A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder.

Nicotinamide adenine dinucleotide (NAD) is essential for embryonic development. To date, biallelic loss-of-function variants in 3 genes encoding nonredundant enzymes of the NAD de novo synthesis pathway - KYNU, HAAO, and NADSYN1 - have been identified in humans with congenital malformations defined as congenital NAD deficiency disorder (CNDD). Here, we identified 13 further individuals with biallelic NADSYN1 variants predicted to be damaging, and phenotypes ranging from multiple severe malformations to the complete absence of malformation. Enzymatic assessment of variant deleteriousness in vitro revealed protein domain-specific perturbation, complemented by protein structure modeling in silico. We reproduced NADSYN1-dependent CNDD in mice and assessed various maternal NAD precursor supplementation strategies to prevent adverse pregnancy outcomes. While for Nadsyn1+/- mothers, any B3 vitamer was suitable to raise NAD, preventing embryo loss and malformation, Nadsyn1-/- mothers required supplementation with amidated NAD precursors (nicotinamide or nicotinamide mononucleotide) bypassing their metabolic block. The circulatory NAD metabolome in mice and humans before and after NAD precursor supplementation revealed a consistent metabolic signature with utility for patient identification. Our data collectively improve clinical diagnostics of NADSYN1-dependent CNDD, provide guidance for the therapeutic prevention of CNDD, and suggest an ongoing need to maintain NAD levels via amidated NAD precursor supplementation after birth.

Genomic Literacy of Registered Nurses and Midwives in Australia: A Cross-Sectional Survey.

PURPOSE: Registered nurses and midwives require a degree of genomic literacy if they are to adequately communicate with other healthcare professionals and provide optimal care to patients, their families, and the community. Several studies have been conducted internationally to assess the genomic literacy of nurses; however, the genomic literacy of Australian registered nurses and midwives has not been investigated. The aim of this study was to measure the genomic literacy of Australian registered nurses and midwives through assessing participants' understandings of genomic concepts most critical to nursing and midwifery practice, as well as their perceived knowledge and attitude towards genomics in nursing and midwifery practice. DESIGN: Cross-sectional survey of Australian registered nurses and midwives using the Genomic Nursing Concept Inventory (GNCI© ), a 31 multiple-choice question survey instrument. Participants were recruited via two key Australian nursing and midwifery organizations over an 8-month period in 2016. METHODS: Descriptive and inferential statistical techniques were used to calculate the total GNCI© score and scores on individual subcategories, as well as relationships between demographic variables and GNCI© scores. FINDINGS: Most respondents worked as clinicians (71.4%) in a hospital or hospital-based setting (61.8%). Most registered nurses (80.5%) and midwives (97.2%) reported that genetics was relevant to clinical practice; however, over 80% of registered nurses and midwives believed their knowledge of genetics was poor or average. Genomic knowledge was assessed using the GNCI© . Scores ranged from 3 to 29 (out of a possible 31), with a mean score of 13.3 (SD 4.559) based on 253 (N = 253) respondents, indicating that genomic literacy is low. There was a significant difference between genomic knowledge scores and education and training level (p = .036). CONCLUSIONS: The genomic literacy of registered nurses and midwives in Australia is low. More must be done to ensure Australian registered nurses and midwives have an adequate level of genomic literacy to provide optimal care to patients, their families, and the community. CLINICAL RELEVANCE: Modern medicine requires a healthcare workforce that is literate in genomics. Findings from this study may serve as the catalyst to improve the genomic literacy of the Australian nursing and midwifery workforce, allowing for improved health outcomes for individuals and the wider Australian public.

Alteration of Neutrophil Reactive Oxygen Species Production by Extracts of Devil's Claw (Harpagophytum).

