Carbon dioxide levels in neonates: what are safe parameters?

There is no consensus on the optimal pCO2 levels in the newborn. We reviewed the effects of hypercapnia and hypocapnia and existing carbon dioxide thresholds in neonates. A systematic review was conducted in accordance with the PRISMA statement and MOOSE guidelines. Two hundred and ninety-nine studies were screened and 37 studies included. Covidence online software was employed to streamline relevant articles. Hypocapnia was associated with predominantly neurological side effects while hypercapnia was linked with neurological, respiratory and gastrointestinal outcomes and Retinpathy of prematurity (ROP). Permissive hypercapnia did not decrease periventricular leukomalacia (PVL), ROP, hydrocephalus or air leaks. As safe pCO2 ranges were not explicitly concluded in the studies chosen, it was indirectly extrapolated with reference to pCO2 levels that were found to increase the risk of neonatal disease. Although PaCO2 ranges were reported from 2.6 to 8.7 kPa (19.5-64.3 mmHg) in both term and preterm infants, there are little data on the safety of these ranges. For permissive hypercapnia, parameters described for bronchopulmonary dysplasia (BPD; PaCO2 6.0-7.3 kPa: 45.0-54.8 mmHg) and congenital diaphragmatic hernia (CDH; PaCO2 ≤ 8.7 kPa: ≤65.3 mmHg) were identified. Contradictory findings on the effectiveness of permissive hypercapnia highlight the need for further data on appropriate CO2 parameters and correlation with outcomes. IMPACT: There is no consensus on the optimal pCO2 levels in the newborn. There is no consensus on the effectiveness of permissive hypercapnia in neonates. A safe range of pCO2 of 5-7 kPa was inferred following systematic review.

Carbon dioxide-dependent signal transduction in mammalian systems.

Carbon dioxide (CO2) is a fundamental physiological gas known to profoundly influence the behaviour and health of millions of species within the plant and animal kingdoms in particular. A recent Royal Society meeting on the topic of 'Carbon dioxide detection in biological systems' was extremely revealing in terms of the multitude of roles that different levels of CO2 play in influencing plants and animals alike. While outstanding research has been performed by leading researchers in the area of plant biology, neuronal sensing, cell signalling, gas transport, inflammation, lung function and clinical medicine, there is still much to be learned about CO2-dependent sensing and signalling. Notably, while several key signal transduction pathways and nodes of activity have been identified in plants and animals respectively, the precise wiring and sensitivity of these pathways to CO2 remains to be fully elucidated. In this article, we will give an overview of the literature relating to CO2-dependent signal transduction in mammalian systems. We will highlight the main signal transduction hubs through which CO2-dependent signalling is elicited with a view to better understanding the complex physiological response to CO2 in mammalian systems. The main topics of discussion in this article relate to how changes in CO2 influence cellular function through modulation of signal transduction networks influenced by pH, mitochondrial function, adenylate cyclase, calcium, transcriptional regulators, the adenosine monophosphate-activated protein kinase pathway and direct CO2-dependent protein modifications. While each of these topics will be discussed independently, there is evidence of significant cross-talk between these signal transduction pathways as they respond to changes in CO2. In considering these core hubs of CO2-dependent signal transduction, we hope to delineate common elements and identify areas in which future research could be best directed.

Landspreading with co-digested cattle slurry, with or without pasteurisation, as a mitigation strategy against pathogen, nutrient and metal contamination associated with untreated slurry.

North Atlantic European grassland systems have a low nutrient use efficiency and high rainfall. This grassland is typically amended with unprocessed slurry, which counteracts soil organic matter depletion and provides essential plant micronutrients but can be mobilised during rainfall events thereby contributing to pathogen, nutrient and metal incidental losses. Co-digesting slurry with waste from food processing mitigates agriculture-associated environmental impacts but may alter microbial, nutrient and metal profiles and their transmission to watercourses, and/or soil persistence, grass yield and uptake. The impact of EU and alternative pasteurisation regimes on transmission potential of these various pollutants is not clearly understood, particularly in pasture-based agricultural systems. This study utilized simulated rainfall (Amsterdam drip-type) at a high intensity indicative of a worst-case scenario of ~11 mm hr-1 applied to plots 1, 2, 15 and 30 days after grassland application of slurry, unpasteurised digestate, pasteurised digestate (two conditions) and untreated controls. Runoff and soil samples were collected and analysed for a suite of potential pollutants including bacteria, nutrients and metals following rainfall simulation. Grass samples were collected for three months following application to assess yield as well as nutrient and metal uptake. For each environmental parameter tested: microbial, nutrient and metal runoff losses; accumulation in soil and uptake in grass, digestate from anaerobic co-digestion of slurry with food processing waste resulted in lower pollution potential than traditional landspreading of slurry without treatment. Reduced microbial runoff from digestate was the most prominent advantage of digestate application. Pasteurisation of the digestate further augmented those environmental benefits, without impacting grass output. Anaerobic co-digestion of slurry is therefore a multi-beneficial circular approach to reducing impacts of livestock production on the environment.

