Solid-state NMR spectra of amino acid enantiomers and their relative intensities.

Under normal experimental conditions in an achiral environment, NMR spectra of enantiomers have chemical shifts and J couplings which are not differentiable. In this work, the reproducibility of spectral intensities for pairs of amino acid enantiomers, as well as factors influencing these intensities, is assessed using 13C and 15N cross-polarization magic-angle spinning (CP/MAS) NMR spectroscopy. Prompted by a recent literature debate over a possible influence of the chirality-induced spin selectivity (CISS) effect on spectral intensities obtained in CP/MAS NMR experiments carried out on enantiomers, a number of control experiments were performed with recycle delays of at least 5T1. These included the analysis of proton-decoupled Bloch decay solid-state NMR spectra as well as solution NMR spectra where the cross polarization process is absent. Bloch decay and CP/MAS NMR spectra yield the same relative intensities for pairs of enantiomers while solution NMR spectra provide relative intensities closest to unity. Differences of plus-or-minus a few percent in the D/L spectral intensity ratios observed in all solid-state NMR experiments are due to sample preparation (i.e., grinding, particle size, partial amorphization) and limitations on sample purity. As previously described in the literature, more drastic intensity differences on the order of 50% are easily created by ball milling the samples. Finally, apodization is shown to invert the apparent D/L ratio in low signal-to-noise 15N CP/MAS NMR spectra of aspartic acid enantiomers. In summary, no spectral intensity differences attributable to enantiomerism are identified.

Sotagliflozin, a dual sodium-glucose co-transporter-1 and sodium-glucose co-transporter-2 inhibitor, reduces the risk of cardiovascular and kidney disease, as assessed by the Steno T1 Risk Engine in adults with type 1 diabetes.

AIMS: Sotagliflozin (SOTA) as adjunct to insulin therapy improves glycemic control, reduces body weight and blood pressure, and increases time in range in adults with type 1 diabetes (T1D). SOTA demonstrated CV and kidney benefits in high-risk adults with type 2 diabetes. These potential benefits using SOTA for T1D may collectively outweigh the risk of diabetic ketoacidosis. The present analysis estimated the risk of CVD and kidney failure in adults with T1D treated with SOTA. MATERIALS AND METHODS: Participant-level data were used from the inTandem trials evaluating 2980 adults with T1D randomized to once-daily placebo, SOTA 200 mg, or SOTA 400 mg for 24 weeks. For each participant, the cumulative risks of developing CVD and kidney failure were estimated using the Steno T1 Risk Engine. A subgroup analysis was performed in participants with BMI ≥ 27 kg/m2 . RESULTS: SOTA significantly reduced the predicted 5- and 10-year CVD risk in the SOTA 200 and 400 mg pooled group with a relative change in the SOTA group compared to the relative change in the placebo group of (mean [95%-confidence interval (CI)]) -6.6 (-7.9, -5.3) % and -6.4 (-7.6, -5.1) % (p < 0.0001 for both) respectively. For the 5-year ESKD risk there was a significant reduction with a relative change of -5.0 (-7.6, -2.3) % (p = 0.0003). Similar results were observed with the individual doses and in participants with BMI ≥ 27 kg/m2 . CONCLUSION: This analysis provides additional clinical results that may positively balance the benefit/risk assessment of SGLT inhibition use in T1D.

Using supervised machine learning approach to predict treatment outcomes of vedolizumab in ulcerative colitis patients.

With recent advances in machine learning, we demonstrated the use of supervised machine learning to optimize the prediction of treatment outcomes of vedolizumab through iterative optimization using VARSITY and VISIBLE 1 data in patients with moderate-to-severe ulcerative colitis. The analysis was carried out using elastic net regularized regression following a 2-stage training process. The model performance was assessed through AUROC, specificity, sensitivity, and accuracy. The generalizable predictive patterns suggest that easily obtained baseline and medical history variables may be able to predict therapeutic response to vedolizumab with clinically meaningful accuracy, implying a potential for individualized prescription of vedolizumab.

A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis).

