Human atherosclerotic plaques that rupture are characterized by relatively low vascular smooth muscle cell (VSMC) and high inflammatory cell contents. Ruptured plaques also contain higher numbers of ...apoptotic VSMCs than do stable lesions, suggesting that VSMC apoptosis may promote plaque rupture. We examined the ability of human monocytes/macrophages to induce apoptosis of VSMCs derived from human carotid plaque, aortic media, and coronary media. Macrophages, but not T lymphocytes, induced a dose-dependent apoptosis of VSMCs, which required monocyte maturation to macrophages and direct cell-cell contact/proximity. VSMC apoptosis was inhibited by neutralizing antibodies to Fas-ligand (Fas-L) or an Fas-Fc fusion protein, indicating the requirement for membrane-bound Fas and Fas-L. Monocyte maturation was associated with increased surface expression of Fas-L, coincident with the onset of cytotoxicity. VSMCs expressed surface Fas, which was increased in plaque VSMCs, and plaque VSMCs also underwent Fas-induced apoptosis. We conclude that human macrophages potently induce human VSMC apoptosis, which requires direct cell-cell interactions and is in part dependent on Fas/Fas-L interactions. Macrophage-induced VSMC apoptosis may therefore directly promote plaque rupture.
The use of meta-regression models based on existing studies to estimate the value of resources at a new policy site has become a popular alternative to collecting original data in recent years. There ...are two prevalent dilemmas associated with classical meta-regression models: The difference in the available set of regressors across source studies and the treatment of methodological explanatory variables in the construction of benefit transfer functions. In this study we illustrate how these issues can be addressed efficiently within a Bayesian meta-regression framework. We find that the Bayesian model, in contrast to its classical counterpart, can estimate a relatively large set of parameters, including indicators of unobserved study heterogeneity, with reasonable accuracy even when the underlying meta-sample is small. The incorporation of information from regressor-deficient source data in the specification of Bayesian priors leads to a better model fit and tighter welfare estimates for Benefit Transfer in our application of freshwater angling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In skin homeostasis, dermal fibroblasts are responsible for coordinating the migration and differentiation of overlying epithelial keratinocytes. As hairy skin heals faster than nonhairy skin, we ...took bio-inspiration from the follicle and hypothesized that follicular fibroblasts would accelerate skin re-epithelialization after injury faster than interfollicular fibroblasts. Using both in vitro and ex vivo models of human skin wound closure, we found that hair follicle dermal papilla fibroblasts could accelerate closure of in vitro scratch wounds by 1.8-fold and epithelial growth capacity by 1.5-fold compared with controls (P < 0.05). We used a cytokine array to determine how the dermal papilla fibroblasts were eliciting this effect and identified two cytokines, sAXL and CCL19, that are released at significantly higher levels by follicular fibroblasts than by interfollicular subtypes. Using sAXL and CCL19 individually, we found that they could also increase closure of epithelial cells in a scratch wound by 1.2- and 1.5-fold, respectively, compared with controls (P < 0.05). We performed an unbiased transcriptional analysis, combined with pathway analysis, and postulate that sAXL accelerates wound closure by promoting migration and inhibiting epithelial differentiation of skin keratinocytes. Long term, we believe these results can be exploited to accelerate wound closure of human skin in vivo.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Biomarkers in asthma and allergic diseases Shamji, Mohamed H.; Boyle, Robert J.
Clinical and experimental allergy,
August 2021, 2021-08-00, 20210801, Volume:
51, Issue:
8
Journal Article
Peer reviewed
Open access
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Eczema is a common chronic skin condition. Probiotics have been proposed as an effective treatment for eczema; their use is increasing, as numerous clinical trials are under way. This is ...an update of a Cochrane Review first published in 2008, which suggested that probiotics may not be an effective treatment for eczema but identified areas in which evidence was lacking.
Objectives
To assess the effects of probiotics for treating patients of all ages with eczema.
Search methods
We updated our searches of the following databases to January 2017: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, the Global Resource of Eczema Trials (GREAT) database, MEDLINE, Embase, PsycINFO, the Allied and Complementary Medicine Database (AMED), and Latin American Caribbean Health Sciences Literature (LILACS). We searched five trials registers and checked the reference lists of included studies and relevant reviews for further references to relevant randomised controlled trials (RCTs). We also handsearched a number of conference proceedings. We updated the searches of the main databases in January 2018 and of trials registries in March 2018, but we have not yet incorporated these results into the review.
