Dietary Docosahexaenoic Acid and Arachidonic Acid in Early Life:What Is the Best Evidence for Policymakers?

Background: A wealth of information on the functional roles of docosahexaenoic acid (DHA) and arachidonic acid (ARA) from cellular, animal, and human studies is available. Yet, there remains a lack of cohesion in policymaking for recommended dietary intakes of DHA and ARA in early life. This is predominantly driven by inconsistent findings from a relatively small number of randomised clinical trials (RCTs), which vary in design, methodology, and outcome measures, all of which were conducted in high-income countries. It is proposed that this selective evidence base may not fully represent the biological importance of DHA and ARA during early and later life and the aim of this paper is to consider a more inclusive and pragmatic approach to evidence assessment of DHA and ARA requirements in infants and young children, which will allow policymaking to reflect the marked diversity of need worldwide. Summary: Data from clinical RCTs is considered in the context of the extensive evidence from experimental, animal and human observational studies. Although the RCT data shows evidence of beneficial effects on visual function and in specific cognitive domains, early methodological approaches do not reflect current thinking and this undermines the strength of evidence. An outline of a framework for an inclusive and pragmatic approach to policy development on dietary DHA and ARA in early life is described. Conclusion: High-quality RCTs that will determine long-term health outcomes in appropriate real-world settings need to be undertaken. In the meantime, a collective pragmatic approach to evidence assessment, may allow public health policymakers to make comprehensive reasoned judgements on the merits, costs, and expediency of dietary DHA and ARA interventions

Cholesterol reduction using manufactured foods high in monounsaturated fatty acids: a randomized crossover study

In two separate studies, the cholesterol-lowering efficacy of a diet high in monounsaturated fatty acids (MUFA) was evaluated by means of a randomized crossover trial. In both studies subjects were randomized to receive either a high-MUFA diet or the control diet first, which they followed for a period of 8 weeks; following a washout period of 4–6 weeks they were transferred onto the opposing diet for a further period of 8 weeks. In one study subjects were healthy middle-aged men (n 30), and in the other they were young men (n 23) with a family history of CHD recruited from two centres (Guildford and Dublin). The two studies were conducted over the same time period using identical foods and study designs. Subjects consumed 38 % energy as fat, with 18 % energy as MUFA and 10 % as saturated fatty acids (MUFA diet), or 13 % energy as MUFA and 16 % as saturated fatty acids (control diet). The polyunsaturated fatty acid content of each diet was 7 %. The diets were achieved by providing subjects with manufactured foods such as spreads, ‘ready meals’, biscuits, puddings and breads, which, apart from their fatty acid compositions, were identical for both diets. Subjects were blind to which of the diets they were following on both arms of the study. Weight changes on the diets were less than 1 kg. In the groups combined (n 53) mean total and LDL-cholesterol levels were significantly lower at the end of the MUFA diet than the control diet by 0⋅29 (SD 0⋅61) mmol/l (

Thermal structure of a gas-permeable lava dome and timescale separation in its response to perturbation

The thermal boundary layer at the surface of a volcanic lava dome is investigated through a continuum model of the thermodynamic advection diffusion processes resulting from magmatic gas flow through the dome matrix. The magmatic gas mass flux, porosity and permeability of the rock are identified as key parameters. New, theoretical, nonlinear steady-state thermal profiles are reported which give a realistic surface temperature of 210 degC for a region of lava dome surface through which a gas flux of 3.5 x 10-3 kg s-1 m-2 passes. This contrasts favourably with earlier purely diffusive thermal models, which cool too quickly. Results are presented for time-dependent perturbations of the steady states as a response to: changes in surface pressure, a sudden rockfall from the lava dome surface, and a change in the magmatic gas mass flux at depth. Together with a generalized analysis using the method of multiple scales, this identifies two characteristic time scales associated with the thermal evolution of a dome carapace: a short time scale of several minutes, over which the magmatic gas mass flux, density, and pressure change to a new quasi-steady-state, and a longer time scale of several days, over which the thermal profile changes to a new equilibrium distribution. Over the longer time scale the dynamic properties of the dome continue to evolve, but only in slavish response to the ongoing temperature evolution. In the light of this time scale separation, the use of surface temperature measurements to infer changes in the magmatic gas flux for use in volcanic hazard prediction is discussed

