Randomised controlled trial of perinatal vitamin D supplementation to prevent early-onset acute respiratory infections among Australian First Nations children: the 'D-Kids' study protocol.

INTRODUCTION: Globally, acute respiratory infections (ARIs) are a leading cause of childhood morbidity and mortality. While ARI-related mortality is low in Australia, First Nations infants are hospitalised with ARIs up to nine times more often than their non-First Nations counterparts. The gap is widest in the Northern Territory (NT) where rates of both acute and chronic respiratory infection are among the highest reported in the world. Vitamin D deficiency is common among NT First Nations neonates and associated with an increased risk of ARI hospitalisation. We hypothesise that perinatal vitamin D supplementation will reduce the risk of ARI in the first year of life. METHODS AND ANALYSIS: 'D-Kids' is a parallel (1:1), double-blind (allocation concealed), randomised placebo-controlled trial conducted among NT First Nations mother-infant pairs. Pregnant women and their babies (n=314) receive either vitamin D or placebo. Women receive 14 000 IU/week or placebo from 28 to 34 weeks gestation until birth and babies receive 4200 IU/week or placebo from birth until age 4 months. The primary outcome is the incidence of ARI episodes receiving medical attention in the first year of life. Secondary outcomes include circulating vitamin D level and nasal pathogen prevalence. Tertiary outcomes include infant immune cell phenotypes and challenge responses. Blood, nasal swabs, breast milk and saliva are collected longitudinally across four study visits: enrolment, birth, infant age 4 and 12 months. The sample size provides 90% power to detect a 27.5% relative reduction in new ARI episodes between groups. ETHICS AND DISSEMINATION: This trial is approved by the NT Human Research Ethics Committee (2018-3160). Study outcomes will be disseminated to participant families, communities, local policy-makers, the broader research and clinical community via written and oral reports, education workshops, peer-reviewed journals, national and international conferences. TRIAL REGISTRATION NUMBER: ACTRN12618001174279.

Biological Effects of Intravenous Vitamin C on Neutrophil Extracellular Traps and the Endothelial Glycocalyx in Patients with Sepsis-Induced ARDS.

(1) Background: The disease-modifying mechanisms of high-dose intravenous vitamin C (HDIVC) in sepsis induced acute respiratory distress syndrome (ARDS) is unclear. (2) Methods: We performed a post hoc study of plasma biomarkers from subjects enrolled in the randomized placebo-controlled trial CITRIS-ALI. We explored the effects of HDIVC on cell-free DNA (cfDNA) and syndecan-1, surrogates for neutrophil extracellular trap (NET) formation and degradation of the endothelial glycocalyx, respectively. (3) Results: In 167 study subjects, baseline cfDNA levels in HDIVC (84 subjects) and placebo (83 subjects) were 2.18 ng/µL (SD 4.20 ng/µL) and 2.65 ng/µL (SD 3.87 ng/µL), respectively, p = 0.45. At 48-h, the cfDNA reduction was 1.02 ng/µL greater in HDIVC than placebo, p = 0.05. Mean baseline syndecan-1 levels in HDIVC and placebo were 9.49 ng/mL (SD 5.57 ng/mL) and 10.83 ng/mL (SD 5.95 ng/mL), respectively, p = 0.14. At 48 h, placebo subjects exhibited a 1.53 ng/mL (95% CI, 0.96 to 2.11) increase in syndecan-1 vs. 0.75 ng/mL (95% CI, 0.21 to 1.29, p = 0.05), in HDIVC subjects. (4) Conclusions: HDIVC infusion attenuated cell-free DNA and syndecan-1, biomarkers associated with sepsis-induced ARDS. Improvement of these biomarkers suggests amelioration of NETosis and shedding of the vascular endothelial glycocalyx, respectively.

Association of Phosphate Containing Solutions with Incident Hypophosphatemia in Critically Ill Patients Requiring Continuous Renal Replacement Therapy.