OBJECTIVES: Inflammasomes are multiprotein complexes that sense pathogens and trigger biological mechanisms to control infection. Nucleotide-binding oligomerisation domain-like receptor (NLR) containing a PYRIN domain 1 (NLRP1), NLRP3 and NLRC4 plays a key role in this innate immune system by directly assembling in inflammasomes and regulating inflammation. Mutations in NLRP3 and NLRC4 are linked to hereditary autoinflammatory diseases, whereas polymorphisms in NLRP1 are associated with autoimmune disorders such as vitiligo and rheumatoid arthritis. Whether human NLRP1 mutation is associated with autoinflammation remains to be determined. METHODS: To search for novel genes involved in systemic juvenile idiopathic arthritis, we performed homozygosity mapping and exome sequencing to identify causative genes. Immunoassays were performed with blood samples from patients. RESULTS: We identified a novel disease in three patients from two unrelated families presenting diffuse skin dyskeratosis, autoinflammation, autoimmunity, arthritis and high transitional B-cell level. Molecular screening revealed a non-synonymous homozygous mutation in NLRP1 (c.2176C>T; p.Arg726Trp) in two cousins born of related parents originating from Algeria and a de novo heterozygous mutation (c.3641C>G, p.Pro1214Arg) in a girl of Dutch origin. The three patients showed elevated systemic levels of caspase-1 and interleukin 18, which suggested involvement of NLRP1 inflammasome. CONCLUSIONS: We demonstrate the responsibility of human NLRP1 in a novel autoinflammatory disorder that we propose to call NAIAD for NLRP1-associated autoinflammation with arthritis and dyskeratosis. This disease could be a novel autoimmuno-inflammatory disease combining autoinflammatory and autoimmune features. Our data, combined with that in the literature, highlight the pleomorphic role of NLRP1 in inflammation and immunity. TRIAL REGISTRATION NUMBER: NCT02067962; Results.

Identification of disrupted AUTS2 and EPHA6 genes by array painting in a patient carrying a de novo balanced translocation t(3;7) with intellectual disability and neurodevelopment disorder.

Intellectual disability (ID) is a frequent feature but is highly clinically and genetically heterogeneous. The establishment of the precise diagnosis in patients with ID is challenging due to this heterogeneity but crucial for genetic counseling and appropriate care for the patients. Among the etiologies of patients with ID, apparently balanced de novo rearrangements represent 0.6%. Several mechanisms explain the ID in patients with apparently balanced de novo rearrangement. Among them, disruption of a disease gene at the breakpoint, is frequently evoked. In this context, technologies recently developed are used to characterize precisely such chromosomal rearrangements. Here, we report the case of a boy with ID, facial features and autistic behavior who is carrying a de novo balanced reciprocal translocation t(3;7)(q11.2;q11.22)dn. Using microarray analysis, array painting (AP) technology combined with molecular study, we have identified the interruption of the autism susceptibility candidate 2 gene (AUTS2) and EPH receptor A6 gene (EPHA6). We consider that the disruption of AUTS2 explains the phenotype of the patient; the exact role of EPHA6 in human pathology is not well defined. Based on the observation of recurrent germinal and somatic translocations involving AUTS2 and the molecular environment content, we put forward the hypothesis that the likely chromosomal mechanism responsible for the translocation could be due either to replicative stress or to recombination-based mechanisms.

Beta-Hydroxybutyrate Levels and Risk of Diabetic Ketoacidosis in Adults with Type 1 Diabetes Treated with Sotagliflozin.

Introduction: Sodium glucose cotransporter inhibitors may increase beta-hydroxybutyrate (BHB) in insulin-requiring patients. We determined factors associated with BHB changes from baseline (ΔBHB) and diabetic ketoacidosis (DKA) in patients with type 1 diabetes (T1D) receiving sotagliflozin as an insulin adjunct. Research Design and Methods: This post hoc analysis compared ΔBHB levels in adults with T1D receiving sotagliflozin 400 mg or placebo for 6 months. We evaluated clinical and metabolic factors associated with ΔBHB and used logistic regression models to determine predictors associated with BHB values >0.6 and >1.5 mmol/L (inTandem3 population; N = 1402) or with DKA events in a pooled analysis (inTandem1-3; N = 2453). Results: From baseline (median, 0.13 mmol/L), median fasting BHB increased by 0.04 mmol/L (95% confidence interval, 0.03-0.05; P < 0.001) at 24 weeks with sotagliflozin versus placebo; 67% of patients had no or minimal changes in BHB over time. Factors associated with on-treatment BHB >0.6 or >1.5 mmol/L included baseline BHB and sotagliflozin use. Age, insulin pump use, sotagliflozin use, baseline BHB, and ΔBHB were significantly associated with DKA episodes. Independent of treatment, DKA risk increased by 18% with each 0.1-mmol/L increase in baseline BHB and by 8% with each 0.1-mmol/L increase from baseline. Conclusion: Incremental increases in baseline BHB and ΔBHB were associated with a higher DKA risk independent of treatment. Adding sotagliflozin to insulin increased median BHB over 24 weeks in patients with T1D and was associated with increased DKA events. These results highlight the importance of BHB testing and monitoring and individualizing patient education on DKA risk, mitigation, identification, and treatment.