The relative effectiveness of empirical and physical models for simulating the dense undercurrent of pyroclastic flows under different emplacement conditions

High concentration pyroclastic density currents (PDCs) are hot avalanches of volcanic rock and gas and are among the most destructive volcanic hazards due to their speed and mobility. Mitigating the risk associated with these flows depends upon accurate forecasting of possible impacted areas, often using empirical or physical models. TITAN2D, VolcFlow, LAHARZ, and ΔH/L or energy cone models each employ different rheologies or empirical relationships and therefore differ in appropriateness of application for different types of mass flows and topographic environments. This work seeks to test different statistically- and physically-based models against a range of PDCs of different volumes, emplaced under different conditions, over different topography in order to test the relative effectiveness, operational aspects, and ultimately, the utility of each model for use in hazard assessments. The purpose of this work is not to rank models, but rather to understand the extent to which the different modeling approaches can replicate reality in certain conditions, and to explore the dynamics of PDCs themselves. In this work, these models are used to recreate the inundation areas of the dense-basal undercurrent of all 13 mapped, land-confined, Soufrière Hills Volcano dome-collapse PDCs emplaced from 1996 to 2010 to test the relative effectiveness of different computational models. Best-fit model results and their input parameters are compared with results using observation- and deposit-derived input parameters. Additional comparison is made between best-fit model results and those using empirically-derived input parameters from the FlowDat global database, which represent “forward” modeling simulations as would be completed for hazard assessment purposes. Results indicate that TITAN2D is able to reproduce inundated areas well using flux sources, although velocities are often unrealistically high. VolcFlow is also able to replicate flow runout well, but does not capture the lateral spreading in distal regions of larger-volume flows. Both models are better at reproducing the inundated area of single-pulse, valley-confined, smaller-volume flows than sustained, highly unsteady, larger-volume flows, which are often partially unchannelized. The simple rheological models of TITAN2D and VolcFlow are not able to recreate all features of these more complex flows. LAHARZ is fast to run and can give a rough approximation of inundation, but may not be appropriate for all PDCs and the designation of starting locations is difficult. The ΔH/L cone model is also very quick to run and gives reasonable approximations of runout distance, but does not inherently model flow channelization or directionality and thus unrealistically covers all interfluves. Empirically-based models like LAHARZ and ΔH/L cones can be quick, first-approximations of flow runout, provided a database of similar flows, e.g., FlowDat, is available to properly calculate coefficients or ΔH/L. For hazard assessment purposes, geophysical models like TITAN2D and VolcFlow can be useful for producing both scenario-based or probabilistic hazard maps, but must be run many times with varying input parameters. LAHARZ and ΔH/L cones can be used to produce simple modeling-based hazard maps when run with a variety of input volumes, but do not explicitly consider the probability of occurrence of different volumes. For forward modeling purposes, the ability to derive potential input parameters from global or local databases is crucial, though important input parameters for VolcFlow cannot be empirically estimated. Not only does this work provide a useful comparison of the operational aspects and behavior of various models for hazard assessment, but it also enriches conceptual understanding of the dynamics of the PDCs themselves

British signals intelligence and the 1916 Easter Rising in Ireland

Historians for decades have placed Room 40, the First World War British naval signals intelligence organization, at the centre of narratives about the British anticipation of and response to the Easter Rising in Ireland in 1916. A series of crucial decrypts of telegrams between the German embassy in Washington and Berlin, it has been believed, provided significant advance intelligence about the Rising before it took place. This article upends previous accounts by demonstrating that Room 40 possessed far less advance knowledge about the Rising than has been believed, with most of the supposedly key decrypts not being generated until months after the Rising had taken place

Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD).