Harpagophytum, Devil's Claw, is a genus of tuberiferous xerophytic plants native to southern Africa. Some of the taxa are appreciated for their medicinal effects and have been traditionally used to relieve symptoms of inflammation. The objectives of this pilot study were to investigate the antioxidant capacity and the content of total phenols, verbascoside, isoverbascoside, and selected iridoids, as well as to investigate the capacity of various Harpagophytum taxa in suppressing respiratory burst in terms of reactive oxygen species produced by human neutrophils challenged with phorbol myristate acetate (PMA), opsonised Staphylococcus aureus, and Fusobacterium nucleatum. Harpagophytum plants were classified into different taxa according to morphology, and DNA analysis was used to confirm the classification. A putative new variety of H. procumbens showed the highest degree of antioxidative capacity. Using PMA, three Harpagophytum taxa showed anti-inflammatory effects with regard to the PBS control. A putative hybrid between H. procumbens and H. zeyheri in contrast showed proinflammatory effect on the response of neutrophils to F. nucleatum in comparison with treatment with vehicle control. Harpagophytum taxa were biochemically very variable and the response in suppressing respiratory burst differed. Further studies with larger number of subjects are needed to corroborate anti-inflammatory effects of different taxa of Harpagophytum.

The endogenous circadian temperature period length (tau) in delayed sleep phase disorder compared to good sleepers.

The currently assumed aetiology for delayed sleep phase disorder (DSPD) is a delay of the circadian system. Clinicians have sought to use bright light therapy, exogenous melatonin or chronotherapy to correct the disorder. However, these treatments have achieved unreliable outcomes for DSPD patients and, as such, one suggestion has been that the disorder may be caused by a longer than normal circadian rhythm period length (i.e. tau). The present study investigated this premise using a 78-h ultradian, ultra-short sleep-wake cycle. This constant bedrest routine was used to simulate a series of 1-h long 'days' by alternating 20-min sleep opportunities and 40 min of enforced wakefulness. Thirteen participants were recruited for the study including, six people diagnosed with DSPD according to the International Classification of Sleep Disorders-2 [mean age = 22.0, standard deviation (SD) = 3.3] and seven good sleepers (mean age = 23.1, SD = 3.9) with normal sleep timing. The DSPD participants' core temperature rhythm tau (mean = 24 h 54 min, SD = 23 min) was significantly longer (t = -2.33, P = 0.04, Cohen's d = 1.91) than the good sleepers' (mean 24 h 29 min, SD = 16 min). The temperature rhythm of the DSPD participants delayed more rapidly (i.e. >25 min day(-1) ) than the good sleepers'. These findings provide an explanation for the difficulty that DSPD patients have in phase advancing to a more conventional sleep time and their frequent relapse following treatment. The outcomes of this study support a vigorous and continued application of chronobiological and behavioural therapies to entrain DSPD patients to their desired earlier sleep times.

A randomized controlled trial of cognitive-behavior therapy plus bright light therapy for adolescent delayed sleep phase disorder.

OBJECTIVE: To evaluate cognitive-behavior therapy plus bright light therapy (CBT plus BLT) for adolescents diagnosed with delayed sleep phase disorder (DSPD). DESIGN: Randomized controlled trial of CBT plus BLT vs. waitlist (WL) control with comparisons at pre- and post-treatment. There was 6-month follow-up for the CBT plus BLT group only. SETTING: Flinders University Child & Adolescent Sleep Clinic, Adelaide, South Australia. PATIENTS: 49 adolescents (mean age 14.6 ± 1.0 y, 53% males) diagnosed with DSPD; mean chronicity 4 y 8 months; 16% not attending school. Eighteen percent of adolescents dropped out of the study (CBT plus BLT: N = 23 vs. WL: N = 17). INTERVENTIONS: CBT plus BLT consisted of 6 individual sessions, including morning bright light therapy to advance adolescents' circadian rhythms, and cognitive restructuring and sleep education to target associated insomnia and sleep hygiene. MEASUREMENTS AND RESULTS: DSPD diagnosis was performed via a clinical interview and 7-day sleep diary. Measurements at each time-point included online sleep diaries and scales measuring sleepiness, fatigue, and depression symptoms. Compared to WL, moderate-to-large improvements (d = 0.65-1.24) were found at post-treatment for CBT plus BLT adolescents, including reduced sleep latency, earlier sleep onset and rise times, total sleep time (school nights), wake after sleep onset, sleepiness, and fatigue. At 6-month follow-up (N = 15), small-to-large improvements (d = 0.24-1.53) continued for CBT plus BLT adolescents, with effects found for all measures. Significantly fewer adolescents receiving CBT plus BLT met DPSD criteria at post-treatment (WL = 82% vs. CBT plus BLT = 13%, P < 0.0001), yet 13% still met DSPD criteria at the 6-month follow-up. CONCLUSIONS: CBT plus BLT for adolescent DSPD is effective for improving multiple sleep and daytime impairments in the immediate and long-term. Studies evaluating the treatment effectiveness of each treatment component are needed. CLINICAL TRIAL INFORMATION: Australia-New Zealand Trials Registry Number: ACTRN12610001041044.