Strain-specific differences in the genetic control of two closely related mycobacteria.

The host response to mycobacterial infection depends on host and pathogen genetic factors. Recent studies in human populations suggest a strain specific genetic control of tuberculosis. To test for mycobacterial-strain specific genetic control of susceptibility to infection under highly controlled experimental conditions, we performed a comparative genetic analysis using the A/J- and C57BL/6J-derived recombinant congenic (RC) mouse panel infected with the Russia and Pasteur strains of Mycobacterium bovis Bacille Calmette Guérin (BCG). Bacillary counts in the lung and spleen at weeks 1 and 6 post infection were used as a measure of susceptibility. By performing genome-wide linkage analyses of loci that impact on tissue-specific bacillary burden, we were able to show the importance of correcting for strain background effects in the RC panel. When linkage analysis was adjusted on strain background, we detected a single locus on chromosome 11 that impacted on pulmonary counts of BCG Russia but not Pasteur. The same locus also controlled the splenic counts of BCG Russia but not Pasteur. By contrast, a locus on chromosome 1 which was indistinguishable from Nramp1 impacted on splenic bacillary counts of both BCG Russia and Pasteur. Additionally, dependent upon BCG strain, tissue and time post infection, we detected 9 distinct loci associated with bacillary counts. Hence, the ensemble of genetic loci impacting on BCG infection revealed a highly dynamic picture of genetic control that reflected both the course of infection and the infecting strain. This high degree of adaptation of host genetics to strain-specific pathogenesis is expected to provide a suitable framework for the selection of specific host-mycobacteria combinations during co-evolution of mycobacteria with humans.

Sex differences in the association between sleep duration, diet and body mass index: a birth cohort study.

Sex differences in the effects of sleep duration on dietary intake and eating behaviours were examined prospectively in relation to overweight/obesity at ages 6 and 7. Using data from a representative sample (QLSCD 1998-2010) of children born in the province of Québec (Canada), 1106 children were followed to age 6 and 1015 to 7years. Average nocturnal sleep duration was surveyed annually from 2.5-6years, food-frequency and eating behaviour questionnaires were administered at age 6, and body weight and height were measured at 6 and 7years. Associations were examined longitudinally and mediation examined with adjustments for potential confounders. In boys and girls, shorter sleep duration patterns were associated significantly with less favourable dietary intakes at 6years: boys consumed vegetables and fruits less frequently and meats/alternatives more frequently than boys with longer sleep patterns; and girls consumed vegetables, fruits and milk products less frequently and soft-drinks more frequently than girls with longer sleep patterns. However, boys with shorter sleep patterns were also more likely to eat at irregular hours or to eat too much/fast at 6years. These behaviours, and not dietary intake, mediated an inverse association between sleep duration and overweight/obesity in boys. Sleep duration did not associate with any problem eating behaviours or overweight/obesity in girls. Shorter sleep in early childhood appears to associate with problematic eating behaviours in boys and diet quality in both sexes, regardless of an association with overweight/obesity. This is important for public health and should be considered in relation to other diet-related diseases.

Higher intakes of energy and grain products at 4 years of age are associated with being overweight at 6 years of age.

