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Objective: To report speech outcomes following Orticochea pharyngoplasty in 43 patients with cleft palate and noncleft velopharyngeal dysfunction. Design: A retrospective surgical audit of patients undergoing Orticochea pharyngoplasty between 2004 and 2012, with speech as a primary outcome measure. Setting: Patients known to a regional UK cleft center. Methods: Forty-three patients underwent Orticochea pharyngoplasty by a single surgeon in a UK regional cleft center. Twenty-one patients had undergone a prior procedure for velopharyngeal dysfunction. Pre- and postoperative speech samples were assessed blindly using the Cleft Audit Protocol for Speech-Augmented by a specialist cleft speech and language therapist, external to the team. Speech samples were rated on the following parameters: hypernasality, hyponasality, audible nasal emission, nasal, turbulence, and passive cleft speech characteristics. Statistical differences in pre- and postoperative speech scores were tested using the Wilcoxon matched-pairs signed-ranks test. Inter- and intrareliability scores were calculated using weighted Cohen κ. Results: Whole group: A statistically significant difference in pre- and postoperative scores for hypernasality ( P < .001), hyponasality ( P < .05), nasal emission ( P < .01), and passive cleft speech characteristics ( P < .01) were reported. Patients with cleft diagnoses: A statistically significant difference in scores for hypernasality ( P < .001), nasal emission ( P < .01), and passive cleft speech characteristics ( P < .01) were reported for this group of patients. Patients with noncleft diagnoses: The only parameter to demonstrate a statistically significant difference was hypernasality ( P < .01) in this group. Conclusions: Orticochea pharyngoplasty is a successful surgical procedure in treating velopharyngeal dysfunction in both the cleft and noncleft populations.

Purpose Prolonged nearwork has been implicated in myopia progression. Accommodation responses of young-adult myopes wearing different multifocal contact lenses were compared. Methods Twenty adults, 18-25 years, with myopia (spherical equivalent refraction -0.50 to -5.50 D, mean -2.1 ± 1.6 D) wore five lens types in random order: Proclear single vision distance (SV), MiSight concentric dual-focus +2.00 D Add (MS), Biofinity aspheric centre distance +1.50 D Add (CD1) and +2.50 D Add (CD2) (all Coopervision), and NaturalVue aspheric (Visioneering Technologies) (NVue). Using a Grand-Seiko WAN-5500 autorefractor with binocular correction and viewing right eye accommodative responses were measured after a 10 min adaptation period at 4.0, 1.0, 0.5, 0.33 and 0.25 m distances. Dynamic measurements were taken for 4 s at 6 Hz. Accommodative stimuli and responses were referenced to 4 m (i.e., refraction differences between 4 m and nearer distances). Accommodation lags and refraction instabilities (standard deviations of dynamic responses) were determined. For comparison, results were obtained for an absolute presbyopic eye, where trial lenses counteracted the accommodation stimulus. Results For SV and MS, accommodation responses were similar to the stimulus values. For aspheric lenses CD1, CD2 and NVue, accommodation responses were approximately 1.0 D lower across the stimulus range than with SV and MS, and rates of change were approximately 0.84 D per 1 D stimulus change. MS produced greater refraction instabilities than other lenses. For the presbyope, changes in refraction matched the trial lenses, indicating that corrections due to measurement through the different lenses were not needed. Conclusion Reductions in accommodation response occurred in young myopes wearing aspheric multifocal contact lenses independent of the labelled 'add' power. The concentric dual-focus MS lens produced minimal lags but had greater instability than the other lenses. The results indicate that the mechanism of multifocal contact lenses slowing myopia progression is unlikely to be through relaxing accommodation, at least in young adults.

OBJECTIVE: To characterise clusters of individuals based on adherence to dietary recommendations and to determine whether changes in Healthy Eating Index (HEI) scores in response to a personalised nutrition (PN) intervention varied between clusters. DESIGN: Food4Me study participants were clustered according to whether their baseline dietary intakes met European dietary recommendations. Changes in HEI scores between baseline and month 6 were compared between clusters and stratified by whether individuals received generalised or PN advice. SETTING: Pan-European, Internet-based, 6-month randomised controlled trial. SUBJECTS: Adults aged 18–79 years (n 1480). RESULTS: Individuals in cluster 1 (C1) met all recommended intakes except for red meat, those in cluster 2 (C2) met two recommendations, and those in cluster 3 (C3) and cluster 4 (C4) met one recommendation each. C1 had higher intakes of white fish, beans and lentils and low-fat dairy products and lower percentage energy intake from SFA (P

The risk for preeclampsia (PE) is enhanced ~4-fold by the presence of maternal type 1 diabetes (T1DM). Vitamin D is essential for healthy pregnancy. We assessed the total, bioavailable, and free concentrations of plasma 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), and vitamin D binding protein (VDBP) at ~12, ~22, and ~32 weeks&rsquo, gestation (&ldquo, Visits&rdquo, (V) 1, 2, and 3, respectively) in 23 T1DM women who developed PE, 24 who remained normotensive, and 19 non-diabetic, normotensive women (reference controls). 25(OH)D deficiency was more frequent in diabetic than non-diabetic women (69% vs. 22%, p &lt, 0.05), but no measure of 25(OH)D predicted PE. By contrast, higher 1,25(OH)2D concentrations at V2 (total, bioavailable, and free: p &lt, 0.01) and V3 (bioavailable: p &lt, 0.05, free: p &lt, 0.01), lower concentrations of VDBP at V3 (p &lt, 0.05), and elevated ratios of 1,25(OH)2D/VDBP (V2, V3: p &lt, 0.01) and 1,25(OH)2D/25(OH)D (V3, p &lt, 0.05) were all associated with PE, and significance persisted in multivariate analyses. In summary, in women with T1DM, concentrations of 1,25(OH)2D were higher, and VDBP lower, in the second and third trimesters in women who later developed PE than in those who did not. 1,25(OH)2D may serve as a new marker for PE risk and could be implicated in pathogenesis.

Little is known about who would benefit from internet-based personalised nutrition (PN) interventions. This study aimed to evaluate the characteristics of participants who achieved greatest improvements (i.e. benefit) in diet, adiposity and biomarkers following an internet-based PN intervention. Adults (n=1607) from seven European countries were recruited into a 6-month, randomized controlled trial (Food4Me) and randomized to receive conventional dietary advice (control) or PN advice. Information on dietary intake, adiposity, physical activity, blood biomarkers and participant characteristics was collected at baseline and month 6. Benefit from the intervention was defined as ≥5% change in the primary outcome (Healthy Eating Index) and secondary outcomes (waist circumference and BMI, physical activity, sedentary time and plasma concentrations of cholesterol, carotenoids and omega-3 index) at month 6. For our primary outcome, benefit from the intervention was greater in older participants and women. Benefit was greater for individuals reporting greater self-efficacy for “sticking to healthful foods” and who “felt weird if [they] didn’t eat healthily”. Participants benefited more if they reported wanting to improve their health and wellbeing. The characteristics of individuals benefiting did not differ by other demographic, health-related, anthropometric or genotypic characteristics. Findings were similar for secondary outcomes. Older individuals, women and individuals with less healthy diets at baseline benefitted more from PN advice. The odds of benefiting did not differ by weight status, genetic risk or socio-economic position. These findings have implications for the design of more effective future PN intervention studies and for tailored nutritional advice in public health and clinical settings.

Jacobsen syndrome (MIM #147791) is a rare multisystem genomic disorder involving craniofacial abnormalities, intellectual disability, other neurodevelopmental defects, and terminal truncation of chromosome 11q, typically deleting ~170 to >340 genes. We describe the first case of Jacobsen syndrome caused by congenital chromoanasynthesis, an extreme form of complex chromosomal rearrangement. Six duplications and five deletions occurred on one copy of chromosome 11q with microhomology signatures in the breakpoint junctions, indicating an all-at-once replication-based rearrangement mechanism in a gametocyte or early post-zygotic cell. Eighteen genes were deleted from the Jacobsen region, including KIRREL3, which is associated with intellectual disability.