Selection criteria
Randomised controlled trials of probiotics (live orally ingested micro‐organisms) compared with no treatment, placebo, or other active intervention with no probiotics for the treatment of eczema diagnosed by a doctor.
Data collection and analysis
We used standard methodological procedures as expected by Cochrane. We recorded adverse events from the included studies and from a separate adverse events search conducted for the first review. We formally assessed reporting bias by preparing funnel plots, and we performed trial sequential analysis for the first primary outcome ‐ eczema symptoms at the end of active treatment.
We used GRADE to assess the quality of the evidence for each outcome (in italic font).
Main results
We included 39 randomised controlled trials involving 2599 randomised participants. We included participants of either gender, aged from the first year of life through to 55 years (only six studies assessed adults), who had mild to severe eczema. Trials were undertaken in primary and secondary healthcare settings, mainly in Europe or Asia. Duration of treatment ranged from four weeks to six months, and duration of follow‐up after end of treatment ranged from zero to 36 months. We selected no standard dose: researchers used a variety of doses and concentrations of probiotics. The probiotics used were bacteria of the Lactobacillus and Bifidobacteria species, which were taken alone or combined with other probiotics, and were given with or without prebiotics. Comparators were no treatment, placebo, and other treatments with no probiotics.
For all results described in this , the comparator was no probiotics. Active treatment ranged from six weeks to three months for all of the following results, apart from the investigator‐rated eczema severity outcome, for which the upper limit of active treatment was 16 weeks. With regard to score, the higher the score, the more severe were the symptoms. All key results reported in this were measured at the end of active treatment, except for adverse events, which were measured during the active treatment period.
Probiotics probably make little or no difference in participant‐ or parent‐rated symptoms of eczema (13 trials; 754 participants): symptom severity on a scale from 0 to 20 was 0.44 points lower after probiotic treatment (95% confidence interval (CI) ‐1.22 to 0.33; moderate‐quality evidence). Trial sequential analysis shows that target sample sizes of 258 and 456, which are necessary to demonstrate a minimum mean difference of ‐2 and ‐1.5, respectively, with 90% power, have been exceeded, suggesting that further trials with similar probiotic strains for this outcome at the end of active treatment may be futile.
We found no evidence suggesting that probiotics make a difference in QoL for patients with eczema (six studies; 552 participants; standardised mean difference (SMD) 0.03, 95% CI ‐0.36 to 0.42; low‐quality evidence) when measured by the participant or the parent using validated disease‐specific QoL instruments.
Probiotics may slightly reduce investigator‐rated eczema severity scores (24 trials; 1596 participants). On a scale of 0 to 103 for total Severity Scoring of Atopic Dermatitis (SCORAD), a score combining investigator‐rated eczema severity score and participant scoring for eczema symptoms of itch and sleep loss was 3.91 points lower after probiotic treatment than after no probiotic treatment (95% CI ‐5.86 to ‐1.96; low‐quality evidence). The minimum clinically important difference for SCORAD has been estimated to be 8.7 points.
We noted significant to extreme levels of unexplainable heterogeneity between the results of individual studies. We judged most studies to be at unclear risk of bias; six studies had high attrition bias, and nine were at low risk of bias overall.
We found no evidence to show that probiotics make a difference in the risk of adverse events during active treatment (risk ratio (RR) 1.54, 95% CI 0.90 to 2.63; seven trials; 402 participants; low‐quality evidence). Studies in our review that reported adverse effects described gastrointestinal symptoms.
Authors' conclusions
Evidence suggests that, compared with no probiotic, currently available probiotic strains probably make little or no difference in improving patient‐rated eczema symptoms. Probiotics may make little or no difference in QoL for people with eczema nor in investigator‐rated eczema severity score (combined with participant scoring for eczema symptoms of itch and sleep loss); for the latter, the observed effect was small and of uncertain clinical significance. Therefore, use of probiotics for the treatment of eczema is currently not evidence‐based. This update found no evidence of increased adverse effects with probiotic use during studies, but a separate adverse events search from the first review revealed that probiotic treatment carries a small risk of adverse events.
Results show significant, unexplainable heterogeneity between individual trial results. Only a small number of studies measured some outcomes.
Future studies should better measure QoL scores and adverse events, and should report on new probiotics. Researchers should also consider studying subgroups of patients (e.g. patients with atopy or food allergies, adults) and standardising doses/concentrations of probiotics given.
