Evaluation of the Predictive Ability, Environmental Regulation and Pharmacogenetics Utility of a BMI-Predisposing Genetic Risk Score during Childhood and Puberty

The authors would like to thank the Spanish children and parents who participated in the study.Polygenetic risk scores (pGRSs) consisting of adult body mass index (BMI) genetic variants have been widely associated with obesity in children populations. The implication of such obesity pGRSs in the development of cardio-metabolic alterations during childhood as well as their utility for the clinical prediction of pubertal obesity outcomes has been barely investigated otherwise. In the present study, we evaluated the utility of an adult BMI predisposing pGRS for the prediction and pharmacological management of obesity in Spanish children, further investigating its implication in the appearance of cardio-metabolic alterations. For that purpose, we counted on genetics data from three well-characterized children populations (composed of 574, 96 and 124 individuals), following both cross-sectional and longitudinal designs, expanding childhood and puberty. As a result, we demonstrated that the pGRS is strongly associated with childhood BMI Z-Score (B = 1.56, SE = 0.27 and p-value = 1.90 × 10−8 ), and that could be used as a good predictor of obesity longitudinal trajectories during puberty. On the other hand, we showed that the pGRS is not associated with cardio-metabolic comorbidities in children and that certain environmental factors interact with the genetic predisposition to the disease. Finally, according to the results derived from a weight-reduction metformin intervention in children with obesity, we discarded the utility of the pGRS as a pharmacogenetics marker of metformin response.Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica (I + D + I), Instituto de Salud Carlos III-Health Research Funding (FONDOS FEDER) PI1102042 PI1102059 PI1601301 PI1600871Spanish Ministry of Health, Social and Equality, General Department for Pharmacy and Health Products EC10-243 EC10-056 EC10-281 EC10-227Regional Government of Andalusia ("Plan Andaluz de investigacion, desarrollo e innovacion (2018)") P18-RT-2248Mapfre Foundation ("Research grants by Ignacio H. de Larramendi 2017")Instituto de Salud Carlos III IFI17/0004

Persistence of anticancer activity in berry extracts after simulated gastrointestinal digestion and colonic fermentation

Fruit and vegetable consumption is associated at the population level with a protective effect against colorectal cancer. Phenolic compounds, especially abundant in berries, are of interest due to their putative anticancer activity. After consumption, however, phenolic compounds are subject to digestive conditions within the gastrointestinal tract that alter their structures and potentially their function. However, the majority of phenolic compounds are not efficiently absorbed in the small intestine and a substantial portion pass into the colon. We characterized berry extracts (raspberries, strawberries, blackcurrants) produced by in vitro-simulated upper intestinal tract digestion and subsequent fecal fermentation. These extracts and selected individual colonic metabolites were then evaluated for their putative anticancer activities using in vitro models of colorectal cancer, representing the key stages of initiation, promotion and invasion. Over a physiologically-relevant dose range (0–50 µg/ml gallic acid equivalents), the digested and fermented extracts demonstrated significant anti-genotoxic, anti-mutagenic and anti-invasive activity on colonocytes. This work indicates that phenolic compounds from berries undergo considerable structural modifications during their passage through the gastrointestinal tract but their breakdown products and metabolites retain biological activity and can modulate cellular processes associated with colon cancer

Metabolically defined body size and body shape phenotypes and risk of postmenopausal breast cancer in the European Prospective Investigation into Cancer and Nutrition

BACKGROUND: Excess body fatness and hyperinsulinemia are both associated with an increased risk of postmenopausal breast cancer. However, whether women with high body fatness but normal insulin levels or those with normal body fatness and high levels of insulin are at elevated risk of breast cancer is not known. We investigated the associations of metabolically defined body size and shape phenotypes with the risk of postmenopausal breast cancer in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. METHODS: Concentrations of C-peptide-a marker for insulin secretion-were measured at inclusion prior to cancer diagnosis in serum from 610 incident postmenopausal breast cancer cases and 1130 matched controls. C-peptide concentrations among the control participants were used to define metabolically healthy (MH; in first tertile) and metabolically unhealthy (MU; >1st tertile) status. We created four metabolic health/body size phenotype categories by combining the metabolic health definitions with normal weight (NW; BMI < 25 kg/m2 , or WC < 80 cm, or WHR < 0.8) and overweight or obese (OW/OB; BMI ≥ 25 kg/m2 , or WC ≥ 80 cm, or WHR ≥ 0.8) status for each of the three anthropometric measures separately: (1) MHNW, (2) MHOW/OB, (3) MUNW, and (4) MUOW/OB. Conditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Women classified as MUOW/OB were at higher risk of postmenopausal breast cancer compared to MHNW women considering BMI (OR = 1.58, 95% CI = 1.14-2.19) and WC (OR = 1.51, 95% CI = 1.09-2.08) cut points and there was also a suggestive increased risk for the WHR (OR = 1.29, 95% CI = 0.94-1.77) definition. Conversely, women with the MHOW/OB and MUNW were not at statistically significant elevated risk of postmenopausal breast cancer risk compared to MHNW women. CONCLUSION: These findings suggest that being overweight or obese and metabolically unhealthy raises risk of postmenopausal breast cancer while overweight or obese women with normal insulin levels are not at higher risk. Additional research should consider the combined utility of anthropometric measures with metabolic parameters in predicting breast cancer risk