BACKGROUND: Hypophosphatemia in critically ill patients is a common electrolyte disturbance associated with a myriad of adverse effects. Critically ill patients requiring continuous renal replacement therapy (CRRT) are at high risk of hypophosphatemia and often require phosphate supplementation during therapy. The aim of this study was to evaluate the association of phosphate versus non-phosphate containing CRRT solutions with incident hypophosphatemia in critically ill patients requiring CRRT. MATERIALS AND METHODS: This is a single-center, retrospective, cohort study at a tertiary academic medical center of 1,396 adult patients requiring CRRT during their intensive care unit stay comprising 7,529 (phosphate containing) and 4,821 (non-phosphate containing) cumulative days of CRRT. Multivariable logistic regression was used to model the primary outcome of hypophosphatemia during CRRT according to exposure to phosphate versus non-phosphate containing CRRT solutions. RESULTS: Incident hypophosphatemia during CRRT, serum phosphate <2.5 mg/dL or 0.81 mmol/L, was significantly higher in the non-phosphate versus phosphate containing solution group: 304/489 (62%) versus 175/853 (21%) (p < 0.001). Cumulative phosphate supplementation was also significantly higher in the non-phosphate versus phosphate containing solution group: 79 (IQR: 0-320) versus 0 (0-16) mmol (p < 0.001). Non-phosphate solutions were associated with an 8-fold increase in the incidence of hypophosphatemia (adjusted OR 8.05; 95% CI 5.77, 11.26; p < 0.001). DISCUSSION/CONCLUSIONS: The use of phosphate containing CRRT solutions was independently associated with reduced risk of incident hypophosphatemia and decreased phosphate supplementation during CRRT. Interventional studies to confirm these findings are needed.

A metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure.

Acute respiratory failure (ARF) requiring mechanical ventilation, a complicating factor in sepsis and other disorders, is associated with high morbidity and mortality. Despite its severity and prevalence, treatment options are limited. In light of accumulating evidence that mitochondrial abnormalities are common in ARF, here we applied broad spectrum quantitative and semiquantitative metabolomic analyses of serum from ARF patients to detect bioenergetic dysfunction and determine its association with survival. Plasma samples from surviving and non-surviving patients (N = 15/group) were taken at day 1 and day 3 after admission to the medical intensive care unit and, in survivors, at hospital discharge. Significant differences between survivors and non-survivors (ANOVA, 5% FDR) include bioenergetically relevant intermediates of redox cofactors nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP), increased acyl-carnitines, bile acids, and decreased acyl-glycerophosphocholines. Many metabolites associated with poor outcomes are substrates of NAD(P)-dependent enzymatic processes, while alterations in NAD cofactors rely on bioavailability of dietary B-vitamins thiamine, riboflavin and pyridoxine. Changes in the efficiency of the nicotinamide-derived cofactors' biosynthetic pathways also associate with alterations in glutathione-dependent drug metabolism characterized by substantial differences observed in the acetaminophen metabolome. Based on these findings, a four-feature model developed with semi-quantitative and quantitative metabolomic results predicted patient outcomes with high accuracy (AUROC = 0.91). Collectively, this metabolomic endotype points to a close association between mitochondrial and bioenergetic dysfunction and mortality in human ARF, thus pointing to new pharmacologic targets to reduce mortality in this condition.

Maternal Anaemia in Pregnancy: A Significantly Greater Risk Factor for Anaemia in Australian Aboriginal Children than Low Birth Weight or Prematurity.

OBJECTIVES: To identify maternal and perinatal risk factors associated with childhood anaemia. METHODS: A retrospective cohort study was conducted in three remote Katherine East Aboriginal communities in Northern Territory, Australia. Children born 2004-2014 in Community A and 2010-2014 in Community B and C, and their respective mothers were recruited into the study. Maternal and child data were linked to provide a longitudinal view of each child for the first 1000 days from conception to 2-years of age. Descriptive analyses were used to calculate mean maternal age, and proportions were used to describe other antenatal and perinatal characteristics of the mother/child dyads. The main outcome was the prevalence of maternal anaemia in pregnancy and risk factors associated with childhood anaemia at age 6 months. RESULTS: Prevalence of maternal anaemia in pregnancy was higher in the third trimester (62%) compared to the first (46%) and second trimesters (48%). There was a strong positive linear association (R2 = 0.46, p < 0.001) between maternal haemoglobin (Hb) in third trimester pregnancy and child Hb at age 6 months. Maternal anaemia in pregnancy (OR 4.42 95% CI 2.08-9.36) and low birth weight (LBW, OR 2.62, 95% CI 1.21-5.70) were associated with an increased risk of childhood anaemia at 6 months of age. CONCLUSIONS FOR PRACTICE: This is the first study to identify the association of maternal anaemia with childhood anaemia in the Australian Aboriginal population. A review of current policies and practices for anaemia screening, prevention and treatment during pregnancy and early childhood would be beneficial to both mother and child. Our findings indicate that administering prophylactic iron supplementation only to children who are born LBW or premature would be of greater benefit if expanded to include children born to anaemic mothers.

