Update on the impact of voluntary folic acid fortification of corn masa flour on red blood cell folate concentrations-National Health and Nutrition Examination Survey, 2011-March 2020.

BACKGROUND: Folic acid is a micronutrient that is effective at preventing neural tube defects (NTDs). In 2016, the FDA authorized the voluntary fortification of corn masa flour (CMF) with folic acid to reduce disparities in NTDs among infants of women who do not regularly consume other fortified cereal grains, in particular Hispanic women of reproductive age (WRA). METHODS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to March 2020 assessing the impact of voluntary fortification of CMF on the folate status of Hispanic WRA. We analyzed folic acid usual intake and red blood cell (RBC) folate concentrations among non-pregnant, non-lactating Hispanic WRA, comparing pre-fortification (2011-2016) to post-fortification (2017-March 2020) data. RBC folate concentrations were used to create model-based estimation of NTD rates. RESULTS: The proportion of Hispanic WRA with folic acid usual intakes <400 µg/d did not change (2011-2016: 86.1% [95% Confidence Interval, CI: 83.7-88.5]; 2017-March 2020: 87.8% [95% CI: 84.8-90.7]; p = .38) nor did the proportion of Hispanic WRA with RBC folate below optimal concentrations (<748 nmol/L, 2011-2016: 16.0% [95% CI: 13.7-18.2]; 2017-March 2020: 18.1% [95% CI: 12.1-24.0]; p = 0.49). Model-based estimates of NTD rates suggest further improvements in the folate status of Hispanic WRA might prevent an additional 157 (95% Uncertainty Interval: 0, 288) NTDs/year. CONCLUSIONS: Voluntary fortification of CMF with folic acid has yet to have a significant impact on the folate status of WRA. Continued monitoring and further research into factors such as fortified product availability, community knowledge, and awareness of folic acid benefits would inform and improve future public health interventions.

Vitamin B12 supplementation during pregnancy for maternal and child health outcomes.