OBJECTIVES: This study aimed to examine changes in intake of discretionary foods and beverages following a personalized nutrition intervention using two national classifications for discretionary foods. METHODS: Participants were recruited into a 6-month RCT across seven European countries (Food4Me) and were randomized to receive generalized dietary advice (Control) or one of three levels of personalized nutrition advice (based on dietary, phenotypic and genotypic information). Dietary intake from a FFQ was used to determine change between baseline and month 6 in (i) % energy, % contribution to total fat, SFA, total sugars and salt and (ii) contribution (%) made by sweets and snacks to intake of total fat, SFA, sugars and salt from discretionary foods and beverages, defined by Food Standards Scotland (FSS) and the Australian Dietary Guidelines (ADG). RESULTS: A total of 1270 adults (40.9 (SD 13.0) years; 57% female) completed the intervention. At month 6, percentage sugars from FSS discretionary items was lower in personalized nutrition vs control (19.0 ± 0.37 vs 21.1 ± 0.65; P = 0.005). Percentage energy (31.2 ± 0.59 vs 32.7 ± 0.59; P = 0.031), % total fat (31.5 ± 0.37 vs 33.3 ± 0.65; P = 0.021), SFA (36.0 ± 0.43 vs 37.8 ± 0.75; P = 0.034) and sugars (31.7 ± 0.44 vs 34.7 ± 0.78; P

OBJECTIVE This study was conducted to determine the utility of tubular (urinary/plasma neutrophil gelatinase-associated lipocalin [NGAL] and urinary kidney injury molecule 1 [KIM-1]) and glomerular (estimated glomerular filtration rate [eGFR]) biomarkers in predicting preeclampsia (PE) in pregnant women with type 1 diabetes mellitus (T1DM) who were free of microalbuminuria and hypertension at the first trimester. RESEARCH DESIGN AND METHODS This was a prospective study of T1DM pregnancy. Maternal urinary and plasma NGAL, urinary KIM-1 (ELISA of frozen samples), and eGFR (Chronic Kidney Disease Epidemiology Collaboration equation) were determined at three study visits (V1: 12.4 ± 1.8; V2: 21.7 ± 1.4; V3: 31.4 ± 1.5 weeks’ gestation [mean ± SD]) in 23 women with T1DM with subsequent PE (DM+PE+), 24 who remained normotensive (DM+PE−), and, for reference, in 19 normotensive pregnant women without diabetes (DM−). The groups with diabetes were matched for age, diabetes duration, and parity. All subjects were normotensive and free of microalbuminuria or albuminuria at V1. All study visits preceded the onset of PE. RESULTS Urinary creatinine-corrected NGAL (uNGALcc, ng/mg) was significantly elevated at V1 in DM+PE+ vs. DM+PE− women (P = 0.01); this remained significant after exclusion of leukocyte-positive samples (5 DM+PE+ and 2 DM+PE−) (P = 0.02). Accounting for BMI, HbA1c, and total daily insulin dose, a doubling of uNGALcc at V1 conferred a sevenfold increase in risk for PE (P = 0.026). In contrast, neither plasma NGAL nor urinary KIM-1 predicted PE. Also at V1, eGFR was elevated in DM+PE+ vs. DM+PE− (P = 0.04). CONCLUSIONS Early tubular and glomerular dysfunction may predict PE in first trimester women with T1DM, even if free of microalbuminuria. These data suggest that subclinical renal tubular and glomerular injury, if present early in pregnancy, may predispose women with T1DM to PE.

Aims/hypothesis: The incidence of pre-eclampsia, a multisystem disorder of pregnancy, is fourfold higher in type 1 diabetic than non-diabetic women; it is also increased in women with features of the metabolic syndrome and insulin resistance. In a prospective study of pregnant women with type 1 diabetes, we measured plasma levels of adipokines known to be associated with insulin resistance: leptin, fatty acid binding protein 4 (FABP4), adiponectin (total and high molecular weight [HMW]; also known as high molecular mass), retinol binding protein 4 (RBP4) and resistin and evaluated associations with the subsequent development of pre-eclampsia. Methods: From an established prospective cohort of pregnant type 1 diabetic women, we studied 23 who developed pre-eclampsia and 24 who remained normotensive; for reference values we included 19 healthy non-diabetic normotensive pregnant women. Plasma adipokines were measured (by ELISA) in stored samples from three study visits (Visit 1– Visit 3) at different gestational ages (mean ± SD): Visit 1, 12.4 ± 1.8 weeks; Visit 2, 21.7 ± 1.4 weeks; and Visit 3, 31.4 ± 1.5 weeks. All the women were free of microalbuminuria and hypertension at enrolment. All study visits preceded the clinical onset of pre-eclampsia. Results: In all groups, leptin, the ratio of leptin to total or HMW adiponectin, FABP4 concentration, ratio of FABP4 to total or HMW adiponectin and resistin level increased, while total and HMW adiponectin decreased, with gestational age. At Visit 1: (1) in diabetic women with vs without subsequent pre-eclampsia, leptin, ratio of leptin to total or HMW adiponectin, and ratio of FABP4 to total or HMW adiponectin, were increased (p 1c, insulin kg−1 day−1 and gestational age), the best predictive models for pre-eclampsia were as follows: Visit 1, doubling of leptin, OR 9.0 (p

Introduction Multiple intravenous doses of ponezumab, an anti-amyloid antibody, were evaluated in subjects with mild-to-moderate Alzheimer's disease (AD). Methods In part A, 77 subjects were randomized to ponezumab 0.1, 0.5, or 1 mg/kg (75 treated) and 26 to placebo (24 treated). In part B, 63 subjects were randomized and treated with ponezumab 3 or 8.5 mg/kg and 32 with placebo. Subjects received 10 infusions over 18 months and were followed for 6 months thereafter. Results Ponezumab was generally safe and well tolerated. Most common adverse events were fall (16.7% ponezumab, 21.4% placebo), headache (13.8%, 21.4%), and cerebral microhemorrhage (13.8%, 19.6%). Plasma ponezumab increased dose-dependently with limited accumulation. Cerebrospinal fluid penetration was low. Plasma Aβ 1–x and Aβ 1–40 showed robust increases, but cerebrospinal fluid biomarkers showed no dose response. Ponezumab had no effects on cognitive/functional outcomes or brain volume. Conclusions Multiple-dose ponezumab was generally safe, but not efficacious, in mild-to-moderate AD.

Background: There has been limited evidence about whether genotype-tailored advice provides extra benefits in reducing obesityrelated traits compared with the benefits of conventional one-size-fitsall advice. Objective: We determined whether the disclosure of information on fat-mass and obesity-associated (FTO) genotype risk had a greater effect on a reduction of obesity-related traits in risk carriers than in nonrisk carriers across different levels of personalized nutrition. Design: A total of 683 participants (women: 51%; age range: 18'73 y) from the Food4Me randomized controlled trial were included in this analysis. Participants were randomly assigned to 4 intervention arms as follows: level 0, control group; level 1, dietary group; level 2, phenotype group; and level 3, genetic group. FTO (single nucleotide polymorphism rs9939609) was genotyped at baseline in all participants, but only subjects who were randomly assigned to level 3 were informed about their genotypes. Level 3 participants were stratified into risk carriers (AA/AT) and nonrisk carriers (TT) of the FTO gene for analyses. Height, weight, and waist circumference (WC) were self-measured and reported at baseline and months 3 and 6. Results: Changes in adiposity markers were greater in participants who were informed that they carried the FTO risk allele (level 3 AT/AA carriers) than in the nonpersonalized group (level 0) but not in the other personalized groups (level 1 and 2). Mean reductions in weight andWC at month 6 were greater for FTO risk carriers than for noncarriers in the level 3 group [-2.28 kg (95% CI: -3.06, -1.48 kg) compared with -1.99 kg (-2.19, -0.19 kg), respectively (P = 0.037); and -4.34 cm(-5.63, -3.08 cm) compared with -1.99 cm (-4.04, -0.05 cm), respectively, (P = 0.048)]. Conclusions: There are greater body weight and WC reductions in risk carriers than in nonrisk carriers of the FTO gene. This trial was registered at clinicaltrials.gov as NCT01530139. © 2017 American Society for Nutrition.

