We have obtained deep Sunyaev-Zel'dovich (SZ) observations towards 15 of the hottest XMM Cluster Survey (XCS) clusters that can be observed with the Arcminute Microkelvin Imager (AMI). We use a ...Bayesian analysis to quantify the significance of our SZ detections. We detect the SZ effect at high significance towards three of the clusters and at lower significance for a further two clusters. Towards the remaining 10 clusters, no clear SZ signal was measured. We derive cluster parameters using the XCS mass estimates as a prior in our Bayesian analysis. For all AMI-detected clusters, we calculate large-scale mass and temperature estimates while for all undetected clusters we determine upper limits on these parameters. We find that the large-scale mean temperatures derived from our AMI SZ measurements (and the upper limits from null detections) are substantially lower than the XCS-based core-temperature estimates. For clusters detected in the SZ, the mean temperature is, on average, a factor of 1.4 lower than temperatures from the XCS. Our upper limits on the cluster temperature of undetected systems are lower than the mean XCS derived temperature.
Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. ...The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs found in all tumor regions (ubiquitous) and those present in a subset of regions (regional). The number of ubiquitous and regional TCRs correlates with the number of ubiquitous and regional nonsynonymous mutations, respectively. Expanded TCRs form part of clusters of TCRs of similar sequence, suggestive of a spatially constrained antigen-driven process. CD8
tumor-infiltrating lymphocytes harboring ubiquitous TCRs display a dysfunctional tissue-resident phenotype. Ubiquitous TCRs are preferentially detected in the blood at the time of tumor resection as compared to routine follow-up. These findings highlight a noninvasive method to identify and track relevant tumor-reactive TCRs for use in adoptive T cell immunotherapy.
New Findings
What is the central question of this study?
Gonadal hormones modulate cerebrovascular function while insulin‐like growth factor 1 (IGF‐1) facilitates exercise‐mediated cerebral ...angiogenesis; puberty is a critical period of neurodevelopment alongside elevated gonadal hormone and IGF‐1 activity: but whether exercise training across puberty enhances cerebrovascular function is unkown.
What is the main finding and its importance?
Cerebral blood flow is elevated in endurance trained adolescent males when compared to untrained counterparts. However, cerebrovascular reactivity to hypercapnia is faster in trained vs. untrained children, but not adolescents. Exercise‐induced improvements in cerebrovascular function are attainable as early as the first decade of life.
Global cerebral blood flow (gCBF) and cerebrovascular reactivity to hypercapnia (CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}$) are modulated by gonadal hormone activity, while insulin‐like growth factor 1 facilitates exercise‐mediated cerebral angiogenesis in adults. Whether critical periods of heightened hormonal and neural development during puberty represent an opportunity to further enhance gCBF and CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}$ is currently unknown. Therefore, we used duplex ultrasound to assess gCBF and CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}$ in n = 128 adolescents characterised as endurance‐exercise trained (males: n = 30, females: n = 36) or untrained (males: n = 29, females: n = 33). Participants were further categorised as pre‐ (males: n = 35, females: n = 33) or post‐ (males: n = 24, females: n = 36) peak height velocity (PHV) to determine pubertal or ‘maturity’ status. Three‐factor ANOVA was used to identify main and interaction effects of maturity status, biological sex and training status on gCBF and CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}$. Data are reported as group means (SD). Pre‐PHV youth demonstrated elevated gCBF and slower CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}$ mean response times than post‐PHV counterparts (both: P ≤ 0.001). gCBF was only elevated in post‐PHV trained males when compared to untrained counterparts (634 (43) vs. 578 (46) ml min−1; P = 0.007). However, CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}$ mean response time was faster in pre‐ (72 (20) vs. 95 (29) s; P ≤ 0.001), but not post‐PHV (P = 0.721) trained youth when compared to untrained counterparts. Cardiorespiratory fitness was associated with gCBF in post‐PHV youth (r2 = 0.19; P ≤ 0.001) and CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}$ mean response time in pre‐PHV youth (r2 = 0.13; P = 0.014). Higher cardiorespiratory fitness during adolescence can elevate gCBF while exercise training during childhood primes the development of cerebrovascular function, highlighting the importance of exercise training during the early stages of life in shaping the cerebrovascular phenotype.
