Summary
Background
Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin‐13, a key driver of atopic dermatitis (AD).
Objectives
To evaluate the efficacy and ...safety of tralokinumab in combination with topical corticosteroids (TCS) in patients with moderate‐to‐severe AD who were candidates for systemic therapy.
Methods
This was a double‐blind, placebo plus TCS controlled phase III trial. Patients were randomized 2 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks (Q2W) with TCS as needed over 16 weeks. Patients who achieved an Investigator’s Global Assessment (IGA) score of 0/1 and/or 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16 with tralokinumab were rerandomized 1 : 1 to tralokinumab Q2W or every 4 weeks (Q4W), with TCS as needed, for another 16 weeks.
Results
At week 16, more patients treated with tralokinumab than with placebo achieved IGA 0/1: 38·9% vs. 26·2% difference (95% confidence interval): 12·4% (2·9–21·9); P = 0·015 and EASI 75: 56·0% vs. 35·7% 20·2% (9·8–30·6); P < 0·001. Of the patients who were tralokinumab responders at week 16, 89·6% and 92·5% of those treated with tralokinumab Q2W and 77·6% and 90·8% treated with tralokinumab Q4W maintained an IGA 0/1 and EASI 75 response at week 32, respectively. Among patients who did not achieve IGA 0/1 and EASI 75 with tralokinumab Q2W at 16 weeks, 30·5% and 55·8% achieved these endpoints, respectively, at week 32. The overall incidence of adverse events was similar across treatment groups.
Conclusions
Tralokinumab 300 mg in combination with TCS as needed was effective and well tolerated in patients with moderate‐to‐severe AD.
What is already known about this topic?
Atopic dermatitis (AD) is a chronic interleukin (IL)‐13‐mediated disease.
In clinical practice, biologics are commonly initiated as add‐on therapy to topical corticosteroids (TCS).
Tralokinumab is a fully human monoclonal antibody that binds specifically to the IL‐13 cytokine with high affinity, thereby preventing receptor interaction and subsequent downstream signalling.
Tralokinumab combined with TCS showed early and sustained efficacy and safety in a 12‐week, phase IIb trial in moderate‐to‐severe AD.
What does this study add?
This is the first phase III trial evaluating a targeted anti‐IL‐13 biologic in combination with TCS.
These data demonstrate that tralokinumab plus TCS can achieve significant improvements in AD signs and symptoms and quality of life, as well as exert a steroid‐sparing effect.
Response with tralokinumab in combination with TCS was maintained over 32 weeks.
Tralokinumab may be considered a targeted biological treatment option for patients with moderate‐to‐severe AD.
Linked Comment: Morra and Drucker. Br J Dermatol 2021; 184:386–387.
Plain language summary available online
In March 2013 the first cases of human avian influenza A(H7N9) were reported to the World Health Organization. Since that time, over 650 cases have been reported. Infections are associated with ...considerable morbidity and mortality, particularly within certain demographic groups. This rapid increase in cases over a brief time period is alarming and has raised concerns about the pandemic potential of the H7N9 virus. Three major factors influence the pandemic potential of an influenza virus: (1) its ability to cause human disease, (2) the immunity of the population to the virus, and (3) the transmission potential of the virus. This paper reviews what is currently known about each of these factors with respect to avian influenza A(H7N9). Currently, sustained human-to-human transmission of H7N9 has not been reported; however, population immunity to the virus is considered very low, and the virus has significant ability to cause human disease. Several statistical and geographical modelling studies have estimated and predicted the spread of the H7N9 virus in humans and avian species, and some have identified potential risk factors associated with disease transmission. Additionally, assessment tools have been developed to evaluate the pandemic potential of H7N9 and other influenza viruses. These tools could also hypothetically be used to monitor changes in the pandemic potential of a particular virus over time.
Patients with hyperlipidemia were assigned to receive the PCSK9 antibody evolocumab or placebo on a background of lipid-lowering therapy. At 52 weeks, the least-squares mean reduction in LDL ...cholesterol from baseline for evolocumab versus placebo was 57%.
Proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease that is produced predominantly in the liver, is secreted into the plasma and plays a major role in regulating levels of low-density lipoprotein (LDL) cholesterol by binding to hepatic LDL receptors and promoting their degradation.
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In short-term (8-to-12-week), placebo-controlled, phase 2 trials, PCSK9 inhibitors have been shown to significantly reduce LDL cholesterol levels.
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Four of these trials involved the use of evolocumab (AMG 145), a fully human monoclonal PCSK9 antibody, and assessed different doses and regimens in diverse patient populations with varying lipid phenotypes, cardiovascular disease risks, and baseline . . .