The risk for preeclampsia (PE) is increased 4-fold in women with type 1 diabetes (T1D), in whom we previously demonstrated that elevated cholesterol-rich lipoproteins confer risk at the 1st trimester. Sphingolipids, including ceramides (Cer) and glycosphingolipids (hexosyl- (HexCer) and lactosyl-ceramides (LacCer)), are lipoprotein constituents that regulate cell signaling. We propose that these bio-active lipids could be modulators of PE risk. In a prospective T1D pregnancy cohort (studied at 12, 22, 32 weeks’ gestation), we used liquid chromatography/electrospray ionization-tandem mass spectrometry to determine plasma levels of 12 species of Cer, HexCer, and LacCer in 23 women with T1DM who did vs. 24 who did not develop PE, and in 19 normotensive nondiabetic pregnant women. All were free of microalbuminuria and hypertension at enrolment; all visits preceded clinical PE onset. Results: Plasma levels of C22-Cer (1st and 3rd study visits); C26:1-Cer (1st and 2nd visits); C26-Cer (1st visit); C18-Cer and C18:1-Cer (2nd visit) were significantly higher in women with T1DM who did vs. did not develop PE. C22-Cer and C26-Cer were significantly lower in T1DM vs. non-T1DM (1st visit). There were no overall PE- or diabetes-related differences in any HexCer- or LacCer species. Longitudinally, most Cer and HexCer species increased throughout pregnancy in all groups (except C14- and C18-Cer; and C14 and C26-HexCer). C16-LacCer increased, while C22:1-, C26-, and C26:1-LacCer decreased as pregnancy advanced, independent of PE status. Independent of LDL-C, total Cer increased throughout pregnancy in all groups. Conclusions: Maternal Cer species may serve as early biomarkers for PE in women with T1DM. T1DM was associated with lower levels of two Cer species. Like cholesterol-rich lipoproteins, Cer, HexCer and some LacCer species increase as pregnancy advances in all groups, but other LacCer species decrease: the significance of these findings requires further study. Disclosure C.B. Kelly: None. S.M. Hammad: None. R.L. Klein: None. M.F. Lopes-Virella: None. M.J. Leyva: None. J. Yu: None. A.J. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. A.J. Nankervis: None. K.F. Hanssen: None. S.K. Garg: Advisory Panel; Self; Eli Lilly and Company, Roche Pharma, Sanofi-Aventis, Zealand Pharma A/S. Research Support; Self; Eli Lilly and Company, WebMD. J.A. Scardo: None. C.E. Aston: None. T. Lyons: None. Funding JDRF; Novo Nordisk; National Institutes of Health

Preeclampsia (PE) occurs four times more frequently in pregnant women with type 1 diabetes (T1D) than in nondiabetic women. We hypothesized that elevated plasma advanced glycoxidation products (AGEs) predict PE in T1D women. In a prospective T1D pregnancy cohort (study visits at 12, 22, 32 weeks' gestation), we used liquid chromatography/mass spectrometry, with internal stable heavy isotope substituted standards, to determine plasma levels of nine AGE and oxidation products (carboxymethyl-lysine [CML], carboxyethyl-lysine [CEL], methylglyoxal-hydroimidazolone [MGHI], 3-deoxyglucosone hydroimidazolones [3DGH], methionine sulfoxide [MetSO], glyoxal hydroimidazolone [GHI], 3-nitrotyrosine [3NT], dityrosine [DT], 2-aminoadipic acid [2AAA]) in 23 women with T1DM who developed PE vs. 24 who did not, and in 19 nondiabetic normotensive pregnant women. These products have been associated with CVD and renal failure in non-pregnant cohorts. All women were free of microalbuminuria and hypertension at enrolment, and all visits preceded clinical PE onset. GFR was estimated (Chronic Kidney Disease Epidemiology Collaboration equation). Results: Plasma CML, CEL, MGHI, 3DGH, MetSO, GHI, and 2AAA did not differ between the three groups at any study visit, and thus did not predict preeclampsia in T1D. In T1D women who later developed PE, eGFR was inversely associated at V3 with CML (p=0.008), CEL (p=0.03), MGH1 (p=0.03), 3DGH (p=0.03), GHI (p Conclusions: Plasma AGEs did not predict PE in well-controlled, previously healthy T1D women, and levels did not differ from healthy nondiabetic controls. Uniquely, in T1D women who developed PE, plasma AGEs were associated with renal function, consistent with the notion that subclinical alterations in renal function precede PE. Disclosure H. Karanchi: None. C.B. Kelly: None. S.M. Hammad: None. R.L. Klein: None. M.F. Lopes-Virella: None. M.J. Leyva: None. J. Yu: None. A.J. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. A.J. Nankervis: None. K.F. Hanssen: None. C.E. Aston: None. S. Howell: Employee; Self; PreventAGE Health Care, LLC. P.J. Beisswenger: Other Relationship; Self; PreventAGE Health Care, LLC. T. Lyons: None.

Statin therapy reduces cardiovascular risk in type 2 diabetes (T2DM), partly by improving dyslipidemia, and partly through ‘pleiotropic’ effects. Sphingolipids, including ceramides, are amphiphilic components of lipoprotein surface monolayers. Sphingolipids regulate lipoprotein surface fluidity, and include key signaling molecules: ceramides are specifically associated with apoptosis and risk for premature coronary heart disease. Effects of statins on the sphingolipid content of lipoproteins are poorly defined. Using liquid chromatography/electrospray ionization-tandem mass spectrometry, we determined fasting plasma concentrations of individual ceramides (Cer), sphingomyelins (SM), and glycosphingolipids (hexosyl- and lactosyl-Cer) in plasma from 19 men and 21 women with T2DM, before and after treatment with rosuvastatin (10 mg/day, 6 weeks). Exclusion criteria were use of ‘statins’ in the preceding 6 months, and any current use of lipid-modifying agents. Using existing lipoprotein compositional data, we calculated effects of rosuvastatin therapy on non-HDL sphingolipid content. Results: Rosuvastatin reduced total cholesterol (C) (by 33%), triglycerides (20%), LDL-C (49%), and non-HDL particle number (34%); HDL-C was unaffected. It decreased total SM (15%), Cer (29%), and hexosyl- (30%) and lactosyl- (34%) Cer, independent of gender. Assuming HDL composition was unaffected, rosuvastatin reduced non-HDL SM by 42% and Cer by 61%: these reductions remained significant after correction for non-HDL-C and/or non-HDL lipoprotein surface area. Conclusions: In T2DM, rosuvastatin lowers not only the number of non-HDL particles, but also the sphingolipid, and especially the Cer, content of each particle. This effect is independent of gender, potentially anti-atherogenic, and may represent a new pleiotropic effect of statins. Further studies are needed to confirm these findings in isolated lipoprotein classes, and to determine mechanism(s). Disclosure C.B. Kelly: None. S.M. Hammad: None. R.L. Klein: None. M.F. Lopes-Virella: None. A. Gosmanova: None. M.J. Leyva: None. C.E. Aston: None. T. Lyons: None.

Preeclampsia (PE), a major cause of maternal and fetal morbidity and mortality worldwide, has significantly higher incidence in women with type 1 diabetes mellitus (T1DM) than in nondiabetic populations (∼20% vs. 5%, respectively). Sphingolipids are key signaling molecules, and have many roles in the structure and regulation of cellular functions. Sphingomyelin (SM) is the most abundant sphingolipid in plasma lipoproteins. There is evidence that altered SM metabolism may contribute to cardiovascular and renal complications in diabetes. We aimed to determine whether plasma concentrations of 12 SM species were associated with PE in T1DM in a prospective study of pregnancy of 23 T1DM women who developed PE and 24 T1DM who remained normotensive. Additionally, 19 normotensive nondiabetic pregnant women were included for reference. All subjects were free of microalbuminuria and hypertension at enrolment, and all visits (12, 22, 32 weeks’ gestation) preceded clinical PE onset. Results: There were no cross-sectional differences in total SM, or in any individual SM species, between diabetic women with and without PE, or between normotensive women with and without diabetes at any stage of gestation. With advancing gestation in all groups, C18-SM, C18:1-SM, C20-SM, C20:1-SM, C22-SM, C22:1-SM, C24-SM, and C24:1-SM increased (all p Conclusions: With advancing gestation, plasma concentrations of most SM species increased, as did LDL and VLDL; however, two long-chain and two very long-chain SM species decreased. Although there were no differences in SM according to diabetes or PE status at any time point, further studies should address the significance of differential changes of SM species during pregnancy. Disclosure C.B. Kelly: None. S.M. Hammad: None. R.L. Klein: None. M.F. Lopes-Virella: None. M.J. Leyva: None. J. Yu: None. A.J. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. A.J. Nankervis: None. K.F. Hanssen: None. S.K. Garg: Advisory Panel; Self; Eli Lilly and Company, Roche Pharma, Sanofi-Aventis, Zealand Pharma A/S. Research Support; Self; Eli Lilly and Company, WebMD. J.A. Scardo: None. C.E. Aston: None. T. Lyons: None. Funding JDRF; Novo Nordisk; National Institutes of Health

