Secukinumab demonstrated sustained retention, effectiveness and safety in a real-world setting in patients with moderate-to-severe plaque psoriasis: long-term results from an interim analysis of the SERENA study.

BACKGROUND: Randomized controlled trials of secukinumab have shown sustained efficacy and a favourable safety profile in multiple manifestations of psoriatic disease. OBJECTIVES: To assess the long-term, real-world retention, effectiveness and safety of secukinumab in routine clinical practice for the treatment of moderate-to-severe plaque-type psoriasis (PsO). METHODS: SERENA (CAIN457A3403) is a large, ongoing, longitudinal, observational study conducted at 438 sites and 19 countries for an expected duration of up to 5 years in adult patients with moderate-to-severe PsO, psoriatic arthritis and ankylosing spondylitis. Patients received ≥16 weeks of secukinumab treatment before enrolment. This interim analysis presents data from PsO patients, who were enrolled in the study between October-2016 and October-2018 and were observed for ≥2 years. RESULTS: In total, 1756 patients (67.3% male) with a mean age of 48.4 years and body mass index of 28.8 kg/m2 were included in the analysis. The secukinumab treatment retention rates after 1, 2 and 3 years in the study were 88.0%, 76.4% and 60.5%, respectively. Of the 648 patients who discontinued the study, the most common reasons included lack of efficacy (42.6%), adverse event (17.4%), physician decision (12.2%) and subject decision (11.6%). Mean ± SD absolute PASI was 21.0 ± 13.0 at the start of treatment (n = 1,564). At baseline, the mean ± SD PASI score reduced to 2.6 ± 4.8 and remained low at Year 1 (2.3 ± 4.3), Year 2 (1.9 ± 3.6) and Year 3 (1.9 ± 3.5). The safety profile of secukinumab during the SERENA study was consistent with its known safety profile, with no new safety signals reported. Particularly, low rates of inflammatory bowel disease (0.3%; Incidence Rate [IR]:0.15), candida infections (3.1%; IR:1.43) and MACE (0.9%; IR:0.37) were observed. CONCLUSIONS: Secukinumab showed high treatment persistence, sustained effectiveness and a favourable safety profile up to 3 years of follow-up in the real-world population of PsO patients observed in SERENA.

The rapid assembly of an elliptical galaxy of 400 billion solar masses at a redshift of 2.3.

Stellar archaeology shows that massive elliptical galaxies formed rapidly about ten billion years ago with star-formation rates of above several hundred solar masses per year. Their progenitors are probably the submillimetre bright galaxies at redshifts z greater than 2. Although the mean molecular gas mass (5 × 10(10) solar masses) of the submillimetre bright galaxies can explain the formation of typical elliptical galaxies, it is inadequate to form elliptical galaxies that already have stellar masses above 2 × 10(11) solar masses at z ≈ 2. Here we report multi-wavelength high-resolution observations of a rare merger of two massive submillimetre bright galaxies at z = 2.3. The system is seen to be forming stars at a rate of 2,000 solar masses per year. The star-formation efficiency is an order of magnitude greater than that of normal galaxies, so the gas reservoir will be exhausted and star formation will be quenched in only around 200 million years. At a projected separation of 19 kiloparsecs, the two massive starbursts are about to merge and form a passive elliptical galaxy with a stellar mass of about 4 × 10(11) solar masses. We conclude that gas-rich major galaxy mergers with intense star formation can form the most massive elliptical galaxies by z ≈ 1.5.

Pre- and post-puberty expression of genes and proteins in the uterus of Bos indicus heifers: the luteal phase effect post-puberty.

