Background TH 17 cells are proposed to play a role in the pathology of asthma, including steroid-resistant (SR) disease. We previously identified a steroid-enhancing function of vitamin D in patients ...with SR asthma in restoring the impaired response to steroids for production of the anti-inflammatory cytokine IL-10. Objective We sought to investigate the production of the TH 17-associated cytokines IL-17A and IL-22 in culture in patients with moderate-to-severe asthma defined on the basis of their clinical response to steroids and the susceptibility of this response to inhibition by steroids and the active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25OH2 D3). Methods PBMCs were stimulated in culture with or without dexamethasone and 1,25(OH)2 D3. A cytometric bead array, ELISA, and intracellular cytokine staining were used to assess cytokine production. The role of CD39 in inhibition of the TH 17 response was studied by using quantitative real-time PCR, flow cytometry, and addition of the antagonist POM-1 to culture. Results Asthmatic patients synthesized much higher levels of IL-17A and IL-22 than nonasthmatic control subjects, with patients with SR asthma expressing the highest levels of IL-17A. Glucocorticoids did not inhibit IL-17A cytokine expression in patients and enhanced production in cultures from control subjects. Treatment with 1,25(OH)2 D3 with or without dexamethasone significantly reduced both IL-17A and IL-22 levels. An antagonist of the ectonucleotidase CD39 reversed 1,25(OH)2 D3-mediated inhibition of the IL-17A response. Conclusion Patients with severe asthma exhibit increased levels of TH 17 cytokines, which are not inhibited by steroids. 1,25(OH)2 D3 inhibits TH 17 cytokine production in all patients studied, irrespective of their clinical responsiveness to steroids, identifying novel steroid-enhancing properties of vitamin D in asthmatic patients.
▸ Vitamin D metabolites are known to enhance antimicrobial immunity in vitro. ▸ We review 39 clinical studies investigating the role of vitamin D in the prevention of acute respiratory infection. ▸ ...Observational studies (n=25) report broadly consistent inverse associations between vitamin D status/intake and risk of acute respiratory infection. ▸ Clinical trials (n=14) report conflicting results: 7 report a protective effect of supplementation, and 7 are null. ▸ Results of clinical trials depend on dose administered and baseline prevalence of vitamin D deficiency among participants.
Vitamin D metabolites enhance immunity to a wide range of respiratory pathogens in vitro. Numerous observational studies have investigated whether vitamin D deficiency is a risk factor for acute respiratory infection, and a number of clinical trials of vitamin D supplementation for the prevention of acute respiratory infection have recently been conducted. Syntheses of this literature are lacking. We therefore conducted a systematic review of clinical studies investigating the association between vitamin D deficiency and susceptibility to acute respiratory infection in humans. A total of 39 studies (4 cross-sectional studies, 8 case-control studies, 13 cohort studies and 14 clinical trials) satisfying review eligibility criteria were identified. Observational studies predominantly reported statistically significant associations between low vitamin D status and increased risk of both upper and lower respiratory tract infections. Results from randomised controlled trials were conflicting however, reflecting heterogeneity in dosing regimens and baseline vitamin D status in study populations. Further trials of vitamin D supplementation for the prevention of acute respiratory infection should be conducted in populations with a high prevalence of vitamin D deficiency at baseline, using doses sufficient to induce sustained elevation of serum 25-hydroxyvitamin D concentrations, and powered to detect clinically important sub-group effects.
This article is part of a Special Issue entitled ‘Vitamin D Workshop’.
Vitamin D for the management of asthma Martineau, Adrian R; Cates, Christopher J; Urashima, Mitsuyoshi ...
Cochrane database of systematic reviews,
09/2016, Letnik:
2019, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Background
Several clinical trials of vitamin D to prevent asthma exacerbation and improve asthma control have been conducted in children and adults, but a meta‐analysis restricted to double‐blind, ...randomised, placebo‐controlled trials of this intervention is lacking.