BACKGROUND: There has been renewal of interest in the use of prophylactic antibiotics to reduce the frequency of exacerbations and improve quality of life in chronic obstructive pulmonary disease (COPD). OBJECTIVES: To determine whether or not regular (continuous, intermittent or pulsed) treatment of COPD patients with prophylactic antibiotics reduces exacerbations or affects quality of life. SEARCH METHODS: We searched the Cochrane Airways Group Trials Register and bibliographies of relevant studies. The latest literature search was performed on 27 July 2018. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared prophylactic antibiotics with placebo in patients with COPD. DATA COLLECTION AND ANALYSIS: We used the standard Cochrane methods. Two independent review authors selected studies for inclusion, extracted data, and assessed risk of bias. We resolved discrepancies by involving a third review author. MAIN RESULTS: We included 14 studies involving 3932 participants in this review. We identified two further studies meeting inclusion criteria but both were terminated early without providing results. All studies were published between 2001 and 2015. Nine studies were of continuous macrolide antibiotics, two studies were of intermittent antibiotic prophylaxis (three times per week) and two were of pulsed antibiotic regimens (e.g. five days every eight weeks). The final study included one continuous, one intermittent and one pulsed arm. The antibiotics investigated were azithromycin, erythromycin, clarithromycin, doxycyline, roxithromycin and moxifloxacin. The study duration varied from three months to 36 months and all used intention-to-treat analysis. Most of the pooled results were of moderate quality. The risk of bias of the included studies was generally low.The studies recruited participants with a mean age between 65 and 72 years and mostly at least moderate-severity COPD. Five studies only included participants with frequent exacerbations and two studies recruited participants requiring systemic steroids or antibiotics or both, or who were at the end stage of their disease and required oxygen. One study recruited participants with pulmonary hypertension secondary to COPD and a further study was specifically designed to asses whether eradication of Chlamydia pneumoniae reduced exacerbation rates.The co-primary outcomes for this review were the number of exacerbations and quality of life.With use of prophylactic antibiotics, the number of participants experiencing one or more exacerbations was reduced (odds ratio (OR) 0.57, 95% CI 0.42 to 0.78; participants = 2716; studies = 8; moderate-quality evidence). This represented a reduction from 61% of participants in the control group compared to 47% in the treatment group (95% CI 39% to 55%). The number needed to treat for an additional beneficial outcome with prophylactic antibiotics given for three to 12 months to prevent one person from experiencing an exacerbation (NNTB) was 8 (95% CI 5 to 17). The test for subgroup difference suggested that continuous and intermittent antibiotics may be more effective than pulsed antibiotics (P = 0.02, I² = 73.3%).The frequency of exacerbations per patient per year was also reduced with prophylactic antibiotic treatment (rate ratio 0.67; 95% CI 0.54 to 0.83; participants = 1384; studies = 5; moderate-quality evidence). Although we were unable to pool the result, six of the seven studies reporting time to first exacerbation identified an increase (i.e. benefit) with antibiotics, which was reported as statistically significant in four studies.There was a statistically significant improvement in quality of life as measured by the St George's Respiratory Questionnaire (SGRQ) with prophylactic antibiotic treatment, but this was smaller than the four unit improvement that is regarded as being clinically significant (mean difference (MD) -1.94, 95% CI -3.13 to -0.75; participants = 2237; studies = 7, high-quality evidence).Prophylactic antibiotics showed no significant effect on the secondary outcomes of frequency of hospital admissions, change in forced expiratory volume in one second (FEV1), serious adverse events or all-cause mortality (moderate-quality evidence). There was some evidence of benefit in exercise tolerance, but this was driven by a single study of lower methodological quality.The adverse events that were recorded varied among the studies depending on the antibiotics used. Azithromycin was associated with significant hearing loss in the treatment group, which was in many cases reversible or partially reversible. The moxifloxacin pulsed study reported a significantly higher number of adverse events in the treatment arm due to the marked increase in gastrointestinal adverse events (P < 0.001). Some adverse events that led to drug discontinuation, such as development of long QTc or tinnitus, were not significantly more frequent in the treatment group than the placebo group but pose important considerations in clinical practice.The development of antibiotic resistance in the community is of major concern. Six studies reported on this, but we were unable to combine results. One study found newly colonised participants to have higher rates of antibiotic resistance. Participants colonised with moxifloxacin-sensitive pseudomonas at initiation of therapy rapidly became resistant with the quinolone treatment. A further study with three active treatment arms found an increase in the degree of antibiotic resistance of isolates in all three arms after 13 weeks treatment. AUTHORS' CONCLUSIONS: Use of continuous and intermittent prophylactic antibiotics results in a clinically significant benefit in reducing exacerbations in COPD patients. All studies of continuous and intermittent antibiotics used macrolides, hence the noted benefit applies only to the use of macrolide antibiotics prescribed at least three times per week. The impact of pulsed antibiotics remains uncertain and requires further research.The studies in this review included mostly participants who were frequent exacerbators with at least moderate-severity COPD. There were also older individuals with a mean age over 65 years. The results of these studies apply only to the group of participants who were studied in these studies and may not be generalisable to other groups.Because of concerns about antibiotic resistance and specific adverse effects, consideration of prophylactic antibiotic use should be mindful of the balance between benefits to individual patients and the potential harms to society created by antibiotic overuse. Monitoring of significant side effects including hearing loss, tinnitus, and long QTc in the community in this elderly patient group may require extra health resources

