Empirically supported psychological treatments have been developed for a range of psychiatric disorders but there is evidence that patients are not receiving them in routine clinical care. ...Furthermore, even when patients do receive these treatments there is evidence that they are often not well delivered. The aim of this paper is to identify the barriers to the dissemination of evidence-based psychological treatments and then propose ways of overcoming them, hence potentially bridging the gap between research findings and clinical practice.
We made new estimates of the Galactic escape speed at various Galactocentric radii using the latest data release of the RAdial Velocity Experiment (RAVE DR4). Compared to previous studies we have a ...database that is larger by a factor of 10, as well as reliable distance estimates for almost all stars. Our analysis is based on statistical analysis of a rigorously selected sample of 90 high-velocity halo stars from RAVE and a previously published data set. We calibrated and extensively tested our method using a suite of cosmological simulations of the formation of Milky Way-sized galaxies. Our best estimate of the local Galactic escape speed, which we define as the minimum speed required to reach three virial radii R340, is 533+54-41 km s-1 (90% confidence), with an additional 4% systematic uncertainty, where R340 is the Galactocentric radius encompassing a mean overdensity of 340 times the critical density for closure in the Universe. From the escape speed we further derived estimates of the mass of the Galaxy using a simple mass model with two options for the mass profile of the dark matter halo: an unaltered and an adiabatically contracted Navarro, Frenk & White (NFW) sphere. If we fix the local circular velocity, the latter profile yields a significantly higher mass than the uncontracted halo, but if we instead use the statistics for halo concentration parameters in large cosmological simulations as a constraint, we find very similar masses for both models. Our best estimate for M340, the mass interiorto R340 (dark matter and baryons), is 1.3+0.4-0.3 × 1012 M⊙ (corresponds to M200 = 1.6+0.5-0.4 × 1012 M⊙). This estimate is in good agreement with recently published, independent mass estimates based on the kinematics of more distant halo stars and the satellite galaxy Leo I.
We present the stellar atmospheric parameters (effective temperature, surface gravity, overall metallicity), radial velocities, individual abundances, and distances determined for 425,561 stars, ...which constitute the fourth public data release of the RAdial Velocity Experiment (RAVE). The stellar atmospheric parameters are computed using a new pipeline, based on the algorithms of MATISSE and DEGAS. The spectral degeneracies and the Two Micron All Sky Survey photometric information are now better taken into consideration, improving the parameter determination compared to the previous RAVE data releases. The individual abundances for six elements (magnesium, aluminum, silicon, titanium, iron, and nickel) are also given, based on a special-purpose pipeline that is also improved compared to that available for the RAVE DR3 and Chemical DR1 data releases. Together with photometric information and proper motions, these data can be retrieved from the RAVE collaboration Web site and the Vizier database.
The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of a variety of mood and cognitive disorders. Neuroendocrine studies have demonstrated HPA axis overactivity ...in major depression, a relationship of HPA axis activity to cognitive performance and a potential role of HPA axis genetic variation in cognition. The present study investigated the simultaneous roles HPA axis activity, clinical symptomatology and HPA genetic variation play in cognitive performance. Patients with major depression with psychotic major depression (PMD) and with nonpsychotic major depression (NPMD) and healthy controls (HC) were studied. All participants underwent a diagnostic interview and psychiatric ratings, a comprehensive neuropsychological battery, overnight hourly blood sampling for cortisol and genetic assessment. Cognitive performance differed as a function of depression subtype. Across all subjects, cognitive performance was negatively correlated with higher cortisol, and PMD patients had higher cortisol than did NPMDs and HCs. Cortisol, clinical symptoms and variation in genes, NR3C1 (glucocorticoid receptor; GR) and NR3C2 (mineralocorticoid receptor; MR) that encode for GRs and MRs, predicted cognitive performance. Beyond the effects of cortisol, demographics and clinical symptoms, NR3C1 variation predicted attention and working memory, whereas NR3C2 polymorphisms predicted memory performance. These findings parallel the distribution of GR and MR in primate brain and their putative roles in specific cognitive tasks. HPA axis genetic variation and activity were important predictors of cognition across the entire sample of depressed subjects and HR. GR and MR genetic variation predicted unique cognitive functions, beyond the influence of cortisol and clinical symptoms. GR genetic variation was implicated in attention and working memory, whereas MR was implicated in verbal memory.
Dopaminergic cell loss due to the accumulation of α-syn is a core feature of the pathogenesis of Parkinson disease. Neuroinflammation specifically induced by α-synuclein has been shown to exacerbate ...neurodegeneration, yet the role of central nervous system (CNS) resident macrophages in this process remains unclear. We found that a specific subset of CNS resident macrophages, border-associated macrophages (BAMs), play an essential role in mediating α-synuclein related neuroinflammation due to their unique role as the antigen presenting cells necessary to initiate a CD4 T cell response whereas the loss of MHCII antigen presentation on microglia had no effect on neuroinflammation. Furthermore, α-synuclein expression led to an expansion in border-associated macrophage numbers and a unique damage-associated activation state. Through a combinatorial approach of single-cell RNA sequencing and depletion experiments, we found that border-associated macrophages played an essential role in immune cell recruitment, infiltration, and antigen presentation. Furthermore, border-associated macrophages were identified in post-mortem PD brain in close proximity to T cells. These results point to a role for border-associated macrophages in mediating the pathogenesis of Parkinson disease through their role in the orchestration of the α-synuclein-mediated neuroinflammatory response.
