The effect of five years versus two years of specialised assertive intervention for first episode psychosis - OPUS II: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>The Danish OPUS I trial randomized 547 patients with first-episode psychosis to a two-year early-specialised assertive treatment programme (OPUS) versus standard treatment. The two years OPUS treatment had significant positive effects on psychotic and negative symptoms, secondary substance abuse, treatment adherence, lower dosage of antipsychotic medication, and a higher treatment satisfaction. However, three years after end of the OPUS treatment, the positive clinical effects were not sustained, except that OPUS-treated patients were significantly less likely to be institutionalised compared with standard-treated patients. The major objective of the OPUS II trial is to evaluate the effects of five years of OPUS treatment versus two years of OPUS treatment.</p> <p>Methods</p> <p>The OPUS II trial is designed as a randomized, open label, parallel group trial with blinded outcome assessment. Based on our sample size estimation, 400 patients treated in OPUS for two years will be randomized to further three years of OPUS treatment versus standard treatment. The specialized assertive OPUS treatment consists of three core elements: assertive community treatment, psycho-educational family treatment, and social skills training.</p> <p>Discussion</p> <p>It has been hypothesized that there is a critical period from onset up to five years, which represents a window of opportunity where a long-term course can be influenced. Extending the specialized assertive OPUS treatment up to five years may allow the beneficial effects to continue beyond the high-risk period, through consolidation of improved social and functional outcome.</p> <p>Trial registration</p> <p>Clinical Trial.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00914238">NCT00914238</a></p

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

The ALICE experiment at the CERN LHC

ALICE (A Large Ion Collider Experiment) is a general-purpose, heavy-ion detector at the CERN LHC which focuses on QCD, the strong-interaction sector of the Standard Model. It is designed to address the physics of strongly interacting matter and the quark-gluon plasma at extreme values of energy density and temperature in nucleus-nucleus collisions. Besides running with Pb ions, the physics programme includes collisions with lighter ions, lower energy running and dedicated proton-nucleus runs. ALICE will also take data with proton beams at the top LHC energy to collect reference data for the heavy-ion programme and to address several QCD topics for which ALICE is complementary to the other LHC detectors. The ALICE detector has been built by a collaboration including currently over 1000 physicists and engineers from 105 Institutes in 30 countries. Its overall dimensions are 161626 m3 with a total weight of approximately 10 000 t. The experiment consists of 18 different detector systems each with its own specific technology choice and design constraints, driven both by the physics requirements and the experimental conditions expected at LHC. The most stringent design constraint is to cope with the extreme particle multiplicity anticipated in central Pb-Pb collisions. The different subsystems were optimized to provide high-momentum resolution as well as excellent Particle Identification (PID) over a broad range in momentum, up to the highest multiplicities predicted for LHC. This will allow for comprehensive studies of hadrons, electrons, muons, and photons produced in the collision of heavy nuclei. Most detector systems are scheduled to be installed and ready for data taking by mid-2008 when the LHC is scheduled to start operation, with the exception of parts of the Photon Spectrometer (PHOS), Transition Radiation Detector (TRD) and Electro Magnetic Calorimeter (EMCal). These detectors will be completed for the high-luminosity ion run expected in 2010. This paper describes in detail the detector components as installed for the first data taking in the summer of 2008

Performance trends of a generic small gas turbine engine

Small gas turbine engines are increasingly used in cruise missile applications. In the design stage of these engines, aero-thermodynamic models are used to evaluate the expected performance of the engine for a given set of component characteristics. The throttle characteristics and altitude-Mach number characteristics of the engine are iteratively analyzed using this model. This paper describes the use of such a model to show the expected performance of a set of design choices at different altitudes and Mach numbers. These small engines are operated at maximum possible Turbine Inlet Temperatures (TIT) for maximum thrust. Theoretical relations that give the slope of the operating line for constant turbine inlet temperature operation is derived. Using these expressions, the reduction of stability at high altitude and low Mach number is shown

Drag characterization of Strut-mounted 'Through Cavity' for scramjet applications

Wall mounted cavity has proven to be a capable candidate for fuel air mixing and flame stabilization for scramjet. Because of inherent advantages like symmetric flow, avoidance of base wall cooling, symmetric fuelling feasibility etc exploration of strut-mounted 'though cavity' has been done. It is a novel configuration formed in the space between two struts immersed in a supersonic flow in tandem. Two variants of the cavity formed by using rectangular and ramp strut as the rear strut and plug nozzle acting as the forward strut, have been used. Drag characterization is carried out by static pressure measurement inside the cavity for different aspect ratios for these two types of cavities formed. Flow visualization has been done using time averaged Z-type schliren technique. Open and closed cavities have been identified using distribution of coefficient of pressure in the cavity and the schlieren images take

Characterization of Strut-mounted 'Through Cavity' for scramjet applications

Scramjet is a variant of ramjet where combustion happens at supersonic speeds. At these supersonic speeds residence time available is of the order of 1 millisecond. So the available time for fuelair mixing, atomization, vaporization and combustion is very low. Wall mounted cavity has proven to be a capable candidate for fuel air mixing and flame stabilization for scramjet. Because of inherent advantages like symmetric flow, avoidance of base wall cooling, symmetric fuelling feasibility etc exploration of strut-mounted ‘through cavity’ has been done. It is a novel configuration formed in the space between two struts immersed in a supersonic flow in tandem. Pressure oscillations inside the cavity are result of unsteadiness in the flow, caused by the interaction of shear layer with the compression wave generated inside the cavity. Experimental characterization is carried out by unsteady pressure measurement inside the cavity for aspect ratios of 2 to 14. Two variants of the cavity, formed by using rectangular and ramp strut as the rear strut and plug nozzle acts as the forward strut, have been used. Width of the cavity has been kept constant. Cavity sees the flow Mach number of 2, total pressure of 7 bar and total temperature of 300 K. Dominant modes of pressure fluctuations are captured at each configuration and effect of aspect ratios and cavity variants are observed. Stable and unstable cavities have been observed. Variation of amplitude of pressure oscillation inside the cavity, along the length of the cavity has also been notice

Flow visualization and supersonic combustion studies of an acoustically open strut cavity

In this study, the supersonic flow over strut cavities was experimentally studied to understand flow features. Instantaneous schlieren imaging in non-reacting flow experiments exhibited the seven types of waves associated with cavity pressure oscillations and the formation of unstable shear layers on both sides. The shear layers moved in and out in synchronous and asynchronous modes at the trailing edge of the strut cavities. The symmetrical wave structure appeared on both sides in the synchronous mode, whereas the shear layers appeared in different stages of the cavity pressure oscillation cycle in the asynchronous mode, resulting in an asymmetrical wave structure. The pressure waves generated at the trailing edge of the strut cavities perturbed the shear layers during their movement toward the leading edge, creating a wavy shear layer with alternate troughs and crests. The pressure oscillations of the strut cavities had high-amplitude cavity modes with broadband noises, and their amplitude decreased from the trailing edge to the leading edge. The estimated recovery factor using the time lag between the signals of the leading and trailing edges showed that the flow inside the strut cavities was low subsonic. The measured dominant pressure oscillation modes had a closer match with the Rossiter modes. The pressure coefficient demonstrated that fluid accumulation inside the cavity increased with an increase in the aspect ratio. Furthermore, a higher fluid mass accumulated at the trailing edge than at the leading edge, and the difference in fluid accumulation increased with an increase in the aspect ratio. Supersonic combustion experiments with strut cavities showed that the strut cavity stabilized the flame. Moreover, the addition of an acoustically open strut cavity ahead of the flame-stabilizing cavity advanced the heat release location upstream