A randomized pilot study of nitrate supplementation with beetroot juice in acute respiratory failure.

Nitrate rich beetroot juice (BRJ) can enhance nitric oxide signaling, leading to improved physical function in healthy and diseased populations, but its safety and biologic efficacy have not been evaluated in a critically ill population. We randomized 22 previously functional acute respiratory failure patients to either BRJ or placebo daily until day 14 or discharge. We measured blood nitrate and nitrite levels and quantified strength and physical function at intensive care unit (ICU) and hospital discharge. Participants were predominantly male (54%), aged 68.5 years with an APACHE III score of 62. BRJ increased plasma nitrate (mean 219.2 µM increase, p = 0.002) and nitrite levels (mean 0.144 µM increase, p = 0.02). We identified no adverse events. The unadjusted and adjusted effect sizes of the intervention on the short physical performance battery were small (d = 0.12 and d = 0.17, respectively). In this pilot trial, administration of BRJ was feasible and safe, increased blood nitrate and nitrate levels, but had a small effect on physical function. Future studies could evaluate the clinical efficacy of BRJ as a therapy to improve physical function in survivors of critical illness.

Effect of Thiamine Administration on Lactate Clearance and Mortality in Patients With Septic Shock.

OBJECTIVES: Mounting evidence has shown that critically ill patients are commonly thiamine deficient. We sought to test the hypothesis that critically ill patients with septic shock exposed to thiamine would demonstrate improved lactate clearance and more favorable clinical outcomes compared with those not receiving thiamine. DESIGN: Retrospective, single-center, matched cohort study. SETTING: Tertiary care academic medical center. PATIENTS: Adult patients admitted with an International Classification of Diseases, 9th Edition, or International Classification of Diseases, 10th Edition, diagnosis code of septic shock to either the medicine or surgery ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients who received IV thiamine supplementation within 24 hours of hospital admission were identified and compared with a matched cohort of patients not receiving thiamine. The primary objective was to determine if thiamine administration was associated with a reduced time to lactate clearance in septic shock. Secondary outcomes included 28-day mortality, acute kidney injury, and need for renal replacement therapy, and vasopressor and mechanical ventilation-free days. Two-thousand two-hundred seventy-two patients were screened, of whom 1,049 were eligible. The study consisted of 123 thiamine-treated patients matched with 246 patients who did not receive thiamine. Based on the Fine-Gray survival model, treatment with thiamine was associated with an improved likelihood of lactate clearance (subdistribution hazard ratio, 1.307; 95% CI, 1.002-1.704). Thiamine administration was also associated with a reduction in 28-day mortality (hazard ratio, 0.666; 95% CI, 0.490-0.905). There were no differences in any secondary outcomes. CONCLUSIONS: Thiamine administration within 24 hours of admission in patients presenting with septic shock was associated with improved lactate clearance and a reduction in 28-day mortality compared with matched controls.

Diaphragm Dysfunction in Critical Illness.

The diaphragm is the major muscle of inspiration, and its function is critical for optimal respiration. Diaphragmatic failure has long been recognized as a major contributor to death in a variety of systemic neuromuscular disorders. More recently, it is increasingly apparent that diaphragm dysfunction is present in a high percentage of critically ill patients and is associated with increased morbidity and mortality. In these patients, diaphragm weakness is thought to develop from disuse secondary to ventilator-induced diaphragm inactivity and as a consequence of the effects of systemic inflammation, including sepsis. This form of critical illness-acquired diaphragm dysfunction impairs the ability of the respiratory pump to compensate for an increased respiratory workload due to lung injury and fluid overload, leading to sustained respiratory failure and death. This review examines the presentation, causes, consequences, diagnosis, and treatment of disorders that result in acquired diaphragm dysfunction during critical illness.

Comparing GABA-dependent physiological measures of inhibition with proton magnetic resonance spectroscopy measurement of GABA using ultra-high-field MRI.

