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We aimed to develop a registry ('Keto-Reg') for individuals with epilepsy referred for ketogenic dietary therapy (KDT) and to test feasibility of its implementation. The purpose of the registry is to provide a platform for collaborative research to answer specific research questions regarding long-term clinical and safety outcomes and to identify the most suitable candidates for KDT. Registry data items were determined via an international Delphi survey of KDT healthcare professionals, and then entered into an electronic platform. Three UK and two other European KDT centres entered data for 10 'patients' and reported on its acceptability and feasibility of use via questionnaire. 25 % of data was validated against medical records. A national survey was distributed and 19 parents and four young people were interviewed about a potential future patient/family section to the registry. Healthcare professionals from six continents responded to the Delphi (n = 153 round 1, n = 79 round 2); 70 items reached the agreement threshold. Registry data entry was accurate (0.3 % errors identified) and reported to be feasible and acceptable in the short-term. Lack of time was identified as the main barrier to longer-term implementation, with funded hours required. 87 % of the 53 survey responders and all interviewees viewed a patient/family section to be positive and feasible. We have shown healthcare professional involvement in Keto-Reg to be feasible in the short-term, and have identified what is necessary for the next stage: prospective longitudinal data entry from a larger number of international centres., Competing Interests: Declaration of competing interest NES was previously supported for a research post by Vitaflo (International). She has received grants from Nutricia Advanced Medical Nutrition, Vitaflo (International), and Matthew's Friends charity, and honoraria from Nutricia Advanced Medical Nutrition, Vitaflo (International), and Dr Schaer. EGN has received consultancy payments and honoraria from Vitaflo (International), Kanso and Cerecin. EVL has received research grants from Nutricia Advanced Medical Nutrition and Vitaflo (international) and stichting de Merel, all money paid to the department. VW has received grants from Nutricia Advanced Medical Nutrition, Vitaflo (International), and Matthew's Friends charity, and honoraria from Nutricia Advanced Medical Nutrition, Vitaflo (International), and Cambrooke Ajinomoto. AMD is on the advisory boards of Nutricia, Takeda, Biocodex; speaker/industry trainer/symposia chair for GW Pharma, Nutricia Advanced Medical Nutrition, UCB, Zogenix. LL is a consultant/speaker for LivaNova, UCB Pharma, Zogenix, Eisai, Shire, Takeda, Novartis and Jazz Pharmaceuticals; and has a patent for Fenfluramine for the treatment of Dravet syndrome and infantile epilepsies assigned to his institution and licensed to Zogenix/UCB. ZS has received honoraria from Vitaflo (International), Nutricia Advanced Medical Nutrition and Danone Trading Medical B.V. JHC received grants from Vitaflo (International), GW Pharmaceuticals, Zogenix, Marinius, and Ovid; has received honoraria from Nutricia; and has a patent nutritional product (WO2013186570) and a patent anticonvulsant compound (WO2016038379A1) issued. CE received honoraria from GW Pharmaceuticals/JAZZ Pharmaceuticals. AS has received freelance payments from Vitaflo (International)., (Copyright © 2024. Published by Elsevier Ltd.)

Ultra-high vacuum scanning tunneling microscopy (UHV-STM) was used to investigate two related molecules pulse-deposited onto Au(111) surfaces: indoline-2-carboxylic acid and proline (pyrrolidine-2-carboxylic acid). Indoline-2-carboxylic acid and proline form both dimers and C 5 -symmetric "pinwheel" pentamers. Enantiomerically pure S -(-)-indoline-2-carboxylic acid and S -proline were used, and the pentamer structures observed for both were chiral. However, the presence of apparently equal numbers of 'right-' and 'left-handed' pinwheels is contrary to the general understanding that the chirality of the molecule dictates supramolecular chirality. A variety of computational methods were used to elucidate pentamer geometry for S -proline. Straightforward geometry optimization proved difficult, as the size of the cluster and the number of possible intermolecular interactions produced an interaction potential with multiple local minima. Instead, the Amber force field was used to exhaustively search all of phase space for chemically reasonable pentamer structures, producing a limited number of candidate structures that were then optimized as gas-phase clusters using density functional theory (DFT). The binding energies of the two lowest-energy pentamers on the Au(111) surface were then calculated by plane-wave DFT using the VASP software, and STM images predicted. These calculations indicate that the right- and left-handed pentamers are instead two different polymorphs.

There is concern that during a low-risk pregnancy, women are consuming more than recommended (400 µg/day) supplemental folic acid and may not meet recommendations for other nutrients. The objective of this study was to determine folic acid supplement use and dietary folate intakes in the second trimester (week 18) of pregnancy in women ( n  = 2996) in the Canadian CHILD cohort study. Vitamin B12 and choline intakes were also assessed because they are metabolically related to folate. The majority of participants (71.6%) were consuming a daily prenatal supplement. Twenty-eight percent of women ( n  = 847) reported consuming a folic acid supplement and of these women, 45.3% had daily supplemental folic acid intakes above the upper intake level (UL; 1000 µg/day). Daily dietary folate intakes were (mean (SD)) 575 (235) DFE µg/day. In contrast, only 24.8% of women met the dietary choline adequate intake (AI) recommendation (AI ≥ 450 mg/day) with a mean (SD) intake of 375 (151) mg/day. Further understanding of the impact of supplemental folic acid intake above the UL and low choline intake during pregnancy requires further investigation., Competing Interests: Authors have no conflicts of interest to disclose.

Background: During the COVID-19 pandemic, Ireland implemented a series of stringent public health measures, including lockdowns and suspension of non-urgent clinical services., Aims: To investigate the impact of the COVID-19 pandemic on the demand for and delivery of speech and language therapy (SLT) services in Ireland in 2020., Methods & Procedures: Two iterations of a cross-sectional, mixed-methods online survey were distributed to speech and language therapists (SLTs) and SLT students in Ireland in the spring and autumn of 2020 using a combination of purposive and snowball sampling. The spring survey yielded 407 responses (including 14 from SLT students), while 197 respondents took part in the autumn (13 students). Survey analysis focused on questions related to the impact of the COVID-19 pandemic on delivery and demand for SLT services (student responses were excluded from analysis owing to low response rate). The largest group in respect of experience were senior SLTs (58% in both surveys). The work settings most strongly represented were HSE primary care (34.4%) and disability services (26.5%) in the spring, and HSE primary care (39.1%), acute hospitals (22.8%) and disability services (20.8%) in the autumn. We used descriptive statistics, including distribution analysis, to analyse the quantitative data. Free text data were interrogated through a variant of a conventional qualitative content analysis., Outcomes & Results: In the spring, cessation of face-to-face services featured prominently (reported by 65.6% versus 14.2% in the autumn), across SLTs' work settings, except acute hospitals. Lower demand was reported by 42.5% in the spring, while in the autumn, 48.7% indicated that demand was higher. SLTs experienced large-scale redeployment (spring: 45.9%, autumn: 38.4%), with HSE primary care SLTs redeployed most (spring: 71.7%; autumn: 62.3%). The need to suddenly pivot to telehealth was a significant challenge in terms of training, technology and logistics. New ways of working emerged and gradually, telehealth became more embedded. SLTs also had to adapt to working with evolving public health measures, such as space restrictions and personal protective equipment (PPE) requirements. Across the two survey iterations, SLTs reported tensions between demands and capacity: while referrals and demand initially decreased in the spring, this led to increased backlog and longer waiting lists, ongoing and increasing pressure on clinicians and services, and negatively impacted clients and families., Conclusions & Implications: The COVID-19 pandemic had a significant negative impact on SLT services in Ireland. Going forward, the SLT profession and its services will require sustained support to mitigate long-term negative consequences, such as increased waiting lists., What This Paper Adds: What is already known on this subject The negative impact of the COVID-19 pandemic on SLT services has been examined in several countries. Ireland imposed more stringent pandemic-management measures than many other countries, and it was therefore warranted to investigate how SLT services in the country were affected. What this study adds to the existing knowledge Face-to-face SLT services effectively ceased in most non-urgent contexts in spring 2020. This coincided with large-scale redeployment of SLTs to non-SLT contexts. By autumn 2020, demand had increased again, but not all services had recommenced, and redeployment was still a factor. Although SLTs adapted to the ongoing changes imposed by the pandemic, they voiced concern about increasing backlogs and longer waiting lists, ongoing and increasing pressure on both SLTs and services, and negative impacts on clients and families. What are the actual and clinical implications of this work? The COVID-19 pandemic had a significant negative impact on SLT services in Ireland. Going forward, the SLT profession and its services will require sustained support to mitigate long-term negative consequences, such as increased waiting lists., (© 2023 The Authors. International Journal of Language & Communication Disorders published by John Wiley & Sons Ltd on behalf of Royal College of Speech and Language Therapists.)