Abstract
Of the more than 3000 radio pulsars currently known, only ∼300 are in binary systems, and only five of these consist of young pulsars with massive nondegenerate companions. We present the ...discovery and initial timing, accomplished using the Canadian Hydrogen Intensity Mapping Experiment (CHIME) telescope, of the sixth such binary pulsar, PSR J2108+4516, a 0.577 s radio pulsar in a 269 day orbit of eccentricity 0.09 with a companion of minimum mass 11
M
⊙
. Notably, the pulsar undergoes periods of substantial eclipse, disappearing from the CHIME 400–800 MHz observing band for a large fraction of its orbit, and displays significant dispersion measure and scattering variations throughout its orbit, pointing to the possibility of a circumstellar disk or very dense stellar wind associated with the companion star. Subarcsecond resolution imaging with the Karl G. Jansky Very Large Array unambiguously demonstrates that the companion is a bright,
V
≃ 11 OBe star, EM* UHA 138, located at a distance of 3.26(14) kpc. Archival optical observations of EM* UHA 138 approximately suggest a companion mass ranging from 17.5
M
⊙
<
M
c
< 23
M
⊙
, in turn constraining the orbital inclination angle to 50.°3 ≲
i
≲ 58.°3. With further multiwavelength follow-up, PSR J2108+4516 promises to serve as another rare laboratory for the exploration of companion winds, circumstellar disks, and short-term evolution through extended-body orbital dynamics.
C-reactive protein (CRP) is a non-specific biomarker of inflammation. Recent research has shown that inflammation is an important step in the genesis of atherosclerosis, and is involved in the ...development of unstable plaques. Measurement of serum levels of CRP using a high sensitivity assay (hsCRP) can demonstrate subclinical inflammatory states, which may reflect vascular inflammation. Clinical studies have shown that elevated hsCRP levels in healthy populations predict vascular events such as myocardial infarction (MI) and stroke as well as the development of diabetes. In patients with acute coronary syndromes, higher hsCRP levels are associated with adverse outcomes and subsequent vascular events. There is data to suggest that aspirin, angiotensin converting enzyme (ACE) inhibitors and HMG Co-A reductase inhibitors (statins), which all reduce vascular event rates, also reduce serum levels of hsCRP and therefore hsCRP levels may potentially guide therapy. As well as having a critical role in risk prediction, recent evidence has emerged implicating CRP directly in atherogenesis. CRP has been found in human atherosclerotic plaque and CRP has been shown to cause endothelial cell dysfunction, oxidant stress and intimal hypertrophy in experimental models. We review the postulated roles of CRP in atherogenesis and prediction of vascular events, as well as discussing current recommendations for CRP testing in patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
The Canadian Hydrogen Intensity Mapping Experiment (CHIME) has emerged as the prime telescope for detecting fast radio bursts (FRBs). CHIME/FRB Outriggers will be a dedicated ...very-long-baseline interferometry (VLBI) instrument consisting of outrigger telescopes at continental baselines working with CHIME and its specialized real-time transient-search backend (CHIME/FRB) to detect and localize FRBs with 50 mas precision. In this paper, we present a minimally invasive clock stabilization system that effectively transfers the CHIME digital backend reference clock from its original GPS-disciplined ovenized crystal oscillator to a passive hydrogen maser. This enables us to combine the long-term stability and absolute time tagging of the GPS clock with the short- and intermediate-term stability of the maser to reduce the clock timing errors between VLBI calibration observations. We validate the system with VLBI-style observations of Cygnus A over a 400 m baseline between CHIME and the CHIME Pathfinder, demonstrating agreement between sky-based and maser-based timing measurements at the 30 ps rms level on timescales ranging from one minute to up to nine days, and meeting the stability requirements for CHIME/FRB Outriggers. In addition, we present an alternate reference clock solution for outrigger stations that lack the infrastructure to support a passive hydrogen maser.
Guidelines for treatment of onychomycosis Roberts, D.T.; Taylor, W.D.; Boyle, J.
British journal of dermatology (1951),
03/2003, Volume:
148, Issue:
3
Journal Article
Peer reviewed
Summary These guidelines for management of onychomycosis have been prepared for dermatologists on behalf of the British Association of Dermatologists. They present evidence‐based guidance for ...treatment, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of epidemiological aspects, diagnosis and investigation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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