Photochemically induced reactions between ozone and halogenated species: A matrix isolation study

The main objective of this research was to study the photochemically induced reactions of ozone with some halogenated species in low temperature matrices, using Fourier-transform infrared spectroscopy, to observe and characterise novel intermediates and to determine pathways for such reactions. Ozone plays a significant role in the chemistry of both the stratosphere and troposphere and thus information concerning the photochemistry of halogenated species in the presence of ozone is of considerable atmospheric importance and is therefore relevant to gas phase atmospheric research. The FT-IR matrix isolation technique is well suited to providing background information on gas phase atmospheric reactions since most atmospheric species exhibit infrared spectra, and the ability to isolate low concentrations of reactive chemical species in the matrix mimics the conditions of dilution in the atmosphere. Thus the results obtained from matrix isolation experiments can complement those obtained from gas phase studies. Since matrix-isolated species are held at very low temperatures, any thermal reactivity is quenched and reactions have to be initiated either photochemically or thermally. In these experiments the matrices are photolysed in order to initiate a reaction by using a range of wavelengths in the visible and UV regions. Any reactive or unstable species produced by irradiation at a particular wavelength are stabilised indefinitely for spectroscopic analysis, thus allowing the photochemical pathway to be revealed. In the matrix the species are held in close proximity to one another allowing secondary reactions to occur that would not have occurred in the gas phase; this has enabled a range of nearest-neighbour complexes to be generated in situ and detected in this study. Of the halogenated species studied, the halogen cyanides, ICN and BrCN, were separately co-deposited with ozone and the photo-induced reactions are reported. Ozone is shown to form a complex with ICN but not with BrCN and so the photochemistry of ozone is altered in the O3/ICN reaction, allowing the formation of several new species to be observed. Harsh UV irradiation is required to initiate a reaction in the O3/BrCN matrix, as well as in the reactions between ozone and the trihalomethanes (CHBr2Cl and CHBrCl2) where several novel carbonyl-Lewis acid and carbon monoxide-Lewis acid complexes were detected. The co-deposition of ozone with each of the halogenated ethenes, BrCH=CHBr and C1CH=CHC1, led to the formation of a charge transfer complex which dissociates to form several new species including carbonyl and carbon monoxide species. Finally, the photo-induced reaction of ozone with some diiodo-species highlights the different photochemical behaviour of a molecule containing two iodine atoms as distinct from one in the presence of ozone. In each case the photoproducts were identified by FT-IR spectroscopy and photochemical pathways proposed. In some instances nitrogen dioxide and solid oxygen matrices were used to provide alternative sources of O atoms for reaction

Assessing the efficacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised controlled trial

SummaryBackgroundSmall studies suggest peanut oral immunotherapy (OIT) might be effective in the treatment of peanut allergy. We aimed to establish the efficacy of OIT for the desensitisation of children with allergy to peanuts.MethodsWe did a randomised controlled crossover trial to compare the efficacy of active OIT (using characterised peanut flour; protein doses of 2–800 mg/day) with control (peanut avoidance, the present standard of care) at the NIHR/Wellcome Trust Cambridge Clinical Research Facility (Cambridge, UK). Randomisation (1:1) was by use of an audited online system; group allocation was not masked. Eligible participants were aged 7–16 years with an immediate hypersensitivity reaction after peanut ingestion, positive skin prick test to peanuts, and positive by double-blind placebo-controlled food challenge (DBPCFC). We excluded participants if they had a major chronic illness, if the care provider or a present household member had suspected or diagnosed allergy to peanuts, or if there was an unwillingness or inability to comply with study procedures. Our primary outcome was desensitisation, defined as negative peanut challenge (1400 mg protein in DBPCFC) at 6 months (first phase). Control participants underwent OIT during the second phase, with subsequent DBPCFC. Immunological parameters and disease-specific quality-of-life scores were measured. Analysis was by intention to treat. Fisher's exact test was used to compare the proportion of those with desensitisation to peanut after 6 months between the active and control group at the end of the first phase. This trial is registered with Current Controlled Trials, number ISRCTN62416244.FindingsThe primary outcome, desensitisation, was recorded for 62% (24 of 39 participants; 95% CI 45–78) in the active group and none of the control group after the first phase (0 of 46; 95% CI 0–9; p<0·001). 84% (95% CI 70–93) of the active group tolerated daily ingestion of 800 mg protein (equivalent to roughly five peanuts). Median increase in peanut threshold after OIT was 1345 mg (range 45–1400; p<0·001) or 25·5 times (range 1·82–280; p<0·001). After the second phase, 54% (95% CI 35–72) tolerated 1400 mg challenge (equivalent to roughly ten peanuts) and 91% (79–98) tolerated daily ingestion of 800 mg protein. Quality-of-life scores improved (decreased) after OIT (median change −1·61; p<0·001). Side-effects were mild in most participants. Gastrointestinal symptoms were, collectively, most common (31 participants with nausea, 31 with vomiting, and one with diarrhoea), then oral pruritus after 6·3% of doses (76 participants) and wheeze after 0·41% of doses (21 participants). Intramuscular adrenaline was used after 0·01% of doses (one participant).InterpretationOIT successfully induced desensitisation in most children within the study population with peanut allergy of any severity, with a clinically meaningful increase in peanut threshold. Quality of life improved after intervention and there was a good safety profile. Immunological changes corresponded with clinical desensitisation. Further studies in wider populations are recommended; peanut OIT should not be done in non-specialist settings, but it is effective and well tolerated in the studied age group.FundingMRC-NIHR partnership