Background: Haptoglobin (Hp) is a plasma protein with anti-oxidant, anti-inflammatory and pro-angiogenic properties. Based on the Hp gene alleles there are three Hp phenotypes (1-1, 2-1 and 2-2). In diabetes, Hp-2 is associated with substantially increased risk of cardiac and renal damage relative to Hp-1. AIMS: To evaluate 1) associations between Hp phenotype and levels; and 2) effects of fenofibrate vs. placebo on Hp levels. Methods: A substudy of 180 adults with type 2 diabetes (T2D) (50% females) from the FIELD trial. Average age was 60±6 years, BMI 30.4±5.1 kg/m2 and HbA1c 6.8±1.3%. Plasma (citrate) samples were evaluated at baseline, after 6-weeks daily 200 mg co-micronised fenofibrate (end of active run-in) and 2-years after randomisation to fenofibrate or placebo. Results: Hp phenotype 1-1 was detected in 19%, Hp 2-1 in 48% and Hp 2-2 in 33% subjects. Hp levels at baseline were 1.44±1.10, 1.31±0.49 and 0.99±0.46 mg/mL in type 1-1, 2-1 and 2-2 respectively (all p Conclusions: Hp levels differ by Hp phenotype in T2D adults. Fenofibrate lowers Hp levels in all phenotypes, however the effect is significantly attenuated in Hp 2-2. Disclosure A.S. Januszewski: None. H.K. Young: Other Relationship; Self; Medtronic. L. Li: None. R.L. OConnell: None. T. Lyons: None. C.B. Kelly: None. D. Sullivan: None. R. Scott: None. A.C. Keech: None. A. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. Funding Sydney Medical School Foundation; National Health and Medical Research Council of Australia

The objective was to evaluate differences in macronutrient intake and to investigate the possible association between consumption of vegetable protein and the risk of overweight/obesity, within the Food4Me randomised, online intervention. Differences in macronutrient consumption among the participating countries grouped by EU Regions (Western Europe, British Isles, Eastern Europe and Southern Europe) were assessed. Relation of protein intake, within isoenergetic exchange patterns, from vegetable or animal sources with risk of overweight/obesity was assessed through the multivariate nutrient density model and a multivariate-adjusted logistic regression. A total of 2413 subjects who completed the Food4Me screening were included, with self-reported data on age, weight, height, physical activity and dietary intake. As success rates on reducing overweight/obesity are very low, form a public health perspective, the elaboration of policies for increasing intakes of vegetable protein and reducing animal protein and sugars, may be a method of combating overweight/obesity at a population level.

In most countries, elderly patients who commence renal replacement therapy (RRT) are more likely to be started on hemodialysis (HD) rather than peritoneal dialysis (PD) despite comparable medical outcomes between the two modalities. In this chapter, we explore the potential benefits of PD for older patients, including the maintenance of independence and treatment flexibility. Additionally, medical benefits of PD such as markedly reduced myocardial stunning and the absence of the need for vascular access are discussed.

ObjectiveTo characterise clusters of individuals based on adherence to dietary recommendations and to determine whether changes in Healthy Eating Index (HEI) scores in response to a personalised nutrition (PN) intervention varied between clusters.DesignFood4Me study participants were clustered according to whether their baseline dietary intakes met European dietary recommendations. Changes in HEI scores between baseline and month 6 were compared between clusters and stratified by whether individuals received generalised or PN advice.SettingPan-European, Internet-based, 6-month randomised controlled trial.SubjectsAdults aged 18–79 years (n 1480).ResultsIndividuals in cluster 1 (C1) met all recommended intakes except for red meat, those in cluster 2 (C2) met two recommendations, and those in cluster 3 (C3) and cluster 4 (C4) met one recommendation each. C1 had higher intakes of white fish, beans and lentils and low-fat dairy products and lower percentage energy intake from SFA (PPPPPConclusionsThe cluster where the fewest recommendations were met (C4) reported greater improvements in HEI following a 6-month trial of PN whereas there was no difference between clusters for those randomised to the Control, non-personalised dietary intervention.

An efficient and robust method to measure vitamin D (25-hydroxy vitamin D3(25(OH)D3) and 25-hydroxy vitamin D2in dried blood spots (DBS) has been developed and applied in the pan-European multi-centre, internet-based, personalised nutrition intervention study Food4Me. The method includes calibration with blood containing endogenous 25(OH)D3, spotted as DBS and corrected for haematocrit content. The methodology was validated following international standards. The performance characteristics did not reach those of the current gold standard liquid chromatography-MS/MS in plasma for all parameters, but were found to be very suitable for status-level determination under field conditions. DBS sample quality was very high, and 3778 measurements of 25(OH)D3were obtained from 1465 participants. The study centre and the season within the study centre were very good predictors of 25(OH)D3levels (P3level on 20 January and a maximum on 21 July. The seasonal amplitude varied from centre to centre. The largest difference between winter and summer levels was found in Germany and the smallest in Poland. The model was cross-validated to determine the consistency of the predictions and the performance of the DBS method. The Pearson’s correlation between the measured values and the predicted values wasr0·65, and thesdof their differences was 21·2 nmol/l. This includes the analytical variation and the biological variation within subjects. Overall, DBS obtained by unsupervised sampling of the participants at home was a viable methodology for obtaining vitamin D status information in a large nutritional study.

Since the inception of hemodialysis (HD) for patients with chronic kidney disease, the "perfect" dialysis prescription has remained elusive. Part of this may relate to the heterogeneity among populations, individual patients, and differences in access to health provision. The optimal balance between dialysis frequency and duration to achieve reductions in patient morbidity and mortality continues to be debated. The concept of dialysis adequacy originated from a post hoc mathematical analysis of the National Cooperative Study and has evolved to become a way of calculating dialysis dose and standardizing the dialysis prescription. In contrast, in its originally conceived sense, dialysis adequacy referred to the effective clearance of small solutes. Given the evolution of dialysis practice, we now aim to consider dialysis adequacy in a broader and more holistic manner particularly in view of our aging population and focus toward important patient-centered outcomes. While the traditional thrice weekly, HD regimen remains the default renal replacement modality, alternative strategies including short daily HD, long conventional HD, and long nocturnal HD are being widely implemented. We aim for optimal solute clearance, effective ultrafiltration to achieve normotension (while avoiding intradialytic symptoms) and maintenance of nutritional parameters all within the caveat that quality of life and autonomy are preserved.

Introduction:\ud \ud This study tested the hypothesis that providing personalized nutritional advice and feedback more frequently would promote larger, more appropriate, and sustained changes in dietary behavior as well as greater reduction in adiposity.\ud Study design:\ud \ud A 6-month RCT (Food4Me) was conducted in seven European countries between 2012 and 2013.\ud Setting/participants:\ud \ud A total of 1,125 participants were randomized to Lower- (n=562) or Higher- (n=563) Frequency Feedback groups.\ud Intervention:\ud \ud Participants in the Lower-Frequency group received personalized nutritional advice at baseline and at Months 3 and 6 of the intervention, whereas the Higher-Frequency group received personalized nutritional advice at baseline and at Months 1, 2, 3 and 6.\ud Main outcome measures:\ud \ud The primary outcomes were change in dietary intake (at food and nutrient levels) and obesity-related traits (body weight, BMI, and waist circumference). Participants completed an online Food Frequency Questionnaire to estimate usual dietary intake at baseline and at Months 3 and 6 of the intervention. Overall diet quality was evaluated using the 2010 Healthy Eating Index. Obesity-related traits were self-measured and reported by participants via the Internet. Statistical analyses were performed during the first quarter of 2018.\ud Results:\ud \ud At 3 months, participants in the Lower- and Higher-Frequency Feedback groups showed improvements in Healthy Eating Index score; this improvement was larger in the Higher-Frequency group than the Lower-Frequency group (Δ=1.84 points, 95% CI=0.79, 2.89, p=0.0001). Similarly, there were greater improvements for the Higher- versus Lower-Frequency group for body weight (Δ= −0.73 kg, 95% CI= −1.07, −0.38, p