BACKGROUND: Vitamin B12 deficiency is a major public health problem worldwide, with the highest burden in elderly people, pregnant women, and young children. Due to its role in DNA synthesis and methylation, folate metabolism, and erythropoiesis, vitamin B12 supplementation during pregnancy may confer longer-term benefits to maternal and child health outcomes. OBJECTIVES: To evaluate the benefits and harms of oral vitamin B12 supplementation during pregnancy on maternal and child health outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP) on 2 June 2023, and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-RCTs, or cluster-RCTs evaluating the effects of oral vitamin B12 supplementation compared to placebo or no vitamin B12 supplementation during pregnancy. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Four review authors independently assessed trial eligibility. Two review authors independently extracted data from included studies and conducted checks for accuracy. Three review authors independently assessed the risk of bias of the included studies using the Cochrane RoB 1 tool. We used GRADE to evaluate the certainty of evidence for primary outcomes. MAIN RESULTS: The review included five trials with 984 pregnant women. All trials were conducted in low- and middle-income countries, including India, Bangladesh, South Africa, and Croatia. At enrolment, 26% to 51% of pregnant women had vitamin B12 deficiency (less than 150 pmol/L), and the prevalence of anaemia (haemoglobin less than 11.0 g/dL) ranged from 30% to 46%. The dosage of vitamin B12 supplementation varied from 5 µg/day to 250 µg/day, with administration beginning at 8 to 28 weeks' gestation through to delivery or three months' postpartum, and the duration of supplementation ranged from 8 to 16 weeks to 32 to 38 weeks. Three trials, involving 609 pregnant women, contributed data for meta-analyses of the effects of vitamin B12 supplementation compared to placebo or no vitamin B12 supplementation. Maternal anaemia: there may be little to no difference for maternal anaemia by intervention group, but the evidence is very uncertain (70.9% versus 65.0%; risk ratio (RR) 1.08, 95% confidence interval (CI) 0.93 to 1.26; 2 trials, 284 women; very low-certainty evidence). Maternal vitamin B12 status: vitamin B12 supplementation during pregnancy may reduce the risk of maternal vitamin B12 deficiency compared to placebo or no vitamin B12 supplementation, but the evidence is very uncertain (25.9% versus 67.9%; RR 0.38, 95% CI 0.28 to 0.51; 2 trials, 272 women; very low-certainty evidence). Women who received vitamin B12 supplements during pregnancy may have higher total vitamin B12 concentrations compared to placebo or no vitamin B12 supplementation (mean difference (MD) 60.89 pmol/L, 95% CI 40.86 to 80.92; 3 trials, 412 women). However, there was substantial heterogeneity (I2 = 85%). Adverse pregnancy outcomes: the evidence is uncertain about the effect on adverse pregnancy outcomes, including preterm birth (RR 0.97, 95% CI 0.55 to 1.74; 2 trials, 340 women; low-certainty evidence), and low birthweight (RR 1.50, 95% CI 0.93 to 2.43; 2 trials, 344 women; low-certainty evidence). Two trials reported data on spontaneous abortion (or miscarriage); however, the trials did not report quantitative data for meta-analysis and there was no clear definition of spontaneous abortion in the study reports. No trials evaluated the effects of vitamin B12 supplementation during pregnancy on neural tube defects. Infant vitamin B12 status: children born to women who received vitamin B12 supplementation had higher total vitamin B12 concentrations compared to placebo or no vitamin B12 supplementation (MD 71.89 pmol/L, 95% CI 20.23 to 123.54; 2 trials, 144 children). Child cognitive outcomes: three ancillary analyses of one trial reported child cognitive outcomes; however, data were not reported in a format that could be included in quantitative meta-analyses. In one study, maternal vitamin B12 supplementation did not improve neurodevelopment status (e.g. cognitive, language (receptive and expressive), motor (fine and gross), social-emotional, or adaptive (conceptual, social, practical) domains) in children compared to placebo (9 months, Bayley Scales of Infant and Toddler Development Third Edition (BSID-III); 1 trial; low-certainty evidence) or neurophysiological outcomes (72 months, event-related potential measures; 1 trial; low-certainty evidence), though children born to women who received vitamin B12 supplementation had improved expressive language domain compared to placebo (30 months, BSID-III; 1 trial; low-certainty evidence). AUTHORS' CONCLUSIONS: Oral vitamin B12 supplementation during pregnancy may reduce the risk of maternal vitamin B12 deficiency and may improve maternal vitamin B12 concentrations during pregnancy or postpartum compared to placebo or no vitamin B12 supplementation, but the evidence is very uncertain. The effects of vitamin B12 supplementation on other primary outcomes assessed in this review were not reported, or were not reported in a format for inclusion in quantitative analyses. Vitamin B12 supplementation during pregnancy may improve maternal and infant vitamin B12 status, but the potential impact on longer-term clinical and functional maternal and child health outcomes has not yet been established.

Coverage, Apparent Consumption, and Monthly Use of Packaged Maize Flour in Morogoro Region, Tanzania.

INTRODUCTION: Tanzania aimed to reduce micronutrient deficiencies and neural tube defects by introducing mandatory fortification of large-scale packaged wheat and maize flour but not for small- and medium-scale mills. OBJECTIVES: Ascertain the proportion of the population in Morogoro region, Tanzania, that consumes packaged maize flour from small-, medium- and large-mills; and understand the impact of monthly apparent purchase and consumption of packaged flour. METHODS: In 2018, a regional, multistage cluster probability study was conducted among residents in Morogoro region living in households that reported consuming maize flour. Interviews collected information on sociodemographic factors and patterns of household flour consumption. Weighted medians estimated daily apparent flour consumption and the estimated average requirement (EAR), according to age. RESULTS: Information was collected on 711 households. Packaged maize flour was purchased 10-12 months of the year by 22.9% of households, 6-9 months by 17.6% of households, 1-5 months by 25.1% of households, and 34.4% did not purchased maize flour. Median apparent daily consumption of maize flour was 209.7 g/d/adult male equivalent (AME). Apparent median daily consumption of maize flour was 230.1 g/d/AME in rural areas and 176.2 g/d/AME in urban areas; 228.7 g/d/AME among males and 196.4 g/d/AME among females. If all packaged maize flour were fortified according to standards, those consuming packaged maize flour 10-12 months of the year would apparently consume 199.9 µg folic acid/d representing 49.7% of daily EAR requirements. CONCLUSIONS: Fortifying packaged maize flour at small-, medium- and large-mills is a promising strategy for increasing access to micronutrients, including folic acid.