Objectives
To evaluate the efficacy of administration of vitamin D and its hydroxylated metabolites in reducing the risk of severe asthma exacerbations (defined as those requiring treatment with systemic corticosteroids) and improving asthma symptom control.
Search methods
We searched the Cochrane Airways Group Trial Register and reference lists of articles. We contacted the authors of studies in order to identify additional trials. Date of last search: January 2016.
Selection criteria
Double‐blind, randomised, placebo‐controlled trials of vitamin D in children and adults with asthma evaluating exacerbation risk or asthma symptom control or both.
Data collection and analysis
Two review authors independently applied study inclusion criteria, extracted the data, and assessed risk of bias. We obtained missing data from the authors where possible. We reported results with 95% confidence intervals (CIs).
Main results
We included seven trials involving a total of 435 children and two trials involving a total of 658 adults in the primary analysis. Of these, one trial involving 22 children and two trials involving 658 adults contributed to the analysis of the rate of exacerbations requiring systemic corticosteroids. Duration of trials ranged from four to 12 months, and the majority of participants had mild to moderate asthma. Administration of vitamin D reduced the rate of exacerbations requiring systemic corticosteroids (rate ratio 0.64, 95% CI 0.46 to 0.90; 680 participants; 3 studies; high‐quality evidence), and decreased the risk of having at least one exacerbation requiring an emergency department visit or hospitalisation or both (odds ratio (OR) 0.39, 95% CI 0.19 to 0.78; number needed to treat for an additional beneficial outcome, 27; 963 participants; 7 studies; high‐quality evidence). There was no effect of vitamin D on % predicted forced expiratory volume in one second (mean difference (MD) 0.48, 95% CI ‐0.93 to 1.89; 387 participants; 4 studies; high‐quality evidence) or Asthma Control Test scores (MD ‐0.08, 95% CI ‐0.70 to 0.54; 713 participants; 3 studies; high‐quality evidence). Administration of vitamin D did not influence the risk of serious adverse events (OR 1.01, 95% CI 0.54 to 1.89; 879 participants; 5 studies; moderate‐quality evidence). One trial comparing low‐dose versus high‐dose vitamin D reported two episodes of hypercalciuria, one in each study arm. No other study reported any adverse event potentially attributable to administration of vitamin D. No participant in any included trial suffered a fatal asthma exacerbation. We did not perform a subgroup analysis to determine whether the effect of vitamin D on risk of severe exacerbation was modified by baseline vitamin D status, due to unavailability of suitably disaggregated data. We assessed two trials as being at high risk of bias in at least one domain; neither trial contributed data to the analysis of the outcomes reported above.
Authors' conclusions
Whilst we are confident that Vitamin D reduced the risk of asthma exacerbation in these trials (high quality GRADE assessment), we recognise that there is uncertainty about how these findings might be applied in practice. More research is needed to clarify whether there is a difference in effect between adults and children and with respect to asthma severity, baseline vitamin D status and doses.
Patients with chronic obstructive pulmonary disease (COPD) often have vitamin D deficiency, which is associated with increased susceptibility to upper respiratory infection-a major precipitant of ...exacerbation. Multicentre trials of vitamin D supplementation for prevention of exacerbation and upper respiratory infection in patients with COPD are lacking. We therefore investigated whether vitamin D3 (colecalciferol) supplementation would reduce the incidence of moderate or severe COPD exacerbations and upper respiratory infections.
We did a randomised, double-blind, placebo-controlled trial of vitamin D3 supplementation in adults with COPD in 60 general practices and four Acute National Health Service Trust clinics in London, UK. Patients were allocated to receive six 2-monthly oral doses of 3 mg vitamin D3 or placebo over 1 year in a 1:1 ratio using computer-generated permuted block randomisation. Participants and study staff were masked to treatment assignment. Coprimary outcomes were time to first moderate or severe exacerbation and first upper respiratory infection. Analysis was by intention to treat. A prespecified subgroup analysis was done to assess whether effects of the intervention on the coprimary outcomes were modified by baseline vitamin D status. This trial is registered with ClinicalTrials.gov, number NCT00977873.