The potential human exposure to antibiotic resistant-Escherichia coli through recreational water.

It is important that bathing water sites are free as possible from antibiotic resistant bacteria (ARB) to prevent the spread of difficult to treat infections throughout the population. This study examines the possible human exposure to antibiotic resistant Escherichia coli (AR-E. coli) through recreational activities at two different bathing water sites located near wastewater treatment plants (WWTPs). A quantitative risk assessment model was created to model the pathway of the AR-E. coli from the WWTPs effluent water through to the bathing water sites. Both sampling data and data from scientific literature were used. The main steps considered for the model were: the dilution and decay of the AR-E. coli from the WWTPs effluent water into the river; the dilution of the river into the bathing water sites and the human exposure to AR-E. coli through recreational activities at the bathing water sites (as a result of water ingestion). The results show the mean predicted human exposure levels ranged between 0.45 and 345.09 cfu/100 ml. A back calculation method determined that in accordance with the European Bathing Water Directive (2006/7/EC) (BWD) to be considered "poor" water quality, the concentration of AR-E. coli in WWTP effluent water would need to exceed 2.45 log cfu/ml at site 1 and exceed 2.71 log cfu/ml at site 2. This study provides valuable information for regulatory bodies and policy makers on the possible human exposure levels to AR-E. coli and the maximum permissible concentrations in WWTP effluent water to ensure compliance with relevant bathing water legislation.

Human exposure to antibiotic resistant-Escherichia coli through irrigated lettuce.

Antibiotic resistant bacteria (ARB) have been found on fresh fruit and vegetables globally. These types of ARB infections are spreading rapidly and are a major human health threat. A quantitative human exposure assessment model was created using scenario analysis to investigate the potential human exposure to antibiotic resistant Escherichia coli (AR-E. coli) through the consumption of lettuce irrigated with surface water. Scientific literature and site specific data were collected to model each process from farm to fork to calculate the concentration of AR-E. coli on the lettuce at the point of human consumption. The processes examined were the adhesion, colonisation and viability of bacteria on the lettuce; the effect of different post-harvest cleaning processes; the effect of consuming the lettuce before, on or after the expiry date; and the effect of the consumer washing the lettuce. The results show the mean human exposure levels ranged between 1.00 × 10-2 and 1.35 × 106 colony forming units (CFU) of AR-E. coli per 100 g of surface water irrigated lettuce for the different scenarios investigated. The mean probability of illness from consuming 100 g of lettuce contaminated with potential pathogenic antibiotic-sensitive E. coli was between 1.46 × 10-9 to 1.88 × 10-2. A back calculation revealed that in order for the EC No 1441/2007 regulation to be exceeded (≥1000 CFU/g of E. coli on lettuce at the manufacturing stage), the mean contamination levels required in the irrigation water would need to be 2.7, 3.1 or 4.8 log CFU/ml using the post-harvest treatments of washing with water, rapid cooling with water and washing with a chlorine solution respectively. The information generated from this model could help to set guidelines for producers on maximum permissible AR-E. coli contamination levels in irrigation water and provides recommendations on the best post-harvest treatment to use.

Development of a Cryptosporidium-arsenic multi-risk assessment model for infant formula prepared with tap water in France.