Folic acid supplementation and malaria susceptibility and severity among people taking antifolate antimalarial drugs in endemic areas.

BACKGROUND: Description of the condition Malaria, an infectious disease transmitted by the bite of female mosquitoes from several Anopheles species, occurs in 87 countries with ongoing transmission (WHO 2020). The World Health Organization (WHO) estimated that, in 2019, approximately 229 million cases of malaria occurred worldwide, with 94% occurring in the WHO's African region (WHO 2020). Of these malaria cases, an estimated 409,000 deaths occurred globally, with 67% occurring in children under five years of age (WHO 2020). Malaria also negatively impacts the health of women during pregnancy, childbirth, and the postnatal period (WHO 2020). Sulfadoxine/pyrimethamine (SP), an antifolate antimalarial, has been widely used across sub-Saharan Africa as the first-line treatment for uncomplicated malaria sTo examine the effects of folic acid supplementation, at various doses, on malaria susceptibility (risk of infection) and severity among people living in areas with various degrees of malaria endemicity. We will examine the interaction between folic acid supplements and antifolate antimalarial drugs. Specifically, we will aim to answer the following. Among uninfected people living in malaria endemic areas, who are taking or not taking antifolate antimalarials for malaria prophylaxis, does taking a folic acid-containing supplement increase susceptibility to or severity of malaria infection? Among people with malaria infection who are being treated with antifolate antimalarials, does folic acid supplementation increase the risk of treatment failure?Criteria for considering studies for this review Types of studies Inclusion criteria Randomized controlled trials (RCTs) Quasi-RCTs with randomization at the individual or cluster level conducted in malaria-endemic areas (areas with ongoing, local malaria transmission, including areas approaching elimination, as listed in the World Malaria Report 2020) (WHO 2020) Exclusion criteria Ecological studies Observational studies In vivo/in vitro studies Economic studies Systematic literature reviews and meta-analyses (relevant systematic literature reviews and meta-analyses will be excluded but flagged for grey literature screening) Types of participants Inclusion criteria Individuals of any age or gender, living in a malaria endemic area, who are taking antifolate antimalarial medications (inclu

Folic Acid and the Prevention of Birth Defects: 30 Years of Opportunity and Controversies.

For three decades, the US Public Health Service has recommended that all persons capable of becoming pregnant consume 400 µg/day of folic acid (FA) to prevent neural tube defects (NTDs). The neural tube forms by 28 days after conception. Fortification can be an effective NTD prevention strategy in populations with limited access to folic acid foods and/or supplements. This review describes the status of mandatory FA fortification among countries that fortify (n = 71) and the research describing the impact of those programs on NTD rates (up to 78% reduction), blood folate concentrations [red blood cell folate concentrations increased ∼1.47-fold (95% CI, 1.27, 1.70) following fortification], and other health outcomes. Across settings, high-quality studies such as those with randomized exposures (e.g., randomized controlled trials, Mendelian randomization studies) are needed to elucidate interactions of FA with vitamin B12 as well as expanded biomarker testing.

Outcomes in pediatric patients with documented delays between ileocolic intussusception diagnosis and therapeutic enema attempt: evaluation of reduction efficacy and complication rate.