240 patients were randomly allocated to the vitamin D3 group (n=122) and placebo group (n=118). Vitamin D3 compared with placebo did not affect time to first moderate or severe exacerbation (adjusted hazard ratio 0·86, 95% CI 0·60-1·24, p=0·42) or time to first upper respiratory infection (0·95, 0·69-1·31, p=0·75). Prespecified subgroup analysis showed that vitamin D3 was protective against moderate or severe exacerbation in participants with baseline serum 25-hydroxyvitamin D concentrations of less than 50 nmol/L (0·57, 0·35-0·92, p=0·021), but not in those with baseline 25-hydroxyvitamin D levels of at least 50 nmol/L (1·45, 0·81-2·62, p=0·21; p=0·021 for interaction between allocation and baseline serum 25-hydroxyvitamin D status). Baseline vitamin D status did not modify the effect of the intervention on risk of upper respiratory infection (pinteraction=0·41).
Vitamin D3 supplementation protected against moderate or severe exacerbation, but not upper respiratory infection, in patients with COPD with baseline 25-hydroxyvitamin D levels of less than 50 nmol/L. Our findings suggest that correction of vitamin D deficiency in patients with COPD reduces the risk of moderate or severe exacerbation.
UK National Institute for Health Research.
Frequency Diverse MIMO Techniques for Radar Sammartino, P. F.; Baker, C. J.; Griffiths, H. D.
IEEE transactions on aerospace and electronic systems,
2013-Jan., 2013-01-00, 20130101, Letnik:
49, Številka:
1
Journal Article
Recenzirano
It has been shown over several decades of radar research that the exploitation of diversity in a number of domains (space, frequency, time, polarization, and, recently, waveform) can provide ...increased agility, flexibility, robustness, and capabilities to the radar system. However this is often achieved either through efforts in system design, increased hardware complexity, or by employing additional resources. A conventional antenna array is considered with the intention of introducing, not major, but minor mismatches, in particular in the carrier frequencies and, eventually in the codes at the element level. The starting point of this analysis is the frequency diverse array (FDA), which has been demonstrated to generate a range-angle pattern. Through a reconsideration of the organization of the array, which we have termed the wavelength array (WA), a new pattern, "orthogonal" to that of the standard phased array, can be achieved. The bistatic combination of a WA and a receiver leads to the frequency diverse bistatic system (FDBS), which can be a significant application of this concept. In a second stage the analysis focuses on the effects of introducing waveform diversity in such a system. In particular, if the elements of an electronically steered array (ESA) simultaneously transmit a number of pseudonoise (PN) codes at slightly different carrier frequencies, the coherent summation of the codes gives rise to a waveform whose shape is a function of both angle and range. In fact this is the consequence of applying the multiple-input multiple-output (MIMO) technique to the FDA, which has the result of associating a waveform to each point range/angle of the space, with the possibility of recovering this information in receive after appropriate processing.
A small population of patients with severe asthma does not respond to glucocorticoids (steroid resistant SR). They have high morbidity, highlighting an urgent need for strategies to enhance ...glucocorticoid responsiveness.
We investigated the immunologic differences between steroid-sensitive (SS) and SR asthmatic patients and the effect on immunophenotype of oral calcitriol treatment because it has been previously shown to beneficially modulate the clinical response to glucocorticoids in patients with SR asthma.
CD8-depleted PBMCs were isolated from 12 patients with SS and 23 patients with SR asthma and cultured for 7 days with anti-CD3 and IL-2 with or without dexamethasone. Cytokine production was assessed in supernatants by using the Cytometric Bead Array. Patients with SR asthma were subsequently randomized to oral calcitriol or placebo therapy, and identical studies were repeated.