Tap water is used in France to reconstitute powder infant formula, although it is not sterile and possibly contaminated by microbiological and chemical hazards. The present study aims to quantify risks of using tap water in France for the preparation of infant formula, during the first six months of life. Cryptosporidium and arsenic were selected as hazards of greatest concern in microbiology and chemistry, respectively. A probabilistic model was developed using French (when available) and European (alternatively) data. Second order Monte Carlo simulation was used to separate uncertainty and variability of inputs. Outputs were expressed at the individual level as probability of illness and at the population level, using a common metric, the DALY (Disability Adjusted Life Year). Two scenarios of milk preparation were considered: with un-boiled or boiled tap water. Consuming infant formula rehydrated with un-boiled tap water during the first six months of life led to a total of 2250 DALYs per 100,000 infants (90% uncertainty interval [960; 7650]) for Cryptosporidium due to diarrhea, and 1 DALY [0.4; 2] for arsenic due to expected lifetime risk of lung and bladder cancer as a result of early exposure in life. For the entire population, boiling water would suppress the risk from Cryptosporidium. In contrast, the incremental cancer risk was low at the population level but elevated for 5% of the population exposed to high levels of arsenic. A stringent monitoring of tap water supply points should be continued. This multi-risk assessment model could help public health authorities and managers in evaluating both microbiological and chemical safety issues associated with using infant formula prepared with tap water.

Human exposure assessment to antibiotic-resistant Escherichia coli through drinking water.

Antibiotic-resistant bacteria (ARB) are a potential threat to human health through drinking water with strong evidence of ARB presence in post treated tap water around the world. This study examines potential human exposure to antibiotic-resistant (AR) Escherichia coli (E. coli) through drinking water, the effect of different drinking water treatments on AR E. coli and the concentration of AR E. coli required in the source water for the EU Drinking Water Directive (DWD) (Council Directive 98/83/EC, 0CFU/100ml of E. coli in drinking water) to be exceeded. A number of scenarios were evaluated to examine different water treatment combinations and to reflect site specific conditions at a study site in Europe. A literature search was carried out to collate data on the effect of environmental conditions on AR E. coli, the effect of different water treatments on AR E. coli and typical human consumption levels of tap water. A human exposure assessment model was developed with probability distributions used to characterise uncertainty and variability in the input data. Overall results show the mean adult human exposure to AR E. coli from tap water consumption ranged between 3.44×10-7 and 2.95×10-1cfu/day for the scenarios tested and varied depending on the water treatments used. The level of AR E. coli required in the source water pre-treatment to exceed the DWD varied between 1 and 5logcfu/ml, depending on the water treatments used. This can be used to set possible monitoring criteria in pre-treated water for potential ARB exposure in drinking water.

Dynamics of silver elution from functionalised antimicrobial nanofiltration membranes.

In an effort to mitigate biofouling on thin film composite membranes such as nanofiltration and reverse osmosis, a myriad of different surface modification strategies has been published. The use of silver nanoparticles (Ag-NPs) has emerged as being particularly promising. Nevertheless, the stability of these surface modifications is still poorly understood, particularly under permeate flux conditions. Leaching or elution of Ag-NPs from the membrane surface can not only affect the antimicrobial characteristics of the membrane, but could also potentially present an environmental liability when applied in industrial-scale systems. This study sought to investigate the dynamics of silver elution and the bactericidal effect of an Ag-NP functionalised NF270 membrane. Inductively coupled plasma-atomic emission spectroscopy was used to show that the bulk of leached silver occurred at the start of experimental runs, and was found to be independent of salt or permeate conditions used. Cumulative amounts of leached silver did, however, stabilise following the initial release, and were shown to have maintained the biocidal characteristics of the modified membrane, as observed by a higher fraction of structurally damaged Pseudomonas fluorescens cells. These results highlight the need to comprehensively assess the time-dependent nature of bactericidal membranes.

Human exposure modelling of quercetin in onions (Allium cepa L.) following thermal processing.

Post-harvest treatment can influence levels of secondary metabolites in fruits and vegetables. Onions contain high levels of quercetin but are commonly heat-treated before consumption. Hence, the objective of this study was to examine the effect of cooking treatments on the flavonoid (3,4'-Qdg and 4'-Qmg) concentrations in onion and to determine, by simulation modelling, probable human exposure. Onion samples (n=3) were cooked using three processes (fry, bake and steam) for three time intervals (5, 10 and 15 min). Frying (<10 min) was the ideal cooking method which retained concentrations of 3,4'-Qdg and 4'-Qmg at >50%. Thermal processing (>10 min) was shown to decrease quercetin content in all samples. The simulation model predicted human absorption and exposure. Steaming (15 min) resulted in the lowest quercetin exposure, with mean values of 4000 and 400 µg/day for 3,4'-Qdg and 4'-Qmg, respectively. Untreated onions had mean exposures of 14,000 and 3000 µg/day for 3,4'-Qdg and 4'-Qmg, respectively.