Imbalances in glutamatergic (excitatory) and GABA (inhibitory) signalling within key brain networks are thought to underlie many brain and mental health disorders, and for this reason there is considerable interest in investigating how individual variability in localised concentrations of these molecules relate to brain disorders. Magnetic resonance spectroscopy (MRS) provides a reliable means of measuring, in vivo, concentrations of neurometabolites such as GABA, glutamate and glutamine that can be correlated with brain function and dysfunction. However, an issue of much debate is whether the GABA observed and measured using MRS represents the entire pool of GABA available for measurement (i.e., metabolic, intracellular, and extracellular) or is instead limited to only some portion of it. GABA function can also be investigated indirectly in humans through the use of non-invasive transcranial magnetic stimulation (TMS) techniques that can be used to measure cortical excitability and GABA-mediated physiological inhibition. To investigate this issue further we collected in a single session both types of measurement, i.e., TMS measures of cortical excitability and physiological inhibition and ultra-high-field (7 T) MRS measures of GABA, glutamate and glutamine, from the left sensorimotor cortex of the same group of right-handed individuals. We found that TMS and MRS measures were largely uncorrelated with one another, save for the plateau of the TMS IO curve that was negatively correlated with MRS-Glutamate (Glu) and intra-cortical facilitation (10ms ISI) that was positively associated with MRS-Glutamate concentration. These findings are consistent with the view that the GABA concentrations measured using the MRS largely represent pools of GABA that are linked to tonic rather than phasic inhibition and thus contribute to the inhibitory tone of a brain area rather than GABAergic synaptic transmission.

Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes.

BACKGROUND: Policies for timing of cord clamping vary, with early cord clamping generally carried out in the first 60 seconds after birth, whereas later cord clamping usually involves clamping the umbilical cord more than one minute after the birth or when cord pulsation has ceased. The benefits and potential harms of each policy are debated. OBJECTIVES: To determine the effects of early cord clamping compared with late cord clamping after birth on maternal and neonatal outcomes SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (13 February 2013). SELECTION CRITERIA: Randomised controlled trials comparing early and late cord clamping. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and quality and extracted data. MAIN RESULTS: We included 15 trials involving a total of 3911 women and infant pairs. We judged the trials to have an overall moderate risk of bias. MATERNAL OUTCOMES: No studies in this review reported on maternal death or on severe maternal morbidity. There were no significant differences between early versus late cord clamping groups for the primary outcome of severe postpartum haemorrhage (risk ratio (RR) 1.04, 95% confidence interval (CI) 0.65 to 1.65; five trials with data for 2066 women with a late clamping event rate (LCER) of ~3.5%, I(2) 0%) or for postpartum haemorrhage of 500 mL or more (RR 1.17 95% CI 0.94 to 1.44; five trials, 2260 women with a LCER of ~12%, I(2) 0%). There were no significant differences between subgroups depending on the use of uterotonic drugs. Mean blood loss was reported in only two trials with data for 1345 women, with no significant differences seen between groups; or for maternal haemoglobin values (mean difference (MD) -0.12 g/dL; 95% CI -0.30 to 0.06, I(2) 0%) at 24 to 72 hours after the birth in three trials. NEONATAL OUTCOMES: There were no significant differences between early and late clamping for the primary outcome of neonatal mortality (RR 0.37, 95% CI 0.04 to 3.41, two trials, 381 infants with a LCER of ~1%), or for most other neonatal morbidity outcomes, such as Apgar score less than seven at five minutes or admission to the special care nursery or neonatal intensive care unit. Mean birthweight was significantly higher in the late, compared with early, cord clamping (101 g increase 95% CI 45 to 157, random-effects model, 12 trials, 3139 infants, I(2) 62%). Fewer infants in the early cord clamping group required phototherapy for jaundice than in the late cord clamping group (RR 0.62, 95% CI 0.41 to 0.96, data from seven trials, 2324 infants with a LCER of 4.36%, I(2) 0%). Haemoglobin concentration in infants at 24 to 48 hours was significantly lower in the early cord clamping group (MD -1.49 g/dL, 95% CI -1.78 to -1.21; 884 infants, I(2) 59%). This difference in haemoglobin concentration was not seen at subsequent assessments. However, improvement in iron stores appeared to persist, with infants in the early cord clamping over twice as likely to be iron deficient at three to six months compared with infants whose cord clamping was delayed (RR 2.65 95% CI 1.04 to 6.73, five trials, 1152 infants, I(2) 82%). In the only trial to report longer-term neurodevelopmental outcomes so far, no overall differences between early and late clamping were seen for Ages and Stages Questionnaire scores. AUTHORS' CONCLUSIONS: A more liberal approach to delaying clamping of the umbilical cord in healthy term infants appears to be warranted, particularly in light of growing evidence that delayed cord clamping increases early haemoglobin concentrations and iron stores in infants. Delayed cord clamping is likely to be beneficial as long as access to treatment for jaundice requiring phototherapy is available.

Increased GABA contributes to enhanced control over motor excitability in Tourette syndrome.