This study examined dietary factors associated with overweight in a population-based sample of 6-y-old children. Analyses of data from the Québec Longitudinal Study of Child Development (QLSCD) included a representative sample (n = 1014) of children born in 1998 in the province of Québec, Canada. Dietary intake was measured by using a 24-h dietary recall administered at 4 y of age. Weight and height were measured using a standard protocol at 6 y. Using logistic regression, higher daily energy intake at 4 y was significantly related to overweight at 6 y. After adjustment for confounding and overweight at 4 y, the relationship remained significant among girls (P = 0.04) but became marginally significant among boys (P = 0.07). Additionally, boys who consumed ≥5 servings of grain products/d at 4 y were more likely to be overweight at 6 y compared to those who did not [adjusted OR = 3.20 (95% CI): 1.72-5.97]. The association attenuated somewhat after adjustment for overweight at 4 y [OR = 1.82 (95% CI): 0.894-3.71; P = 0.09]. The findings provide support for the revisions made in the Canadian dietary guidelines for young children, which now recommend 4-7 servings of grain products daily for children aged 4-8 y rather than the excessive 5-12 servings of previous recommendations.

Demographic and socio-economic factors related to food intake and adherence to nutritional recommendations in a cohort of pre-school children.

OBJECTIVE: To examine: (i) children's food intake and adherence to both Canada's Food Guide for Healthy Eating and Dietary Reference Intakes; and (ii) the social and demographic factors related to children's food intake. DESIGN: A cross-sectional study. SETTING: Data were obtained through the Quebec Longitudinal Study of Child Development 1998-2010, a representative sample (n 2103) of children born in 1998 in the province of Quebec, Canada. Information on energy, macronutrient and food consumption was derived from responses to a 24 h dietary recall interview addressed to children's mothers and day-care staff when the children were 4 years old. SUBJECTS: A total of 1549 children aged 4 years who participated in a nutritional sub-study. RESULTS: The mean daily total energy intake was 6360 kJ (1520 kcal) for girls and 6916 kJ (1653 kcal) for boys. For boys and girls alike, energy intake was comprised of approximately 54 % carbohydrates, 31 % fats and 15 % proteins. The mean number of servings consumed from each of the four essential food groups closely approached the dietary recommendations made by Canada's Food Guide for Healthy Eating; however, <2 % of the children in the present study actually met the full dietary guidelines. The dietary intake of pre-school children was associated with socio-economic and demographic factors, most notably mother's level of education, mother's immigrant status and sex of the child. CONCLUSIONS: Diet-related disparities associated with socio-economic and demographic factors exist from as early as 4 years of age.

Household food insecurity and childhood overweight in Jamaica and Québec: a gender-based analysis.

BACKGROUND: Childhood overweight is not restricted to developed countries: a number of lower- and middle-income countries are struggling with the double burden of underweight and overweight. Another public health problem that concerns both developing and, to a lesser extent, developed countries is food insecurity. This study presents a comparative gender-based analysis of the association between household food insecurity and overweight among 10-to-11-year-old children living in the Canadian province of Québec and in the country of Jamaica. METHODS: Analyses were performed using data from the 2008 round of the Québec Longitudinal Study of Child Development and the Jamaica Youth Risk and Resiliency Behaviour Survey of 2007. Cross-sectional data were obtained from 1190 10-year old children in Québec and 1674 10-11-year-old children in Jamaica. Body mass index was derived using anthropometric measurements and overweight was defined using Cole's age- and sex-specific criteria. Questionnaires were used to collect data on food insecurity. The associations were examined using chi-square tests and multivariate regression models were used to estimate odds ratios (OR) and 95% confidence intervals. RESULTS: The prevalence of overweight was 26% and 11% (p < 0.001) in the Québec and Jamaican samples, respectively. In Québec, the adjusted odds ratio for being overweight was 3.03 (95% CI: 1.8-5.0) among children living in food-insecure households, in comparison to children living in food-secure households. Furthermore, girls who lived in food-insecure households had odds of 4.99 (95% CI: 2.4-10.5) for being overweight in comparison to girls who lived in food-secure households; no such differences were observed among boys. In Jamaica, children who lived in food-insecure households had significantly lower odds (OR 0.65, 95% CI: 0.4-0.9) for being overweight in comparison to children living in food-secure households. No gender differences were observed in the relationship between food-insecurity and overweight/obesity among Jamaican children. CONCLUSIONS: Public health interventions which aim to stem the epidemic of overweight/obesity should consider gender differences and other family factors associated with overweight/obesity in both developed and developing countries.

Parental overweight/obesity, social factors, and child overweight/obesity at 7 years of age.