Patients with SR asthma produced significantly increased IL-17A and IFN-γ levels compared with those in patients with SS asthma, although it was evident that cells from individual patients might overproduce one or the other of these cytokines. Production of IL-17A was inversely and production of IL-13 was positively associated with the clinical response to prednisolone. Oral calcitriol, compared with placebo, therapy of the patients with SR asthma significantly improved dexamethasone-induced IL-10 production in vitro while suppressing dexamethasone-induced IL-17A production. This effect mirrored the previously demonstrated improvement in clinical response to oral glucocorticoids in calcitriol-treated patients with SR asthma.
IL-17A(high) and IFN-γ(high) immunophenotypes exist in patients with SR asthma. These data identify immunologic pathways that likely underpin the beneficial clinical effects of calcitriol in patients with SR asthma by directing the SR cytokine profile toward a more SS immune phenotype, suggesting strategies for identifying vitamin D responder immunophenotypes.
A previous aggregate data meta-analysis of randomised controlled trials showed that vitamin D supplementation reduces the rate of asthma exacerbations requiring treatment with systemic ...corticosteroids. Whether this effect is restricted to patients with low baseline vitamin D status is unknown.
For this systematic review and one-step and two-step meta-analysis of individual participant data, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science for double-blind, placebo-controlled, randomised controlled trials of vitamin D
or vitamin D
supplementation in people with asthma that reported incidence of asthma exacerbation, published between database inception and Oct 26, 2016. We analysed individual participant data requested from the principal investigator for each eligible trial, adjusting for age and sex, and clustering by study. The primary outcome was the incidence of asthma exacerbation requiring treatment with systemic corticosteroids. Mixed-effects regression models were used to obtain the pooled intervention effect with a 95% CI. Subgroup analyses were done to determine whether effects of vitamin D on risk of asthma exacerbation varied according to baseline 25-hydroxyvitamin D (25OHD) concentration, age, ethnic or racial origin, body-mass index, vitamin D dosing regimen, use of inhaled corticosteroids, or end-study 25(OH)D levels; post-hoc subgroup analyses were done according to sex and study duration. This study was registered with PROSPERO, number CRD42014013953.
Our search identified 483 unique studies, eight of which were eligible randomised controlled trials (total 1078 participants). We sought individual participant data for each and obtained it for seven studies (955 participants). Vitamin D supplementation reduced the rate of asthma exacerbation requiring treatment with systemic corticosteroids among all participants (adjusted incidence rate ratio aIRR 0·74, 95% CI 0·56-0·97; p=0·03; 955 participants in seven studies; high-quality evidence). There were no significant differences between vitamin D and placebo in the proportion of participants with at least one exacerbation or time to first exacerbation. Subgroup analyses of the rate of asthma exacerbations treated with systemic corticosteroids revealed that protective effects were seen in participants with baseline 25(OH)D of less than 25 nmol/L (aIRR 0·33, 0·11-0·98; p=0·046; 92 participants in three studies; moderate-quality evidence) but not in participants with higher baseline 25(OH)D levels (aIRR 0·77, 0·58-1·03; p=0·08; 764 participants in six studies; moderate-quality evidence; p
=0·25). p values for interaction for all other subgroup analyses were also higher than 0·05; therefore, we did not show that the effects of this intervention are stronger in any one subgroup than in another. Six studies were assessed as being at low risk of bias, and one was assessed as being at unclear risk of bias. The two-step meta-analysis did not reveal evidence of heterogeneity of effect (I
=0·0, p=0·56).
Vitamin D supplementation reduced the rate of asthma exacerbations requiring treatment with systemic corticosteroids overall. We did not find definitive evidence that effects of this intervention differed across subgroups of patients.
Health Technology Assessment Program, National Institute for Health Research (reference number 13/03/25).