BACKGROUND: Ileocolic intussusception is considered a pediatric emergency, with concerns for risk of significant morbidity in children with a prolonged intussusception state. Emergent therapy is standard of care, as prior studies have shown poor outcomes in patients with long delays (> 24 h) before intervention. Various factors can result in shorter delays, and there are limited studies evaluating outcomes in these patients. This study aimed to determine if there were differences in reduction success rates associated with short in-hospital time delays. OBJECTIVE: This study is to determine enema success rate and morbidity in patients with documented time delays between intussusception diagnosis and therapeutic enema. MATERIALS AND METHODS: A retrospective evaluation of pediatric patients with intussusception at a single children's hospital between 2007 and 2019 was performed. Patient's records were reviewed for time of symptom onset, radiologic diagnosis, and attempted enema. Ultrasounds and radiographs were reviewed for bowel obstruction, free peritoneal fluid, trapped fluid around the intussusceptum, and absent bowel wall perfusion. Patients were evaluated for efficacy of reduction attempt, requirement for surgical reduction, and complications including bowel resection and bowel perforation. RESULTS: There were 175 cases of ileocolic intussusception requiring enema reduction. Successful reduction occurred in 72.2% (13/18) of cases performed within 1 h of diagnosis; 74.3% (78/105) between 1 and3 h; 73.2% (30/41) between 3 and 6 h; and 81.2% (9/11) with greater than 6 h. Need for bowel resection was not associated with short delays between diagnosis and reduction attempts (p = .07). CONCLUSIONS: There was no difference in intussusception reduction efficacy or complication rate in patients with increasing time between imaging diagnosis of ileocolic intussusception and reduction attempt, including delay intervals up to 8 h.

Improvements in vascular function in response to acute lower limb heating in young healthy males and females.

Regular exposure to passive heat stress improves vascular function, but the optimal heating prescription remains undefined. Local limb heating is more feasible than whole body heating, but the evidence demonstrating its efficacy is lacking. The purpose of this study was to determine whether acute improvements in vascular function can be achieved with lower limb heating in 16 young healthy individuals (8 female, 8 male). In separate visits, participants underwent 45 min of ankle- and knee-level hot water immersion (45°C). A subset of seven participants also participated in a time-control visit. Endothelial function was assessed through simultaneous brachial and superficial femoral artery flow-mediated dilation (FMD) tests. Macrovascular function was quantified by %FMD, whereas microvascular function was quantified by vascular conductance during reactive hyperemia. Arterial stiffness was assessed through carotid-femoral and femoral-foot pulse wave velocity (PWV). Plasma concentrations of interleukin-6 and extracellular heat shock protein-72 (eHSP72) were used as indicators of inflammation. Our findings showed that 45 min of lower limb heating-regardless of condition-acutely improved upper limb macrovascular endothelial function (i.e., brachial %FMD; Pre: 4.6 ± 1.7 vs. Post: 5.4 ± 2.0%; P = 0.004) and lower limb arterial stiffness (i.e., femoral-foot PWV; Pre: 8.4 ± 1.2 vs. Post: 7.7 ± 1.1 m/s; P = 0.011). However, only knee-level heating increased upper limb microvascular function (i.e., brachial peak vascular conductance; Pre: 6.3 ± 2.7 vs. Post: 7.8 ± 3.5 mL/min â‹… mmHg; P ≤ 0.050) and plasma eHSP72 concentration (Pre: 12.4 ± 9.4 vs. Post: 14.8 ± 9.8 ng/mL; P ≤ 0.050). These findings show that local lower limb heating acutely improves vascular function in younger individuals, with knee-level heating improving more outcome measures.NEW & NOTEWORTHY This study demonstrates that lower limb hot water immersion is an effective strategy for acutely improving vascular function in young, healthy males and females, thereby encouraging the development of accessible modes of heat therapy for vascular health.

Impact of Voluntary Folic Acid Fortification of Corn Masa Flour on RBC Folate Concentrations in the U.S. (NHANES 2011-2018).