Folic acid supplementation is recommended during pregnancy to support healthy fetal development; (6 S )-5-methyltetrahydrofolic acid ((6 S )-5-MTHF) is available in some commercial prenatal vitamins as an alternative to folic acid, but its effect on blood folate status during pregnancy is unknown. To address this, we randomised sixty pregnant individuals at 8-21 weeks' gestation to 0·6 mg/d folic acid or (6 S )-5-MTHF × 16 weeks. Fasting blood specimens were collected at baseline and after 16 weeks (endline). Erythrocyte and serum folate were quantified via microbiological assay (as globally recommended) and plasma unmetabolised folic acid (UMFA) via LC-MS/MS. Differences in biochemical folate markers between groups were explored using multivariable linear/quantile regression, adjusting for baseline concentrations, dietary folate intake and gestational weeks. At endline ( n 54), the mean values and standard deviations (or median, inter-quartile range) of erythrocyte folate, serum folate and plasma UMFA (nmol/l) in those supplemented with (6 S )-5-MTHF v . folic acid, respectively, were 1826 (sd 471) and 1998 (sd 421); 70 (sd 13) and 78 (sd 17); 0·5 (0·4, 0·8) and 1·3 (0·9, 2·1). In regression analyses, erythrocyte and serum folate did not differ by treatment group; however, concentrations of plasma UMFA in pregnancy were 0·6 nmol/l higher (95 % CI 0·2, 1·1) in those supplementing with folic acid as compared with (6 S )-5-MTHF. In conclusion, supplementation with (6 S )-5-MTHF may reduce plasma UMFA by ∼50 % as compared with supplementation with folic acid, the biological relevance of which is unclear. As folate is currently available for purchase in both forms, the impact of circulating maternal UMFA on perinatal outcomes needs to be determined.

This paper investigates how office-based physicians respond to Medicare reimbursement changes. Using variation from an Affordable Care Act policy that increased reimbursements for office-based care in four states, we use a triple difference analysis, comparing physicians with higher and lower reimbursement changes in treated states to similar physicians in untreated states. We find two mechanisms through which physicians respond. First, the reimbursement change affected integration-physicians with larger increases in office-based reimbursement were less likely to vertically integrate with hospitals and more likely to continue providing office-based care than physicians with smaller reimbursement increases. Second, we find some evidence that physicians who continued practicing in an office setting increased the volume of services provided., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Epidemiological studies have reported discrepant findings on the relationship between folic acid intake during pregnancy and risk for gestational diabetes mellitus (GDM). To begin to understand how folic acid impacts metabolic health during pregnancy, we determined the effects of excess folic acid supplementation (5× recommendation) on maternal and fetal offspring metabolic health. Using a mouse (female C57BL/6J) model of diet-induced diabetes in pregnancy (western diet) and control mice, we show that folic acid supplementation improved insulin sensitivity in the female mice fed the western diet and worsened insulin sensitivity in control mice. We found no unmetabolized folic acid in liver from supplemented mice suggesting the metabolic effects of folic acid supplementation are not due to unmetabolized folic acid. Male fetal (gestational day 18.5) offspring from folic acid supplemented dams (western and control) had greater beta cell mass and density than those from unsupplemented dams; this was not observed in female offspring. Differential sex-specific hepatic gene expression profiles were observed in the fetal offspring from supplemented dams but this differed between western and controls. Our findings suggest that folic acid supplementation affects insulin sensitivity in female mice, but is dependent on their metabolic phenotype and has sex-specific effects on offspring pancreas and liver., (© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Prenatal exposure to maternal depression and serotonin reuptake inhibitor (SRI) antidepressants both affect the development of the hypothalamic-pituitary-adrenal (HPA) system, possibly via the neurotransmitter serotonin (5HT). In a community cohort, we investigated the impact of two factors that shape prenatal 5HT signaling (prenatal SRI [pSRI] exposure and child SLC6A4 genotype) on HPA activity at age 6 years. Generalized estimating equation (GEE) models were used to study associations between cortisol reactivity, pSRI exposure, and child SLC6A4 genotype, controlling for maternal depression, child age, and sex (48 pSRI exposed, 74 nonexposed). Salivary cortisol levels were obtained at five time points during a laboratory stress challenge: arrival at the laboratory, following two sequential developmental assessments, and then 20 and 40 min following the onset of a stress-inducing cognitive/social task. Cortisol decreased from arrival across both developmental assessments, and then increased across both time points following the stress challenge in both groups. pSRI-exposed children had lower cortisol levels across all time points. In a separate GEE model, we observed a lower cortisol stress response among children with L G /S alleles compared with children with La/La alleles, and this was particularly evident among children of mothers reporting greater third trimester depressed mood. Our findings suggest that pSRI exposure and a genetic factor associated with modulating 5HT signaling shaped HPA reactivity to a laboratory stress challenge at school age., (© 2023 Wiley Periodicals LLC.)

Solvent exchange of synthesis solvent within metal-organic frameworks (MOFs) is an essential process for the activation of coordinatively unsaturated sites (CUS) to achieve an optimal surface area; activation of the CUS is required to exploit the versatile applications of MOFs. However, it is challenging to replace CUS-bound synthesis solvent prior to MOF activation, which can lead to a structural collapse and reduced surface area post-evacuation. Herein, we quantify the exchange behavior of a copper paddlewheel-based CUS-MOF (HKUST-1) in the presence of three different solvents: ethanol (EtOH), dichloromethane (DCM), and N , N -dimethylformamide (DMF). The DMF release profiles are monitored via in situ observation of the exchange solvent composition via 1 H NMR and Raman spectroscopy at the macroscopic scale. Furthermore, the change in solvent within a single crystal is measured to directly elucidate the exchange behavior. We demonstrate the DMF release profile from HKUST-1 exhibits different rate laws depending on whether the solvent exchange occurs at the CUS or is purely diffusive through the pores. This contribution represents the first characterization of release from a CUS-MOF as a function exchange solvent and reveals that solvent exchange in a CUS-MOF is not diffusion-limited, but rather is limited by the solvent exchange kinetics at the metal center. Insights from this study can be generalized to the variety of copper-paddlewheel-based MOFs, informing best practices for solvent exchange.