Silver migration from nanosilver and a commercially available zeolite filler polyethylene composites to food simulants.

Polyethylene composites containing Agion(TM) commercial silver ion filler at three different percentage fill rates (0.5, 1.0 and 2% w/w) and polyethylene composites containing laboratory produced silver nanoparticles (Agnps) at two different percentage fill rates (0.1 and 0.5% w/w) underwent migration tests according to Commission Regulation (EU) No. 10/2011. Migrated silver in the two simulants (acidified water with 3% acetic acid and distilled water) was quantified using two techniques: inductively coupled atomic emission spectroscopy (ICPAES) and Hach Lange spectroscopy. The former had higher sensitivity with mean silver migration from Agion composites (n = 12) ranging from < 0.001 to 1.50 × 10(-2) mg l(-1). Mean silver migration from Agnps composites ranged from 4.65 × 10(-2) to 0.38 mg l(-1) and 8.92 × 10(-2) and 5.15 × 10(-2) mg l(-1) for Hach Lange spectrophotometry and ICPAES, respectively. Both percentage fill rate in the composite and the simulant type, as factors, were found to be significant in both silver migration from Agion (p < 0.0001 and < 0.01, respectively) and Agnps (p < 0.05 and < 0.01, respectively). Transmission electron microscopy (TEM) imagery showed differences in size distributions and morphology of particles (shape and degree of agglomeration) before and after migration. PE composites containing 0.5% Agion, simulating contact with non-acidic foods, was the only scenario that did not exceed the permitted migration level of non-authorised substances given in EU 10/2011. This study illustrates the need for careful engineering of the composite filler system to conform to limits with cognisance of food pH and percentage fill rate.

Evaluation and simulation of silver and copper nanoparticle migration from polyethylene nanocomposites to food and an associated exposure assessment.

Silver nanoparticles (nanosilver) and copper nanoparticles (nanocopper) exhibit antimicrobial activity and have been incorporated into polymers to create antimicrobial packaging materials. Their use in conjunction with food has caused concerns regarding the potential risk of particle migration, resulting in human exposure to nanoparticles. A migration experiment was carried out to investigate the effect of time and temperature on the migration of nanosilver and nanocopper particles from polyethylene (PE) nanocomposites to boneless chicken breasts. Migration of silver ranged from 0.003 to 0.005 mg/dm², while migration of copper ranged from 0.024 to 0.049 mg/dm², for a set of four different scenarios representing typical storage conditions. Effects of time and temperature were not significant (p > 0.1). A migration and exposure model was developed on the basis of mathematical relationships defining migratability and subsequent migratables using the Williams-Landel-Ferry equation for time-temperature superposition. The results of the model accurately predicted the nanosilver levels detected in the laboratory migration tests (R values ranging from 0.43 to 0.99); however, the model was less accurate in predicting nanocopper levels (R values ranging from 0.65 to 0.99), probably because of the highly variable background levels of copper observed in the real food matrix. The 95th percentile of the simulated human exposure to nanosilver based on laboratory experimental results of four scenarios ranged from 5.89 × 10⁻5 to 8.9 × 10⁻5 mg kg(bw)⁻¹ day⁻¹. For the measured migration of copper under the same storage conditions, the exposure ranged from 2.26 × 10⁻5 to 1.17 × 10⁻4 mg kg(bw)⁻¹ day⁻¹. This study highlights the potential migration of nanoparticles from PE composite packaging to a food material and the potential for simulation models to accurately capture this migration potential; however, variable background levels of copper in the food matrix can make prediction more difficult for trace migration of nanocopper.

Faecal calprotectin testing for differentiating amongst inflammatory and non-inflammatory bowel diseases: systematic review and economic evaluation.