BACKGROUND: This study used gender-based analyses to examine whether child overweight/obesity is related to parental overweight/obesity and sociodemographic factors, in a representative population-based cohort of 7-year-old children. METHODS: Data from the Québec Longitudinal Study of Child Development 1998-2010 was used. Children (n= 1336) were randomly selected from each public health region of Québec. The study was based on face-to-face interviews and a set of questionnaires addressed to mothers and fathers. RESULTS: Compared to children with no overweight/obese parent, the adjusted odds ratio (OR) of being overweight/obese with two overweight/obese parents was 5 for boys (95% confidence interval [CI]: 2.31-10.85) and 5.87 for girls (95%CI: 2.63-13.12). Gender differences appeared when one parent was overweight/obese. For girls, having either an overweight/obese mother (OR, 3.10; 95%CI: 1.14-8.38) or father (OR, 3.64; 95%CI: 1.68-7.91) significantly increased the odds of being overweight/obese at 7 years. For boys, however, having only an overweight/obese father (OR, 2.05; 95%CI: 1.01-4.16) was related to overweight/obesity, but having only an overweight/obese mother was not related to overweight/obesity at 7 years for boys. In girls, but not in boys, having an immigrant mother also significantly related to overweight/obesity (OR, 2.71; 95%CI: 1.28-5.75) at 7 years, after controlling for other social factors. CONCLUSIONS: Gender differences in socialization may explain why at 7 years of age, girls' bodyweight is influenced by having even one overweight/obese parent (mother or father), while boys' bodyweight appears to be influenced only by father's overweight/obesity when only one parent is overweight/obese.

Psychosocial determinants of the early introduction of complementary foods.

Infant feeding guidelines recommend exclusive breast-feeding to the age of 6 months; complementary foods should not be introduced before this age. This study examined parent and infant psychosocial determinants of the early introduction of complementary foods. Analyses were conducted on a representative sample of children born in Québec (Canada) in 1998 (n = 2,223), surveyed through the Québec Longitudinal Study of Child Development. Of the children, 61% received complementary foods prior to the age of 4 months. A multiple logistic regression analysis revealed the early introduction of complementary foods was more likely when mothers were younger, less educated, of lower socioeconomic class, and when they felt they had little influence on their child's development. Higher parental confidence in caring for the infant was also associated with the early introduction of complementary foods (p < or = .05). Future research must carefully consider the psychosocial aspects involved in adhering to infant feeding guidelines.

Problem eating behaviors related to social factors and body weight in preschool children: A longitudinal study.

BACKGROUND: Despite the increasing prevalence of overweight/obesity and its association to eating patterns in adolescents and adults, little is known about the relationship between problematic eating behaviours and body weight in the preschool years within the context of various social factors. This research aims to analyze the relationship between social factors, mothers' perceptions of their child's eating behaviour (picky eating and overeating), and body weight in preschool years, in a population-based cohort of preschoolers from Québec (Canada). METHODS: Analyses were performed on 1498 children from the Longitudinal Study of Child Development in Québec, a representative sample of children born in 1998 in the Canadian province of Québec. Eating behaviours (picky eating and overeating) were derived from questionnaires at 2.5, 3.5, and 4.5 years of age. BMI was calculated from children's measured height and weight at 4.5 years. Children's sex and birth weight, mothers' age, immigrant status, smoking status during pregnancy, and education level, family type, annual household income and income sufficiency, the number of overweight/obese parents, children's day-care attendance, and food insufficiency were part of the analysis. Multivariate logistic regressions were used to determine odds ratios for different body weight profiles (underweight, normal weight, at risk of overweight, overweight), and one-way analysis-of-variances (ANOVA) allowed for group comparisons of means. RESULTS: The proportion of children reported for each eating behaviour category remained quite stable across the years studied. Picky eating and overeating related to body weight among 4.5-year-old children, even when social and parental factors were accounted for in multivariate analysis. Picky eaters were twice as likely to be underweight at 4.5 years as children who were never picky eaters. Adjusted odds ratios revealed overeaters were 6 times more likely to be overweight at 4.5 years than were children who were never overeaters. CONCLUSION: Given the association between eating behaviours and bodyweight among 4.5-year-old children, particularly among those from less educated, lower income families and younger mothers, health professionals should target parents of children at risk of overweight/obesity and underweight with focussed messages and strategies for the management of emerging problematic eating behaviours.