Folic acid supplementation is recommended perinatally, but may increase unmetabolized folic acid (UMFA) in human milk; this is concerning as it is an inactive form which may be less bioavailable for the infant. "Natural" (6S)-5-methyltetrahydrofolic acid [(6S)-5-MTHF] is available as an alternative to folic acid, and may prevent the accumulation of UMFA in human milk. Pregnant women (n = 60) were enrolled at 8-21 weeks of gestation and randomized to 0.6 mg/day folic acid or (6S)-5-MTHF. At ~ 1-week postpartum, participants provided a human milk specimen. Total human milk folate (nmol/L) and concentrations of UMFA (nmol/L) were quantified via LC-MS/MS. Differences between groups were evaluated using multivariable quantile/linear regression, adjusting for dietary folate, weeks supplementing, and milk collection methods. No significant difference in total milk folate was found; however, the median milk UMFA concentration was 11 nmol/L higher in those receiving folic acid versus (6S)-5-MTHF (95% CI = 6.4-17 nmol/L), with UMFA representing 28% and 2% of total milk folate. In conclusion, the form of supplemental folate had markedly differential effects on the human milk folate profile, with folic acid increasing the mean proportion of milk UMFA by ~ 14-fold. Investigation of whether increased UMFA impacts folate-related metabolism and infant health outcomes is required., (© 2023. The Author(s).)

Maternal nutrition during pregnancy may have profound effects on the developing fetus and impact risk for cardiovascular disease later in life. Here, we provide a narrative review on the impact of maternal diet during pregnancy on offspring vascular function. We review studies reporting effects of maternal micronutrient (folic acid, iron) intakes, high-fat diets, dietary energy restriction, and low protein intake on offspring endothelial function. We discuss the differences in study design and outcomes and potential underlying mechanisms contributing to the vascular phenotypes observed in the offspring. We further highlight key gaps in the literature and identify targets for future investigations., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Choline, folate, and vitamin B12 are required for growth and development, but there is limited information on the intakes and relationships to biomarkers of status in children., Objectives: The objective of this study was to determine the choline and B-vitamin intakes and relationship to biomarkers of status in children., Methods: A cross-sectional study was conducted in children (n = 285, aged 5-6 y) recruited from Metro Vancouver, Canada. Dietary information was collected by using 3 24-h recalls. Nutrient intakes were estimated by using the Canadian Nutrient File and United States Department of Agriculture database for choline. Supplement information was collected by using questionnaires. Plasma biomarkers were quantified by using mass spectrometry and commercial immunoassays, and relationships to dietary and supplement intake were determined by using linear models., Results: Daily dietary intakes of choline, folate, and vitamin B12 were [mean (SD)] 249 (94.3) mg, 330 (120) DFE μg, and 3.60 (1.54) μg, respectively. Top food sources of choline and vitamin B12 were dairy, meats, and eggs (63%-84%) and for folate, were grains, fruits, and vegetables (67%). More than half of the children (60%) were consuming a supplement containing B-vitamins, but not choline. Only 40% of children met the choline adequate intake (AI) recommendation for North America (≥250 mg/d); 82% met the European AI (≥170 mg/d). Less than 3% of children had inadequate folate and vitamin B12 total intakes. Some children (5%) had total folic acid intakes above the North American tolerable upper intake level (UL; >400 μg/d); 10% had intakes above the European UL (>300 μg/d). Dietary choline intake was positively associated with plasma dimethylglycine, and total vitamin B12 intake was positively associated with plasma B12 (adjusted models; P < 0.001)., Conclusions: These findings suggest that many children are not meeting the dietary choline recommendations, and some children may have excessive folic acid intakes. The impact of imbalanced one-carbon nutrient intakes during this active period of growth and development requires further investigation., (Copyright © 2022 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Riboflavin in its coenzyme forms, flavin mononucleotide and flavin adenine dinucleotide, is essential for multiple redox reactions necessary for energy production, antioxidant protection, and metabolism of other B vitamins, such as niacin, pyridoxine, and folate. Erythrocyte glutathione reductase activity coefficient (EGRac) is a biomarker of riboflavin status; ratios ≥1.40 are commonly interpreted as indicating biochemical deficiency. Most research on riboflavin status comes from low-income countries and rural settings, which reported high rates of riboflavin deficiency and inadequate intake. However, some studies suggest that riboflavin deficiency, based on the functional indicator EGRac, is also of concern in middle- and high-income countries. Biochemical riboflavin deficiency that does not cause clinical symptoms may contribute to anemia, particularly among women and children. Riboflavin enhances iron absorption, and riboflavin deficiency decreases iron mobilization from stores. The current knowledge on riboflavin's role in metabolic processes and its biochemical status is summarized in this review, and the available evidence on the role of riboflavin in anemia among different populations is discussed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Control of RNA Polymerase II (pol II) elongation is a critical component of gene expression in mammalian cells. The PNUTS-PP1 complex controls elongation rates, slowing pol II after polyadenylation sites to promote termination. The Kaposi's sarcoma-associated herpesvirus (KSHV) co-opts pol II to express its genes, but little is known about its regulation of pol II elongation. We identified PNUTS as a suppressor of a KSHV reporter gene in a genome-wide CRISPR screen. PNUTS depletion enhances global KSHV gene expression and overall viral replication. Mechanistically, PNUTS requires PP1 interaction, binds viral RNAs downstream of polyadenylation sites, and restricts transcription readthrough of viral genes. Surprisingly, PNUTS also represses productive elongation at the 5´ ends of the KSHV reporter and the KSHV T1.4 RNA. From these data, we conclude that PNUTS' activity constitutes an intrinsic barrier to KSHV replication likely by suppressing pol II elongation at promoter-proximal regions., (© 2022. The Author(s).)

Introduction/aims: Most mouse models of muscular dystrophy (MD) show mild phenotypes, which limits the translatability of experimental therapies to patients. A growing body of evidence suggests that MD is accompanied by metabolic abnormalities that could potentially exacerbate the primary muscle wasting process. Since thermoneutral (TN) housing of mice (~30°C) has been shown to affect many metabolic parameters, particularly when combined with a Western diet (WD), our aim was to determine whether the combination of TN and WD exacerbates muscle wasting in dysferlin-deficient BLAJ mice, a common model of limb-girdle MD type 2b (LGMD2b)., Methods: The 2-mo-old wild-type (WT) and BLAJ mice were housed at TN or room temperature (RT) and fed a WD or regular chow for 9 mo. Ambulatory function, muscle histology, and protein immunoblots of skeletal muscle were assessed., Results: BLAJ mice at RT and fed a chow diet showed normal ambulation function similar to WT mice, whereas 90% of BLAJ mice under WD and TN combination showed ambulatory dysfunction (p < 0.001), and an up to 4.1-fold increase in quadriceps and gastrocnemius fat infiltration. Western blotting revealed decreased autophagy marker microtubules-associated protein 1 light chain 3-B (LC3BII/LC3BI) ratio and up-regulation of protein kinase B/AKT and ribosomal protein S6 phosphorylation, suggesting inefficient cellular debris and protein clearance in TN BLAJ mice fed a WD. Male and female BLAJ mice under TN and WD combination showed heterogenous fibro-fatty infiltrate composition., Discussion: TN and WD combination exacerbates rodent LGMD2b without affecting WT mice. This improves rodent modeling of human MD and helps elucidate how metabolic abnormalities may play a causal role in muscle wasting., (© 2022 Wiley Periodicals LLC.)