BACKGROUND: Irritable bowel syndrome (IBS) is common, and causes pain, bloating and diarrhoea and/or constipation. It is a troublesome condition that reduces the quality of life but causes no permanent damage. Inflammatory bowel disease (IBD) comprises mainly ulcerative colitis (UC) and Crohn's disease (CD). Both cause serious complications and may lead to sections of the bowel having to be removed, although this is more common with CD. The presenting symptoms of IBS and IBD can be similar. Distinguishing them on clinical signs and symptoms can be difficult. Until recently, colonoscopy was often required to rule out IBD. In younger people, > 60% of colonoscopies showed no abnormality. Faecal calprotectin (FC) is a protein released by the white blood cells, neutrophils, found in inflamed areas of the bowel in IBD. Determining the level of FC in stool samples may help distinguish IBS from IBD. OBJECTIVE: To review the value of FC for distinguishing between IBD and non-IBD. DATA SOURCES: Sources included MEDLINE, EMBASE, The Cochrane Library, Web of Science, websites of journals and the European Crohn's and Colitis Organisation (conference abstracts 2012 and 2013), and contact with experts. REVIEW METHODS: Systematic review and economic modelling. Review Manager (RevMan) version 5.2 (The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark) was used for most analysis, with statistical analyses done in Stata version 12 (StataCorp LP, College Station, TX, USA). Forest plots and receiver operating characteristic curves were produced. Quality Assessment of Diagnostic Accuracy Studies was used for quality assessment. Economic modelling was done in Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA, USA). LIMITATIONS: Studies were often small, most used only one calprotectin cut-off level, and nearly all came from secondary care populations. RESULTS: Twenty-eight studies provided data for 2 × 2 tables and were included in meta-analyses, with seven in the most important comparison in adults (IBS vs. IBD) and eight in the key comparison in paediatrics (IBD vs. non-IBD). Most studies used laboratory enzyme-linked immunosorbent assay (ELISA) tests. For distinguishing between IBD and IBS in adults, these gave pooled sensitivity of 93% and specificity of 94% at FC cut-off level of 50 µg/g. Sensitivities at that cut-off ranged from 83% to 100%, and specificities from 60% to 100%. For distinguishing between IBD and non-IBD in paediatric populations with ELISA tests, sensitivities ranged from 95% to 100% at cut-off of 50 µg/g and specificities of 44-93%. Few studies used point-of-care testing but that seemed as reliable as ELISA, though perhaps less specific. The evidence did not provide any grounds for preferring one test over others on clinical effectiveness grounds. FC testing in primary care could reduce the need for referral and colonoscopies. Any quality-adjusted life-year gains are likely to be small because of the low prevalence of IBD and the high sensitivities of all of the tests, resulting in few false negatives with IBD. However, considerable savings could accrue. Areas of uncertainty include the optimum management of people with borderline results (50-150 µg/g), most of whom do not have IBD. Repeat testing may be appropriate before referral. CONCLUSIONS: Faecal calprotectin can be a highly sensitive way of detecting IBD, although there are inevitably trade-offs between sensitivity and specificity, with some false positives (IBS with positive calprotectin) if a low calprotectin cut-off is used. In most cases, a negative calprotectin rules out IBD, thereby sparing most people with IBS from having to have invasive investigations, such as colonoscopy. STUDY REGISTRATION: PROSPERO CRD 42012003287. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Systematic review of the clinical effectiveness and cost-effectiveness, and economic evaluation, of denosumab for the treatment of bone metastases from solid tumours.