Progesterone signaling and uterine function are crucial in terms of pregnancy establishment. To investigate how the uterine tissue and its secretion changes in relation to puberty, we sampled tissue and uterine fluid from six pre- and six post-pubertal Brahman heifers. Post-pubertal heifers were sampled in the luteal phase. Gene expression of the uterine tissue was investigated with RNA-sequencing, whereas the uterine fluid was used for protein profiling with mass spectrometry. A total of 4034 genes were differentially expressed (DE) at a nominal P-value of 0.05, and 26 genes were significantly DE after Bonferroni correction (P < 3.1 × 10-6 ). We also identified 79 proteins (out of 230 proteins) that were DE (P < 1 × 10-5 ) in the uterine fluid. When we compared proteomics and transcriptome results, four DE proteins were identified as being encoded by DE genes: OVGP1, GRP, CAP1 and HBA. Except for CAP1, the other three had lower expression post-puberty. The function of these four genes hypothetically related to preparation of the uterus for a potential pregnancy is discussed in the context of puberty. All DE genes and proteins were also used in pathway and ontology enrichment analyses to investigate overall function. The DE genes were enriched for terms related to ribosomal activity. Transcription factors that were deemed key regulators of DE genes are also reported. Transcription factors ZNF567, ZNF775, RELA, PIAS2, LHX4, SOX2, MEF2C, ZNF354C, HMG20A, TCF7L2, ZNF420, HIC1, GTF3A and two novel genes had the highest regulatory impact factor scores. These data can help to understand how puberty influences uterine function.

Multipass OPCPA system at 100 kHz pumped by a CPA-free solid-state amplifier.

We present a compact few-cycle 100 kHz OPCPA system pumped by a CPA-free picosecond Nd:YVO4 solid-state amplifier with all-optical synchronization to an ultra-broadband Ti:sapphire oscillator. This pump approach shows an exceptional conversion rate into the second harmonic of almost 78%. Efficient parametric amplification was realized by a two stage double-pass scheme with following chirped mirror compressor. The amount of superfluorescence was measured by an optical cross-correlation. Pulses with a duration of 8.7 fs at energies of 18 µJ are demonstrated. Due to the peak power of 1.26 GW, this simple OPCPA approach forms an ideal high repetition rate driving source for high-order harmonic generation.

Seventy kilovolt ultra-low dose CT of the paranasal sinus: first clinical results.

AIM: To evaluate the diagnostic image quality and radiation dose of low-dose 70 kV computed tomography (CT) of the paranasal sinus in comparison to 100 and 120 kV CT. MATERIALS AND METHODS: CT of the paranasal sinus was performed in 127 patients divided into three groups using different tube voltages and currents (70 kV/75 mAs, ultra-low dose protocol, n = 44; 100 kV/40 mAs, standard low-dose protocol, n = 42; 120 kV/40 mAs, standard protocol, n = 41). CT dose index (CTDIvol), dose-length product (DLP), attenuation, image noise and signal-to-noise ratio (SNR) were compared between the groups using Wilcoxon-Mann-Whitney U-test. Subjective diagnostic image quality was compared by using a five-point scale (1 = non-diagnostic, 5 = excellent, read by two readers in consensus) and Cohen's weighted kappa analysis for interobserver agreement. RESULTS: Radiation dose was significantly lower with 70 kV acquisition than 100 and 120 kV (DLP: 31 versus 52 versus 82 mGy·cm; CTDI 2.33 versus 3.95 versus 6.31 mGy, all p < 0.05). Mean SNR (70 kV: 0.37; 100 kV: 0.21; 120 kV: 0.13; p < 0.05) and organ attenuation increased significantly with lower voltages. All examinations showed diagnostic image quality. Subjective diagnostic image quality was higher with standard protocols than the 70 kV protocol (120 kV: 5.0; 100 kV: 4.5; 70 kV: 3.5, p < 0.05) without significant differences with substantial interobserver agreement (κ > 0.59). CONCLUSION: The ultra-low dose (70 kV) CT imaging of the paranasal sinus allowed for significant dose reduction by 61% and an increased attenuation of organ structures in comparison to standard acquisition while maintaining diagnostic image quality with a slight reduction in subjective image quality.

Evaluation of image quality and dose reduction of 80 kVp neck computed tomography in patients with suspected peritonsillar abscess.