Background: Second-generation antipsychotics (SGAs) are used to treat children for mental health disorders but in some children they cause cardiometabolic complications including weight gain and type 2 diabetes. Genetic variants can place a child at risk of developing these metabolic complications. The fat mass and obesity-associated ( FTO ) rs9939609 A allele has been associated with obesity and dietary energy intakes in healthy children but its relation to metabolic complications in SGA-treated children is not known., Objectives: This study investigated the association of the FTO rs9939609 variant and SGA treatment with cardiometabolic complications and dietary intakes in children with mental health disorders., Methods: A cross-sectional population of children (≤18 y; n  = 506) with mental health disorders that were SGA-treated ( n  = 197) and SGA-naïve ( n  = 309) were recruited through the Department of Psychiatry at BC Children's Hospital. Dietary intakes were estimated using 3-d food records in a subset of children ( n  = 73)., Results: Genotype frequencies were not different between SGA-treated (TT genotype 42.6%, TA genotype 38.6%, AA genotype 18.8%) and SGA-naïve (TT 41.1%, TA 39.5%, AA 19.4%) children. Children with the A allele had lower BMI z -sores compared with the TT genotype (0.84 ± 1.19 compared with 1.19 ± 1.36; P  = 0.005, adjusted for ethnicity). We observed an interaction between FTO genotype and SGA status on fasting glucose ( P  = 0.036). SGA-naïve children with the A allele had higher fasting glucose than those with the TT genotype (4.96 ± 0.35 compared with 4.81 ± 0.35 mmol/L; P  = 0.001), in adjusted models (age, sex, ethnicity, and BMI z -score). This was not observed in SGA-treated children. Children with the A allele had higher daily total energy intakes compared with the TT genotype (1994 ± 619 compared with 1814 ± 484 kcal/d; P  = 0.048), in adjusted models (age, sex, ethnicity, and BMI z -score); no effect of SGA-treatment was observed., Conclusions: Our findings suggest the A allele of the FTO rs9939609 variant is associated with higher BMI in children with mental health disorders, but only in those not treated with SGAs., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Hospitalized preterm infants experience painful medical procedures. Oral sucrose is the nonpharmacological standard of care for minor procedural pain relief. Infants are treated with numerous doses of sucrose, raising concerns about potential long-term effects. The objective of this study was to determine the long-term effects of neonatal oral sucrose treatment on growth and liver metabolism in a mouse model. Neonatal female and male mice were randomly assigned to one of two oral treatments ( n = 7-10 mice/group/sex): sterile water or sucrose. Pups were treated 10 times/day for the first 6 days of life with 0.2 mg/g body wt of respective treatments (24% solution; 1-4 μL/dose) to mimic what is given to preterm infants. Mice were weaned at age 3 wk onto a control diet and fed until age 16 wk. Sucrose-treated female and male mice gained less weight during the treatment period and were smaller at weaning than water-treated mice ( P ≤ 0.05); no effect of sucrose treatment on body weight was observed at adulthood. However, adult sucrose-treated female mice had smaller tibias and lower serum insulin-like growth factor-1 than adult water-treated female mice ( P ≤ 0.05); these effects were not observed in males. Lower liver S -adenosylmethionine, phosphocholine, and glycerophosphocholine were observed in adult sucrose-treated compared with water-treated female and male mice ( P ≤ 0.05). Sucrose-treated female, but not male, mice had lower liver free choline and higher liver betaine compared with water-treated female mice ( P < 0.01). Our findings suggest that repeated neonatal sucrose treatment has long-term sex-specific effects on growth and liver methionine and choline metabolism.

Objective: Second-generation antipsychotics (SGAs) are used for a variety of mental disorders and are associated with cardiometabolic side effects in children. The objective of this study was to assess the cardiovascular health of children with mental disorders that are SGA-treated or SGA-naive., Methods: SGA-treated ( n = 47) or SGA-naive ( n = 37) children (aged 6 to 18 years) with mental disorders and control children ( n = 83, no mental disorder) underwent assessment for cardiac function and morphology by echocardiography, aortic pulse wave velocity (PWV), and carotid intima-media thickness (cIMT). Body mass index (BMI) z -scores, waist circumference z -scores, systolic and diastolic blood pressure (BP) percentiles for height and sex, and fasting plasma glucose, insulin, triglycerides, and cholesterol were also assessed. Differences between SGA-treated, SGA-naive, and control children were assessed by linear and log-linear regression models., Results: SGA-treated children had greater BMI z -scores and overweight/obesity (BMI ≥ 85th percentile for age and sex) and hypertension than SGA-naive and control children. The PWV geometric mean was 11.1% higher in SGA-treated (95%CI, 3.95 to 18.77) and 12.9% higher in SGA-naive children (95% CI, 5.60 to 20.59) compared to controls in models adjusted for age, sex, BMI, and systolic BP percentile. Left ventricular (LV) end-diastolic dimension/body surface area (BSA), LV end-systolic dimension/BSA, and LV ejection fraction were lower in SGA-treated and SGA-naive children compared to controls in models adjusted for sex and age., Conclusions: Children with mental disorders have greater arterial stiffness and altered cardiac structure/function than children with no mental health diagnosis. SGA treatment in children is not associated with alterations in cardiovascular structure/function.

Aim: To understand how the social networks of a new recovery community can help sustain recovery, focusing on processes of social identity change, in the context of the wider UK recovery movement., Methods: A cross-sectional, mixed-methods social network analysis (SNA) of ego-network sociograms to map network transitions, using retrospective measures. Ten men were recruited from a peer-worker programme, in the South Ayrshire Alcohol and Drug Partnership (ADP), West of Scotland. Network measures were compared between two timepoints, just prior to current recovery and the present time. Measures included size and density, closeness of members, and their positive or negative influence, proportion of alcohol and other drug (AOD) using and recovery peers, and extent of separate subgroups. These were complemented with qualitative interview data., Findings: There was a significant transition in network composition, with the replacing of AOD-using peers with recovery peers and a broader transformation from relationships being framed as negative to positive. However, there was no significant transition in network structure, with AOD-using and recovery networks both consisting of strong ties and a similar density of connections between people in the networks., Conclusions: The transition in network composition between pre-recovery and the present indicates a different set of social influences, while the similarities in network structure indicate that the recovery network replaced the role of the using network in providing close bonds. This helped reduce social isolation experienced in early-recovery and provided a pathway into more structured opportunities for volunteering and employment., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

There is limited evidence regarding the potential risk of untargeted iron supplementation, especially among individuals who are iron-replete or have genetic hemoglobinopathies. Excess iron exposure can increase the production of reactive oxygen species, which can lead to cellular damage. We evaluated the effect of daily oral supplementation on relative leukocyte telomere length (rLTL) and blood mitochondrial DNA (mtDNA) content in non-pregnant Cambodian women (18-45 years) who received 60 mg of elemental iron as ferrous sulfate ( n = 190) or a placebo ( n = 186) for 12 weeks. Buffy coat rLTL and mtDNA content were quantified by monochrome multiplex quantitative polymerase chain reaction. Generalized linear mixed-effects models were used to predict the absolute and percent change in rLTL and mtDNA content after 12 weeks. Iron supplementation was not associated with an absolute or percent change in rLTL after 12 weeks compared with placebo (ß-coefficient: -0.04 [95% CI: -0.16, 0.08]; p = 0.50 and ß-coefficient: -0.96 [95% CI: -2.69, 0.77]; p = 0.28, respectively). However, iron supplementation was associated with a smaller absolute and percent increase in mtDNA content after 12 weeks compared with placebo (ß-coefficient: -11 [95% CI: -20, -2]; p = 0.02 and ß-coefficient: -11 [95% CI: -20, -1]; p = 0.02, respectively). Thus, daily oral iron supplementation for 12 weeks was associated with altered mitochondrial homeostasis in our study sample. More research is needed to understand the risk of iron exposure and the biological consequences of altered mitochondrial homeostasis in order to inform the safety of the current global supplementation policy.