Girls' early sweetened carbonated beverage intake predicts different patterns of beverage and nutrient intake across childhood and adolescence.

BACKGROUND: Information is limited on persistence of early beverage patterns throughout childhood and adolescence and their influence on long-term dietary intake. OBJECTIVE: To describe changes in beverage intake during childhood and assess beverage and nutrient intake from ages 5 to 15 years among girls who were consuming or not consuming sweetened carbonated beverages (soda) at age 5 years. DESIGN/SUBJECTS: Participants were part of a longitudinal study of non-Hispanic white girls and their parents (n=170) assessed biennially from age 5 to 15 years starting fall 1996. STATISTICAL ANALYSES: At each assessment, intakes of beverages (milk, fruit juice, fruit drinks, soda, and tea/coffee), energy, macronutrients, and micronutrients were assessed using three 24-hour recalls. Analyses of longitudinal changes and the interaction between beverage type and age were conducted using a mixed modeling approach. Girls were categorized as either soda consumers or nonconsumers at age 5 years. A mixed modeling approach was used to assess longitudinal differences and patterns of change in beverage and nutrient intake between soda consumption groups. RESULTS: Early differences in soda intake were predictive of later soda and milk intake and of differences in selected nutrients. Relative to girls who were not consuming soda beverages at age 5 years, soda consumers at age 5 years had higher subsequent soda intake, lower milk intake, higher intake of added sugars, lower protein, fiber, vitamin D, calcium, magnesium, phosphorous, and potassium from ages 5 to 15 years. CONCLUSIONS: Soda consumption at age 5 years predicted patterns of nutrient intake that persisted during childhood and into adolescence. Diets of soda consumers were higher in added sugars and lower in protein, fiber, calcium, vitamin D, magnesium, phosphorous, and potassium. Findings provide a more complex picture regarding the emergence of early beverage patterns and their predictive effects on nutrient intake across childhood and adolescence.

Dietary screening tool identifies nutritional risk in older adults.

BACKGROUND: No rapid methods exist for screening overall dietary intakes in older adults. OBJECTIVE: The purpose of this study was to develop and evaluate a scoring system for a diet screening tool to identify nutritional risk in community-dwelling older adults. DESIGN: This cross-sectional study in older adults (n = 204) who reside in rural areas examined nutrition status by using an in-person interview, biochemical measures, and four 24-h recalls that included the use of dietary supplements. RESULTS: The dietary screening tool was able to characterize 3 levels of nutritional risk: at risk, possible risk, and not at risk. Individuals classified as at nutritional risk had significantly lower indicators of diet quality (Healthy Eating Index and Mean Adequacy Ratio) and intakes of protein, most micronutrients, dietary fiber, fruit, and vegetables. The at-risk group had higher intakes of fats and oils and refined grains. The at-risk group also had the lowest serum vitamin B-12, folate, beta-cryptoxanthin, lutein, and zeaxanthin concentrations. The not-at-nutritional-risk group had significantly higher lycopene and beta-carotene and lower homocysteine and methylmalonic acid concentrations. CONCLUSION: The dietary screening tool is a simple and practical tool that can help to detect nutritional risk in older adults.

The relationship between insomnia and body temperatures.