Tourette syndrome (TS) is a developmental neurological disorder characterized by vocal and motor tics and associated with cortical-striatal-thalamic-cortical circuit dysfunction, hyperexcitability within cortical motor areas, and altered intracortical inhibition. TS often follows a developmental time course in which tics become increasingly more controlled during adolescence in many individuals, who exhibit enhanced control over their volitional movements. Importantly, control over motor outputs appears to be brought about by a reduction in the gain of motor excitability. Here we present a neurochemical basis for a localized gain control mechanism. We used ultra-high-field (7 T) magnetic resonance spectroscopy to investigate in vivo concentrations of γ-aminobutyric acid (GABA) within primary and secondary motor areas of individuals with TS. We demonstrate that GABA concentrations within the supplementary motor area (SMA)--a region strongly associated with the genesis of motor tics in TS--are paradoxically elevated in individuals with TS and inversely related to fMRI blood oxygen level-dependent activation. By contrast, GABA concentrations in control sites do not differ from those of a matched control group. Importantly, we also show that GABA concentrations within the SMA are inversely correlated with cortical excitability in primary motor cortex and are predicted by motor tic severity and white-matter microstructure (FA) within a region of the corpus callosum that projects to the SMA within each hemisphere. Based upon these findings, we propose that extrasynaptic GABA contributes to a form of control, based upon localized tonic inhibition within the SMA, that may lead to the suppression of tics.

High folate levels in Aboriginal children after subsidised fruit and vegetables and mandatory folic acid fortification.

OBJECTIVE: To evaluate the impact of a fruit and vegetable (F&V) subsidy program for disadvantaged Aboriginal children in Australia, implemented alongside the introduction of mandatory folic acid fortification of bread-making flour. METHODS: A before-and-after evaluation was undertaken of a F&V subsidy program at three Aboriginal community-controlled health services in New South Wales. The program provided a weekly box of subsidised F&V linked to preventive health services and nutrition promotion for families. In this analysis, red blood cell (RBC) folate was assessed together with self-reported dietary intake at baseline and 12 months later in a cohort of 125 children (aged 0-17 years). RESULTS: No children had low RBC folate at baseline or at follow-up; however, 33 children (26%) exceeded the reference range of RBC folate at baseline and 38 children (30%) exceeded the reference range at follow-up. Mean RBC folate levels increased substantially in children at follow-up (mean RBC folate z-score increased +0.55 (95%CI 0.36-0.74). Change in F&V intake (p=0.196) and mean bread intake (p=0.676) were not statistically significant predictors for change in RBC folate levels. CONCLUSIONS: RBC folate levels increased among these disadvantaged Aboriginal children following mandatory folic acid fortification and participation in a subsidised F&V program. Even before mandatory folic acid fortification, none of these children had low RBC folate. IMPLICATIONS: The effect on health of mandatory fortification of foods with folate is not clear, hence, ongoing population-based monitoring of folate levels to assess the impact of mandatory folic acid fortification is important.

tDCS-induced alterations in GABA concentration within primary motor cortex predict motor learning and motor memory: a 7 T magnetic resonance spectroscopy study.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that alters cortical excitability in a polarity specific manner and has been shown to influence learning and memory. tDCS may have both on-line and after-effects on learning and memory, and the latter are thought to be based upon tDCS-induced alterations in neurochemistry and synaptic function. We used ultra-high-field (7 T) magnetic resonance spectroscopy (MRS), together with a robotic force adaptation and de-adaptation task, to investigate whether tDCS-induced alterations in GABA and Glutamate within motor cortex predict motor learning and memory. Note that adaptation to a robot-induced force field has long been considered to be a form of model-based learning that is closely associated with the computation and 'supervised' learning of internal 'forward' models within the cerebellum. Importantly, previous studies have shown that on-line tDCS to the cerebellum, but not to motor cortex, enhances model-based motor learning. Here we demonstrate that anodal tDCS delivered to the hand area of the left primary motor cortex induces a significant reduction in GABA concentration. This effect was specific to GABA, localised to the left motor cortex, and was polarity specific insofar as it was not observed following either cathodal or sham stimulation. Importantly, we show that the magnitude of tDCS-induced alterations in GABA concentration within motor cortex predicts individual differences in both motor learning and motor memory on the robotic force adaptation and de-adaptation task.

Respiratory exacerbations in indigenous children from two countries with non-cystic fibrosis chronic suppurative lung disease/bronchiectasis.