Preeclampsia (PE) occurs more frequently in pregnant diabetic than nondiabetic women (∼20% vs. ∼5%). Early identification of high risk women is needed. Dyslipidemia is implicated: we previously showed that early in pregnancy, increased cholesterol-rich lipoproteins are associated with subsequent PE in type 1 diabetes (T1D). Haptoglobin (Hp) is a plasma protein that binds free hemoglobin, and has two allelic forms, Hp-1, Hp-2, hence three phenotypes. Among people with diabetes, Hp 2-2 phenotype (present in ≈50%) has been associated with oxidative stress, cardiovascular risk and renal decline. We investigated whether maternal Hp phenotype is associated with PE in T1D, and/or modulates lipoprotein-related risks for PE. A prospective study of pregnancy included 23 T1DM women (cases) who developed PE, and 24 T1DM (controls) who remained normotensive. All were free of microalbuminuria and hypertension at enrolment. Hp phenotype was determined by ELISA (Savyon Diagnostics Ltd.). Lipid profiles were measured at three study visits (V1-V3), all preceding PE onset: (mean ± SD) 12.4 ± 1.8, 21.7 ± 1.4, and 31.3 ± 1.4 weeks gestation. Results: Hp phenotype did not differ between women with and without PE, and lipid profiles did not differ by Hp phenotype. In PE cases vs. controls, by univariate analysis, HDL-C was lower at V1 (1.9±0.4 vs. 2.2±0.5 mmol/l (mean ± SD)), while LDL-C was higher at V2 (3.1± 1.0 vs. 2.6± 0.8 mmol/l), as were triacylglycerols (1.6± 0.4 vs. 1.3± 0.4 mmol/l) (p Conclusion: In T1D women, lipoprotein-related risks for PE may be limited to those with Hp 2-2 phenotype. The data provide further evidence of a role for Hp phenotype as a modulator of vascular risk in diabetes. Disclosure C.B. Kelly: None. J. Yu: None. A. Jenkins: Research Support; Self; Medtronic, Mylan, Sanofi-Aventis. A.J. Nankervis: None. K.F. Hanssen: None. S.K. Garg: Research Support; Self; Dexcom, Inc., Eli Lilly and Company, Sanofi US. Advisory Panel; Self; Sanofi US. Research Support; Self; MannKind Corporation, Diasome Pharmaceuticals, Inc., Labstyle Innovations, Lexicon Pharmaceuticals, Inc., Medtronic. Advisory Panel; Self; Novo Nordisk A/S. C.E. Aston: None. T. Lyons: None.

We thank Foussard et al. (1) for their interest in our study (2). We agree that caution is required when identifying predictive markers of clinical interest in pregnant women with diabetes with regard to preeclampsia (PE). Accurate estimation of renal function is critical for the care of pregnant patients. Alper et al. (3) highlighted the limitations of currently available formulas for accurately predicting the glomerular filtration rate (GFR) in patients with PE. Our study focused on markers of renal function early in pregnancy prior to the clinical onset of PE. We studied a population with type 1 diabetes, thus at high risk of …

Background National guidelines emphasize healthy eating to promote wellbeing and prevention of non-communicable diseases. The perceived healthiness of food is determined by many factors affecting food intake. A positive perception of healthy eating has been shown to be associated with greater diet quality. Internet-based methodologies allow contact with large populations. Our present study aims to design and evaluate a short nutritional perception questionnaire, to be used as a screening tool for assessing nutritional status, and to predict an optimal level of personalisation in nutritional advice delivered via the Internet. Methods Data from all participants who were screened and then enrolled into the Food4Me proof-of-principle study (n = 2369) were used to determine the optimal items for inclusion in a novel screening tool, the Nutritional Perception Screening Questionnaire-9 (NPSQ9). Exploratory and confirmatory factor analyses were performed on anthropometric and biochemical data and on dietary indices acquired from participants who had completed the Food4Me dietary intervention (n = 1153). Baseline and intervention data were analysed using linear regression and linear mixed regression, respectively. Results A final model with 9 NPSQ items was validated against the dietary intervention data. NPSQ9 scores were inversely associated with BMI (β = −0.181, p

Over a decade since the completion of the human genome sequence, the promise of personalised nutrition available to all has yet to become a reality. While the definition was originally very gene-focused, in recent years, a model of personalised nutrition has emerged with the incorporation of dietary, phenotypic and genotypic information at various levels. Developing on from the idea of personalised nutrition, the concept of targeted nutrition has evolved which refers to the delivery of tailored dietary advice at a group level rather than at an individual level. Central to this concept is metabotyping or metabolic phenotyping, which is the ability to group similar individuals together based on their metabolic or phenotypic profiles. Applications of the metabotyping concept extend from the nutrition to the medical literature. While there are many examples of the metabotype approach, there is a dearth in the literature with regard to the development of tailored interventions for groups of individuals. This review will first explore the effectiveness of personalised nutrition in motivating behaviour change and secondly, examine potential novel ways for the delivery of personalised advice at a population level through a metabotyping approach. Based on recent findings from our work, we will demonstrate a novel strategy for the delivery of tailored dietary advice at a group level using this concept. In general, there is a strong emerging evidence to support the effectiveness of personalised nutrition; future work should ascertain if targeted nutrition can motivate behaviour change in a similar manner.

The purpose of this study was to compare IVIM values in pediatric renal transplants with histopathology and clinical management change. Fifteen pediatric renal transplant recipients (mean 15.7±2.9 years) were prospectively scanned on a 3T MR scanner with multi-b DTI, prior to same-day transplant biopsy. IVIM maps from 14 subjects were analyzed (one excluded due to motion). Mean values were computed from cortical ROIs and medullary ROIs corresponding to the biopsy site. Subjects were also grouped according to whether or not the biopsy resulted in a change in clinical management. Cortico-medullary IVIM estimates and histopathologic Banff scores were correlated with KT. Cortico-medullary IVIM differences between the "change" and "no change" groups was compared with Mann-Whitney U test. Cortical Dp showed significant moderate negative correlation with Banff t and ci scores (KT=-0.497, P=.035 and KT=-0.46, P=.046) and moderate positive correlation with Banff i score (KT=0.527, P=.028). Cortical Pf showed significant moderate correlation with ci and ct scores (KT=0.489, P=.035 and KT=0.457, P=.043). Tissue diffusivity, Dt , estimated with IVIM was significantly different between the "change" and "no change" groups in medullary ROIs (U=6, P=.021). IVIM analysis has potential as a noninvasive biomarker in assessment of pediatric renal allograft pathology.

ObjectiveTo characterise participants who dropped out of the Food4Me Proof-of-Principle study.DesignThe Food4Me study was an Internet-based, 6-month, four-arm, randomised controlled trial. The control group received generalised dietary and lifestyle recommendations, whereas participants randomised to three different levels of personalised nutrition (PN) received advice based on dietary, phenotypic and/or genotypic data, respectively (with either more or less frequent feedback).SettingSeven recruitment sites: UK, Ireland, The Netherlands, Germany, Spain, Poland and Greece.SubjectsAdults aged 18–79 years (n 1607).ResultsA total of 337 (21 %) participants dropped out during the intervention. At baseline, dropouts had higher BMI (0·5 kg/m2; PPP=0·015), less than 45 years old (2·57; 1·95, 3·39; PPPP=0·008), and less likely if participants claimed to eat healthily frequently (0·62; 0·45, 0·86; P=0·003).ConclusionsAttrition did not differ between participants receiving generalised or PN advice but more frequent feedback was related to attrition for those randomised to PN interventions. Better strategies are required to minimise dropouts among younger and obese individuals participating in PN interventions and more frequent feedback may be an unnecessary burden.

Background Although the Clinical Dementia Rating Scale-Sum of Boxes score (CDR-SB) is a widely accepted and commonly used global scale, validated clinical endpoints of cognitive changes are unavailable in the predementia stages of Alzheimer's disease (AD), and a new clinical assessment with reliability and sensitivity is needed in the mild cognitive impairment (MCI) population. Methods Using Alzheimer's Disease Neuroimaging Initiative (ADNI)-1/GO data, signal-to-noise ratios (SNRs) were calculated to quantify the sensitivity of a measure for detecting disease progression and hypothetical treatment effects. All possible combinations of selected sensitive measures were assessed for developing composite scores. The analyses were performed in the MCI population and subpopulations enriched by apolipoprotein E4 ( APOE e4), hippocampal volume, and cerebrospinal fluid β-amyloid. Results The best composite score was "Word Recall + Delayed Word Recall + Orientation + CDR-SB + FAQ", more sensitive than 13-item Alzheimer's Disease Assessment Scale-cognitive subscale or CDR-SB. Conclusion The proposed composite score derived from the existing clinical endpoints demonstrated higher sensitivity in the MCI population and is easy to implement and standardize across studies.