Sleepiness and sleep propensity are strongly influenced by our circadian clock as indicated by many circadian rhythms, most commonly by that of core body temperature. Sleep is most conducive in the temperature minimum phase, but is inhibited in a "wake maintenance zone" before the minimum phase, and is disrupted in a zone following that phase. Different types of insomnia symptoms have been associated with abnormalities of the body temperature rhythm. Sleep onset insomnia is associated with a delayed temperature rhythm presumably, at least partly, because sleep is attempted during a delayed evening wake maintenance zone. Morning bright light has been used to phase advance circadian rhythms and successfully treat sleep onset insomnia. Conversely, early morning awakening insomnia has been associated with a phase advanced temperature rhythm and has been successfully treated with the phase delaying effects of evening bright light. Sleep maintenance insomnia has been associated not with a circadian rhythm timing abnormality, but with nocturnally elevated core body temperature. Combination of sleep onset and maintenance insomnia has been associated with a 24-h elevation of core body temperature supporting the chronic hyper-arousal model of insomnia. The possibility that these last two types of insomnia may be related to impaired thermoregulation, particularly a reduced ability to dissipate body heat from distal skin areas, has not been consistently supported in laboratory studies. Further studies of thermoregulation are needed in the typical home environment in which the insomnia is most evident.

Intensive Sleep Retraining treatment for chronic primary insomnia: a preliminary investigation.

The aim of this study was to assess the effectiveness of Intensive Sleep Retraining, a novel, short duration behavioural therapy in treating chronic primary insomnia. Seventeen consecutive volunteers from the general public (mean age = 39.1 years), meeting selection criteria for chronic primary insomnia participated in the treatment study. The study was performed as a case replication series. Assessment involved sleep diary, actigraph and questionnaire measures of sleep and daytime functioning for a period of 2 weeks prior to, immediately after, and 6 weeks following the treatment. Treatment involved a single night of sleep deprivation, facilitating short sleep latencies (mean: 6.9 min) to a series of 50 brief nap opportunities. Following treatment, Sleep Onset Latency significantly decreased by a mean of 30.5 min (SD = 28.3), Wake Time after Sleep Onset significantly decreased by a mean of 28 min (SD = 34.0), and Total Sleep Time significantly increased by 64.6 min (SD = 45.5). Significant improvements were also seen in the daytime functioning and psychological measures of fatigue and vigour, cognitive sleep anticipatory anxiety and self-efficacy for sleep. This brief therapy was effective in improving sleep and some daytime functioning and psychological questionnaire measures. These improvements were maintained up to 2 months following the treatment weekend. Further exploration of this brief therapy is needed, with larger, randomized, placebo-controlled trials over longer follow-up periods, and in comparison to other traditional therapies for insomnia.

Treating chronobiological components of chronic insomnia.

Circadian rhythms have a strong effect on the ability to sleep across the 24-h period. Maximum sleepiness occurs at the phase of lower endogenous core body temperature. This period is bracketed by two periods of alertness: a "wake-maintenance zone" occurring 6-10h before the time of core temperature minimum, and a "wake-up zone" occurring 4-7h after the minimum. Therefore, if the circadian rhythm drifts earlier with respect to the attempted sleep period, the wake-up zone can impinge on the end of the normal sleep period resulting in premature awakening and the development of early morning awakening insomnia. Similarly, a delay of the circadian rhythm can impose the wake-maintenance zone on the attempted bedtime and lead to sleep onset insomnia. Therefore, these two types of insomnia should be treatable with chronobiologic effects such as bright light and, possibly, melatonin administration. Bright light stimulation at normal wake-up time and melatonin administration 4-8h before normal bedtime can phase advance circadian rhythms to an earlier time. While morning bright light has been efficacious for sleep onset insomnia, evening melatonin administration has yet to be tested. Early morning awakening insomnia has been treated with phase delays imposed by evening bright light but not yet with morning melatonin administration. There is now sufficient evidence to warrant the consideration of chronobiologic manipulations such as bright light therapy for the treatment of chronic sleep onset and early morning awakening insomnia that show evidence of circadian delay or advance, respectively.

Clinical management of delayed sleep phase disorder.

Delayed Sleep Phase Disorder is a circadian rhythm disorder that results in a late timed sleep pattern. Individuals have difficulty falling asleep at a conventional hour and difficulty waking in the morning. We discuss the contributing factors and consequences of a delayed sleep phase and describe treatment approaches. These include therapies to phase change the delayed sleep circadian rhythm such as morning bright light exposure, exogenous melatonin administration, and chronotherapy as well as some behavioral strategies.