BACKGROUND: Acute respiratory exacerbations (AREs) cause morbidity and lung function decline in children with chronic suppurative lung disease (CSLD) and bronchiectasis. In a prospective longitudinal cohort study, we determined the patterns of AREs and factors related to increased risks for AREs in children with CSLD/bronchiectasis. METHODS: Ninety-three indigenous children aged 0.5 to 8 years with CSLD/bronchiectasis in Australia (n = 57) and Alaska (n = 36) during 2004 to 2009 were followed for > 3 years. Standardized parent interviews, physical examinations, and medical record reviews were undertaken at enrollment and every 3 to 6 months thereafter. RESULTS: Ninety-three children experienced 280 AREs (median = 2, range = 0-11 per child) during the 3-year period; 91 (32%) were associated with pneumonia, and 43 (15%) resulted in hospitalization. Of the 93 children, 69 (74%) experienced more than two AREs over the 3-year period, and 28 (30%) had more than one ARE in each study year. The frequency of AREs declined significantly over each year of follow-up. Factors associated with recurrent (two or more) AREs included age < 3 years, ARE-related hospitalization in the first year of life, and pneumonia or hospitalization for ARE in the year preceding enrollment. Factors associated with hospitalizations for AREs in the first year of study included age < 3 years, female caregiver education, and regular use of bronchodilators. CONCLUSIONS: AREs are common in children with CSLD/bronchiectasis, but with clinical care and time AREs occur less frequently. All children with CSLD/bronchiectasis require comprehensive care; however, treatment strategies may differ for these patients based on their changing risks for AREs during each year of care.

L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Vitamin D (vitD) and L-arginine have important antimycobacterial effects in humans. Adjunctive therapy with these agents has the potential to improve outcomes in active tuberculosis (TB). METHODS: In a 4-arm randomised, double-blind, placebo-controlled factorial trial in adults with smear-positive pulmonary tuberculosis (PTB) in Timika, Indonesia, we tested the effect of oral adjunctive vitD 50,000 IU 4-weekly or matching placebo, and L-arginine 6.0 g daily or matching placebo, for 8 weeks, on proportions of participants with negative 4-week sputum culture, and on an 8-week clinical score (weight, FEV1, cough, sputum, haemoptysis). All participants with available endpoints were included in analyses according to the study arm to which they were originally assigned. Adults with new smear-positive PTB were eligible. The trial was registered at ClinicalTrials.gov NCT00677339. RESULTS: 200 participants were enrolled, less than the intended sample size: 50 received L-arginine + active vitD, 49 received L-arginine + placebo vit D, 51 received placebo L-arginine + active vitD and 50 received placebo L-arginine + placebo vitD. According to the factorial model, 99 people received arginine, 101 placebo arginine, 101 vitamin D, 99 placebo vitamin D. Results for the primary endpoints were available in 155 (4-week culture) and 167 (clinical score) participants. Sputum culture conversion was achieved by week 4 in 48/76 (63%) participants in the active L-arginine versus 48/79 (61%) in placebo L-arginine arms (risk difference -3%, 95% CI -19 to 13%), and in 44/75 (59%) in the active vitD versus 52/80 (65%) in the placebo vitD arms (risk difference 7%, 95% CI -9 to 22%). The mean clinical outcome score also did not differ between study arms. There were no effects of the interventions on adverse event rates including hypercalcaemia, or other secondary outcomes. CONCLUSION: Neither vitD nor L-arginine supplementation, at the doses administered and with the power attained, affected TB outcomes. REGISTRY: ClinicalTrials.gov. Registry number: NCT00677339.

Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes.