Sickle cell disease (SCD) is an inherited hemoglobinopathy caused by a variant (rs344) in the HBB gene encoding the β-globin subunit of hemoglobin. Chronic hemolytic anemia and increased erythropoiesis and RBC turnover in individuals with SCD can result in increased needs for folate and other B-vitamins. We assessed B-vitamin status, and the distribution of folate forms, including unmetabolized folic acid (UMFA), in Canadian children with SCD supplemented with 1 mg/d folic acid (current routine practice). Non-fasted serum and plasma samples were analyzed for concentrations of folate, and vitamins B-2, B-6, and B-12. Eleven individuals (45% male; SCD type: HbSS n = 8, HbSC n = 2, HbSβ 0 -Thal n = 1), with a median (IQR) age of 14 (7, 18) years, were included. Total folate concentrations were 3-27 times above the deficiency cut-off (10 nmol/L), and 64% of children had elevated folate levels (>45.3 nmol/L). UMFA (>0.23 nmol/L) was detected in all children, and 36% of participants had elevated levels of UMFA (>5.4 nmol/L). All children were vitamin B-12 sufficient (>150 pmol/L), and the majority (55%) had sufficient B-6 status (>30 nmol/L). Among this sample of Canadian children with SCD, there was limited evidence of B-vitamin deficiencies, but UMFA was detectable in all children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Williams, Mayer, McCartney, Devlin, Lamers, Vercauteren, Wu and Karakochuk.)

Background: Nutrition surveys suggest that <10% of Canadian adults have inadequate riboflavin intakes. However, biochemical riboflavin deficiency [erythrocyte glutathione reductase activity coefficient (EGRac) ≥1.40] has been reported in 41% of young adult women living in Metro Vancouver. Canadian Chinese ethnicity comprise >25% of Vancouver's population and are postulated to have poorer riboflavin status than those of European ethnicity because they could be less likely to consume dairy products and fortified wheat., Objectives: The objectives of this study were to determine dietary riboflavin intake and food sources, and to assess the association between riboflavin intake and status in young women of European ( n  = 107) and Chinese ( n  = 91) ethnicities living in Metro Vancouver, Canada., Methods: This was a cross-sectional study conducted in women (aged 19-45 y). Women were healthy, not pregnant or breastfeeding, of European or Chinese ethnicities, and not taking riboflavin-containing supplements for the past 4 mo. Dietary riboflavin intake was assessed using the past-year Diet History Questionnaire II, and riboflavin status (EGRac) was measured in fasting venous blood samples., Results: Only 7% of participants had dietary riboflavin intakes below the Estimated Average Requirement (0.9 mg/d), but 40% of women had biochemical riboflavin deficiency (EGRac ≥1.40). Although more Canadian women of European ethnicity than Chinese ethnicity had biochemical riboflavin deficiency (46% and 34%; P  < 0.001), median dietary riboflavin intake did not differ (1.73 and 1.82 mg/d; P  = 0.587). Dairy products and vegetables contributed the most to riboflavin intake. Energy-adjusted dietary riboflavin intake was inversely associated with EGRac (B = -0.04, 95% CI: -0.07, -0.01). However, after further adjustment the relation was not significant., Conclusions: Overall, women of reproductive age living in Metro Vancouver, Canada, had a low prevalence of inadequate dietary riboflavin intake despite the high prevalence of apparent biochemical riboflavin deficiency., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Over 1 million Canadian children are estimated to have a mental health disorder, which are commonly treated with medications, such as second-generation antipsychotics (SGAs). Estimates suggest that SGA prescriptions to children are increasing in Canada. Although these medications are important and lifesaving components of psychiatric treatment, they are not without side effects. For some children, SGA treatment is associated with adverse metabolic complications including rapid weight gain, dyslipidemia, elevated blood pressure, and risk for type 2 diabetes. It is not clear why these complications develop, but it is assumed that SGAs stimulate appetite and food intake, and reduce resting energy expenditure leading to weight gain and that the metabolic complications occur secondary to the weight gain. Understanding the mechanisms underlying these complications is key to being able to identify children at risk and prevent and optimize treatment. In this narrative review, we provide an overview of the literature pertaining to the weight gain and metabolic complications in children treated with SGAs, highlighting the scope of the problem and the current limited research on how diet and physical activity can be used to prevent or lessen the severity of the metabolic complications and improve the long-term health trajectories of SGA-treated children. Novelty: Children are increasingly being treated with second-generation antipsychotics for mental health disorders. Dietary and physical activity assessments are not commonly considered in clinical settings. Randomized controlled trials of lifestyle interventions are needed to determine the effectiveness of mitigating the cardiometabolic complications in second-generation antipsychotic-treated children.

The San Patrignano drug recovery community, Italy, is regarded as one of the most successful in the world. However, if this model is to be transferred to other countries, it is necessary to clarify its underlying mechanisms and how far their success is context dependent. This qualitative study investigated these features of the San Patrignano model. Data collection included semi-structured interviews with six key stakeholders and 10 days' observational field notes. Data were synthesised using frameworks and analysis was informed by realist principles. Individual level mechanisms include: commitment to change, removal from former social environment, communal living, peer mentor with lived experience and meaningful work. These operate in the context of a free of charge, long term (3-4 year) residential community. Organisational level mechanisms are: visionary leadership, staff dedication, social enterprise and adaptable learning. Organisational contextual factors include: a gap in suitable provision for drug recovery and the region's high level of social capital. Articulating the programme theory of the recovery model and its contextual dependency helps clarify which elements should be transferred and how far they need to be adapted for different socio-cultural settings. The recognition of context is crucial when considering transfer of effective complex interventions across countries., Competing Interests: Disclosure statement No potential conflict of interest was reported by the author(s).

Maternal obesity during pregnancy can adversely affect adult offspring vascular endothelial function. This study examined whether maternal exercise during pregnancy and lactation mitigates the adverse effects of maternal obesity on offspring vascular endothelial function. Female (C57BL/6N) mice were fed from weaning a control diet (10% kcal fat) or western diet (45% kcal fat) to induce excess adiposity (maternal obesity). After 13 weeks, the female mice were bred and maintained on the diets, with and without access to a running wheel (exercise), throughout breeding, pregnancy, and lactation. Offspring were weaned onto the control or western diet and fed for 13 weeks; male offspring were studied. Maternal exercise prevented the adverse effects of maternal obesity on offspring vascular endothelial function. However, this was dependent on offspring diet and the positive effect of maternal exercise was only observed in offspring fed the western diet. This was accompanied by alterations in aorta and liver one-carbon metabolism, suggesting a role for these pathways in the improved endothelial function observed in the offspring. Obesity and exercise had no effect on endothelial function in the dams but did affect aorta and liver one-carbon metabolism, suggesting the phenotype observed in the offspring may be due to obesity and exercise-induced changes in one-carbon metabolism in the dams. Our findings demonstrate that maternal exercise prevented vascular dysfunction in male offspring from obese dams and is associated with alterations in one-carbon metabolism., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Kaposi's sarcoma-associated herpesvirus (KSHV) is a human oncogenic nuclear DNA virus that expresses its genes using the host cell transcription and RNA processing machinery. As a result, KSHV transcripts are subject to degradation by at least two host-mediated nuclear RNA decay pathways, the PABPN1- and poly(A) polymerase α/γ (PAPα/γ)-mediated RNA decay (PPD) pathway and an ARS2-dependent decay pathway. Here, we present global analyses of viral transcript levels to further understand the roles of these decay pathways in KSHV gene expression. Consistent with our recent report that the KSHV ORF57 protein increases viral transcript stability by impeding ARS2-dependent decay, ARS2 knockdown has only modest effects on viral gene expression 24 h after lytic reactivation of wild-type virus. In contrast, inactivation of PPD has more widespread effects, including premature accumulation of late transcripts. The upregulation of late transcripts does not require the primary late-gene-specific viral transactivation factor, suggesting that cryptic transcription produces the transcripts that then succumb to PPD. Remarkably, PPD inactivation has no effect on late transcripts at their proper time of expression. We show that this time-dependent PPD evasion by late transcripts requires the host factor n uclear R NAi- de fective 2 (NRDE2), which has previously been reported to protect cellular RNAs by sequestering decay factors. From these studies, we conclude that KSHV uses PPD to fine-tune the temporal expression of its genes by preventing their premature accumulation. IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus that causes Kaposi's sarcoma and other lymphoproliferative disorders. Nuclear expression of KSHV genes results in exposure to at least two host-mediated nuclear RNA decay pathways, the PABPN1- and PAPα/γ-mediated RNA decay (PPD) pathway and an ARS2-mediated decay pathway. Perhaps unsurprisingly, we previously found that KSHV uses specific mechanisms to protect its transcripts from ARS2-mediated decay. In contrast, here we show that PPD is required to dampen the expression of viral late transcripts that are prematurely transcribed, presumably due to cryptic transcription early in infection. At the proper time for their expression, KSHV late transcripts evade PPD through the activity of the host factor NRDE2. We conclude that KSHV fine-tunes the temporal expression of its genes by modulating PPD activity. Thus, the virus both protects from and exploits the host nuclear RNA decay machinery for proper expression of its genes., (Copyright © 2020 American Society for Microbiology.)

