younger cohort, 0.9% of those non-obese and 2.9% of those with 100% to <120%BMI
had impaired glucose tolerance (IGT) compared to 8.6% of those with ≥140%BMI
. In the older cohort, 2.9% of those non-obese and 9.8% of those with 100% to <120%BMI
had IGT compared to 13.3% of those with ≥160%BMI
. The incidence of youth-onset diabetes was 3.8 and 4.9/1000 person-years in the child and adolescent cohorts, respectively, and before the age of 45 was 12.3 and 16.8/1000 person-years, respectively. Incidence rates of youth-onset diabetes in those with the most severe obesity (≥140%BMI
) were 2.3 to 5.1 times as high as in those with the least severe obesity (100 to <120%BMI
), and for onset of diabetes before the age of 45 were 1.6 to 2.2 times as high.
Severe obesity in an American Indian population is a major driver of type 2 diabetes developing in adolescents and young adults.
In recent years the Illumina HumanMethylation450 (HM450) BeadChip has provided a user-friendly platform to profile DNA methylation in human samples. However, HM450 lacked coverage of distal ...regulatory elements. Illumina have now released the MethylationEPIC (EPIC) BeadChip, with new content specifically designed to target these regions. We have used HM450 and whole-genome bisulphite sequencing (WGBS) to perform a critical evaluation of the new EPIC array platform.
EPIC covers over 850,000 CpG sites, including >90 % of the CpGs from the HM450 and an additional 413,743 CpGs. Even though the additional probes improve the coverage of regulatory elements, including 58 % of FANTOM5 enhancers, only 7 % distal and 27 % proximal ENCODE regulatory elements are represented. Detailed comparisons of regulatory elements from EPIC and WGBS show that a single EPIC probe is not always informative for those distal regulatory elements showing variable methylation across the region. However, overall data from the EPIC array at single loci are highly reproducible across technical and biological replicates and demonstrate high correlation with HM450 and WGBS data. We show that the HM450 and EPIC arrays distinguish differentially methylated probes, but the absolute agreement depends on the threshold set for each platform. Finally, we provide an annotated list of probes whose signal could be affected by cross-hybridisation or underlying genetic variation.
The EPIC array is a significant improvement over the HM450 array, with increased genome coverage of regulatory regions and high reproducibility and reliability, providing a valuable tool for high-throughput human methylome analyses from diverse clinical samples.
Skeletal muscle fat infiltration (known as myosteatosis) is an ectopic fat depot that increases with aging and is recognized to negatively correlate with muscle mass, strength, and mobility and ...disrupt metabolism (insulin resistance, diabetes). An interdisciplinary workshop convened by the National Institute on Aging Division of Geriatrics and Clinical Gerontology on September 2018, discussed myosteatosis in the context of skeletal muscle function deficit (SMFD). Its purpose was to gain a better understanding of the roles of myosteatosis in aging muscles and metabolic disease, particularly its potential determinants and clinical consequences, and ways of properly assessing it. Special attention was given to functional status and standardization of measures of body composition (including the value of D
-creatine dilution method) and imaging approaches including ways to better use dual-energy X-ray absorptiometry (DXA) through the shape and appearance modeling to assess lean mass, sarcopenia, and myosteatosis. The workshop convened innovative new areas of scientific relevance to light such as the effect of circadian rhythms and clock disruption in skeletal muscle structure, function, metabolism, and potential contribution to increased myosteatosis. A muscle-bone interaction perspective compared mechanisms associated with myosteatosis and bone marrow adiposity. Potential preventive and therapeutic approaches highlighted ongoing work on physical activity, myostatin treatment, and calorie restriction. Myosteatosis' impact on cancer survivors raised new possibilities to identify its role and to engage in cross-disciplinary collaboration. A wide range of research opportunities and challenges in planning for the most appropriate study design, interpretation, and translation of findings into clinical practice were discussed and are presented here.