Association of Mediterranean diet with survival after breast cancer diagnosis in women from nine European countries: results from the EPIC cohort study

BACKGROUND: The Mediterranean diet has been associated with lower risk of breast cancer (BC) but evidence from prospective studies on the role of Mediterranean diet on BC survival remains sparse and conflicting. We aimed to investigate whether adherence to Mediterranean diet prior to diagnosis is associated with overall and BC-specific mortality. METHODS: A total of 13,270 incident breast cancer cases were identified from an initial sample of 318,686 women in 9 countries from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Adherence to Mediterranean diet was estimated through the adapted relative Mediterranean diet (arMED), a 16-point score that includes 8 key components of the Mediterranean diet and excludes alcohol. The degree of adherence to arMED was classified as low (score 0-5), medium (score 6-8), and high (score 9-16). Multivariable Cox proportional hazards models were used to analyze the association between the arMED score and overall mortality, and Fine-Gray competing risks models were applied for BC-specific mortality. RESULTS: After a mean follow-up of 8.6 years from diagnosis, 2340 women died, including 1475 from breast cancer. Among all BC survivors, low compared to medium adherence to arMED score was associated with a 13% higher risk of all-cause mortality (HR 1.13, 95%CI 1.01-1.26). High compared to medium adherence to arMED showed a non-statistically significant association (HR 0.94; 95% CI 0.84-1.05). With no statistically significant departures from linearity, on a continuous scale, a 3-unit increase in the arMED score was associated with an 8% reduced risk of overall mortality (HR3-unit 0.92, 95% CI: 0.87-0.97). This result sustained when restricted to postmenopausal women and was stronger among metastatic BC cases (HR3-unit 0.81, 95% CI: 0.72-0.91). CONCLUSIONS: Consuming a Mediterranean diet before BC diagnosis may improve long-term prognosis, particularly after menopause and in cases of metastatic breast cancer. Well-designed dietary interventions are needed to confirm these findings and define specific dietary recommendations

The completed SDSS-IV extended Baryon Oscillation Spectroscopic Survey: Measurement of the BAO and growth rate of structure of the emission line galaxy sample from the anisotropic power spectrum between redshift 0.6 and 1.1

We analyse the large-scale clustering in Fourier space of emission line galaxies (ELG) from the Data Release 16 of the Sloan Digital Sky Survey IV extended Baryon Oscillation Spectroscopic Survey. The ELG sample contains 173 736 galaxies covering 1170 deg^{2} in the redshift range 0.6 < z < 1.1. We perform a BAO measurement from the post-reconstruction power spectrum monopole, and study redshift space distortions (RSD) in the first three even multipoles. Photometric variations yield fluctuations of both the angular and radial survey selection functions. Those are directly inferred from data, imposing integral constraints which we model consistently. The full data set has only a weak preference for a BAO feature (1.4σ). At the effective redshift z_{eff} = 0.845 we measure D_{V}(z_{eff})/r_{drag}=18.33\tfrac{+0.57}{−0.62⁠},with DV the volume-averaged distance and r_{drag} the comoving sound horizon at the drag epoch. In combination with the RSD measurement, at z_{eff} = 0.85 we find fσ_{8}(z_{eff})=0.289\tfrac{+0.085}{−0.096⁠}, with f the growth rate of structure and σ_{8} the normalization of the linear power spectrum, D_{H}(z_{eff})/r_{drag} = 20.0\tfrac{2.4}{-2.2} and D_{M}(z_[eff})/r_{drag} = 19.17 ± 0.99 with D_{H} and D_{M} the Hubble and comoving angular distances, respectively. These results are in agreement with those obtained in configuration space, thus allowing a consensus measurement of fσ_{8}(z_{eff}) = 0.315 ± 0.095, D_{H}(z_{eff})/r_{drag} = 19.6\tfrac{+2.2}{−2.1} and D_{M}(z_{eff})/r_{drag} = 19.5 ± 1.0. This measurement is consistent with a flat ΛCDM model with Planck parameters