Background: Sickle cell disease (SCD) is a genetic disorder which causes dysfunctional red blood cells (RBC) and is thought to increase requirements for folate, an essential B vitamin, due to increased RBC production and turnover in the disease. High-dose supplementation with 1-5 mg/d folic acid, synthetic folate, has been the standard recommendation for children with SCD. There is concern about whether children with SCD need such high doses of folic acid, following mandatory folic acid fortification of enriched grains in Canada, and advancements in medical therapies which extend the average lifespan of RBCs. In animal and human studies, high folic acid intakes (1 mg/d) have been associated with accelerated growth of some cancers, and the biological effects of circulating unmetabolized folic acid (UMFA), which can occur with doses of folic acid ≥ 0.2 mg/d, are not fully understood. The objective of this study is to determine efficacy of, and alterations in folate metabolism from high-dose folic acid in children with SCD during periods of folic acid supplementation versus no supplementation., Methods: In this double-blind randomized controlled cross-over trial, children with SCD (n = 36, aged 2-19 years) will be randomized to either receive 1 mg/d folic acid, the current standard of care, or a placebo for 12 weeks. After a 12-week washout period, treatments will be reversed. Total folate concentrations (serum and RBC), different folate forms (including UMFA), folate-related metabolites, and clinical outcomes will be measured at baseline and after treatment periods. The sum of the values measured in the two periods will be calculated for each subject and compared across the two sequence groups by means of a test for independent samples for the primary (RBC folate concentrations) and secondary (UMFA) outcomes. Dietary intake will be measured at the beginning of each study period., Discussion: As the first rigorously designed clinical trial in children with SCD, this trial will inform and assess current clinical practice, with the ultimate goal of improving nutritional status of children with SCD., Trial Registration: ClinicalTrials.gov NCT04011345 . Registered on July 8, 2019.

Background: North American health authorities recommend 0.4 mg/day folic acid before conception and throughout pregnancy to reduce the risk of neural tube defects. Folic acid is a synthetic form of folate that must be reduced by dihydrofolate reductase and then further metabolized. Recent evidence suggests that the maximal capacity for this process is limited and unmetabolized folic acid has been detected in the circulation. The biological effects of unmetabolized folic acid are unknown. A natural form of folate, (6S)-5-methyltetrahydrofolic acid (Metafolin®), may be a superior alternative because it does not need to be reduced in the small intestine. Metafolin® is currently used in some prenatal multivitamins; however, it has yet to be evaluated during pregnancy., Methods/design: This double-blind, randomized trial will recruit 60 pregnant women aged 19-42 years. The women will receive either 0.6 mg/day folic acid or an equimolar dose (0.625 mg/day) of (6S)-5-methyltetrahydrofolic acid for 16 weeks. The trial will be initiated at 8-21 weeks' gestation (after neural tube closure) to reduce the risk of harm should (6S)-5-methyltetrahydrofolic acid prove less effective. All women will also receive a prenatal multivitamin (not containing folate) to ensure adequacy of other nutrients. Baseline and endline blood samples will be collected to assess primary outcome measures, including serum folate, red blood cell folate and unmetabolized folic acid. The extent to which the change in primary outcomes from baseline to endline differs between treatment groups, controlling for baseline level, will be estimated using linear regression. Participants will have the option to continue supplementing until 1 week postpartum to provide a breastmilk and blood sample. Exploratory analyses will be completed to evaluate breastmilk and postpartum blood folate concentrations., Discussion: This proof-of-concept trial is needed to obtain estimates of the effect of (6S)-5-methyltetrahydrofolic acid compared to folic acid on circulating biomarkers of folate status during pregnancy. These estimates will inform the design of a definitive trial which will be powered to assess whether (6S)-5-methyltetrahydrofolic acid is as effective as folic acid in raising blood folate concentrations during pregnancy. Ultimately, these findings will inform folate supplementation policies for pregnant women., Trial Registration: ClinicalTrials.gov, ID: NCT04022135. Registered on 14 July 2019.

Background/objective: Blood pressure abnormalities may play an important role in macrovascular damage in type 1 diabetes. Little is known about blood pressure abnormalities and macrovascular damage in children with type 1 diabetes., Methods: Children with type 1 diabetes (n = 57) for a short (3 months-2 years; n = 24) or long duration (≥5 years; n = 33) and a group of control children without diabetes (n = 29) completed 24-h ambulatory blood pressure monitoring (ABPM). Carotid intima media thickness (cIMT), a subclinical indicator of atherosclerosis, was assessed by carotid ultrasound., Results: ABPM abnormalities were more prevalent (57% vs 24%, respectively), and daytime, nighttime and 24-h systolic, diastolic, and mean arterial blood pressure indices were higher in children with type 1 diabetes compared to control children. The odds estimate of an ABPM abnormality was 6.68 (95% confidence interval: 1.95, 22.9; P = .003) in children with type 1 diabetes compared to controls after adjusting for age, sex, and BMI standardized for age and sex (zBMI). An interaction between ABPM and zBMI on cIMT was observed. In children with type 1 diabetes and ABPM abnormalities, every 1 SD increase in zBMI was associated with a 0.030 mm increase in cIMT (95% confidence interval: 0.002, 0.041; P = .031). This was not observed in control children with ABPM abnormalities or in children with normal ABPM, regardless of type 1 diabetes status., Conclusions: Children with type 1 diabetes have a high prevalence of ABPM abnormalities independent of disease duration and this is related to early indicators of cardiovascular damage., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Long-chain n-6 and n-3 PUFAs are important for growth and development. However, little is known about requirements and current dietary intakes of these fatty acids in toddlers., Objectives: This study assessed dietary intakes of n-6 and n-3 PUFAs and determined the relation to circulating PUFAs in toddlers at ages 1 and 2 y., Methods: This is a secondary analysis of data from toddlers enrolled in a double-blind randomized controlled trial of arachidonic acid (ARA) and DHA supplementation between ages 1 and 2 y. Dietary intakes of fatty acids were estimated by 3-d food records, and fatty acid composition in plasma total phospholipids, red blood cell phosphatidylethanolamine (PE), and phosphatidylcholine (PC) were assessed by GC at baseline in all subjects (n = 110; mean age 1.12 y; 64% male) and in the control subjects at 2 y (n = 43)., Results: The dietary intakes of ARA, EPA, and DHA at age 1 y (baseline) were [mean (median)] 36.8 (30.0), 16.0 (0.00), and 31.1 (10.0) mg/d, respectively. Dietary intakes increased to 52.7 (45.0), 35.8 (0.00), and 64.8 (20.0) mg/d, respectively, at age 2 y (P < 0.05). The predominant dietary source of EPA and DHA was fish/seafood; eggs were an important source of ARA and DHA. Dietary DHA intakes were positively associated with plasma PE and PC DHA (P < 0.05). No relations between dietary ARA intakes and plasma PE and PC ARA (P > 0.05) were observed., Conclusions: These findings suggest that most toddlers are not meeting the recommendation for dietary PUFA intakes and that higher dietary DHA intakes are reflected in plasma PE and PC DHA composition. Further work is required to investigate a biomarker for dietary ARA intake. This trial is registered at clinicaltrials.gov as NCT01263912., (Copyright © The Author(s) 2019.)