BACKGROUND: Denosumab offers an alternative, or additional, treatment for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumours. OBJECTIVES: The aim of this review was to assess the clinical effectiveness and cost-effectiveness of denosumab, within its licensed indication, for the prevention of SREs in patients with bone metastases from solid tumours. DATA SOURCES: Databases searched were MEDLINE (1948 to April 2011), EMBASE (1980 to March 2011), The Cochrane Library (all sections; Issue 1, 2011) and Web of Science with Conference Proceedings (1970 to May 2011). REVIEW METHODS: Only randomised controlled trials (RCTs) assessing denosumab, bisphosphonates (BPs) or best supportive care (BSC) in patients with bone metastases were included. Systematic reviews and observational studies were used for safety and quality-of-life assessments. Study quality was assessed using the Cochrane risk of bias tool. Studies suitable for meta-analysis were synthesised using network meta-analysis (NMA). A systematic review was conducted for cost, quality-of-life and cost-effectiveness studies. The results of this informed the cost-utility modelling. This principally estimated the cost-effectiveness of denosumab relative to zoledronic acid for when BPs are currently recommended and relative to BSC when BPs are not recommended or are contraindicated. RESULTS: A literature search identified 39 studies (eight suitable for NMA). Denosumab was effective in delaying time to first SRE and reducing the risk of multiple SREs compared with zoledronic acid. Generally speaking, denosumab was similar to zoledronic acid for quality of life, pain, overall survival and safety. The NMA demonstrated that denosumab was more effective in delaying SREs than placebo, but was limited by numerous uncertainties. Cost-utility modelling results for denosumab relative to zoledronic acid were driven by the availability of the patient access scheme (PAS) for denosumab. Without this, denosumab was not estimated to be cost-effective compared with zoledronic acid. With it, the cost-effectiveness ranged between dominance for breast and prostate cancer, to between £5400 and £15,300 per quality-adjusted life-year (QALY) for other solid tumours (OSTs) including non-small cell lung cancer (NSCLC) and £12,700 per QALY for NSCLC. Owing to small patient gains estimated, the cost-effectiveness of denosumab was very sensitive to the zoledronic acid price. Denosumab was not estimated to be cost-effective compared with BSC. LIMITATIONS: Only subgroup data were available for denosumab for NSCLC, and OSTs excluding NSCLC. The NMA was subject to numerous uncertainties. Owing to small patient gains estimated, the cost-effectiveness of denosumab was very sensitive to the zoledronic acid price. CONCLUSION: Denosumab, compared with zoledronic acid and placebo, is effective in delaying SREs, but is similar with regard to quality of life and pain. Cost-effectiveness showed that without the PAS denosumab was not estimated to be cost-effective relative to either zoledronic acid or BSC. With the PAS, denosumab was estimated to be cost-effective relative to zoledronic acid but not BSC. STUDY REGISTRATION: PROSPERO number CRD42011001418. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The effect of hospital effluent on antimicrobial resistant E. coli within a municipal wastewater system.

There is a concern that hospital effluent potentially containing antimicrobial compounds, antimicrobial resistant (AMR) bacteria and genetic determinants of resistance may contribute to the emergence, dissemination and persistence of AMR bacteria in municipal wastewaters. Hence, it is of interest to investigate the effect, if any, hospital effluent has on the percentage of AMR bacteria within wastewater. Water from two wastewater treatment plants (WWTPs) (one receives and treats hospital effluent (WWTPhe) and the second does not (WWTPc)) were examined for E. coli expressing resistance to seven antimicrobials (ampicillin, streptomycin, cefoxitin, cefotaxime, tetracycline, sulphonamide and ciprofloxacin). A two-sample t-test showed that AMR E. coli are present in WWTP influent and effluent, irrespective of receiving hospital effluent, and are being released into the environment (no statistical difference in count between the two WWTPs). The effect of hospital effluent on resistance varies for each AMR bacteria. Excluding tetracycline, sulphonamide and ciprofloxacin, the results suggest that the release of hospital effluent does not significantly affect the frequency with which AMR E. coli are detected in effluent. For some hospital specific antimicrobial agents, such as ciprofloxacin, the release of hospital effluent is associated with an increased proportion of antimicrobial resistance. The results suggest resistance to AMR E. coli may already be well developed in the community, making the effect of hospital effluent on AMR E. coli indistinguishable. However, for hospital specific antimicrobials, there may be a selective effect and hence limiting the release of hospital effluent containing such antimicrobials may impact the proportion of antimicrobial resistance. This research has provided statistical evidence to support necessary mitigation and remediation of antimicrobial residue release and subsequent resistance in the environment.

Migration and exposure assessment of silver from a PVC nanocomposite.