AIM: To evaluate neck computed tomography (CT) with a reduced tube voltage of 80 kVp in patients with suspected peritonsillar abscess (PTA) regarding objective and subjective image quality, and the potential for dose reduction. MATERIALS AND METHODS: Forty-seven patients with clinically suspected PTA were retrospectively analysed. Patients were examined using dual-source CT in dual-energy mode. The objective and subjective image quality of 80 kVp images were compared with linearly blended 120 kVp images (M_0.3; 30% of 80 kV, 70% of 140 kV spectrum). Attenuation of abscess rim enhancement, central necrosis, and several other anatomical landmarks were measured. The signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and rim-to-abscess CNR (raCNR) were calculated. Radiation dose was assessed as size-specific dose estimates (SSDE). Subjective image quality was assessed according to the European guidelines on quality criteria for CT. Interobserver agreement was calculated using the intraclass correlation coefficient (ICC). RESULTS: Attenuation of inflamed soft tissue (141.7 ± 16.3 versus 93.7 ± 9.3 HU, p < 0.001), CNR (9.6 ± 4.8 versus 5.6 ± 3.8, p = 0.001), raCNR (14.3 ± 5.9 versus 12.4 ± 4.4, p = 0.02), and subjective image sharpness (3.6 ± 0.6 versus 2.8 ± 0.7, p < 0.001) were significantly increased in the 80 kVp compared to 120 kVp, whereas subjective and objective image noise were significantly increased with 80 kVp acquisition (p < 0.001). Overall interobserver agreement was almost perfect (ICC, 0.87). Calculated SSDE of 80 kVp acquisition was decreased by 49.7% compared to 120 kVp (10.58 ± 0.76 versus 21.04 ± 1.43 mGy, p < 0.001). CONCLUSION: Low-tube-voltage 80 kVp neck CT provides increased enhancement of soft-tissue inflammation, CNR, raCNR, and improved abscess delineation in patients with PTA compared to standard 120 kVp acquisition while resulting in a significant reduction of radiation exposure.

Non-linear image blending improves visualization of head and neck primary squamous cell carcinoma compared to linear blending in dual-energy CT.

AIM: To compare non-linear and linear image-blending post-processing techniques in dual-energy CT (DECT) of primary head and neck squamous cell carcinoma (SCC) regarding subjective and objective image quality. MATERIALS AND METHODS: Head and neck DECT studies from 69 patients (48 male, 21 female; mean age 62.3 years) were retrospectively evaluated. All tumour lesions were histologically confirmed SCC. Linearly blended 80/140 kVp images series with varying weighting factors of 0.3 (M_0.3), 0.6 and 0.8 were compared with non-linearly blended images. Attenuation of tumour lesion, various soft-tissue structures, the internal jugular vein, and image noise were measured, tumour signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. Overall image quality, delineation of tumour lesion, image sharpness, and noise level were rated individually by three radiologists using five-point Likert scales. Interobserver agreement was calculated using intraclass correlation coefficient (ICC). RESULTS: Enhancement of tumour lesions (non-linear, 137.5 ± 20.1 HU; M_0.3, 92.7 ± 14.4 HU; M_0.6, 110 ± 15.4 HU; M_0.8, 123 ± 18.2 HU), CNR (non-linear, 12 ± 8; M_0.3, 4 ± 4.7; M_0.6, 7.5 ± 5.5; M_0.8, 8 ± 5.5), subjective overall image quality and tumour delineation were significantly increased (all p < 0.001) with the non-linear blending technique compared to all investigated linear blending weighting factors. Overall interobserver agreement was substantial (ICC 0.70; 95% CI: 0.66-0.73). CONCLUSION: Post-processing of DECT using a non-linear blending technique provides improved objective and subjective image quality of head and neck SCC compared to linearly blended images series.

Body packers on your examination table: How helpful are plain x-ray images? A definitive low-dose CT protocol as a diagnosis tool for body packers.