Background: Riboflavin is required for several redox reactions. Clinical riboflavin deficiency occurs mainly in low-income countries, where it is associated with anemia. The functional significance of suboptimal riboflavin status in different populations and its role in anemia is not well understood., Objectives: We assessed the biomarker status of riboflavin and its association with hemoglobin concentration and anemia in women living in Vancouver, Canada, and Kuala Lumpur, Malaysia., Methods: Healthy nonpregnant, nonbreastfeeding women (19-45 y) were recruited from Canada ( n = 206) and Malaysia (n = 210) via convenience sampling. Fasting blood was collected to assess riboflavin status [erythrocyte glutathione reductase activity coefficient (EGRac)], hematological indicators, soluble transferrin receptor (sTfR), ferritin, vitamin A, folate, and vitamin B-12 concentrations. Linear and logistic regression models were used to assess the association of riboflavin status with hemoglobin concentration and anemia., Results: EGRac (mean ± SD) values were higher, indicating poorer riboflavin status, in Malaysian compared with Canadian women (1.49 ± 0.17 compared with 1.38 ± 0.11). Likewise, riboflavin biomarker deficiency (EGRac ≥1.40) was significantly more prevalent among Malaysians than Canadians (71% compared with 40%). More Malaysian than Canadian women were anemic (hemoglobin <120 g/L; 18% compared with 7%). With use of linear regression (pooled sample; n = 416), EGRac values were negatively associated with hemoglobin concentration (r = -0.18; P < 0.001). This relation remained significant (P = 0.029) after adjusting for age, parity, ethnicity, vitamin B-12, folate, sTfR, ferritin, and vitamin A. Women with riboflavin deficiency (EGRac ≥1.40) were twice as likely to present with anemia (adjusted OR: 2.38; 95% CI: 1.08, 5.27) compared with women with EGRac <1.40., Conclusions: Biochemical riboflavin deficiency was observed in Canadian and Malaysian women, with higher rates of deficiency among Malaysian women. Deficient biomarker status of riboflavin was a weak but significant predictor of hemoglobin and anemia, suggesting that the correction of riboflavin deficiency may potentially play a small protective role in anemia, but this requires further investigation., (Copyright © American Society for Nutrition 2019.)

Objective: This study assessed associations between maternal depressive symptoms, prenatal maternal antidepressant treatment, maternal estimates of child physical activity (PA), dietary total intake, and markers of adiposity., Methods: Mothers and their children (N = 116) were part of a longitudinal cohort study examining the effects of prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants and maternal depression (SSRI exposed, n = 42; nonexposed, n = 74). Maternal depression symptoms were assessed prenatally and postnatally. At 6 years, PA was assessed using maternal report, 3-day dietary total intakes were obtained using objective records of intake, portion sizes, and product brand names, and birth weight, weight, height, and waist circumference (WC) at age 6 years were also collected. Body mass index (BMI) and WC z-scores standardized for sex and age were computed as markers of adiposity., Results: Children with SSRI exposure had lower levels of PA than children without SSRI exposure. Total dietary energy intakes did not vary between exposure groups. SSRI exposure was not associated with BMI or WC z-scores of the children. Importantly, although lower birth weight was observed in SSRI-exposed children, differences did not remain, accounting for gestational age., Conclusion: Although SSRI exposure was associated with lower estimates of PA, such exposure was not associated with markers of adiposity or total diet energy intake at age 6 years. The implications across subsequent measures in childhood remain to be determined.

Introduction: There is increasing interest in the transferability of parenting interventions from high-income countries (HICs) to low-income countries (LICs) in order to improve child development and health outcomes. This is based on the premise that associations between parenting practices and child outcomes are similar in both settings. Many parenting interventions in HICs are evidence-based, but less evidence exists on associations of parenting practices with child outcomes in LICs, in particular, sub-Saharan African (SSA) countries. This review synthesises evidence on the association of parenting practices with child outcomes in SSA in order to compare findings with those from HICs., Methods: We searched electronic databases-Web of Science, ASSIA, Embase, IBSS and PsycINFO-to identify studies from SSA that reported quantitative associations between parenting practices and child health or psychosocial outcomes (eg, sexual and reproductive health (SRH), mental health, conduct disorders). Due to inconsistent conceptual framing of parenting across studies, we used a modified version of the international WHO classification of parenting dimensions to guide synthesis of the results., Results: Forty-four studies met our inclusion criteria. They were conducted in 13 SSA countries and included cross-sectional and longitudinal studies, and were predominantly descriptive studies rather than intervention research. Synthesis of results showed that associations between patterns of parenting ('positive'/'harsh') and child outcomes (including SRH, mental health and conduct disorders) in studies from SSA were broadly similar to those found in HICs., Conclusions: These findings suggest that the impacts of parenting practices on child outcomes are similar across contrasting global regions and, therefore, parenting interventions from HICs might be successfully transferred to SSA, subject to appropriate adaptation. However, this review also highlights the paucity of evidence in this area and the urgent need for higher quality studies to confirm these findings to help develop effective parenting interventions in SSA., Competing Interests: Competing interests: None declared.

Background: Second-generation antipsychotics (SGAs) are commonly used to treat children with mental health conditions (MHCs) but are associated with adverse effects including obesity, hypertension, dyslipidemia, and type 2 diabetes. The mechanisms underlying these complications are unknown, but it has been suggested that SGAs increase appetite leading to weight gain. The present objective was to perform a pilot study to investigate appetite and satiety hormones in SGA-treated (risperidone or quetiapine) and SGA-naive children with similar mental health conditions., Methods: Oral glucose tolerance tests (OGTTs) were conducted in SGA-naive (n = 18), risperidone-treated (n = 20), and quetiapine-treated (n = 16) children recruited from the British Columbia Children's Hospital Psychiatry Department. Over 5 time-points during the OGTT, appetite questionnaires using a visual analogue scale were administered, and blood was collected to measure ghrelin, peptide YY, glucose-dependent insulinotropic polypeptide, glucagon-like protein 1, leptin, and adiponectin. Mixed model analyses were conducted to examine between-group differences., Results: The children were similar in age, psychiatric diagnosis, and global assessment of functioning scores. Body mass index z-scores were also similar between groups. Appetite was increased during the OGTT in the risperidone-treated compared with the SGA-naive group for 2 questions ("How strong is your desire to eat"; P = 0.003 and "How much food do you think you can eat"; P = 0.028). No differences in satiety hormones were observed between the 3 groups., Conclusions: Risperidone treatment in youth is associated with elevated appetite during an OGTT, with no differences in gut peptides or adipocytokines to explain risperidone's effect on appetite. Further research is needed to explore other mediators of weight gain and metabolic dysfunction in SGA-treated youth.