Nanotechnology is the manipulation of matter at the nanoscale, generally between 1 and 100 nm. The discovery of unique nanomaterial properties has lead to novel applications in the food industry, one of which is antimicrobial food packaging materials. The objective of this study was to evaluate the migration of silver from plasticised polyvinyl chloride (PVC) nanocomposites to chicken meat following varying storage time and temperature conditions. The silver content of the chicken was quantified using inductively coupled plasma mass spectroscopy (ICPMS) and migration was found to occur within a range of 0.03-8.4 mg/kg. An exposure assessment revealed that human exposure to silver (assuming a worst case scenario that all silver is in its most harmful nanoform), is likely to be below current migration limits for conventional migrants and a provisional toxicity limit; however it is acknowledged there is still considerable uncertainty about the potential harmful effects of particles at the nanoscale. A sensitivity analysis revealed that silver migration from the nanocomposite to the food surface was influenced most by the percentage fill (p<0.01), followed by storage time (p<0.01) and storage temperature (p<0.05). This study represents an initial and much needed attempt to quantify human risks from the use of nanomaterials in the food industry.

Succinate is an inflammatory signal that induces IL-1ß through HIF-1α.

Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1ß but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1ß as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1ß production during inflammation.

Neuropsychological effects of the CSMD1 genome-wide associated schizophrenia risk variant rs10503253.

The single-nucleotide polymorphism (SNP) rs10503253, located within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2, was recently identified as genome-wide significant for schizophrenia (SZ), but is of unknown function. We investigated the neurocognitive effects of this CSMD1 variant in vivo in patients and healthy participants using behavioral and imaging measures of brain structure and function. We compared carriers and non-carriers of the risk 'A' allele on measures of neuropsychological performance typically impaired in SZ (general cognitive ability, episodic and working memory and attentional control) in independent samples of Irish patients (n = 387) and controls (n = 171) and German patients (205) and controls (n = 533). Across these groups, the risk 'A' allele at CSMD1 was associated with deleterious effects across a number of neurocognitive phenotypes. Specifically, the risk allele was associated with poorer performance on neuropsychological measures of general cognitive ability and memory function but not attentional control. These effects, while significant, were subtle, and varied between samples. Consistent with previous evidence suggesting that CSMD1 may be involved in brain mechanisms related to memory and learning, these data appear to reflect the deleterious effects of the identified 'A' risk allele on neurocognitive function, possibly as part of the mechanism by which CSMD1 is associated with SZ risk.

Liraglutide for the treatment of type 2 diabetes.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of liraglutide in the treatment of type 2 diabetes mellitus, based upon the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The manufacturer proposed the use of liraglutide as a second or third drug in patients with type 2 diabetes whose glycaemic control was unsatisfactory with metformin, with or without a second oral glucose-lowering drug. The submission included six manufacturer-sponsored trials that compared the efficacy of liraglutide against other glucose-lowering agents. Not all of the trials were relevant to the decision problem. The most relevant were Liraglutide Effects and Actions in Diabetes 5 (LEAD-5) (liraglutide used as part of triple therapy and compared against insulin glargine) and LEAD-6 [liraglutide in triple therapy compared against another glucagon-like peptide-1 agonist, exenatide]. Five of the six trials were published in full and one was then unpublished. Two doses of liraglutide, 1.2 and 1.8 mg, were used in some trials, but in the two comparisons in triple therapy, against glargine and exenatide, only the 1.8-mg dose was used. Liraglutide in both doses was found to be clinically effective in lowering blood glucose concentration [glycated haemoglobin (HbA1c)], reducing weight (unlike other glucose-lowering agents, such as sulphonylureas, glitazones and insulins, which cause weight gain) and also reducing systolic blood pressure (SBP). Hypoglycaemia was uncommon. The ERG carried out meta-analyses comparing the 1.2- and 1.8-mg doses of liraglutide, which suggested that there was no difference in control of diabetes, and only a slight difference in weight loss, insufficient to justify the extra cost. The cost-effectiveness analysis was carried out using the Center for Outcomes Research model. The health benefit was reported as quality-adjusted life-years (QALYs). The manufacturer estimated the cost-effectiveness to be £ 15,130 per QALY for liraglutide 1.8 mg compared with glargine, £ 10,054 per QALY for liraglutide 1.8 mg compared with exenatide, £ 10,465 per QALY for liraglutide 1.8 mg compared with sitagliptin, and £ 9851 per QALY for liraglutide 1.2 mg compared with sitagliptin. The ERG conducted additional sensitivity analyses and concluded that the factors that carried most weight were: in the comparison with glargine, the direct utility effects of body mass index (BMI) changes and SBP, with some additional contribution from HbA1c, in the comparison with exenatide, HbA1c, with some additional effects from cholesterol and triglycerides in the comparison with sitagliptin, HbA1c and direct utility effects of BMI changes. The European Medicines Agency has approved liraglutide in dual therapy with other oral glucose-lowering agents. NICE guidance recommends the use of liraglutide 1.2 mg in triple therapy when glycaemic control remains or becomes inadequate with a combination of two oral glucose-lowering drugs. The use of liraglutide 1.2 mg in a dual therapy is indicated only in patients who are intolerant of, or have contraindications to, three oral glucose-lowering drugs. The use of liraglutide 1.8 mg was not approved by NICE. The ERG recommends research into the (currently unlicensed) use of liraglutide in combination with long-acting insulin.