Surveillance data have highlighted continued disparities in neural tube defects (NTDs) by race-ethnicity in the United States. Starting in 2016, the Food and Drug Administration (FDA) authorized voluntary folic acid fortification of corn masa flour to reduce the risk of neural tube defects (NTDs) among infants of Hispanic women of reproductive age. To assess the impact of voluntary corn masa fortification, cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2011-2018 for Hispanic women of reproductive age with available red blood cell (RBC) folate concentrations were analyzed, with additional analyses conducted among Hispanic women whose sole source of folic acid intake was fortified foods (enriched cereal grain products (ECGP) only), excluding ready-to-eat cereals and supplements. RBC folate concentration (adjusted geometric mean) among Hispanic women of reproductive age did not differ between 2011-2016 and 2017-2018, though RBC folate concentration increased significantly among lesser acculturated Hispanic women consuming ECGP only. Concentrations of RBC folate for those born outside the U.S and residing in the U.S <15 years increased from 894 nmol/L (95% CI: 844-946) in 2011-2016 to 1018 nmol/L (95% CI: 982-1162; p < 0.001) in 2017-2018. Primarily Spanish-speaking Hispanic women of reproductive age who only consumed ECGP saw an increase from 941 nmol/L (95% CI: 895-990) in 2011-2016 to 1034 nmol/L (95% CI: 966-1107; p = 0.03) in 2017-2018. By subpopulation, we observed no significant changes in the proportion at risk of NTDs (<748 nmol/L) and no changes in the model-based estimated NTD rates following voluntary corn masa fortification. This analysis suggests that there is a remaining risk among Hispanics for folate sensitive NTDs, though continued monitoring of folate status in future NHANES data cycles will help inform the long-term efficacy of voluntary fortification of corn masa flour.

Folate status in the US population 20 y after the introduction of folic acid fortification.

BACKGROUND: Enriched cereal-grain products have been fortified in the United States for >20 y to improve folate status in women of reproductive age and reduce the risk of folic acid-responsive neural tube birth defects (NTDs). OBJECTIVES: Our objectives were to assess postfortification changes in folate status in the overall US population and in women aged 12-49 y and to characterize recent folate status by demographic group and use of folic acid-containing supplements. METHODS: We examined cross-sectional serum and RBC folate data from the NHANES 1999-2016. RESULTS: Serum folate geometric means increased from 2007-2010 to 2011-2016 in persons aged ≥1 y (38.7 compared with 40.6 nmol/L) and in women (35.3 compared with 37.0 nmol/L), whereas RBC folate showed no significant change. Younger age groups, men, and Hispanic persons showed increased serum and RBC folate concentrations, whereas non-Hispanic black persons and supplement nonusers showed increased serum folate concentrations. The folate insufficiency prevalence (RBC folate <748 nmol/L; NTD risk) in women decreased from 2007-2010 (23.2%) to 2011-2016 (18.6%) overall and in some subgroups (e.g., women aged 20-39 y, Hispanic and non-Hispanic black women, and supplement nonusers). After covariate adjustment, RBC folate was significantly lower in all age groups (by ∼10-20%) compared with persons aged ≥60 y and in Hispanic (by 8.2%), non-Hispanic Asian (by 12.1%), and non-Hispanic black (by 20.5%) compared with non-Hispanic white women (2011-2016). The 90th percentile for serum (∼70 nmol/L) and RBC (∼1800 nmol/L) folate in supplement nonusers aged ≥60 y was similar to the geometric mean in users (2011-2014). CONCLUSIONS: Blood folate concentrations in the US population overall and in women have not decreased recently, and folate insufficiency rates are ∼20%. Continued monitoring of all age groups is advisable given the high folate status particularly in older supplement users.

Chemically induced neurite-like outgrowth reveals a multicellular network function in patient-derived glioblastoma cells.