Perampanel is an adjunctive treatment for epilepsy that works through the direct inhibition of AMPA receptors. The same molecular mechanism has recently been shown for a fatty acid, decanoic acid, prescribed in the medium chain triglyceride ketogenic diet for the treatment of patients with drug-resistant epilepsy. Because each compound has been proposed to act through a distinct AMPA receptor binding site, we predicted that perampanel and decanoic acid would act synergistically against AMPA receptors and, consequently, seizures. Here, we show a synergistic interaction between perampanel and decanoic acid in direct AMPA receptor inhibition, in an ex vivo model of seizure activity, and against seizure-induced activity in human brain slices. These data support a potential role for combination treatment using perampanel and dietary decanoic acid to provide enhanced seizure control., (© 2018 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

Objectives: As a follow-up to the CHIPS trial (Control of Hypertension In Pregnancy Study) of 'less tight' (versus 'tight') control of maternal blood pressure in pregnancy, CHIPS-Child investigated potential developmental programming of maternal blood pressure control in pregnancy, by examining measures of postnatal growth rate and hypothalamic-pituitary adrenal (HPA) axis activation., Methods: CHIPS follow-up was extended to 12 ± 2 months corrected post-gestational age for anthropometry (weight, length, head/waist circumference). For eligible children with consent for a study visit, we collected biological samples (hair/buccal samples) to evaluate HPA axis function (hair cortisol levels) and epigenetic change (DNA methylation analysis of buccal cells). The primary outcome was 'change in z-score for weight' between birth and 12 ± 2 mos. Secondary outcomes were hair cortisol and genome-wide DNA methylation status., Results: Of 683 eligible babies, 183 (26.8%) were lost to follow-up, 83 (12.2%) declined, 3 (0.4%) agreed only to ongoing contact, and 414 (60.6%) consented. 372/414 (89.9%) had weight measured at 12mos. In 'less tight' (vs. 'tight') control, the primary outcome was similar [-0.26 (-0.53, +0.01); p = 0.14, p adjusted  = 0.06]; median (95% confidence interval) hair cortisol (N = 35 samples) was lower [-496 (-892, -100) ng/g; p = 0.02], and buccal swab DNA methylation (N = 16 samples) was similar. No differences in growth rate could be demonstrated up to 5 years., Conclusions: Results demonstrate no compelling evidence for developmental programming of growth or the HPA axis. Clinicians should look to the clinical findings of CHIPS to guide practice. Researchers should seek to replicate these findings and extend outcomes to paediatric blood pressure and neurodevelopment., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Epidemiologic studies have reported relationships between maternal high folate and/or low B 12 status during pregnancy and greater adiposity and insulin resistance in children. The goal of this study was to determine the effects of maternal folic acid supplementation (10 mg/kg diet), with (50 μg/kg diet) and without B 12 , on adult female offspring adiposity and glucose homeostasis. Female C57BL/6J mice were fed 1 of 3 diets from weaning and throughout breeding, pregnancy, and lactation: control (2 mg/kg diet folic acid, 50 μg/kg diet B 12 ), supplemental folic acid with no B 12 (SFA-B 12 ), or supplemental folic acid with adequate B 12 (SFA+B 12 ). Female offspring were weaned onto the control diet or a Western diet (45% energy fat, 2 mg/kg diet folic acid, 50 μg/kg diet B 12 ) for 35 wk. After weaning, control diet-fed offspring with SFA-B 12 dams had fasting hyperglycemia, glucose intolerance, lower β cell mass, and greater islet hepatocyte nuclear factor 1 homeobox α and nuclear receptor subfamily 1 group H member 3 mRNA than did offspring from control dams. In Western diet-fed offspring, those with SFA-B 12 dams had lower fasting blood glucose and plasma insulin concentrations, and were smaller than control offspring. Our findings suggest that maternal folic acid supplementation with B 12 deficiency during pregnancy/lactation programs the metabolic health of adult female offspring but is dependent on offspring diet.-Henderson, A. M., Tai, D. C., Aleliunas, R. E., Aljaadi, A. M., Glier, M. B., Xu, E. E., Miller, J. W., Verchere, C. B., Green, T. J., Devlin, A. M. Maternal folic acid supplementation with vitamin B 12 deficiency during pregnancy and lactation affects the metabolic health of adult female offspring but is dependent on offspring diet.

Background: Choline is an important nutrient during development. However, there are limited data on dietary choline intake and status in toddlers and the relation to neurodevelopmental outcomes., Objective: This study assessed dietary choline intake and status in healthy toddlers at ages 1 and 2 y and determined the relation to neurodevelopmental outcomes., Methods: This is a secondary analysis of data from healthy toddlers enrolled in a double-blind, randomized controlled trial of long-chain polyunsaturated fatty acid supplementation between ages 1 and 2 y. Dietary intakes of betaine and choline were estimated by 3-d food records; plasma free choline, betaine, and dimethylglycine were quantified by liquid chromatography-tandem mass spectrometry. Developmental outcomes were assessed at age 2 y with the use of the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III), Cognitive and Language composites, and the Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery-VMI)., Results: The mean ± SD daily intake for total choline at age 1 y was 174 ± 56.2 mg/d and increased (P < 0.001) to 205 ± 67.5 mg/d at age 2 y. At ages 1 and 2 y, 71.8% and 55.8%, respectively, of toddlers did not meet the recommended 200-mg/d Adequate Intake (AI) for dietary choline. At age 1 y, mean ± SD plasma free choline, betaine, and dimethylglycine concentrations were 10.4 ± 3.3, 41.1 ± 15.4, and 4.1 ± 1.9 µmol/L, respectively. Plasma free choline (8.5 ± 2.3 µmol/L) and dimethylglycine (3.2 ± 1.3 µmol/L) concentrations were lower (P < 0.001) at age 2 y. Plasma betaine concentrations were positively associated with the Beery-VMI (β = 0.270; 95% CI: 0.026, 0.513; P = 0.03) at age 2 y., Conclusions: These findings suggest that most toddlers are not meeting the recommended AI for dietary choline and that higher plasma betaine concentrations are associated with better visual-motor development at age 2 y. Further work is required to investigate choline metabolism and its role in neurodevelopment in toddlers. The trial is registered at clinicaltrials.gov as NCT01263912.

Prenatal exposure to maternal mood disturbances shapes children's cognitive development reflected in the critical construct of executive functions (EFs). Little is known, however, about underlying mechanisms. By examining cortisol responses in both everyday and lab challenge settings, we tested whether the child/offspring hypothalamic-pituitary-adrenal axis mediates effects of prenatal maternal mood on child EFs at age 6. In 107 Canadian children born to women with a wide range of anxious and depressive symptoms during pregnancy, we found that in boys but not girls, depressed and/or anxious prenatal maternal mood is associated with heightened diurnal cortisol levels in everyday settings, as well as heightened cortisol reactivity to a lab challenge and that this heightened reactivity was associated with poorer EFs. Among boys we also observed that cortisol reactivity but not diurnal cortisol mediated the association between depressed and/or anxious prenatal maternal mood and EFs. Depressed and/or anxious prenatal maternal mood was related to child EFs for both girls and boys. To our knowledge, this is the first study to demonstrate a mediating role for child stress regulation in the association between prenatal maternal stress-related mood disturbances and child EFs, providing evidence of a mechanism contributing to fetal programming of cognition.