The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data

Background: Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malaria-endemic settings. Methods: We searched PubMed for clinical trials that enrolled and treated patients with artemether-lumefantrine and were published from 1960 to December, 2012. We merged individual patient data from these trials by use of standardised methods. The primary endpoint was the PCR-adjusted risk of Plasmodium falciparum recrudescence by day 28. Secondary endpoints consisted of the PCR-adjusted risk of P falciparum recurrence by day 42, PCR-unadjusted risk of P falciparum recurrence by day 42, early parasite clearance, and gametocyte carriage. Risk factors for PCR-adjusted recrudescence were identified using Cox's regression model with frailty shared across the study sites. Findings: We included 61 studies done between January, 1998, and December, 2012, and included 14 327 patients in our analyses. The PCR-adjusted therapeutic efficacy was 97·6% (95% CI 97·4-97·9) at day 28 and 96·0% (95·6-96·5) at day 42. After controlling for age and parasitaemia, patients prescribed a higher dose of artemether had a lower risk of having parasitaemia on day 1 (adjusted odds ratio [OR] 0·92, 95% CI 0·86-0·99 for every 1 mg/kg increase in daily artemether dose; p=0·024), but not on day 2 (p=0·69) or day 3 (0·087). In Asia, children weighing 10-15 kg who received a total lumefantrine dose less than 60 mg/kg had the lowest PCR-adjusted efficacy (91·7%, 95% CI 86·5-96·9). In Africa, the risk of treatment failure was greatest in malnourished children aged 1-3 years (PCR-adjusted efficacy 94·3%, 95% CI 92·3-96·3). A higher artemether dose was associated with a lower gametocyte presence within 14 days of treatment (adjusted OR 0·92, 95% CI 0·85-0·99; p=0·037 for every 1 mg/kg increase in total artemether dose). Interpretation: The recommended dose of artemether-lumefantrine provides reliable efficacy in most patients with uncomplicated malaria. However, therapeutic efficacy was lowest in young children from Asia and young underweight children from Africa; a higher dose regimen should be assessed in these groups. Funding: Bill and Melinda Gates Foundation

Completed SDSS-IV extended Baryon Oscillation Spectroscopic Survey: Cosmological implications from two decades of spectroscopic surveys at the Apache Point Observatory

We present the cosmological implications from final measurements of clustering using galaxies, quasars, and Ly α forests from the completed Sloan Digital Sky Survey (SDSS) lineage of experiments in large-scale structure. These experiments, composed of data from SDSS, SDSS-II, BOSS, and eBOSS, offer independent measurements of baryon acoustic oscillation (BAO) measurements of angular-diameter distances and Hubble distances relative to the sound horizon, r_{d}, from eight different samples and six measurements of the growth rate parameter, fσ_{8}, from redshift-space distortions (RSD). This composite sample is the most constraining of its kind and allows us to perform a comprehensive assessment of the cosmological model after two decades of dedicated spectroscopic observation. We show that the BAO data alone are able to rule out dark-energy-free models at more than eight standard deviations in an extension to the flat, Λ CDM model that allows for curvature. When combined with Planck Cosmic Microwave Background (CMB) measurements of temperature and polarization, under the same model, the BAO data provide nearly an order of magnitude improvement on curvature constraints relative to primary CMB constraints alone. Independent of distance measurements, the SDSS RSD data complement weak lensing measurements from the Dark Energy Survey (DES) in demonstrating a preference for a flat Λ CDM cosmological model when combined with Planck measurements. The combined BAO and RSD measurements indicate σ_{8} = 0.85 ± 0.03, implying a growth rate that is consistent with predictions from Planck temperature and polarization data and with General Relativity. When combining the results of SDSS BAO and RSD, Planck, Pantheon Type Ia supernovae (SNe Ia), and DES weak lensing and clustering measurements, all multiple-parameter extensions remain consistent with a Λ CDM model. Regardless of cosmological model, the precision on each of the three parameters, Ω_{Λ}, H_{0}, and σ_{8}, remains at roughly 1%, showing changes of less than 0.6% in the central values between models. In a model that allows for free curvature and a time-evolving equation of state for dark energy, the combined samples produce a constraint Ω_{k} = −0.0022 ± 0.0022. The dark energy constraints lead to w_{0} = −0.909 ± 0.081 and w_{a} = −0.49^{+0.35}_{-0.30}, corresponding to an equation of state of w_{p} = 1.018 ± 0.032 at a pivot redshift z_{p} = 0.29 and a Dark Energy Task Force Figure of Merit of 94. The inverse distance ladder measurement under this model yields H_{0} = 68.18 ± 0.79 km s^{-1} Mpc^{-1}, remaining in tension with several direct determination methods; the BAO data allow Hubble constant estimates that are robust against the assumption of the cosmological model. In addition, the BAO data allow estimates of H_{0} that are independent of the CMB data, with similar central values and precision under a Λ CDM model. Our most constraining combination of data gives the upper limit on the sum of neutrino masses at ∑m_{v} < 0.115 eV (95% confidence). Finally, we consider the improvements in cosmology constraints over the last decade by comparing our results to a sample representative of the period 2000–2010. We compute the relative gain across the five dimensions spanned by w, Ω_{k}, ∑m_{v}, H_{0}, H_{0}, and σ_{8} and find that the SDSS BAO and RSD data reduce the total posterior volume by a factor of 40 relative to the previous generation. Adding again the Planck, DES, and Pantheon SN Ia samples leads to an overall contraction in the five-dimensional posterior volume of 3 orders of magnitude