Tumor stem cells and malignant multicellular networks have been separately implicated in the therapeutic resistance of glioblastoma multiforme (GBM), the most aggressive type of brain cancer in adults. Here, we show that small-molecule inhibition of RHO-associated serine/threonine kinase proteins (ROCKi) significantly promoted the outgrowth of neurite-like cell projections in cultures of heterogeneous patient-derived GBM stem-like cells. These projections formed de novo-induced cellular network (iNet) 'webs', which regressed after withdrawal of ROCKi. Connected cells within the iNet web exhibited long range Ca2+ signal transmission, and significant lysosomal and mitochondrial trafficking. In contrast to their less-connected vehicle control counterparts, iNet cells remained viable and proliferative after high-dose radiation. These findings demonstrate a link between ROCKi-regulated cell projection dynamics and the formation of radiation-resistant multicellular networks. Our study identifies means to reversibly induce iNet webs ex vivo, and may thereby accelerate future studies into the biology of GBM cellular networks.

Defining the plasma folate concentration associated with the red blood cell folate concentration threshold for optimal neural tube defects prevention: a population-based, randomized trial of folic acid supplementation.

BACKGROUND: For women of reproductive age, a population-level red blood cell (RBC) folate concentration below the threshold 906 nmol/L or 400 ng/mL indicates folate insufficiency and suboptimal neural tube defect (NTD) prevention. A corresponding population plasma/serum folate concentration threshold for optimal NTD prevention has not been established. OBJECTIVE: The aim of this study was to examine the association between plasma and RBC folate concentrations and estimated a population plasma folate insufficiency threshold (pf-IT) corresponding to the RBC folate insufficiency threshold (RBCf-IT) of 906 nmol/L. METHODS: We analyzed data on women of reproductive age (n = 1673) who participated in a population-based, randomized folic acid supplementation trial in northern China. Of these women, 565 women with anemia and/or vitamin B-12 deficiency were ineligible for folic acid intervention (nonintervention group); the other 1108 received folic acid supplementation for 6 mo (intervention group). We developed a Bayesian linear model to estimate the pf-IT corresponding to RBCf-IT by time from supplementation initiation, folic acid dosage, methyltetrahydrofolate reductase (MTHFR) genotype, body mass index (BMI), vitamin B-12 status, or anemia status. RESULTS: Using plasma and RBC folate concentrations of the intervention group, the estimated median pf-IT was 25.5 nmol/L (95% credible interval: 24.6, 26.4). The median pf-ITs were similar between the baseline and postsupplementation samples (25.7 compared with 25.2 nmol/L) but differed moderately (±3-4 nmol/L) by MTHFR genotype and BMI. Using the full population-based baseline sample (intervention and nonintervention), the median pf-IT was higher for women with vitamin B-12 deficiency (34.6 nmol/L) and marginal deficiency (29.8 nmol/L) compared with the sufficient group (25.6 nmol/L). CONCLUSIONS: The relation between RBC and plasma folate concentrations was modified by BMI and genotype and substantially by low plasma vitamin B-12. This suggests that the threshold of 25.5 nmol/L for optimal NTD prevention may be appropriate in populations with similar characteristics, but it should not be used in vitamin B-12 insufficient populations. This trial was registered at clinicaltrials.gov as NCT00207558.

Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion.

Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors.

The impact of acute mental stress on brachial artery flow-mediated dilation in women diagnosed with depression.

Endothelial function, assessed by flow-mediated dilation (FMD), may be transiently attenuated in healthy adults following acute mental stress. However, the impact of acute mental stress on endothelial function in the context of clinical depression is unknown. This study examined the impact of acute mental stress on FMD in women with a diagnosis of a depressive disorder. Forty-three otherwise healthy women (33 ±â€¯14 years) participated. Brachial artery diameter and blood velocity were assessed with ultrasound. FMD was assessed immediately prior to and 15 min following the Trier Social Stress Test (TSST). The FMD protocol included 5 min of forearm cuff occlusion (pressure = 250 mm Hg), followed by release. Shear stress was estimated by calculating shear rate (SR = brachial artery blood velocity/diameter). Stress reactivity was assessed via changes in mean arterial pressure (MAP), heart rate (HR) and salivary cortisol. Results are mean ±â€¯SD. A significant stress response was elicited by the TSST [MAP, HR and salivary cortisol increased (p < 0.05)]. Neither the SR stimulus nor FMD response differed pre-versus post-stress (p = 0.124 and p = 0.641, respectively). There was a modest negative correlation between cortisol reactivity and change in FMD from pre- to post-stress (R = -0.392, p = 0.011). To conclude, acute mental stress did not consistently impair endothelial function in women diagnosed with a depressive disorder; however, higher cortisol reactivity may increase the likelihood of post-stress endothelial dysfunction. Further research is required to better understand the factors influencing the relationship between acute mental stress, cortisol and endothelial function in women with depression.