AIM: To analyze the clinical value and radiation dose of plain x-rays and CT in examining patients suspected of ingesting drug-filled packets. MATERIALS AND METHODS: Thirty-eight patients with suspected internal concealment of drug-filled packets who were examined with plain x-rays or CT or both were included in the study. CT studies were performed using low-dose and standard-dose techniques. All radiographic images were analysed by two radiologists regarding identification of the packets and estimating the effective radiation dose from standard- and low-dose CT versus conventional x-ray examinations. Descriptive calculations were made regarding the number and density of packs and radiation dosage. The diagnostic performance of both radiologists with standard- and low-dose CT was calculated by analysing differences in the mean number of packs found. RESULTS: Thirty-one patients were positively identified as body packers with an average of 13 packs (min: n = 1, max: n = 58, total: n = 390); seven patients were not concealing drug packets. X-ray images were taken of 24 patients prior to CT, thus allowing a direct comparison between the two methods. The correct diagnosis was made in 42%, in 33% the radiologists were uncertain, and in 25% of drug packets were either not or wrongly identified. X-ray imaging had a positive predictive value of 20% with a negative predictive value of 81%. A total of 55 CT examinations were performed on all patients with a mean effective dose of 2 mSv (low dose) versus 9.3 mSv (standard dose). The visibility of packets on low-dose CT images compared to high-dose CT was not reduced: the radiologists identified 385 and 381 of the packets, respectively, with no difference regarding the examination technique (p = 0.24 and p = 0.253, respectively). The radiodensity of all drug-filled packets at CT ranged from 26-292 HU (mean 181.2 HU). CONCLUSION: X-ray imaging of supposed body packers leads to a significant risk of diagnostic errors and additional need for CT. Instead, a single abdominal low-dose CT examination will deliver the correct diagnoses in most cases, leading to safe clinical management of the suspects.

Functional anatomy of ventromedial prefrontal cortex: implications for mood and anxiety disorders.

In recent years, an increasing number of neuroimaging studies have sought to identify the brain anomalies associated with mood and anxiety disorders. The results of such studies could have significant implications for the development of novel treatments for these disorders. A challenge currently facing the field is to assimilate the large and growing corpus of imaging data to inform a systems-level model of the neural circuitry underlying the disorders. One prominent theoretical perspective highlights the top-down inhibition of amygdala by ventromedial prefrontal cortex (vmPFC) as a crucial neural mechanism that may be defective in certain mood and anxiety disorders, such as major depression and post-traumatic stress disorder. In this article, we provide a critical review of animal and human data related to this model. In particular, we emphasize the considerable body of research that challenges the veracity (or at least completeness) of the predominant model. We propose a framework for constructing a more comprehensive model of vmPFC function, with the goal of fostering further progress in understanding the neuropathophysiological basis of mood and anxiety disorders.

Advancing analytical electron microscopy methodologies to characterise microstructural features in superalloys.

Electron backscatter diffraction (EBSD) generally links crystallographic orientation to the microstructure of crystalline materials. EBSD datasets are now commonly used to identify phases, grains, and their orientations using off-the-shelf software, although substantial additional information may be extracted. Due to the lack of commercially available software, advanced analyses are often done manually and provide only localised information, lacking statistical significance. Here we introduce novel automated methodologies for advanced analyses of microstructural features in Ni-based superalloys. Our methodologies provide additional insights into the characteristics of these features and their underlying physical phenomena. We showcase how to correct wrongly indexed γ/γ' interface artefacts in combined EBSD and energy-dispersive X-ray spectroscopy (EDS) measurements, how to classify recrystallised grains based on their location, how to assess and visualise grain boundary planes, and how to study the evolution of Σ3 twins during hot deformation. We further demonstrate how phase fractions and grain sizes are more accurately determined in combined EBSD-EDS measurements. The classification of recrystallised grains into different groups enables individual analyses, facilitating the straightforward identification of the underlying recrystallisation mechanism. Our grain boundary plane analysis provides insights into the coherence of Σ3 twins and the potential boundary planes of incoherent Σ3 boundaries. The current paper is a tutorial-style guide for these methodologies. The algorithms are made freely available and, although demonstrated here on Ni-based superalloys, can also be applied to other systems.

Successful pregnancy complicated by persistent pneumothorax in a patient with lymphangioleiomyomatosis (LAM) on sirolimus.

We report a successful pregnancy in a patient with longstanding LAM on treatment with sirolimus. During temporary discontinuation fo sirolimus in early pregnancy, lung function declined but recovered after resumption of sirolimus. Pregnancy was complicated by a persistent pneumothorax which was treated surgically postnatally. The child has had a normal development despite exposure to low dose sirolimus intermittently during early embryonal and mid-fetal life.

Resveratrol and its antifungal activity against Candida species.

Resveratrol is a natural stilbene synthesised by plants. This compound has been shown to inhibit the growth of Candida albicans TIMM 1768 efficiently. Till date, no information is available for other Candida species. The evaluation of the antimicrobial activity of resveratrol was analysed by the inhibition of the growth and metabolism assays. Our data indicate that resveratrol is not effective against Candida albicans and non-C. albicans species (C. dubliniensis, C. glabrata, C. tropicalis, C. parapsilosis and C. krusei) in vitro. The potential candidacidal activity could not be confirmed.

