Competition and collusion in the British railway track fittings industry : the case of the Anderston Foundry, 1800-1960.

In 2 volsAvailable from British Library Document Supply Centre- DSC:D98378 / BLDSC - British Library Document Supply CentreSIGLEGBUnited Kingdo

The identification and psychological treatment of panic disorder in adolescents: a survey of CAMHS clinicians

Background Panic disorder is experienced by around 1% of adolescents, and has a significant impact on social and academic functioning. Preliminary evidence supports the effectiveness of panic disorder specific treatment in adolescents with panic disorder, however panic disorder may be overlooked in adolescents due to overlapping symptoms with other anxiety disorders and other difficulties being more noticeable to others. The aim of this study was to establish what training National Health Service (NHS) Child and Adolescent Mental Health Services (CAMHS) clinicians have received in psychological therapies and panic disorder and how they identify and treat panic disorder in adolescents. Method CAMHS clinicians from a range of professions (n = 427), who were delivering psychological treatments to children and adolescents with anxiety disorders, participated. They completed a cross-sectional, online survey, including a vignette describing an adolescent with panic disorder, and were asked to identify the main diagnosis or presenting problem. Results Less than half the clinicians (48.6%) identified panic disorder or panic symptoms as the main presenting problem from the vignette. The majority of clinicians suggested CBT would be their treatment approach. However, few identified an evidence-based treatment protocol for working with young people with panic disorder. Almost half the sample had received no training in cognitive behaviour therapy (CBT) and around a fifth had received no training in delivering psychological treatments. Conclusions Only half of CAMHS clinicians identified panic disorder from a vignette and although CBT treatments are widely offered, only a minority of adolescents with panic disorder are receiving treatments developed for, and evaluated with young people with panic disorder. There is a vital need for clinician training, the use of tools that aid identification and the implementation of evidence-based treatments within CAMHS

Dabrafenib, alone or in combination with trametinib, in BRAF V600–mutated pediatric Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a rare, heterogenous, neoplastic disorder primarily affecting children. BRAF mutations have been reported in >50% of patients with LCH. The selective BRAF inhibitor, dabrafenib, in combination with the MEK1/2 inhibitor, trametinib, has been approved in select BRAF V600–mutant solid tumors. Two open-label phase 1/2 studies were conducted in pediatric patients with BRAF V600–mutant, recurrent/refractory malignancies treated with dabrafenib monotherapy (CDRB436A2102; NCT01677741) or dabrafenib plus trametinib (CTMT212X2101; NCT02124772). The primary objectives of both studies were to determine safe and tolerable doses that achieve similar exposure to the approved doses for adults. Secondary objectives included safety, tolerability, and preliminary antitumor activity. Thirteen and 12 patients with BRAF V600–mutant LCH received dabrafenib monotherapy and in combination with trametinib, respectively. Investigator-assessed objective response rates per Histiocyte Society criteria were 76.9% (95% confidence interval [CI], 46.2-95.0) and 58.3% (95% CI, 27.7-84.8) in the monotherapy and combination studies, respectively. More than 90% of responses were ongoing at study completion. The most common treatment-related adverse events (AEs) were vomiting and increased blood creatinine with monotherapy and pyrexia, diarrhea, dry skin, decreased neutrophil count, and vomiting with combination therapy. Two patients each discontinued treatment with monotherapy and combination therapy because of AEs. Overall, dabrafenib monotherapy or in combination with trametinib demonstrated clinical efficacy and manageable toxicity in relapsed/refractory BRAF V600–mutant pediatric LCH, with most responses ongoing. Safety was consistent with that reported in other pediatric and adult conditions treated with dabrafenib plus trametinib

Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600–Mutant Low-Grade Glioma

PURPOSE: BRAF V600 mutations occur in many childhood cancers, including approximately 20% of low-grade gliomas (LGGs). Here, we describe a phase I/II study establishing pediatric dosing and pharmacokinetics of trametinib with or without dabrafenib, as well as efficacy and safety in a disease-specific cohort with BRAF V600–mutant LGG; other cohorts will be reported elsewhere. METHODS: This is a four-part, phase I/II study (ClinicalTrials.gov identifier: NCT02124772 ) in patients age < 18 years with relapsed/refractory malignancies: trametinib monotherapy dose finding (part A) and disease-specific expansion (part B), and dabrafenib + trametinib dose finding (part C) and disease-specific expansion (part D). The primary objective assessed in all patients in parts A and C was to determine pediatric dosing on the basis of steady-state pharmacokinetics. Disease-specific efficacy and safety (across parts A-D) were secondary objectives. RESULTS: Overall, 139 patients received trametinib (n = 91) or dabrafenib + trametinib (n = 48). Trametinib dose-limiting toxicities in > 1 patient (part A) included mucosal inflammation (n = 3) and hyponatremia (n = 2). There were no dose-limiting toxicities with combination therapy (part C). The recommended phase II dose of trametinib, with or without dabrafenib, was 0.032 mg/kg once daily for patients age < 6 years and 0.025 mg/kg once daily for patients age ≥ 6 years; dabrafenib dosing in the combination was as previously identified for monotherapy. In 49 patients with BRAF V600–mutant glioma (LGG, n = 47) across all four study parts, independently assessed objective response rates were 15% (95% CI, 1.9 to 45.4) for monotherapy (n = 13) and 25% (95% CI, 12.1 to 42.2) for combination (n = 36). Adverse event–related treatment discontinuations were more common with monotherapy (54% v 22%). CONCLUSION: The trial design provided efficient evaluation of pediatric dosing, safety, and efficacy of single-agent and combination targeted therapy. Age-based and weight-based dosing of trametinib with or without dabrafenib achieved target concentrations with manageable safety and demonstrated clinical efficacy and tolerability in BRAF V600–mutant LGG

A Bright Submillimeter Source in the Bullet Cluster (1E0657--56) Field Detected with BLAST

We present the 250, 350, and 500 micron detection of bright submillimeter emission in the direction of the Bullet Cluster measured by the Balloon-borne Large Aperture Submillimeter Telescope (BLAST). The 500 micron centroid is coincident with an AzTEC 1.1 mm point-source detection at a position close to the peak lensing magnification produced by the cluster. However, the 250 micron and 350 micron centroids are elongated and shifted toward the south with a differential shift between bands that cannot be explained by pointing uncertainties. We therefore conclude that the BLAST detection is likely contaminated by emission from foreground galaxies associated with the Bullet Cluster. The submillimeter redshift estimate based on 250-1100 micron photometry at the position of the AzTEC source is z_phot = 2.9 (+0.6 -0.3), consistent with the infrared color redshift estimation of the most likely IRAC counterpart. These flux densities indicate an apparent far-infrared luminosity of L_FIR = 2E13 Lsun. When the amplification due to the gravitational lensing of the cluster is removed, the intrinsic far-infrared luminosity of the source is found to be L_FIR <= 10^12 Lsun, consistent with typical luminous infrared galaxies.Comment: Accepted for publication in the Astrophysical Journal. Maps are available at http://blastexperiment.info

Over half of the far-infrared background light comes from galaxies at z >= 1.2

Submillimetre surveys during the past decade have discovered a population of luminous, high-redshift, dusty starburst galaxies. In the redshift range 1 <= z <= 4, these massive submillimetre galaxies go through a phase characterized by optically obscured star formation at rates several hundred times that in the local Universe. Half of the starlight from this highly energetic process is absorbed and thermally re-radiated by clouds of dust at temperatures near 30 K with spectral energy distributions peaking at 100 microns in the rest frame. At 1 <= z <= 4, the peak is redshifted to wavelengths between 200 and 500 microns. The cumulative effect of these galaxies is to yield extragalactic optical and far-infrared backgrounds with approximately equal energy densities. Since the initial detection of the far-infrared background (FIRB), higher-resolution experiments have sought to decompose this integrated radiation into the contributions from individual galaxies. Here we report the results of an extragalactic survey at 250, 350 and 500 microns. Combining our results at 500 microns with those at 24 microns, we determine that all of the FIRB comes from individual galaxies, with galaxies at z >= 1.2 accounting for 70 per cent of it. As expected, at the longest wavelengths the signal is dominated by ultraluminous galaxies at z > 1.Comment: Accepted to Nature. Maps available at http://blastexperiment.info