Girls' calcium intake is associated with bone mineral content during middle childhood.

We examined longitudinally the association between calcium intake and total body bone mineral content (TBBMC) in 151 non-Hispanic white girls. Intakes of dairy, energy, and calcium were assessed using three 24-h dietary recalls in girls at ages 5, 7, 9, and 11 y. We assessed their total-body bone mineral content with dual-energy X-ray absorptiometry at ages 9 and 11 y. Dairy foods comprised the major contributor (70%) to calcium intake over the 6-y period; 28% of calcium came from other foods, and 2% from supplements. By age 9 and 11 y, the majority of girls did not meet calcium recommendations. Higher calcium intake at ages 7 and 9 y was associated with higher TBBMC at age 11 y. Calcium intake at age 9 y was also positively associated with TBBMC gained from age 9 to 11 y. Calcium intake at age 11 y was not correlated with TBBMC at the same age. Relations between calcium intake and TBBMC did not differ for total calcium and for calcium from dairy sources, likely reflecting the fact that dairy products were the major source of calcium in this sample. Results from the present study provide new longitudinal evidence that calcium intake, especially calcium from dairy foods, can have a favorable effect on girls' TBBMC during middle childhood.

Dairy and dairy-related nutrient intake during middle childhood.

OBJECTIVE: To characterize patterns of dairy intake among girls in middle childhood. DESIGN: Longitudinal data were used to characterize girls' patterns of dairy intake at age 5, 7, 9, and 11 years. SUBJECTS: Participants were 151 girls from predominately middle-class and exclusively non-Hispanic white families living in central Pennsylvania. STATISTICAL ANALYSES: Intakes of dairy, energy, macronutrients, vitamin D, calcium, and phosphorus were assessed using three 24-hour dietary recalls in 151 non-Hispanic white girls at age 5, 7, 9, and 11 years. Analyses of changes over time were conducted using repeated measures analysis of variance. McNemar's chi(2) test was used to analyze change in percentage of dairy consumers over time. RESULTS: From age 5 to 11 years, girls' total dairy intake remained stable. Total milk consumption declined, due to a decline in intake of milk as a beverage, while intakes of cheese and dairy desserts increased. Much of the decline in milk intake from age 5 to 11 years, especially for milk as a beverage, was due to a reduction in the percentage of girls consuming milk as a beverage, not simply due to a decline in the servings of milk as a beverage consumed by consumers. On average, girls met vitamin D recommendations over time; however, by age 9 and 11 years girls failed to meet calcium and phosphorus recommendations. CONCLUSIONS: Although girls' dairy intake was stable over time, at age 7, 9, and 11 years girls did not meet the recommended three servings per day, leading to suboptimal intakes of calcium and phosphorus at age 9 and 11 years. Increasing milk intake among all children should continue to be a major focus of interventions.

The treatment of early-morning awakening insomnia with 2 evenings of bright light.

STUDY OBJECTIVE: To assess the effectiveness of brief bright-light therapy for the treatment of early-morning awakening insomnia. PARTICIPANTS: Twenty-four healthy adults with early-morning awakening insomnia were assigned to either the bright-light condition (2,500-lux white light) or the control (dim red light) condition. MEASUREMENTS AND RESULTS: The circadian phase of rectal temperature and urinary melatonin rhythms were assessed with 26-hour constant routines before and after 2 evenings of light therapy. Sleep and daytime functioning were monitored using sleep diaries, activity monitors, and mood scales before light therapy and for 4 weeks during the follow-up period. While there were no significant circadian phase changes in the dim-light control group, the bright-light group had significant 2-hour phase delays of circadian temperature and melatonin rhythm. Compared to pretreatment measures, over the 4-week follow-up period, the bright-light group had a greater reduction of time awake after sleep onset, showed a trend toward waking later, and had a greater increase of total sleep time. Participants in the bright-light condition also tended to report greater reductions of negative daytime symptoms, including significantly fewer days of feeling depressed at the 4-week follow-up, as compared with the control group. CONCLUSION: Two evenings of bright-light exposure phase delayed the circadian rhythms of early-morning awakening insomniacs. It also improved diary and actigraphy sleep measures and improved some indexes of daytime functioning for up to 1 month after light exposure. The study suggests that a brief course of evening bright-light therapy can be an effective treatment for early-morning awakening insomniacs who have relatively phase advanced circadian rhythms.