Expression of Linear and Novel Circular Forms of an INK4/ARF-Associated Non-Coding RNA Correlates with Atherosclerosis Risk

Human genome-wide association studies have linked single nucleotide polymorphisms (SNPs) on chromosome 9p21.3 near the INK4/ARF (CDKN2a/b) locus with susceptibility to atherosclerotic vascular disease (ASVD). Although this locus encodes three well-characterized tumor suppressors, p16INK4a, p15INK4b, and ARF, the SNPs most strongly associated with ASVD are ∼120 kb from the nearest coding gene within a long non-coding RNA (ncRNA) known as ANRIL (CDKN2BAS). While individuals homozygous for the atherosclerotic risk allele show decreased expression of ANRIL and the coding INK4/ARF transcripts, the mechanism by which such distant genetic variants influence INK4/ARF expression is unknown. Here, using rapid amplification of cDNA ends (RACE) and analysis of next-generation RNA sequencing datasets, we determined the structure and abundance of multiple ANRIL species. Each of these species was present at very low copy numbers in primary and cultured cells; however, only the expression of ANRIL isoforms containing exons proximal to the INK4/ARF locus correlated with the ASVD risk alleles. Surprisingly, RACE also identified transcripts containing non-colinear ANRIL exonic sequences, whose expression also correlated with genotype and INK4/ARF expression. These non-polyadenylated RNAs resisted RNAse R digestion and could be PCR amplified using outward-facing primers, suggesting they represent circular RNA structures that could arise from by-products of mRNA splicing. Next-generation DNA sequencing and splice prediction algorithms identified polymorphisms within the ASVD risk interval that may regulate ANRIL splicing and circular ANRIL (cANRIL) production. These results identify novel circular RNA products emanating from the ANRIL locus and suggest causal variants at 9p21.3 regulate INK4/ARF expression and ASVD risk by modulating ANRIL expression and/or structure

Ibero-American Consensus on Low- and No-Calorie Sweeteners: Safety, Nutritional Aspects and Benefits in Food and Beverages

International scientific experts in food, nutrition, dietetics, endocrinology, physical activity, paediatrics, nursing, toxicology and public health met in Lisbon on 2-4 July 2017 to develop a Consensus on the use of low- and no-calorie sweeteners (LNCS) as substitutes for sugars and other caloric sweeteners. LNCS are food additives that are broadly used as sugar substitutes to sweeten foods and beverages with the addition of fewer or no calories. They are also used in medicines, health-care products, such as toothpaste, and food supplements. The goal of this Consensus was to provide a useful, evidence-based, point of reference to assist in efforts to reduce free sugars consumption in line with current international public health recommendations. Participating experts in the Lisbon Consensus analysed and evaluated the evidence in relation to the role of LNCS in food safety, their regulation and the nutritional and dietary aspects of their use in foods and beverages. The conclusions of this Consensus were: (1) LNCS are some of the most extensively evaluated dietary constituents, and their safety has been reviewed and confirmed by regulatory bodies globally including the World Health Organisation, the US Food and Drug Administration and the European Food Safety Authority; (2) Consumer education, which is based on the most robust scientific evidence and regulatory processes, on the use of products containing LNCS should be strengthened in a comprehensive and objective way; (3) The use of LNCS in weight reduction programmes that involve replacing caloric sweeteners with LNCS in the context of structured diet plans may favour sustainable weight reduction. Furthermore, their use in diabetes management programmes may contribute to a better glycaemic control in patients, albeit with modest results. LNCS also provide dental health benefits when used in place of free sugars; (4) It is proposed that foods and beverages with LNCS could be included in dietary guidelines as alternative options to products sweetened with free sugars; (5) Continued education of health professionals is required, since they are a key source of information on issues related to food and health for both the general population and patients. With this in mind, the publication of position statements and consensus documents in the academic literature are extremely desirable