DNA replication timing is known to facilitate the establishment of the epigenome, however, the intimate connection between replication timing and changes to the genome and epigenome in cancer remain ...largely uncharacterised. Here, we perform Repli-Seq and integrated epigenome analyses and demonstrate that genomic regions that undergo long-range epigenetic deregulation in prostate cancer also show concordant differences in replication timing. A subset of altered replication timing domains are conserved across cancers from different tissue origins. Notably, late-replicating regions in cancer cells display a loss of DNA methylation, and a switch in heterochromatin features from H3K9me3-marked constitutive to H3K27me3-marked facultative heterochromatin. Finally, analysis of 214 prostate and 35 breast cancer genomes reveal that late-replicating regions are prone to cis and early-replication to trans chromosomal rearrangements. Together, our data suggests that the nature of chromosomal rearrangement in cancer is related to the spatial and temporal positioning and altered epigenetic states of early-replicating compared to late-replicating loci.
Sleep is critical for proper memory consolidation. The locus coeruleus (LC) releases norepinephrine throughout the brain except when the LC falls silent throughout rapid eye movement (REM) sleep and ...prior to each non-REM (NREM) sleep spindle. We hypothesize that these transient LC silences allow the synaptic plasticity that is necessary to incorporate new information into pre-existing memory circuits. We found that spontaneous LC activity within sleep spindles triggers a decrease in spindle power. By optogenetically stimulating norepinephrine-containing LC neurons at 2 Hz during sleep, we reduced sleep spindle occurrence, as well as NREM delta power and REM theta power, without causing arousals or changing sleep amounts. Stimulating the LC during sleep following a hippocampus-dependent food location learning task interfered with consolidation of newly learned locations and reconsolidation of previous locations, disrupting next-day place cell activity. The LC stimulation-induced reduction in NREM sleep spindles, delta, and REM theta and reduced ripple-spindle coupling all correlated with decreased hippocampus-dependent performance on the task. Thus, periods of LC silence during sleep following learning are essential for normal spindle generation, delta and theta power, and consolidation of spatial memories.
•Locus coeruleus (LC) spikes coincide with the waning phase of sleep spindles•LC activity during sleep interferes with NREM delta, sleep spindles, and REM theta•Sleep with abnormal LC activity hampers next day CA1 spatial mapping•Normal LC silences during sleep are necessary for proper memory consolidation
Swift et al. show that overactivity of the locus coeruleus, the main source of norepinephrine to the forebrain, during sleep interferes with signatures of NREM sleep and REM sleep associated with sleep-dependent memory consolidation. Maladaptive LC activity can impair next day hippocampal spatial encoding, producing long-term behavioral deficits.
Elevated branched chain amino acids (BCAAs) are associated with obesity and insulin resistance. How long-term dietary BCAAs impact late-life health and lifespan is unknown. Here, we show that when ...dietary BCAAs are varied against a fixed, isocaloric macronutrient background, long-term exposure to high BCAA diets leads to hyperphagia, obesity and reduced lifespan. These effects are not due to elevated BCAA
or hepatic mTOR activation, but rather due to a shift in the relative quantity of dietary BCAAs and other AAs, notably tryptophan and threonine. Increasing the ratio of BCAAs to these AAs resulted in hyperphagia and is associated with central serotonin depletion. Preventing hyperphagia by calorie restriction or pair-feeding averts the health costs of a high BCAA diet. Our data highlight a role for amino acid quality in energy balance and show that health costs of chronic high BCAA intakes need not be due to intrinsic toxicity but, rather, a consequence of hyperphagia driven by AA imbalance.
Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers.
In this multicenter, prospective, ...open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication.
The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval CI, 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up.
On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).
The growth and progression of solid tumors involves dynamic cross-talk between cancer epithelium and the surrounding microenvironment. To date, molecular profiling has largely been restricted to the ...epithelial component of tumors; therefore, features underpinning the persistent protumorigenic phenotype of the tumor microenvironment are unknown. Using whole-genome bisulfite sequencing, we show for the first time that cancer-associated fibroblasts (CAFs) from localized prostate cancer display remarkably distinct and enduring genome-wide changes in DNA methylation, significantly at enhancers and promoters, compared to nonmalignant prostate fibroblasts (NPFs). Differentially methylated regions associated with changes in gene expression have cancer-related functions and accurately distinguish CAFs from NPFs. Remarkably, a subset of changes is shared with prostate cancer epithelial cells, revealing the new concept of tumor-specific epigenome modifications in the tumor and its microenvironment. The distinct methylome of CAFs provides a novel epigenetic hallmark of the cancer microenvironment and promises new biomarkers to improve interpretation of diagnostic samples.
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