BACKGROUND: Policies for timing of cord clamping vary, with early cord clamping generally carried out in the first 60 seconds after birth, whereas later cord clamping usually involves clamping the umbilical cord more than one minute after the birth or when cord pulsation has ceased. The benefits and potential harms of each policy are debated. OBJECTIVES: To determine the effects of early cord clamping compared with late cord clamping after birth on maternal and neonatal outcomes SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (13 February 2013). SELECTION CRITERIA: Randomised controlled trials comparing early and late cord clamping. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and quality and extracted data. MAIN RESULTS: We included 15 trials involving a total of 3911 women and infant pairs. We judged the trials to have an overall moderate risk of bias. Maternal outcomes: No studies in this review reported on maternal death or on severe maternal morbidity. There were no significant differences between early versus late cord clamping groups for the primary outcome of severe postpartum haemorrhage (risk ratio (RR) 1.04, 95% confidence interval (CI) 0.65 to 1.65; five trials with data for 2066 women with a late clamping event rate (LCER) of ~3.5%, I(2) 0%) or for postpartum haemorrhage of 500 mL or more (RR 1.17 95% CI 0.94 to 1.44; five trials, 2260 women with a LCER of ~12%, I(2) 0%). There were no significant differences between subgroups depending on the use of uterotonic drugs. Mean blood loss was reported in only two trials with data for 1345 women, with no significant differences seen between groups; or for maternal haemoglobin values (mean difference (MD) -0.12 g/dL; 95% CI -0.30 to 0.06, I(2) 0%) at 24 to 72 hours after the birth in three trials. Neonatal outcomes: There were no significant differences between early and late clamping for the primary outcome of neonatal mortality (RR 0.37, 95% CI 0.04 to 3.41, two trials, 381 infants with a LCER of ~1%), or for most other neonatal morbidity outcomes, such as Apgar score less than seven at five minutes or admission to the special care nursery or neonatal intensive care unit. Mean birthweight was significantly higher in the late, compared with early, cord clamping (101 g increase 95% CI 45 to 157, random-effects model, 12 trials, 3139 infants, I(2) 62%). Fewer infants in the early cord clamping group required phototherapy for jaundice than in the late cord clamping group (RR 0.62, 95% CI 0.41 to 0.96, data from seven trials, 2324 infants with a LCER of 4.36%, I(2) 0%). Haemoglobin concentration in infants at 24 to 48 hours was significantly lower in the early cord clamping group (MD -1.49 g/dL, 95% CI -1.78 to -1.21; 884 infants, I(2) 59%). This difference in haemoglobin concentration was not seen at subsequent assessments. However, improvement in iron stores appeared to persist, with infants in the early cord clamping over twice as likely to be iron deficient at three to six months compared with infants whose cord clamping was delayed (RR 2.65 95% CI 1.04 to 6.73, five trials, 1152 infants, I(2) 82%). In the only trial to report longer-term neurodevelopmental outcomes so far, no overall differences between early and late clamping were seen for Ages and Stages Questionnaire scores. AUTHORS' CONCLUSIONS: A more liberal approach to delaying clamping of the umbilical cord in healthy term infants appears to be warranted, particularly in light of growing evidence that delayed cord clamping increases early haemoglobin concentrations and iron stores in infants. Delayed cord clamping is likely to be beneficial as long as access to treatment for jaundice requiring phototherapy is available.

Health outcomes of a subsidised fruit and vegetable program for Aboriginal children in northern New South Wales.

OBJECTIVE: To evaluate the impact of a fruit and vegetable subsidy program on short-term health outcomes of disadvantaged Aboriginal children. DESIGN, SETTING AND PARTICIPANTS: A before-and-after study involving clinical assessments, health record audits and blood testing of all children aged 0-17 2013s (n = 167) from 55 participating families at baseline and after 12 months at three Aboriginal community-controlled health services in New South Wales. All assessments were completed between December 2008 and September 2010. INTERVENTION: A weekly box of subsidised fruit and vegetables linked to preventive health services and nutrition promotion at an Aboriginal Medical Service. MAIN OUTCOME MEASURES: Change in episodes of illness, health service and emergency department attendances, antibiotic prescriptions and anthropometry. RESULTS: There was a significant decrease in oral antibiotics prescribed (- 0.5 prescriptions/2013; 95% CI, - 0.8 to - 0.2) during 12 months of participation in the program compared with the 12 months before the program. The proportion of children classified as overweight or obese at baseline was 28.3% (38/134) and the proportion in each weight category did not change (P = 0.721) after 12 months. A small but significant increase in mean haemoglobin level (3.1 g/L; 95% CI, 1.4-4.8 g/L) was shown, although the proportion with iron deficiency (baseline, 41%; follow-up, 37%; P = 0.440) and anaemia (baseline, 8%; follow-up, 5%; P = 0.453) did not change significantly. CONCLUSION: it and vegetable subsidy program was associated with improvements in some indicators of short-term health status among disadvantaged Aboriginal children. A controlled trial is warranted to investigate the sustainability and feasibility of healthy food subsidy programs in Australia.

Nutritional impacts of a fruit and vegetable subsidy programme for disadvantaged Australian Aboriginal children.