Seizure care in the emergency department. Identifying and bridging the gaps. A study of care and outcomes from 644 seizure presentations.

Care for seizures in an emergency department setting can be variable, and there are disparities in access to onward specialist referral. The purpose of this study was to evaluate the utilization and implementation of an evidence-based seizure care pathway in a busy urban tertiary referral center. A total of 644 seizure presentations over two time points were examined. Initial pathway utilization rates were low at 26.2% but increased to 61.6% after environmental barriers had been addressed. We found that patients placed on the care pathway had higher rates of neurological examination, documentation of safety and legal guidelines as regards driving, and lower rates of seizure readmission. Twelve patients not placed on the pathway had passed away at follow-up (1.86%); the cause of death were related to significant comorbidities rather than the seizures themselves though in five, seizures could potentially have been a contributing factor. For the first time we have demonstrated that an evidence-based guideline for seizure management can be implemented in Ireland and used to standardize care for seizures in the emergency department improving documentation rates and clinical evaluation.

Mono- and diglycerides improve lutein absorption in healthy adults: a randomised, double-blind, cross-over, single-dose study.

With the association between increased carotenoid intake and lower risk of chronic diseases, the absorption of lutein from the diet becomes an important factor in its delivery and physiological action. The primary objective of this study was to gain an understanding of how a new formulation technology (mixture of mono- and diglycerides (MDG)), affected lutein absorption. Subjects (n 24) were randomised in a cross-over, double-blind study to receive a single dose of 6 mg lutein (FloraGLO 20 %) provided as capsules containing either high-oleic safflower (SAF) oil or a MDG oil. Subjects receiving a single dose of lutein in MDG showed a significantly greater change from baseline (0 h) to 4, 6, 8, 12, 24, 48 and 336 h (P<0·05) and baseline adjusted AUC for plasma lutein at 48 and 336 h (P<0·001) as compared with subjects given lutein in SAF. Analysis of the 48 h absorption kinetics of lutein showed that the time to peak level of lutein (12 h) was the same for SAF and MDG groups, but the change in plasma lutein at 12 and 48 h were 129 and 320 % higher, respectively, for MDG compared with SAF. This difference continued as the adjusted AUC 0-48 and 0-336 h for the MDG group was 232 and 900 % higher, respectively, v. SAF. The study data show that by changing the lipid that is combined with a lutein supplement results in significant increases in lutein absorption in healthy adults.

Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH).

The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine-substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold. Herein, we report the discovery of 1 (tropifexor, LJN452), a novel and highly potent agonist of FXR. Potent in vivo activity was demonstrated in rodent PD models by measuring the induction of FXR target genes in various tissues. Tropifexor has advanced into phase 2 human clinical trials in patients with NASH and PBC.

Impact of a mindfulness-based stress reduction program from the perspective of adolescents with serious mental health concerns.