The long-distance quantum transfer between electron-spin qubits in semiconductors is important for realising large-scale quantum computing circuits. Electron-spin to photon-polarisation conversion is ...a promising technology for achieving free-space or fibre-coupled quantum transfer. In this work, using only regular lithography techniques on a conventional 15 nm GaAs quantum well, we demonstrate acoustically-driven generation of single photons from single electrons, without the need for a self-assembled quantum dot. In this device, a single electron is carried in a potential minimum of a surface acoustic wave (SAW) and is transported to a region of holes to form an exciton. The exciton then decays and creates a single optical photon within 100 ps. This SAW-driven electroluminescence, without optimisation, yields photon antibunching with g
(0) = 0.39 ± 0.05 in the single-electron limit (g
(0) = 0.63 ± 0.03 in the raw histogram). Our work marks the first step towards electron-to-photon (spin-to-polarisation) qubit conversion for scaleable quantum computing architectures.
Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolites induce antimycobacterial immunity in vitro. Clinical trials investigating the effect of adjunctive vitamin D on ...sputum culture conversion are absent.
We undertook a multicentre randomised controlled trial of adjunctive vitamin D in adults with sputum smear-positive pulmonary tuberculosis in London, UK. 146 patients were allocated to receive 2·5 mg vitamin D
3 or placebo at baseline and 14, 28, and 42 days after starting standard tuberculosis treatment. The primary endpoint was time from initiation of antimicrobial treatment to sputum culture conversion. Patients were genotyped for
TaqI and
FokI polymorphisms of the vitamin D receptor, and interaction analyses were done to assess the influence of the vitamin D receptor genotype on response to vitamin D
3. This trial is registered with
ClinicalTrials.gov number
NCT00419068.
126 patients were included in the primary efficacy analysis (62 assigned to intervention, 64 assigned to placebo). Median time to sputum culture conversion was 36·0 days in the intervention group and 43·5 days in the placebo group (adjusted hazard ratio 1·39, 95% CI 0·90–2·16; p=0.14).
TaqI genotype modified the effect of vitamin D supplementation on time to sputum culture conversion (p
interaction=0·03), with enhanced response seen only in patients with the
tt genotype (8·09, 95% CI 1·36–48·01; p=0·02).
FokI genotype did not modify the effect of vitamin D supplementation (p
interaction=0·85). Mean serum 25-hydroxyvitamin D concentration at 56 days was 101·4 nmol/L in the intervention group and 22·8 nmol/L in the placebo group (95% CI for difference 68·6–88·2; p<0·0001).
Administration of four doses of 2·5 mg vitamin D
3 increased serum 25-hydroxyvitamin D concentrations in patients receiving intensive-phase treatment for pulmonary tuberculosis. Vitamin D did not significantly affect time to sputum culture conversion in the whole study population, but it did significantly hasten sputum culture conversion in participants with the
tt genotype of the
TaqI vitamin D receptor polymorphism.
British Lung Foundation.
This study explores the impact that recent Bronze Age hoard finds have had on our understanding of hoarding practices across Britain and Northern Ireland. Changes to the legislation of Treasure and ...the onset of the Portable Antiquities Scheme in England and Wales have produced a wealth of new information on Bronze Age hoards. Beyond a handful of studies which have focused on specific groups of hoards or the distinction between dryland/wetland deposition, however, many of these more recent finds have been overlooked. Our regional understanding of hoarding practices across Britain is also largely based on studies which are now significantly out of date. This paper aims to address this problem by providing a snapshot of hoards and hoarding practices, based on a substantial dataset of 385 hoards (containing 7210 objects) that were reported on between 1997 and 2021. Broad chronological and spatial trends in the distribution are highlighted, with precedence given to characterising these enigmatic deposits based on their size and the categories of objects within them. This investigation provides fresh insights into the selection of certain object groups – particularly axes – during certain periods and within specific regions, whilst also exploring ideas so that we might better understand the scale of metalwork deposition. This research not only demonstrates how recent hoard finds fit into traditional narratives but also how they have the potential to enhance our understanding of regional hoarding practices, offering new and exciting avenues for future research.
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