Healthy food subsidy programmes have not been widely implemented in high-income countries apart from the USA and the UK. There is, however, interest being expressed in the potential of healthy food subsidies to complement nutrition promotion initiatives and reduce the social disparities in healthy eating. Herein, we describe the impact of a fruit and vegetable (F&V) subsidy programme on the nutritional status of a cohort of disadvantaged Aboriginal children living in rural Australia. A before-and-after study was used to assess the nutritional impact in 174 children whose families received weekly boxes of subsidised F&V organised through three Aboriginal medical services. The nutritional impact was assessed by comparing 24 h dietary recalls and plasma carotenoid and vitamin C levels at baseline and after 12 months. A general linear model was used to assess the changes in biomarker levels and dietary intake, controlled for age, sex, community and baseline levels. Baseline assessment in 149 children showed low F&V consumption. Significant increases (P< 0.05) in ß-cryptoxanthin (28.9 nmol/l, 18%), vitamin C (10.1 µmol/l, 21%) and lutein-zeaxanthin (39.3 nmol/l, 11%) levels were observed at the 12-month follow-up in 115 children, although the self-reported F&V intake was unchanged. The improvements in the levels of biomarkers of F&V intake demonstrated in the present study are consistent with increased F&V intake. Such dietary improvements, if sustained, could reduce non-communicable disease rates. A controlled study of healthy food subsidies, together with an economic analysis, would facilitate a thorough assessment of the costs and benefits of subsidising healthy foods for disadvantaged Aboriginal Australians.

Intraoperative autologous blood transfusion use during radical hysterectomy for cervical cancer: long-term follow-up of a prospective trial.

PURPOSE: A primary operative complication of radical hysterectomy for cervical cancer is hemorrhage. Intraoperative autologous blood transfusion (ABT) may be beneficial in reducing the need for homologous blood transfusion. METHODS: Our institution published a prospective cohort study examining the use of ABT in cervical cancer patients undergoing radical hysterectomy in 1995. Patients who were initially consented to participate in this prospective trial using intraoperative ABT (cell saver) were evaluated with a median follow-up of 3 years. We sought to update this original report with 16-year follow-up data collected from the clinical charts, Tumor Registry, and the Social Security Death Index. RESULTS: Two groups of patients undergoing radical hysterectomy were compared: patients who received ABT, and those who did not. Of the 71 original patients, all were included in this updated review, with an average follow-up of 12.4 years for both groups. Originally, thirty-one patients received an ABT. In this group, 1 patient was lost to follow-up, and 4 (12.9 %) are deceased including 1 (3 %) with disease. In the non-autologous group, there were 7 (17.5 %) patient deaths, including 3 (7.5 %) with disease. Eighty-three percent were alive after 12 years in both groups. The ABT group had 1 patient (3 %) who developed a secondary malignancy, a colon adenocarcinoma. The non-autologous group had 2 patients (5 %) who developed a secondary malignancy; one patient developed multiple myeloma and one patient developed a verrucous cancer of the tongue. CONCLUSIONS: Autologous blood transfusion during radical hysterectomy for cervical cancer appears safe and effective.

The effects of fasting and refeeding with a 'metabolic preconditioning' drink on substrate reserves and mononuclear cell mitochondrial function.

BACKGROUND AND AIMS: Preoperative fasting induces metabolic stress and leads to reduced postoperative insulin sensitivity, changes attenuated by preoperative carbohydrate loading. However, the mechanisms underlying these effects remain unknown. We investigated the dynamic changes in substrate metabolism and mononuclear cell mitochondrial function after fasting followed by refeeding with a drink [ONS (Fresenius Kabi, Germany)] designed to improve metabolic function preoperatively. METHODS: Twelve healthy volunteers took part in this study. They were fed a standardized meal and studied 4h later (baseline 'fed' state), after 12 and 24h of fasting, and 2, 4 and 6h after ingestion of ONS (contained 100g carbohydrate, 30g glutamine, and antioxidants). Changes in liver and muscle glycogen and lipids were studied using (13)C and (1)H magnetic resonance spectroscopy. The activities of mitochondrial electron transport chain complexes I, II and IV in blood mononuclear cells were measured spectrophotometrically. RESULTS: Compared to the baseline fed state, 12 and 24h fasts led to 29% and 57% decreases (P<0.001) in liver glycogen content, respectively. Fasting for 24h decreased mitochondrial membrane complexes I (-72%, P<0.05), II (-49%, P<0.01) and IV (-41%, P<0.05) activities compared to those following a 12h fast. A 23% increase (P<0.05) in calf intramyocellular lipid (IMCL) content occurred after a 24h fast. Liver glycogen reserves increased by 47% (P<0.05) by 2h following ingestion of ONS. CONCLUSIONS: Short-term fasting (up to 24h) affected mononuclear cell mitochondrial function adversely and increased IMCL content. Refeeding with ONS partially reversed the changes in liver glycogen.