Abstract
We present a study of the low-frequency radio properties of star-forming (SF) galaxies and active galactic nuclei (AGNs) up to redshift z = 2.5. The new spectral window probed by the Low ...Frequency Array (LOFAR) allows us to reconstruct the radio continuum emission from 150 MHz to 1.4 GHz to an unprecedented depth for a radio-selected sample of 1542 galaxies in ∼ 7 deg2 of the LOFAR Boötes field. Using the extensive multiwavelength data set available in Boötes and detailed modelling of the far-infrared to ultraviolet spectral energy distribution (SED), we are able to separate the star formation (N = 758) and the AGN (N = 784) dominated populations. We study the shape of the radio SEDs and their evolution across cosmic time and find significant differences in the spectral curvature between the SF galaxy and AGN populations. While the radio spectra of SF galaxies exhibit a weak but statistically significant flattening, AGN SEDs show a clear trend to become steeper towards lower frequencies. No evolution of the spectral curvature as a function of redshift is found for SF galaxies or AGNs. We investigate the redshift evolution of the infrared–radio correlation for SF galaxies and find that the ratio of total infrared to 1.4-GHz radio luminosities decreases with increasing redshift: q
1.4 GHz = (2.45 ± 0.04) (1 + z)−0.15 ± 0.03. Similarly, q
150 MHz shows a redshift evolution following q
150 GHz = (1.72 ± 0.04) (1 + z)−0.22 ± 0.05. Calibration of the 150 MHz radio luminosity as a star formation rate tracer suggests that a single power-law extrapolation from q
1.4 GHz is not an accurate approximation at all redshifts.
We have carried out the largest randomised trial to date of newly diagnosed myeloma patients, in which lenalidomide has been used as an induction and maintenance treatment option and here report its ...impact on second primary malignancy (SPM) incidence and pathology. After review, 104 SPMs were confirmed in 96 of 2732 trial patients. The cumulative incidence of SPM was 0.7% (95% confidence interval (CI) 0.4-1.0%), 2.3% (95% CI 1.6-2.7%) and 3.8% (95% CI 2.9-4.6%) at 1, 2 and 3 years, respectively. Patients receiving maintenance lenalidomide had a significantly higher SPM incidence overall (P=0.011). Age is a risk factor with the highest SPM incidence observed in transplant non-eligible patients aged >74 years receiving lenalidomide maintenance. The 3-year cumulative incidence in this group was 17.3% (95% CI 8.2-26.4%), compared with 6.5% (95% CI 0.2-12.9%) in observation only patients (P=0.049). There was a low overall incidence of haematological SPM (0.5%). The higher SPM incidence in patients receiving lenalidomide maintenance therapy, especially in advanced age, warrants ongoing monitoring although the benefit on survival is likely to outweigh risk.
Allergic rhinoconjunctivitis (AR) is an allergic disorder of the nose and eyes affecting about a fifth of the general population. Symptoms of AR can be controlled with allergen avoidance measures and ...pharmacotherapy. However, many patients continue to have ongoing symptoms and an impaired quality of life; pharmacotherapy may also induce some side‐effects. Allergen immunotherapy (AIT) represents the only currently available treatment that targets the underlying pathophysiology, and it may have a disease‐modifying effect. Either the subcutaneous (SCIT) or sublingual (SLIT) routes may be used. This Guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on AIT for AR and is part of the EAACI presidential project “EAACI Guidelines on Allergen Immunotherapy.” It aims to provide evidence‐based clinical recommendations and has been informed by a formal systematic review and meta‐analysis. Its generation has followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included involvement of the full range of stakeholders. In general, broad evidence for the clinical efficacy of AIT for AR exists but a product‐specific evaluation of evidence is recommended. In general, SCIT and SLIT are recommended for both seasonal and perennial AR for its short‐term benefit. The strongest evidence for long‐term benefit is documented for grass AIT (especially for the grass tablets) where long‐term benefit is seen. To achieve long‐term efficacy, it is recommended that a minimum of 3 years of therapy is used. Many gaps in the evidence base exist, particularly around long‐term benefit and use in children.
Cellular lipid requirements are achieved through a combination of biosynthesis and import programs. Using isotope tracer analysis, we show that type I interferon (IFN) signaling shifts the balance of ...these programs by decreasing synthesis and increasing import of cholesterol and long chain fatty acids. Genetically enforcing this metabolic shift in macrophages is sufficient to render mice resistant to viral challenge, demonstrating the importance of reprogramming the balance of these two metabolic pathways in vivo. Unexpectedly, mechanistic studies reveal that limiting flux through the cholesterol biosynthetic pathway spontaneously engages a type I IFN response in a STING-dependent manner. The upregulation of type I IFNs was traced to a decrease in the pool size of synthesized cholesterol and could be inhibited by replenishing cells with free cholesterol. Taken together, these studies delineate a metabolic-inflammatory circuit that links perturbations in cholesterol biosynthesis with activation of innate immunity.
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•Identification of a cholesterol metabolism-type I interferon (IFN) inflammatory circuit•Type I interferon reprograms cholesterol homeostasis•Perturbing cholesterol synthesis engages type I IFN signaling•STING/TBK1 links cholesterol metabolism with type I interferon pathway
Cholesterol metabolism and type I interferon response are co-regulated in macrophages, creating an immuno-metabolic circuit that allows innate immune cells to coordinate metabolism changes with immune activation required for antiviral responses.
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