High-soluble-fiber foods in conjunction with a telephone-based, personalized behavior change support service result in favorable changes in lipids and lifestyles after 7 weeks.

OBJECTIVE: To evaluate whether an intervention of foods high in soluble fiber from psyllium and/or oats plus a telephone-based, personalized behavior change support service improves serum lipids and elicits cholesterol-managing lifestyle changes vs usual care. DESIGN: 7-week randomized, controlled intervention. SUBJECTS/SETTING: 150 moderately hypercholesterolemic men and women, age range 25 to 70 years. INTERVENTION: The intervention group consumed 4 servings/day of high-fiber foods and had weekly telephone conversations with a personal coach who offered support and guidance in making lifestyle changes consistent with the National Cholesterol Education Program's (NCEP) cholesterol-lowering guidelines. The usual care group received a handout describing the NCEP Step-1 diet. MAIN OUTCOME MEASURES: Serum lipids and lipoproteins and self-reported lifestyle changes. STATISTICAL ANALYSES: For physiologic and dietary changes, mixed linear models for repeated measures were applied. Models were simplified using analysis of covariance where age in years was the covariate. Traditional general linear models were used to assess lifestyle changes. RESULTS: In the intervention group total cholesterol (TC) decreased 5.6%, low-density lipoprotein (LDL) cholesterol 7.1%, LDL/high-density lipoprotein (HDL) cholesterol ratio 5.6%, and triglycerides (TG) 14.2% (P<.0167); decreases in TC and LDL were significantly different from the usual care group. In the usual care group TC decreased 1.9%, LDL 1.2%, LDL/HDL 1.9%, and TG 4.4% (all not significant). The intervention group also reported an increase in their knowledge, ability, and confidence to make cholesterol-managing diet and exercise changes compared with the usual care group (P<.05). The intervention group had a greater decrease in energy intake from saturated fat (-1.6%) and increase in soluble fiber intake (7.3%) than the usual care group (P<.05). The intervention group reported an increase in exercise vs the usual care group (P<.05). Both intervention and control groups had a minimal reduction (<1%) in body weight compared with baseline (P<.0167). APPLICATIONS/CONCLUSIONS: A 7-week intervention that includes both functional foods and individualized, interactive support for behavior change could be an effective model for dietitians to use with patients at risk for CVD, pending results of long-term studies.

Maternal influences on 5- to 7-year-old girls' intake of multivitamin-mineral supplements.

OBJECTIVE: To examine diet quality of girls who do or do not take multivitamin-mineral (MVM) supplements and to evaluate predictors of girls' MVM use, including maternal eating behaviors, MVM use, beliefs, attitudes, and perceptions about child feeding, eating, and health. DESIGN: Participants were 192 mother and daughter pairs. Daughters were categorized as MVM supplement users or nonusers based on whether girls were consistently given MVM supplements at 5 and 7 years. Girls' and mothers' nutrient and food group intakes, maternal child-feeding practices, and maternal eating behavior were compared between the groups. RESULTS: Mothers who used MVM supplements were more likely to give MVM supplements to daughters. Excluding nutrients from MVM supplements, MVM users and nonusers did not differ in vitamin and mineral intake, either for girls or mothers, and patterns of food group intake were similar for users and nonusers. Mothers of MVM users reported the following: higher levels of pressuring their daughters to eat healthier diets, more monitoring of daughters' food intake, more success in dieting for weight control, more positive evaluations of their success in eating healthy diets, and lower body mass indexes than mothers who did not give MVMs to daughters. CONCLUSIONS: Daughters' MVM supplement use was predicted by mothers' beliefs, attitudes, perceptions, and practices regarding mothers' own eating and child feeding practices, rather than by daughters' diet quality. For both MVM users and nonusers, daughters' food group servings were below recommendations, whereas vitamin and mineral intakes exceeded recommendations, a pattern indicative of girls' relatively high intakes of fortified foods. Mothers should be encouraged to foster healthier patterns of food intake in daughters, rather than providing MVM supplements.