Background: PF-04447943 is a potent, selective phosphodiesterase 9A (PDE9A) inhibitor that elevates guanoscine 3’,5’ – cyclic monophosphate (cGMP) in brain and cerebrospinal fluid. PDE9A inhibition enhances synaptic plasticity and improves memory in preclinical cognition models, and prevents decreases in dendritic spine density in transgenic mice that overexpress amyloid precursor protein (APP) leading to high levels of amyloid beta (A β) production (Tg2576). Objective: This Phase 2 multicenter study was designed to assess the efficacy, safety and pharmacokinetics of PF-04447943 compared with placebo in mild to moderate probable Alzheimer’s disease (AD). Methods: Subjects in overall good health with Mini Mental State Examination (MMSE) scores of 14-26 were randomized to 12 weeks treatment with PF-04447943 25 mg q12h (n=91) or placebo (n=100). Concomitant acetylcholinesterase inhibitor or memantine use was excluded. The primary outcome was the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog). The Neuropsychiatric Inventory (NPI), Clinical Global Impression-Improvement scale (CGI-I) and standard safety measures were secondary outcomes. Results: Completion rates were similar, 87% PF-04447943 vs 92% placebo. At week 12 the mean (SE) baseline adjusted decrease from baseline in ADAS cog for PF-04447943-treated patients was -1.91 (0.54). Placebo treated patients had a change of -1.60 (0.50). The difference between treatments was -0.31 (90% CI of -1.52, 0.90). Corresponding values for the NPI were -2.86 (0.72) vs -2.70 (0.67) with a treatment difference of -0.16 (90% CI of -1.78, 1.48). Neither these changes nor the distribution of CGI-I scores were statistically significantly different between groups. The incidence of serious adverse events (AEs) was similar between groups with 2 deaths in the placebo group. The PF-04447943 group reported more gastrointestinal AEs including diarrhea (5.5% vs 3%) and nausea (5.5% vs 1%) and had a higher rate of discontinuation due to AEs (6.6% vs 2%). Conclusions: Although generally safe and well-tolerated, 12 weeks PF-04447943 treatment did not improve cognition, behavior, and global change compared with placebo.

Growth hormone receptor-null (GHR(-/-)) mice are dwarf, insulin sensitive, and long-lived in spite of increased adiposity. However, their adiposity is not uniform, with select white adipose tissue (WAT) depots enlarged. To study WAT depot-specific effects on insulin sensitivity and life span, we analyzed individual WAT depots of 12- and 24-month-old GHR(-) (/-) and wild-type (WT) mice, as well as their plasma levels of selected hormones. Adipocyte sizes and plasma insulin, leptin, and adiponectin levels decreased with age in both GHR(-) (/-) and WT mice. Two-dimensional gel electrophoresis proteomes of WAT depots were similar among groups, but several proteins involved in endocytosis and/or cytoskeletal organization (Ehd2, S100A10, actin), anticoagulation (S100A10, annexin A5), and age-related conditions (alpha2-macroglobulin, apolipoprotein A-I, transthyretin) showed significant differences between genotypes. Because Ehd2 may regulate endocytosis of Glut4, we measured Glut4 levels in the WAT depots of GHR(-) (/-) and WT mice. Inguinal WAT of 12-month-old GHR(-) (/-) mice displayed lower levels of Glut4 than WT. Overall, the protein changes detected in this study offer new insights into possible mechanisms contributing to enhanced insulin sensitivity and extended life span in GHR(-) (/-) mice.

Background: It is hypothesised that individuals with knowledge of their genetic risk are more likely to make health-promoting dietary and lifestyle changes. The present study aims to test this hypothesis using data from the Food4Me study. This was a 6-month Internet-based randomised controlled trial conducted across seven centres in Europe where individuals received either general healthy eating advice or varying levels of personalised nutrition advice. Participants who received genotype-based personalised advice were informed whether they had the risk (CT/TT) (n = 178) or non-risk (CC) (n = 141) alleles of the methylenetetrahydrofolate reductase (MTHFR) gene in relation to cardiovascular health and the importance of a sufficient intake of folate. General linear model analysis was used to assess changes in folate intake between the MTHFR risk, MTHFR non-risk and control groups from baseline to month 6 of the intervention.Results: There were no differences between the groups for age, gender or BMI. However, there was a significant difference in country distribution between the groups (p = 0.010). Baseline folate intakes were 412 ± 172, 391 ± 190 and 410 ± 186 μg per 10 MJ for the risk, non-risk and control groups, respectively. There were no significant differences between the three groups in terms of changes in folate intakes from baseline to month 6. Similarly, there were no changes in reported intake of food groups high in folate.Conclusions: These results suggest that knowledge of MTHFR 677C → T genotype did not improve folate intake in participants with the risk variant compared with those with the non-risk variant.Trial registration: ClinicalTrials.gov NCT01530139

Background: Optimal nutritional choices are linked with better health, but many current interventions to improve diet have limited effect. We tested the hypothesis that providing personalized nutrition (PN) advice based on information on individual diet and lifestyle, phenotype and/or genotype would promote larger, more appropriate, and sustained changes in dietary behaviour.\ud \ud Methods: Adults from seven European countries were recruited to an internet-delivered intervention (Food4Me) and randomized to: (i) conventional dietary advice (control) or to PN advice based on: (ii) individual baseline diet; (iii) individual baseline diet plus phenotype (anthropometry and blood biomarkers); or (iv) individual baseline diet plus phenotype plus genotype (five diet-responsive genetic variants). Outcomes were dietary intake, anthropometry and blood biomarkers measured at baseline and after 3 and 6 months’ intervention.\ud \ud Results: At baseline, mean age of participants was 39.8 years (range 18–79), 59% of participants were female and mean body mass index (BMI) was 25.5 kg/m2. From the enrolled participants, 1269 completed the study. Following a 6-month intervention, participants randomized to PN consumed less red meat [-5.48 g, (95% confidence interval:-10.8,-0.09), P = 0.046], salt [-0.65 g, (−1.1,-0.25), P = 0.002] and saturated fat [-1.14 % of energy, (−1.6,-0.67), P

Background: The apolipoprotein E (APOE) risk allele (e4) is associated with higher total cholesterol (TC), amplified response to saturated fatty acid (SFA) reduction, and increased cardiovascular disease. Although knowledge of gene risk may enhance dietary change, it is unclear whether e4 carriers would benefit from gene-based personalized nutrition (PN). Objectives: The aims of this study were to 1) investigate interactions between APOE genotype and habitual dietary fat intake and modulations of fat intake on metabolic outcomes; 2) determine whether gene-based PN results in greater dietary change than do standard dietary advice (level 0) and nongene-based PN (levels 1-2); and 3) assess the impact of knowledge of APOE risk (risk: E4+, nonrisk: E42) on dietary change after gene-based PN (level 3). Design: Individuals (n = 1466) recruited into the Food4Me pan- European PN dietary intervention study were randomly assigned to 4 treatment arms and genotyped for APOE (rs429358 and rs7412). Diet and dried blood spot TC and v-3 (n-3) index were determined at baseline and after a 6-mo intervention. Data were analyzed with the use of adjusted general linear models. Results: Significantly higher TC concentrations were observed in E4+ participants than in E42 (P , 0.05). Although there were no significant differences in APOE response to gene-based PN (E4+ compared with E42), both groups had a greater reduction in SFA (percentage of total energy) intake than at level 0 (mean 6 SD: E4+, 20.72% 6 0.35% compared with 21.95% 6 0.45%, P = 0.035; E42, 20.31% 6 0.20% compared with 21.68% 6 0.35%, P = 0.029). Gene-based PN was associated with a smaller reduction in SFA intake than in nongene-based PN (level 2) for E42 participants (21.68% 6 0.35% compared with 22.56% 6 0.27%, P = 0.025). Conclusions: The APOE e4 allele was associated with higher TC. Although gene-based PN targeted to APOE was more effective in reducing SFA intake than standard dietary advice, there was no difference between APOE "risk" and "nonrisk" groups. Furthermore, disclosure of APOE nonrisk may have weakened dietary response to PN. This trial was registered at clinicaltrials.gov as NCT01530139. Am J Clin Nutr 2016;104:827-36. © 2016 American Society for Nutrition.