A Putative P-Type ATPase Required for Virulence and Resistance to Haem Toxicity in Listeria monocytogenes

Regulation of iron homeostasis in many pathogens is principally mediated by the ferric uptake regulator, Fur. Since acquisition of iron from the host is essential for the intracellular pathogen Listeria monocytogenes, we predicted the existence of Fur-regulated systems that support infection. We examined the contribution of nine Fur-regulated loci to the pathogenicity of L. monocytogenes in a murine model of infection. While mutating the majority of the genes failed to affect virulence, three mutants exhibited a significantly compromised virulence potential. Most striking was the role of the membrane protein we designate FrvA (Fur regulated virulence factor A; encoded by frvA [lmo0641]), which is absolutely required for the systemic phase of infection in mice and also for virulence in an alternative infection model, the Wax Moth Galleria mellonella. Further analysis of the ΔfrvA mutant revealed poor growth in iron deficient media and inhibition of growth by micromolar concentrations of haem or haemoglobin, a phenotype which may contribute to the attenuated growth of this mutant during infection. Uptake studies indicated that the ΔfrvA mutant is unaffected in the uptake of ferric citrate but demonstrates a significant increase in uptake of haem and haemin. The data suggest a potential role for FrvA as a haem exporter that functions, at least in part, to protect the cell against the potential toxicity of free haem

NHR-49 Helps Germline-Less Worms Chew the Fat

In C. elegans, removal of the germline extends lifespan significantly. We demonstrate that the nuclear hormone receptor, NHR-49, enables the response to this physiological change by increasing the expression of genes involved in mitochondrial β-oxidation and fatty-acid desaturation. The coordinated augmentation of these processes is critical for germline-less animals to maintain their lipid stores and to sustain de novo fat synthesis during adulthood. Following germline ablation, NHR-49 is up-regulated in somatic cells by the conserved longevity determinants DAF-16/FOXO and TCER-1/TCERG1. Accordingly, NHR-49 overexpression in fertile animals extends their lifespan modestly. In fertile adults, nhr-49 expression is DAF-16/FOXO and TCER-1/TCERG1 independent although its depletion causes age-related lipid abnormalities. Our data provide molecular insights into how reproductive stimuli are integrated into global metabolic changes to alter the lifespan of the animal. They suggest that NHR-49 may facilitate the adaptation to loss of reproductive potential through synchronized enhancement of fatty-acid oxidation and desaturation, thus breaking down some fats ordained for reproduction and orchestrating a lipid profile conducive for somatic maintenance and longevity