Screening for hyperglycaemia in pregnancy: a rapid update for the National Screening Committee.

BACKGROUND: Screening for gestational diabetes has long been a controversial topic. A previous Health Technology Assessment (HTA) report reviewed literature on screening for gestational diabetes mellitus (GDM) and assessed the case for screening against the criteria set by the National Screening Committee. OBJECTIVE: To update a previous HTA report which reviewed the literature on screening for GDM by examining evidence that has emerged since that last report, including the Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS), the Maternal and Fetal Medicine Units Network (MFMUN) trial and the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study. To review data on recent trends in maternal age at birth and on the prevalence of overweight and obesity and the effect on prevalence of GDM. DATA SOURCES: A systematic review and meta-analysis of the literature was carried out. The bibliographic databases used were MEDLINE (1996 to January 2009), EMBASE (1996 to December 2009), the Cochrane Library 2008 issue 4, the Centre for Reviews and Dissemination database and the Web of Science. REVIEW METHODS: For the review of treatment with oral drugs versus insulin, a full systematic review and meta-analysis was carried out. The results of the ACHOIS, MFMUN and HAPO studies were summarised and their implications discussed. Findings of a selection of other recent studies, relevant to the continuum issue, were summarised. Some recent screening studies were reviewed, including a particular focus on studies of screening earlier in pregnancy. RESULTS: The HAPO results showed a linear relationship between plasma glucose and adverse outcomes - there is a continuum of risk with no clear threshold which could divide women into those with gestational diabetes and those without. There was good evidence from trials and the meta-analysis that women who fail to control hyperglycaemic in pregnancy on lifestyle measures alone can be safely and effectively be treated with oral agents, metformin or glibenclamide, rather than going directly to insulin. Evidence showed few differences in results between glibenclamide and insulin and metformin and insulin. The exceptions were that there was less maternal hypoglycaemia with glibenclamide, but less neonatal hypoglycaemia and lower birthweight with insulin, and there was less maternal weight gain with metformin. The ACHOIS and MFMUN trials showed reductions in perinatal complications among infants born to mothers who were provided with more intensive dietary advice, blood glucose monitoring and insulin when required. The HAPO study demonstrated adverse outcomes over a much wider range of blood glucose (BG) than the traditional definition of GDM. In the HAPO study, no one measure of BG came out as being clearly the best, although fasting plasma glucose (FPG) was as good as any, and had advantages of being more convenient than an oral glucose tolerance test (OGTT), but correlations between fasting and post-load levels were quite poor. Two screening strategies dominated; (1) selection by the American Diabetes Association criteria followed by the 75-g OGTT [incremental cost-effectiveness ratio (ICER) 3678 pounds], and (2) selection by high-risk ethnicity followed by the 75-g OGTT (ICER 21,739 pounds). Studies indicated that costs are about 1833 pounds higher for pregnancies complicated by gestational diabetes, suggesting that prevention would be worthwhile. LIMITATIONS: Not all of the HAPO results have been published, and none of the reviewed economic studies resolved the most difficult issue - at what level of BG does intervention become cost-effective? CONCLUSIONS: The evidence base has improved since the last HTA review in 2002. There is now good evidence for treatment of oral drugs instead of insulin and it looks increasingly as if FPG could be the test of choice. However some key uncertainties remain to be resolved, which can be done by further analysis of the already collected HAPO data and by using the UK model used in developing the NICE guidelines to assess the cost-effectiveness of intervention in each of the seven HAPO categories.