To determine whether self-regulated flexible dosing with varenicline tartrate is safe and effective for smoking cessation.320 healthy, motivated-to-quit smokers (or =10 cigarettes/day) aged 18-65 years, entered a multicenter, randomized, double-blind, placebo-controlled study - conducted between December 26, 2001 and June 24, 2003 - with a 12-week treatment phase and 40-week, double-blind, non-treatment follow-up. Treatment consisted of varenicline or placebo in fixed doses (Week 1: titrated from 0.5 to 1.0 mg/day) followed by a self-regulated flexible schedule (Weeks 2-12: 0.5-2.0 mg/day).Primary outcomes included carbon monoxide-confirmed continuous abstinence rate (CAR) from smoking for Weeks 4 through 7, 9 through 12, and 9 through 52. Secondary outcomes included CAR from Weeks 9 through 24, 7-day point prevalence of abstinence, safety assessments, and measures of craving, withdrawal, and smoking reward.Superior CARs were observed in varenicline-treated (n = 157) versus placebo participants (n=155) for Weeks 4 through 7 (38.2 vs. 11.6%), 9 through 12 (40.1 vs. 11.6%), 9 through 24 (28.0 vs. 9.0%), and 9 through 52 (22.3 vs. 7.7%) (all p0.001). Seven-day point prevalence was higher in varenicline-treated than placebo participants at Weeks 12 (46.5 vs. 14.2%; p0.001), 24 (32.5 vs. 13.5%; p0.001), and 52 (28.0 vs. 13.5%; p=0.001). Overall, medication compliance was high, although varenicline-treated, but not placebo, participants tended to taper down their dosage over time. Total treatment-emergent AEs were 77.1% (varenicline: 121/157) and 65.8% (placebo: 102/155). Few AEs led to treatment discontinuation (varenicline: 11/157, 7.0% and placebo: 7/155, 4.5%). Participants were primarily healthy Caucasians, so more research is necessary to determine how applicable these findings are to other populations.A self-regulated, flexible dosing regimen of varenicline is well tolerated, with superior effectiveness versus placebo for smoking cessation.

Receptor-mediated airway smooth muscle (ASM) contraction via G(alphaq), and relaxation via G(alphas), underlie the bronchospastic features of asthma and its treatment. Asthma models show increased ASM G(alphai) expression, considered the basis for the proasthmatic phenotypes of enhanced bronchial hyperreactivity to contraction mediated by M(3)-muscarinic receptors and diminished relaxation mediated by beta(2)-adrenergic receptors (beta(2)ARs). A causal effect between G(i) expression and phenotype has not been established, nor have mechanisms whereby G(i) modulates G(q)/G(s) signaling. To delineate isolated effects of altered G(i), transgenic mice were generated overexpressing G(alphai2) or a G(alphai2) peptide inhibitor in ASM. Unexpectedly, G(alphai2) overexpression decreased contractility to methacholine, while G(alphai2) inhibition enhanced contraction. These opposite phenotypes resulted from different crosstalk loci within the G(q) signaling network: decreased phospholipase C and increased PKCalpha, respectively. G(alphai2) overexpression decreased beta(2)AR-mediated airway relaxation, while G(alphai2) inhibition increased this response, consistent with physiologically relevant coupling of this receptor to both G(s) and G(i). IL-13 transgenic mice (a model of asthma), which developed increased ASM G(alphai), displayed marked increases in airway hyperresponsiveness when G(alphai) function was inhibited. Increased G(alphai) in asthma is therefore a double-edged sword: a compensatory event mitigating against bronchial hyperreactivity, but a mechanism that evokes beta-agonist resistance. By selective intervention within these multipronged signaling modules, advantageous G(s)/G(q) activities could provide new asthma therapies.

The THRB gene encodes the well-described thyroid hormone (T3) receptor (TR) isoforms TRbeta1 and TRbeta2 and two additional variants, TRbeta3 and TRDeltabeta3, of unknown physiological significance. TRbeta1, TRbeta2, and TRbeta3 are bona fide T3 receptors that bind DNA and T3 and regulate expression of T3-responsive target genes. TRDeltabeta3 retains T3 binding activity but lacks a DNA binding domain and does not activate target gene transcription. TRDeltabeta3 can be translated from a specific TRDeltabeta3 mRNA or is coexpressed with TRbeta3 from a single transcript that contains an internal TRDeltabeta3 translation start site. In these studies, we provide evidence that the TRbeta3/Deltabeta3 locus is present in rat but not in other vertebrates, including humans. We compared the activity of TRbeta3 with other TR isoforms and investigated mechanisms of action of TRDeltabeta3 at specific thyroid hormone response elements (TREs) in two cell types. TRbeta3 was the most potent isoform, but TR potency was TRE dependent. TRDeltabeta3 acted as a cell-specific and TRE-dependent modulator of TRbeta3 when coexpressed at low concentrations. At higher concentrations, TRDeltabeta3 was a TRE-selective and cell-specific antagonist of TRalpha1, -beta1, and -beta3. Both TRbeta3 and TRDeltabeta3 were expressed in the nucleus in the absence and presence of hormone, and their actions were determined by cell type and TRE structure, whereas TRDeltabeta3 actions were also dependent on the TR isoform with which it interacted. Analysis of these complex responses implicates a range of nuclear corepressors and coactivators as cell-, TR isoform-, and TRE-specific modulators of T3 action.

We assessed the safety of long-term varenicline administration for smoking cessation.In this randomized, double-blind, multicenter trial, eligible adult smokers (18-75 years) who smoked an average ofor =10 cigarettes/day were randomized to either varenicline 1 mg twice daily (BID) or placebo for 52 weeks. Subjects made weekly clinic visits until week 8, and then every 4 weeks until week 52, with a follow-up visit at week 53. The target quit date was the morning of the week 1 clinic visit. Brief counseling was provided at each visit, and vital signs, adverse events (AEs), and smoking status were documented. Other laboratory measures were collected at specified visits.A total of 251 subjects were randomized to varenicline and 126 to placebo. Approximately half of the subjects in each arm completed the study (53.8% varenicline; 46.8% placebo). Treatment-emergent AEs were observed in 96.4% of varenicline- and 82.5% of placebo-treated subjects during the study. Common varenicline-associated AEs were nausea (40.2%), abnormal dreams (22.7%), and insomnia (19.1%). Most AEs were considered mild or moderate in intensity. AEs leading to discontinuation of varenicline treatment included nausea (7.6%), insomnia (3.2%), and abnormal dreams (2.4%). A single varenicline-related serious AE, bilateral subcapsular cataracts, was observed. At week 52, 7-day point prevalence abstinence rates were 36.7% (varenicline) and 7.9% (placebo).Varenicline 1 mg BID can be safely administered for up to 1 year. Varenicline was also a more effective smoking cessation aid than placebo throughout the study, supporting both its short- (12-week) and long-term (52-week) efficacy.

The current guidelines for the evaluation and prediction of adverse cardiovascular events (CVEs) following vascular surgery in high-risk patients recommends serial electrocardiograms (ECGs) but not biomarkers such as cTn-I and CK-MB. The objective of this study was to determine whether biomarkers should be routinely measured in high-risk patients undergoing vascular surgery. A multicenter, prospective study with investigators blinded to core laboratory results was conducted. cTn-I and CK-MB were obtained on the day of surgery, as well as 24 hours, 72 hours and 120 hours after surgery, 24 hours prior to planned hospital discharge and at the onset of symptoms of a suspected CVE. The CVE was adjudicated by an endpoint committee using ECG, biomarker and symptoms data and was defined as cardiac death or myocardial infarction (MI) occurring up to 30 days after surgery. A total of 784 patients, with a mean age of 70.1 (SD ± 9.8), underwent vascular surgery. Of the 83 patients with a CVE, cTn-I was positive in 42 and CK-MB was positive in 29 on or before the day of the CVE. The number of patients not classified as having a CVE but positive for elevation of cTn-I or CK-MB was 64 and 20, respectively. cTn-I was more sensitive than CK-MB (50.6% versus 34.9%) for predicting a CVE. The optimum time for measuring cTn-I after surgery with the highest positive predictive value was 24 hours. In conclusion, these data support routine serial measurement of cTn-I after vascular surgery.

Improving lifestyle behaviours has considerable potential for reducing the global burden of non-communicable diseases, promoting better health across the life-course and increasing well-being. However, realising this potential will require the development, testing and implementation of much more effective behaviour change interventions than are used conventionally. Therefore, the aim of this study was to conduct a multi-centre, web-based, proof-of-principle study of personalised nutrition (PN) to determine whether providing more personalised dietary advice leads to greater improvements in eating patterns and health outcomes compared to conventional population-based advice. A total of 5,562 volunteers were screened across seven European countries; the first 1,607 participants who fulfilled the inclusion criteria were recruited into the trial. Participants were randomly assigned to one of the following intervention groups for a 6-month period: Level 0-control group-receiving conventional, non-PN advice; Level 1-receiving PN advice based on dietary intake data alone; Level 2-receiving PN advice based on dietary intake and phenotypic data; and Level 3-receiving PN advice based on dietary intake, phenotypic and genotypic data. A total of 1,607 participants had a mean age of 39.8 years (ranging from 18 to 79 years). Of these participants, 60.9 % were women and 96.7 % were from white-European background. The mean BMI for all randomised participants was 25.5 kg m(-2), and 44.8 % of the participants had a BMI >/= 25.0 kg m(-2). Food4Me is the first large multi-centre RCT of web-based PN. The main outcomes from the Food4Me study will be submitted for publication during 2015.