BACKGROUND: While studies on mindfulness-based stress reduction (MBSR) for youth have recently emerged, there is a shortage of research on how adolescents from clinical populations experience MBSR. The purpose of this qualitative study was to explore the impact of MBSR from the subjective perspective of adolescents with serious mental health concerns. METHOD: Adolescents (n = 28) from a residential treatment center participated in an adapted 8-week MBSR program in which they learned a range of mindfulness skills and were encouraged to apply the skills to their everyday lives. At the end of the program and at a 3-month follow-up, the youth participated in semistructured interviews in which they were asked to describe the impact of the program from their perspectives. Basic interpretive qualitative analysis methods were used to code the data and to group the codes into higher level themes. RESULTS: Six main themes were found, including improved mood, enhanced relationship to self, increased self-control, improved problem-solving, awareness of the present, and enhanced interpersonal relationships. DISCUSSION: Results from this study suggest that the MBSR program was perceived as beneficial both in the short-term and follow-up in several aspects of emotional, cognitive, and interpersonal functioning.

Vitamin D levels and perinatal depressive symptoms in women at risk: a secondary analysis of the mothers, omega-3, and mental health study.

BACKGROUND: Vitamin D insufficiency may be associated with depressive symptoms in non-pregnant adults. We performed this study to evaluate whether low maternal vitamin D levels are associated with depressive symptoms in pregnancy. METHODS: This study was a secondary analysis of a randomized trial designed to assess whether prenatal omega-3 fatty acid supplementation would prevent depressive symptoms. Pregnant women from Michigan who were at risk for depression based on Edinburgh Postnatal Depression Scale Score or history of depression were enrolled. Participants completed the Beck Depression Inventory (BDI) and Mini International Neuropsychiatric Interview at 12-20 weeks, 26-28 weeks, 34-36 weeks, and 6-8 weeks postpartum. Vitamin D levels were measured at 12-20 weeks (N = 117) and 34-36 weeks (N = 112). Complete datasets were available on 105 subjects. Using regression analyses, we evaluated the relationship between vitamin D levels with BDI scores as well as with MINI diagnoses of major depressive disorder and generalized anxiety disorder. Our primary outcome measure was the association of maternal vitamin D levels with BDI scores during early and late pregnancy and postpartum. RESULTS: We found that vitamin D levels at 12-20 weeks were inversely associated with BDI scores both at 12-20 and at 34-36 weeks' gestation (P < 0.05, both). For every one unit increase in vitamin D in early pregnancy, the average decrease in the mean BDI score was .14 units. Vitamin D levels were not associated with diagnoses of major depressive disorder or generalized anxiety disorder. CONCLUSIONS: In women at risk for depression, early pregnancy low vitamin D levels are associated with higher depressive symptom scores in early and late pregnancy. Future investigations should study whether vitamin D supplementation in early pregnancy may prevent perinatal depressive symptoms. TRIAL REGISTRATION: https://clinicaltrials.gov/ REGISTRATION NUMBER: NCT00711971.

CA19-9 Normalization During Pre-operative Treatment Predicts Longer Survival for Patients with Locally Progressed Pancreatic Cancer.

BACKGROUND: Compared to the widely adopted 2-4 months of pre-operative therapy for patients with borderline resectable (BR) or locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC), our institution tends to administer a longer duration before considering surgical resection. Using this unique approach, the aim of this study was to determine pre-operative variables associated with survival. METHODS: Records from patients with BR/LA PDAC who underwent attempt at surgical resection from 1992-2014 were reviewed. RESULTS: After a median duration of 6 months of pre-operative treatment, 109 patients with BR/LA PDAC (BR 63, LA 46) were explored; 93 (85.3 %) underwent pancreatectomy. Those who received at least 6 months of pre-operative treatment had longer median overall survival (OS) than those who received less (52.8 vs. 32.1 months, P = 0.044). On multivariate analysis, pre-operative treatment duration was the strongest predictor of survival (hazard ratio (HR) 4.79, P = 0.043). However, OS was similar in those whose CA19-9 normalized regardless of whether they received more or less than 6 months of chemotherapy (71.4 vs. 101.8 months, P = 0.930). CONCLUSIONS: Pre-operative CA19-9 decline can guide treatment duration in patients with BR/LA PDAC. We endorse 6 months of therapy except in those patients whose values normalize, where surgery can be considered after a shorter course.