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

Perspectives on laser-plasma physics in the relativistic transparency regime

With the advent of multi-petawatt lasers, the relativistic transparency regime of laser-plasma interactions becomes readily accessible for near-solid density targets. Initially opaque targets that undergo relativistic self-induced transparency (RSIT) have already shown to result in promising particle acceleration and radiation generation mechanisms, as well as relativistic optical and photonics phenomena that modify the spatial, temporal, spectral and polarization properties of the laser pulse itself. At the maximum laser intensities currently available, this opaque-to-RSIT transition regime can be achieved through ultrafast ionization, heating and expansion of initially ultrathin foil targets. Here, we review findings from our programme of work exploring this regime experimentally and numerically, including changes to the laser energy absorption, mechanisms for laser-driven particle acceleration and the generation of a relativistic plasma aperture. New physics induced by this aperture, such as the production of intense light with higher order spatial modes and higher harmonics, and spatially-structured and temporally-varying polarization states, is summarized. Prospects for exploring the physics of the RSIT regime with higher intensity and high repetition rate lasers, including expected new phenomena such as high-field effects and the application of new techniques such as machine learning, are also discussed; outlining directions for the future development of this promising laser-plasma interaction regime

Appetite, appetite hormone and energy intake responses to two consecutive days of aerobic exercise in healthy young men

Single bouts of exercise do not cause compensatory changes in appetite, food intake or appetite regulatory hormones on the day that exercise is performed. It remains possible that such changes occur over an extended period or in response to a higher level of energy expenditure. This study sought to test this possibility by examining appetite, food intake and appetite regulatory hormones (acylated ghrelin, total peptide-YY, leptin and insulin) over two days, with acute bouts of exercise performed on each morning. Within a controlled laboratory setting, 15 healthy males completed two, 2-day long (09:00–16:00) experimental trials (exercise and control) in a randomised order. On the exercise trial participants performed 60 min of continuous moderate-high intensity treadmill running (day one: 70.1 ± 2.5% VO2peak, day two: 70.0 ± 3.2% VO2max (mean ± SD)) at the beginning of days one and two. Across each day appetite perceptions were assessed using visual analogue scales and appetite regulatory hormones were measured from venous blood samples. Ad libitum energy and macronutrient intakes were determined from meals provided two and six hours into each day and from a snack bag provided in-between trial days. Exercise elicited a high level of energy expenditure (total = 7566 ± 635 kJ across the two days) but did not produce compensatory changes in appetite or energy intake over two days (control: 29,217 ± 4006 kJ; exercise: 28,532 ± 3899 kJ, P > 0.050). Two-way repeated measures ANOVA did not reveal any main effects for acylated ghrelin or leptin (all P > 0.050). However a significant main effect of trial (P = 0.029) for PYY indicated higher concentrations on the exercise vs. control trial. These findings suggest that across a two day period, high volume exercise does not stimulate compensatory appetite regulatory changes

International Study of Chaplains’ Attitudes About Research

An online survey was conducted by twelve professional chaplain organizations to assess chaplains’ attitudes about and involvement in research. A total of 2,092 chaplains from 23 countries responded to the survey. Over 80% thought research was definitely important and nearly 70% thought chaplains should definitely be research literate. Just over 40% said they regularly read research articles and almost 60% said they occasionally did. The respondents rated their own research literacy as 6.5 on a 0–10 scale. Significant positive inter-correlations were found among all four measures: importance of (a) research and (b) research literacy; (c) frequency of reading articles; and (d) research literacy rating. Approximately 35% were never involved, 37% had been involved, 17% were currently involved, and 11% expected to be involved in research. The last three groups were significantly more likely to think research and research literacy were important and to read research articles than chaplains who were never involved in research. Given chaplains’ interest in research, actions should be undertaken to facilitate further research engagement

The evolution of metazoan extracellular matrix

The modular domain structure of extracellular matrix (ECM) proteins and their genes has allowed extensive exon/domain shuffling during evolution to generate hundreds of ECM proteins. Many of these arose early during metazoan evolution and have been highly conserved ever since. Others have undergone duplication and divergence during evolution, and novel combinations of domains have evolved to generate new ECM proteins, particularly in the vertebrate lineage. The recent sequencing of several genomes has revealed many details of this conservation and evolution of ECM proteins to serve diverse functions in metazoa.Howard Hughes Medical Institut

Synergisitic role of ADP and Ca2+ in diastolic myocardial stiffness

Heart failure (HF) with diastolic dysfunction has been attributed to increased myocardial stiffness that limits proper filling of the ventricle. Altered cross-bridge interaction may significantly contribute to high diastolic stiffness, but this has not been shown thus far. Cross-bridge interactions are dependent on cytosolic [Ca2+] and the regeneration of ATP from ADP. Depletion of myocardial energy reserve is a hallmark of HF leading to ADP accumulation and disturbed Ca2+-handling. Here, we investigated if ADP elevation in concert with increased diastolic [Ca2+] promotes diastolic cross-bridge formation and force generation and thereby increases diastolic stiffness. ADP dose-dependently increased force production in the absence of Ca2+ in membrane-permeabilized cardiomyocytes from human hearts. Moreover, physiological levels of ADP increased actomyosin force generation in the presence of Ca2+ both in human and rat membrane-permeabilized cardiomyocytes. Diastolic stress measured at physiological lattice spacing and 37°C in the presence of pathologicallevels of ADP and diastolic [Ca2+] revealed a 76±1% contribution of cross-bridge interaction to total diastolic stress in rat membrane-permeabilized cardiomyocytes. Inhibition of creatine kinase (CK), which increases cytosolic ADP, in enzyme-isolated intact rat cardiomyocytes impaired diastolic re-lengthening associated with diastolic Ca2+- overload. In isolated Langendorff-perfused rat hearts, CK-inhibition increased ventricular stiffness only in the presence of diastolic [Ca2+]. We propose that elevations of intracellular ADP in specific types of cardiac disease, including those where myocardial energy reserve is limited, contribute to diastolic dysfunction by recruiting cross-bridges even at low Ca2+ and thereby increase myocardial stiffness

The Evolution of Extracellular Matrix

We present a perspective on the molecular evolution of the extracellular matrix (ECM) in metazoa that draws on research publications and data from sequenced genomes and expressed sequence tag libraries. ECM components do not function in isolation, and the biological ECM system or “adhesome” also depends on posttranslational processing enzymes, cell surface receptors, and extracellular proteases. We focus principally on the adhesome of internal tissues and discuss its origins at the dawn of the metazoa and the expansion of complexity that occurred in the chordate lineage. The analyses demonstrate very high conservation of a core adhesome that apparently evolved in a major wave of innovation in conjunction with the origin of metazoa. Integrin, CD36, and certain domains predate the metazoa, and some ECM-related proteins are identified in choanoflagellates as predicted sequences. Modern deuterostomes and vertebrates have many novelties and elaborations of ECM as a result of domain shuffling, domain innovations and gene family expansions. Knowledge of the evolution of metazoan ECM is important for understanding how it is built as a system, its roles in normal tissues and disease processes, and has relevance for tissue engineering, the development of artificial organs, and the goals of synthetic biology

HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.

Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (∼1-5%) who could have selective therapeutic sensitivity to PARP inhibition