Background: The high prevalence of physical inactivity worldwide calls for innovative and more effective ways to promote physical activity (PA). There are limited objective data on the effectiveness of Web-based personalized feedback on increasing PA in adults. Objective: It is hypothesized that providing personalized advice based on PA measured objectively alongside diet, phenotype, or genotype information would lead to larger and more sustained changes in PA, compared with nonpersonalized advice. Methods: A total of 1607 adults in seven European countries were randomized to either a control group (nonpersonalized advice, Level 0, L0) or to one of three personalized groups receiving personalized advice via the Internet based on current PA plus diet (Level 1, L1), PA plus diet and phenotype (Level 2, L2), or PA plus diet, phenotype, and genotype (Level 3, L3). PA was measured for 6 months using triaxial accelerometers, and self-reported using the Baecke questionnaire. Outcomes were objective and self-reported PA after 3 and 6 months. Results: While 1270 participants (85.81% of 1480 actual starters) completed the 6-month trial, 1233 (83.31%) self-reported PA at both baseline and month 6, but only 730 (49.32%) had sufficient objective PA data at both time points. For the total cohort after 6 months, a greater improvement in self-reported total PA ( P =.02) and PA during leisure (nonsport) ( P =.03) was observed in personalized groups compared with the control group. For individuals advised to increase PA, we also observed greater improvements in those two self-reported indices ( P =.006 and P =.008, respectively) with increased personalization of the advice (L2 and L3 vs L1). However, there were no significant differences in accelerometer results between personalized and control groups, and no significant effect of adding phenotypic or genotypic information to the tailored feedback at month 3 or 6. After 6 months, there were small but significant improvements in the objectively measured physical activity level ( P

The study reported had three purposes, namely, to analyze the effect of aging (cohort groups 20–29, 60–69, 70–79, and 80–89 years of age), step length, and self-efficacy on the time to reacquire stability after the execution of a step. The analysis of force-platform data showed that the time to reacquire a stable posture after taking a step increased with increments of age. Correlation analysis showed that older adults were less confident in their ability to complete daily activities without falling or losing balance and that participants with lower levels of balance-related efficacy required a longer time to reacquire stability. These findings provide evidence that aging imposes temporal limitations in the regaining of postural stability that are related to individuals’ perceptions of balance and falls efficacy.

Thyroid hormone (T3) regulates bone turnover and mineralization in adults and is essential for skeletal development during childhood. Hyperthyroidism is an established risk factor for osteoporosis. Nevertheless, T3 actions in bone remain poorly understood. Patients with resistance to thyroid hormone, due to mutations of the T3-receptor beta (TRbeta) gene, display variable phenotypic abnormalities, particularly in the skeleton. To investigate the actions of T3 during bone development, we characterized the skeleton in TRbetaPV mutant mice. TRbetaPV mice harbor a targeted resistance to thyroid hormone mutation in TRbeta and recapitulate the human condition. A severe phenotype, which includes shortened body length, was evident in homozygous TRbetaPV/PV animals. Accelerated growth in utero was associated with advanced endochondral and intramembranous ossification. Advanced bone formation resulted in postnatal growth retardation, premature quiescence of the growth plates, and shortened bone length, together with increased bone mineralization and craniosynostosis. In situ hybridization demonstrated increased expression of fibroblast growth factor receptor-1, a T3-regulated gene in bone, in TRbetaPV/PV perichondrium, growth plate chondrocytes, and osteoblasts. Thus, the skeleton in TRbetaPV/PV mice is thyrotoxic and displays phenotypic features typical of juvenile hyperthyroidism.

Reduced GH levels have been associated with improved glucose metabolism and increased longevity despite obesity in multiple mouse lines. However, one mouse line, the GH receptor antagonist (GHA) transgenic mouse, defies this trend because it has reduced GH action and increased adiposity, but glucose metabolism and life span are similar to controls. Slight differences in glucose metabolism and adiposity profiles can become exaggerated on a high-fat (HF) diet. Thus, in this study, male and female GHA and wild-type (WT) mice in a C57BL/6 background were placed on HF and low-fat (LF) diets for 11 weeks, starting at 10 weeks of age, to assess how GHA mice respond to additional metabolic stress of HF feeding. On a HF diet, all mice showed significant weight gain, although GHA gained weight more dramatically than WT mice, with males gaining more than females. Most of this weight gain was due to an increase in fat mass with WT mice increasing primarily in the white adipose tissue perigonadal depots, whereas GHA mice gained in both the sc and perigonadal white adipose tissue regions. Notably, GHA mice were somewhat protected from detrimental glucose metabolism changes on a HF diet because they had only modest increases in serum glucose levels, remained glucose tolerant, and did not develop hyperinsulinemia. Sex differences were observed in many measures with males reacting more dramatically to both a reduction in GH action and HF diet. In conclusion, our findings show that GHA mice, which are already obese, are susceptible to further adipose tissue expansion with HF feeding while remaining resilient to alterations in glucose homeostasis.

Scope Personalised nutrition can be defined as dietary advice that is tailored to an individual. In recent years, the concept of targeted nutrition has evolved, which involves delivering specific dietary advice to a group of phenotypically similar individuals or metabotypes. This study examined whether cluster analysis could be used to define metabotypes and developed a strategy for the delivery of targeted dietary advice. Method and results K-means clustering was employed to identify clusters based on four markers of metabolic health (triacylglycerols, total cholesterol, direct HDL cholesterol and glucose) (n = 896) using data from the National Adult Nutrition Survey. A decision tree approach was developed for the delivery of targeted dietary advice per cluster based on biochemical characteristics, anthropometry and blood pressure. The appropriateness of the advice was tested by comparison with individualised dietary advice manually compiled (n = 99). A mean match of 89.1% between the methods was demonstrated with a 100% match for two-thirds of participants. Conclusion Good agreement was found between the individualised and targeted methods demonstrating the ability of this framework to deliver targeted dietary advice. This approach has the potential to be a fast and novel method for the delivery of targeted nutrition in clinical settings.

Diagnosis of neurological conversion disorder is difficult. Considerable overlap in symptomatology occurs with progressive neurological degenerative disease, pervasive refusal syndrome, depressive illness, chronic fatigue syndrome, and other conditions. Conversion symptoms can also coincide with organic neurological disease. Successful management requires a sensitive, confident, multidisciplinary approach. Multiple or repeated investigations can be counterproductive in resolving symptoms. This report describes three children, one male and two female, aged between 9 and 10 years, who were referred for evaluation of progressive neurological symptoms. Each progressed to a completely dependent state within 8 weeks of referral, requiring nasogastric feeding and total assisted care. A convincing psychosocial trigger was not identified in any case. Improvement occurred only when investigations were ceased and rehabilitation commenced. Long-term follow-up has revealed an excellent outcome for all three children.

GH receptor (GHR) gene-disrupted mice (GHR−/−) have provided countless discoveries as to the numerous actions of GH. Many of these discoveries highlight the importance of GH in adipose tissue. For example GHR−/− mice are insulin sensitive yet obese with preferential enlargement of the sc adipose depot. GHR−/− mice also have elevated levels of leptin, resistin, and adiponectin, compared with controls leading some to suggest that GH may negatively regulate certain adipokines. To help clarify the role that GH exerts specifically on adipose tissue in vivo, we selectively disrupted GHR in adipose tissue to produce Fat GHRKnockout (FaGHRKO) mice. Surprisingly, FaGHRKOs shared only a few characteristics with global GHR−/− mice. Like the GHR−/− mice, FaGHRKO mice are obese with increased total body fat and increased adipocyte size. However, FaGHRKO mice have increases in all adipose depots with no improvements in measures of glucose homeostasis. Furthermore, resistin and adiponectin levels in FaGHRKO mice are similar to controls (or slightly decreased) unlike the increased levels found in GHR−/− mice, suggesting that GH does not regulate these adipokines directly in adipose tissue in vivo. Other features of FaGHRKO mice include decreased levels of adipsin, a near-normal GH/IGF-1 axis, and minimal changes to a large assortment of circulating factors that were measured such as IGF-binding proteins. In conclusion, specific removal of GHR in adipose tissue is sufficient to increase adipose tissue and decrease circulating adipsin. However, removal of GHR in adipose tissue alone is not sufficient to increase levels of resistin or adiponectin and does not alter glucose metabolism.