Abstract Objective Recent studies have demonstrated improved outcomes in patients receiving early surgery for degenerative mitral regurgitation (MR) rather than adhering to conventional guidelines ...for surgical intervention. However, studies providing a mechanistic basis for these findings are limited. Methods Left ventricular (LV) myocardium from 22 patients undergoing mitral valve repair for American Heart Association class I indications was evaluated for desmin, the voltage-dependent anion channel, α-B-crystallin, and α, β-unsaturated aldehyde 4-hydroxynonenal by fluorescence microscopy. The same was evaluated in 6 normal control LV autopsy specimens. Cardiomyocyte ultrastructure was examined by transmission electron microscopy. Magnetic resonance imaging with tissue tagging was performed in 55 normal subjects and 22 MR patients before and 6 months after mitral valve repair. Results LV end-diastolic volume was 1.5-fold ( P < .0001) higher and LV mass-to-volume ratio was lower in MR ( P = .004) hearts versus normal hearts and showed improvement 6 months after mitral valve surgery. However, LV ejection fraction decreased from 65% ± 7% to 52% ± 9% ( P < .0001) and LV circumferential ( P < .0001) and longitudinal strain decreased significantly below normal values ( P = .002) after surgery. Hearts with MR had a 53% decrease in desmin ( P < .0001) and a 2.6-fold increase in desmin aggregates ( P < .0001) versus normal, along with substantial, intense perinuclear staining of α, β-unsaturated aldehyde 4-hydroxynonenal in areas of mitochondrial breakdown and clustering. Transmission electron microscopy demonstrated numerous electron-dense deposits, myofibrillar loss, Z-disc abnormalities, and extensive granulofilamentous debris identified as desmin-positive by immunogold transmission electron microscopy. Conclusions Despite well-preserved preoperative LV ejection fraction, severe oxidative stress and disruption of cardiomyocyte desmin-mitochondrial sarcomeric architecture may explain postoperative LV functional decline and further supports the move toward earlier surgical intervention.
Quasi-periodic signals have yielded important constraints on the masses of black holes in galactic X-ray binaries, and here we extend this to active galactic nuclei (AGNs). We employ a wavelet ...technique to analyze 19 observations of 10 AGNs obtained with the XMM-Newton EPIC pn camera. We report the detection of a candidate 3.3 ks quasi period in 3C 273. If this period represents an orbital timescale originating near a last stable orbit of 3R sub(s), it implies a central black hole mass of image M sub(image). For a maximally rotating black hole with a last stable orbit of 0.6image, a central black hole mass of image M sub(image) is implied. Both of these estimates are substantially lower than previous reverberation-mapping results, which place the central black hole mass of 3C 273 at about image M sub(image). Assuming that this reverberation mass is correct, the X-ray quasi period would be caused by a higher order oscillatory mode of the accretion disk.
We have previously reported primary endpoints of a clinical trial testing two vaccine platforms for the delivery of
malaria DBPRII: viral vectors (ChAd63, MVA), and protein/adjuvant (PvDBPII with ...50µg Matrix-M™ adjuvant). Delayed boosting was necessitated due to trial halts during the pandemic and provides an opportunity to investigate the impact of dosing regimens. Here, using flow cytometry - including agnostic definition of B cell populations with the clustering tool CITRUS - we report enhanced induction of DBPRII-specific plasma cell and memory B cell responses in protein/adjuvant versus viral vector vaccinees. Within protein/adjuvant groups, delayed boosting further improved B cell immunogenicity compared to a monthly boosting regimen. Consistent with this, delayed boosting also drove more durable anti-DBPRII serum IgG. In an independent vaccine clinical trial with the
malaria RH5.1 protein/adjuvant (50µg Matrix-M™) vaccine candidate, we similarly observed enhanced circulating B cell responses in vaccinees receiving a delayed final booster. Notably, a higher frequency of vaccine-specific (putatively long-lived) plasma cells was detected in the bone marrow of these delayed boosting vaccinees by ELISPOT and correlated strongly with serum IgG. Finally, following controlled human malaria infection with
parasites in the DBPRII trial,
growth inhibition was observed to correlate with DBPRII-specific B cell and serum IgG responses. In contrast, the CD4+ and CD8+ T cell responses were impacted by vaccine platform but not dosing regimen and did not correlate with
growth inhibition in a challenge model. Taken together, our DBPRII and RH5 data suggest an opportunity for protein/adjuvant dosing regimen optimisation in the context of rational vaccine development against pathogens where protection is antibody-mediated.