Regular sugar-sweetened beverage consumption between meals increases risk of overweight among preschool-aged children.

OBJECTIVE: To examine the relationship between consumption of sugar-sweetened beverages (eg, nondiet carbonated drinks and fruit drinks) and the prevalence of overweight among preschool-aged children living in Canada. DESIGN: Data come from the Longitudinal Study of Child Development in Québec (1998-2002). SUBJECTS/SETTING: A representative sample (n=2,103) of children born in 1998 in Québec, Canada. A total of 1,944 children (still representative of the same-age children in this population) remaining at 4 to 5 years in 2002 participated in the nutrition study. STATISTICAL ANALYSES PERFORMED: Data were collected via 24-hour dietary recall interview. Frequency of sugar-sweetened beverage consumption between meals at age 2.5, 3.5, and 4.5 years was recorded and children's height and weight were measured. Multivariate regression analysis was done with Statistical Analysis System software. Weighted data were adjusted for within-child variability and significance level was set at 5%. RESULTS: Overall, 6.9% of children who were nonconsumers of sugar-sweetened beverages between meals between the ages of 2.5 to 4.5 years were overweight at 4.5 years, compared to 15.4% of regular consumers (four to six times or more per week) at ages 2.5 years, 3.5 years, and 4.5 years. According to multivariate analysis, sugar-sweetened beverage consumption between meals more than doubles the odds of being overweight when other important factors are considered in multivariate analysis. Children from families with insufficient income who consume sugar-sweetened beverages regularly between the ages of 2.5 and 4.5 years are more than three times more likely to be overweight at age 4.5 years compared to nonconsuming children from sufficient income households. CONCLUSIONS: Regular sugar-sweetened beverage consumption between meals may put some young children at a greater risk for overweight. Parents should limit the quantity of sweetened beverages consumed during preschool years because it may increase propensity to gain weight.

Genetic and environmental influences on body size in early childhood: a twin birth-cohort study.

Genetic and environmental contributions to body size from birth to 5 years in a population-based twin cohort were studied. Sex differences in gene-environment etiology were also explored. Analyses used data from the Quebec Newborn Twin Study (QNTS), a population-based birth cohort of 672 twin pairs. The final sample consisted of 177 complete twin pairs. Heritability of weight was moderate at birth while common environmental factors accounted for almost half of the variance. Influence of family environment disappeared by 5 months and genetic effects were high (approximately 90%) for both sexes at 5 months and 5 years. Adjustment of weight for height yielded similar results as for weight alone. Slight but significant sex-limitation of genetic effects was observed at 5 months. Overall, genetic factors accounted for 40% of birthweight variance, with intrauterine environment influences explaining almost half. However, genetic factors accounted for most of the variance in weight. These results do not imply a lack of environmental effects on body weight, but rather a lack of: (1) environmental effects that are independent from genetic liability, and/or (2) a lack of significant environmental variation in the population (e.g., uniform nutritional habits) that leaves genetic differences between children to generate most of the variance in weight.

Determinants of high birth weight by geographic region in Canada.

This study aims to analyze the determinants of high birth weight (> 4000 grams) by various geographic regions of Canada. Analyses were performed using the data from cycles 1 to 4 (1994-2001; N=20,002 children) of the Canadian National Longitudinal Survey of Children and Youth (NLSCY). Children were grouped into five geographic residential area categories: the Atlantic provinces, Quebec, Ontario, the Prairie provinces and British Columbia. Determinants analyzed in the study include sex, gestational age and birth rank of children; maternal age and education; maternal smoking during pregnancy; family type; family socioeconomic status (SES) and maternal health (postpartum depression; hypertension and prescription drug use during pregnancy). In comparison to Quebec, the odds of giving birth to a high-birth-weight child were 25 percent higher in Ontario, 41 percent higher in the Atlantic provinces and 53 percent higher in British Columbia. In Quebec, non-smoking mothers of higher SES had increased odds of delivering a baby weighing more than 4000 grams, while in British Columbia, the odds of having a birth weight greater than 4000 grams doubled for children of non-smoking mothers from the lowest SES quintiles. The relationship between social disparities and macrosomia was found to vary by geographic region.