The quorum-sensing molecule E,E-farnesol--its variable secretion and its impact on the growth and metabolism of Candida species.

Diseases caused by Candida species are an increasing problem. Candida species are associated with high overall mortality, due to a variety of virulence factors such as the yeast-to-hyphal switch and proteolytic enzymes. The phenomenon of microbial communication known as quorum sensing also seems to play an important role. The main characteristics of the quorum-sensing molecule E,E-farnesol are well known for C. albicans. The present study focused on two questions. One of them concerned the secretion of E,E-farnesol by C. albicans and involved a close examination of the effect of the medium (serum) and the origin of the isolates used. The second one dealt with the activity of E,E-farnesol in non-C. albicans species, such as C. tropicalis and C. parapsilosis, e.g. its impact on biofilm formation and growth. Under serum conditions, C. albicans produced up to 58% more E,E-farnesol at 37 degrees C than at 30 degrees C. The growth of all isolates was reduced and delayed by the administration of E,E-farnesol. Of all Candida species, C. tropicalis isolates were most strongly affected by the addition of E,E-farnesol. Biofilm formation on polystyrene was affected by E,E-farnesol treatment in all non-C. albicans species and C. albicans. E,E-farnesol exerts its main effect by altering the metabolic activity and growth inhibition of treated Candida species. The results obtained indicate that the presence of E,E-farnesol in the environment not only regulates the morphology of the Candida species but also affects its fitness. In this regard, the secretion of E,E-farnesol might provide an advantage for members of the microbial community.

Experimental observation of the crystallization of a paired holon state.

An excitation at 201 meV is observed in the doped-hole ladder cuprate Sr14Cu24O41, using ultraviolet resonance Raman scattering with incident light at 3.7 eV polarized along the rungs. The excitation is of charge nature, with a temperature independent excitation energy, and can be understood via an intraladder pair-breaking process. The intensity tracks closely the order parameter of the charge density wave in the ladder CDW(L), but persists above its transition temperature T(CDW(L)), indicating a strong local pairing above the T(CDW(L)). The 201 meV excitation vanishes in La6Ca8Cu24O(41+δ), and La5Ca9Cu24O41 which are samples with no holes in the ladders. Our results suggest that the doped holes in the ladder are composite bosons consisting of paired holons that order below T(CDW).

Optical detection of heterogeneous single molecule diffusion in thin liquid crystal films.

Lateral diffusion of three different dye molecules (terrylene and two perylene diimides) in 4 to 225 nm thin films of 8CB liquid crystals in the smectic-A phase has been investigated on a single molecule level. The influence of film thickness on tracer diffusion can be qualitatively modeled by a hydrodynamic approach. Molecular tracking experiments as well as fluorescence correlation (FCS) studies reveal the presence of diffusion dynamics which span a range of at least more than one order of magnitude in time, which is much larger than the reported anisotropic self-diffusion observed for 8CB bulk samples. We tentatively assign the heterogeneity to the formation of diffusion limiting domains on a micrometer scale within the 8CB films or at the interfaces.

[Solitary fibrous tumor and haemangiopericytoma: what is new?]. / Solitärer fibröser Tumor und Hämangioperizytom : Was ist neu?

Soft-tissue tumors with haemangiopericytoma (HPC)-like growth patterns can now be divided into three categories: (1) The solitary fibrous tumour (SFT) group with its variants; (2) lesions showing clear evidence of myoid/pericytic differentiation and corresponding to "true" HPCs (myopericytoma/glomangiopericytoma and a subset of sinonasal HPCs); (3) neoplasms that occasionally display HPC-like features (e.g. synovial sarcoma). In this study 268 intrathoracic and extrathoracic SFTs from the German consultation and reference center of soft tissue tumors in Jena were evaluated and analyzed immunohistochemically with antibodies CD34, Bcl-2, CD99, SMA, S100, PanCK and Ki-67. Furthermore, SFTs were categorized into the newly proposed SFT designation: Fibrous variant, cellular variant (more than 90% hypercellularity), fat-forming variant, giant cell-rich variant and malignant SFTs. This article should provide insights into the diagnosis of this entity with emphasis on the new international standard.