Summary
This review forms part of a series of annual updates that summarize the evidence base for atopic eczema (AE), providing a succinct guide for clinicians and patients. It provides a summary of ...key findings from 15 systematic reviews that were published during 2015, and focuses on the epidemiology and methodology issues of AE. For systematic reviews on the prevention and treatment of AE, see Part 2 of this update. The worldwide prevalence of AE during childhood has been calculated to be 7.89% (95% CI 7.88–7.89), based on studies of 1 430 329 children from 102 countries. Children with AE are four times more likely than controls to have allergic rhinitis and asthma relative risk (RR) = 4.24, 95% CI 3.75–4.79. Twin studies show the heritability of AE to be about 75%. AE is more prevalent in patients with vitiligo and alopecia, and is positively associated with a high body mass index in America and Asia but not in Europe. Possible relationships between AE and exercise, maternal folate supplementation, maternal stress and autism spectrum disorder (ASD) have been assessed, but more high‐quality studies are needed for definitive conclusions. The Harmonising Outcomes Measures for Eczema (HOME) Initiative is developing a core set of outcome measures for AE trials. Suitable instruments for measuring quality of life are yet to be agreed, and use of Investigator Global Assessment in trials requires standardization. Transparent reporting of AE trials remains problematic.
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National Audit Data highlight persistent sub‐optimum control among increasing numbers of people living with diabetes, with severe consequences for the individual and the NHS. The aim of the present ...review was to introduce a new cohesive, holistic model of care, tailored to individual needs to support optimum diabetes outcomes. This model of diabetes is necessary in order to understand the driving forces behind behaviour and their impact on diabetes management. Feelings (an emotional state or reaction) and beliefs (an acceptance that something is true or real) are fundamental behavioural drivers and influence diabetes self‐management choices. Individually, these explain some of the complexities of behaviour and, collectively, they impact on personal motivation (rationale/desire to act) to achieve a specific outcome. Inevitably, they independently affect diabetes self‐management and the environment in which individuals live. A model of care that proposes the encompassing of environment, intrinsic thought and therapy regimens to provide tailored, personalized healthcare should support enhanced diabetes self‐management and outcomes from diagnosis. The Kaleidoscope model of care could be deliverable in routine care, incorporating each of the influences on diabetes self‐management, and should benefit both individuals with diabetes and healthcare professionals.
What's new?
The Kaleidoscope model of care presents a novel, holistic, tailored and individualized approach to healthcare delivery for people with diabetes through an assessment of an individual's current regimen, barriers and motivation and available support resources.
The model promotes the specific needs of individuals with diabetes.
These needs are dynamic, taking a different shape at different points in time, recognizing and adapting to the range of care needed.
It is a flexible model that can be applied in different healthcare settings.
We have assembled a large sample of virialized systems, comprising 66 galaxy clusters, groups and elliptical galaxies with high-quality X-ray data.To each system we have fitted analytical profiles ...describing the gas density and temperature variation with radius, corrected for the effects of central gas cooling.We present an analysis of the scaling properties of these systems and focus in this paper on the gas distribution and M—TX relation.In addition to clusters and groups, our sample includes two early-type galaxies, carefully selected to avoid contamination from group or cluster X-ray emission.We compare the properties of these objects with those of more massive systems and find evidence for a systematic difference between galaxy-sized haloes and groups of a similar temperature. We derive a mean logarithmic slope of the M—TX relation within R200 of 1.84 ± 0.06, although there is some evidence of a gradual steepening in the M—TX relation, with decreasing mass.We recover a similar slope using two additional methods of calculating the mean temperature.Repeating the analysis with the assumption of isothermality, we find the slope changes only slightly, to 1.89 ± 0.04, but the normalization is increased by 30 per cent.Correspondingly, the mean gas fraction within R200 changes from (0.13 ± 0.01) h−3/270 to (0.11 ± 0.01) h−3/270, for the isothermal case, with the smaller fractional change reflecting different behaviour between hot and cool systems.There is a strong correlation between the gas fraction within 0.3R200 and temperature.This reflects the strong (5.8σ) trend between the gas density slope parameter, β, and temperature, which has been found in previous work. These findings are interpreted as evidence for self-similarity breaking from galaxy feedback processes, active galactic nuclei heating or possibly gas cooling.We discuss the implications of our results in the context of a hierarchical structure formation scenario.
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