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Study of induction of Tolerance to Oral Peanut: a randomised controlled trial of desensitisation using peanut oral immunotherapy in children (STOP II)

Background: Peanut allergy is a common disease that causes severe and fatal food allergic reactions. Currently, the best treatment is avoidance as repeated reactions can occur. Quality of life (QoL) is reduced by fear of severe reactions and social limitations. Oral immunotherapy (OIT) is a novel treatment that may be an effective treatment for peanut allergy. Objectives: To determine the efficacy of peanut OIT in children. Design: A phase 2 randomised, controlled, crossover trial (open label). Setting: Single UK centre study. Participants: Children aged 7–15 years with peanut allergy diagnosed by double-blind, placebo-controlled food challenge (DBPCFC). No children were excluded because of anaphylaxis or asthma. Interventions: Daily immunotherapy (2 mg, 5 mg, 12.5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400 mg and 800 mg of peanut protein) was administered as peanut flour (containing 50% peanut protein). Doses were increased at 2-weekly intervals to a maintenance dose of 800 mg of protein. The control group underwent peanut avoidance for 6 months during phase 1. Main outcome measure: A peanut DBPCFC up to 1400 mg of peanut protein was performed in both groups at 6 months. The highest amount of peanut tolerated was the main outcome measure. Randomisation: Randomised by online audited system to active or control group (1 : 1). Blinding: The intervention arm allocation was not blinded. Methods: We assigned 99 participants aged 7–16 years with peanut allergy of all severities to active OIT or control (peanut avoidance/current standard of care). The primary outcome was desensitisation, defined as negative peanut challenge (1400 mg of protein DBPCFC) at 6 months (phase 1). Control participants underwent OIT during phase 2, followed by DBPCFC. Immunological parameters and disease-specific QoL scores were measured. Results: The primary outcome, desensitisation, was observed in 62% (24/39) of the active group and none (0/46) of the control group after phase 1 [95% confidence interval (CI) 45% to 78% vs. 0% to 9%; p < 0.001]; 84% (95% CI 70% to 93%) of the active group tolerated daily ingestion of 800 mg of protein (≈ five peanuts). Median increase in peanut threshold after OIT was 1345 mg (range 45–1400 mg; p < 0.001) or 2.5-fold (range 1.82–280-fold; p < 0.001). After phase 2, 54% (95% CI 35% to 72%) tolerated a 1400-mg challenge (≈ 10 peanuts) and 91% (95% CI 79% to 98%) tolerated a daily ingestion of 800 mg of protein. QoL scores improved (decreased) after OIT (median change –1.61; p < 0.001). Side effects were mostly mild with gastrointestinal symptoms being the most common: oral pruritus occurred after 6.3% of doses, wheeze occurred after 0.41% of doses (one-fifth of participants) and intramuscular epinephrine was required after 0.01% of doses (one participant). Conclusion: In children with peanut allergy of any severity, OIT successfully induced desensitisation in the majority, with a clinically meaningful increase in peanut threshold. QoL improved after intervention and there was a good safety profile. Immunological changes reflected clinical desensitisation. Peanut OIT should not be undertaken in non-specialist settings. Future work will include a phase 3 confirmatory study and studies of long-term tolerance; similar studies of other allergens are also required. Trial registration: Current Controlled Trials ISRCTN62416244. Funding: This project was awarded by the Efficacy and Mechanism Evaluation programme and is funded by the Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC–NIHR partnership, and jointly sponsored by the University of Cambridge and Addenbrooke’s Hospital [Cambridge University Hospital Foundation Trust (RD authorisation A091686)]. The project will be published in full in Efficacy and Mechanism Evaluation; Vol. 1, No. 4. See the NIHR Journals Library website for further project information