Aetiology of Canine Infectious Respiratory Disease Complex and Prevalence of its Pathogens in Europe.

The canine infectious respiratory disease complex (CIRDC) is an endemic worldwide syndrome involving multiple viral and bacterial pathogens. Traditionally, Bordetella bronchiseptica (Bb), canine adenovirus type 2 (CAV-2), canine distemper virus (CDV), canine herpesvirus (CHV) and canine parainfluenza virus (CPiV) were considered the major causative agents. Lately, new pathogens have been implicated in the development of CIRDC, namely canine influenza virus (CIV), canine respiratory coronavirus (CRCoV), canine pneumovirus (CnPnV), Mycoplasma cynos and Streptococcus equi subspecies zooepidemicus. To better understand the role of the different pathogens in the development of CIRDC and their epidemiological relevance in Europe, prevalence data were collected from peer-reviewed publications and summarized. Evidence of exposure to Bb is frequently found in healthy and diseased dogs and client-owned dogs are as likely to be infected as kennelled dogs. Co-infections with viral pathogens are common. The findings confirm that Bb is an important cause of CIRDC in Europe. CAV-2 and CDV recovery rates from healthy and diseased dogs are low and the most likely explanation for this is control through vaccination. Seroconversion to CHV can be demonstrated following CIRDC outbreaks and CHV has been detected in the lower respiratory tract of diseased dogs. There is some evidence that CHV is not a primary cause of CIRDC, but opportunistically re-activates at the time of infection and exacerbates the disease. The currently available data suggest that CIV is, at present, neither a prevalent nor a significant pathogen in Europe. CPiV remains an important pathogen in CIRDC and facilitates co-infection with other viral and bacterial pathogens. CnPnV and CRCoV are important new elements in the aetiology of CIRDC and spread particularly well in multi-dog establishments. M. cynos is common in Europe and is more likely to occur in younger and kennelled dogs. This organism is frequently found together with other CIRDC pathogens and is significantly associated with more severe respiratory signs. S. zooepidemicus infection is not common and appears to be a particular problem in kennels. Protective immunity against respiratory diseases is rarely complete, and generally only a reduction in clinical signs and excretion of pathogen can be achieved through vaccination. However, even vaccines that only reduce and do not prevent infection carry epidemiological advantages. They reduce spread, increase herd immunity and decrease usage of antimicrobials. Recommending vaccination of dogs against pathogens of CIRDC will directly provide epidemiological advantages to the population and the individual dog.

The pilin O-glycosylation pathway of pathogenic Neisseria is a general system that glycosylates AniA, an outer membrane nitrite reductase.

O-Glycosylation is emerging as a common posttranslational modification of surface exposed proteins in bacterial mucosal pathogens. In pathogenic Neisseria an O-glycosylation pathway modifies a single abundant protein, pilin, the subunit protein that forms pili. Here, we identify an additional outer membrane glycoprotein in pathogenic Neisseria, the nitrite reductase AniA, that is glycosylated in its C-terminal repeat region by the pilin glycosylation pathway. To our knowledge, this is the first report of a general O-glycosylation pathway in a prokaryote. We also show that AniA displays polymorphisms in residues that map to the surface of the protein. A frame-shift mutation abolishes AniA expression in 34% of Neisseria meningitidis strains surveyed, however, all Neisseria gonorrhoeae strains examined are predicted to express AniA, implying a crucial role for AniA in gonococcal biology.

A "Double-Diamond Superlattice" Built Up of Cd17S4(SCH2CH2OH)26 Clusters.

A simple preparation of Cd(17)S(4)(SCH(2)CH(2)OH)(26) clusters in aqueous solution leads to the formation of colorless blocky crystals. X-ray structure determinations revealed a superlattice framework built up of covalently linked clusters. This superlattice is best described as two enlarged and interlaced diamond or zinc blende lattices. Because both the superlattice and the clusters display the same structural features, the crystal structure resembles the self-similarities known from fractal geometry. The optical spectrum of the cluster solution displays a sharp transition around 290 nanometers with a large absorption coefficient ( approximately 84,000 per molar per centimeter).