Nonreciprocal microwave devices are ubiquitous in radar and radio communication and indispensable in the readout chains of superconducting quantum circuits. Since they commonly rely on ferrite ...materials requiring large magnetic fields that make them bulky and lossy, there has been significant interest in magnetic-field-free on-chip alternatives, such as those recently implemented using the Josephson nonlinearity. Here, we realize reconfigurable nonreciprocal transmission between two microwave modes using purely optomechanical interactions in a superconducting electromechanical circuit. The scheme relies on the interference in two mechanical modes that mediate coupling between the microwave cavities and requires no magnetic field. We analyse the isolation, transmission and the noise properties of this nonreciprocal circuit. Finally, we show how quantum-limited circulators can be realized with the same principle. All-optomechanically mediated nonreciprocity demonstrated here can also be extended to directional amplifiers, and it forms the basis towards realizing topological states of light and sound.Nonreciprocal optical devices traditionally rely on magnetic fields and magnetic-free approaches are rather recent. Here, Bernier et al. propose and demonstrate a purely optomechanical circulator with reconfigurable transmission without the need for direct coupling between input and output modes.
Summary
Background
The interleukin‐17 cytokine family plays a central role in psoriasis pathogenesis.
Objectives
To evaluate the efficacy and safety of brodalumab, a human anti‐interleukin‐17 ...receptor antibody, in treating patients with moderate‐to‐severe plaque psoriasis.
Methods
In this phase III, double‐blind, placebo‐controlled study (NCT01708590; AMAGINE‐1), adult patients in the U.S.A., Canada and Europe were randomized to brodalumab (140 or 210 mg) or placebo every 2 weeks (Q2W), with an additional dose at week 1, for a 12‐week induction phase. At week 12, patients receiving brodalumab who achieved static Physician's Global Assessment 0 or 1 (sPGA success) were rerandomized to the placebo or induction dose. After week 16, patients with sPGA ≥ 3 were re‐treated with the induction dose. After ≥ 12 weeks of retreatment, patients with sPGA 2 for ≥ 4 weeks or sPGA ≥ 3 were rescued with brodalumab 210 mg Q2W. At week 12, patients randomized to brodalumab with sPGA ≥ 2 or placebo received brodalumab 210 mg Q2W. Coprimary end points were the percentage of patients with ≥ 75% improvement in Psoriasis Area and Severity Index score (PASI 75) and sPGA success at week 12.
Results
There were 661 patients randomized: 220 placebo, 219 brodalumab 140 mg and 222 brodalumab 210 mg. At week 12, 60% (140 mg) and 83% (210 mg) vs. 3% (placebo) achieved PASI 75, and 54% (140 mg) and 76% (210 mg) vs. 1% (placebo) achieved sPGA success. The safety profile was considered acceptable.
Conclusions
Brodalumab therapy resulted in significant clinical benefit and an acceptable safety profile in patients with moderate‐to‐severe plaque psoriasis.
What's already known about this topic?
Anti‐interleukin (anti‐IL)‐17 receptor A and anti‐IL‐17A antibodies have been shown to be efficacious in treating patients with moderate‐to‐severe plaque psoriasis.
What does this study add?
This study further demonstrates that brodalumab therapy in patients with moderate‐to‐severe plaque psoriasis results in a high degree of complete skin clearance.
This study also further elucidates the safety profile of brodalumab.
Linked Comment: Ormerod. Br J Dermatol 2016; 175:243–244
Plain language summary available online
Background
Secukinumab, a fully human monoclonal antibody that selectively neutralizes IL‐17A, has been shown to have significant efficacy and a favourable safety profile in the treatment of ...moderate‐to‐severe psoriasis and psoriatic arthritis.
Objective
To assess the efficacy and safety of secukinumab through 5 years of treatment in moderate‐to‐severe psoriasis.
Methods
In the core SCULPTURE study, Psoriasis Area and Severity Index (PASI) 75 responders at Week 12 continued receiving subcutaneous secukinumab until Year 1. Thereafter, patients entered the extension phase and continued treatment as per the core trial. Treatment was double‐blinded until the end of Year 3 and open‐label from Year 4. Here, we focus on the 300 mg fixed‐interval (every 4 weeks) treatment, the recommended per label dose. Efficacy data are primarily reported as observed, but multiple imputation (MI) and last observation carried forward (LOCF) techniques were also undertaken as supportive analyses.
Results
At Year 1, 168 patients entered the extension study and at the end of Year 5, 126 patients completed 300 mg (every 4 weeks) treatment. PASI 75/90/100 responses at Year 1 (88.9%, 68.5% and 43.8%, respectively) were sustained to Year 5 (88.5%, 66.4% and 41%). PASI responses were consistent regardless of the analysis undertaken (as observed, MI, or LOCF). The average improvement in mean PASI was approximately 90% through 5 years compared with core study baseline. DLQI (dermatology life quality index) 0/1 response also sustained through 5 years (72.7% at Year 1 and 65.5% at Year 5). The safety profile of secukinumab remained favourable, with no cumulative or unexpected safety concerns identified.
Conclusion
Secukinumab 300 mg treatment delivered high and sustained levels of skin clearance and improved quality of life through 5 years in patients with moderate‐to‐severe psoriasis. Favourable safety established in the secukinumab phase 2/3 programme was maintained through 5 years.
Electrospinning has recently been recognized as a potential method for use in biomedical applications such as nanofiber-based drug delivery or tissue engineering scaffolds. The present study aimed to ...demonstrate the electrospinning preparation and suitability of β-tricalcium phosphate-modified aerogel containing polyvinyl alcohol/chitosan fibrous meshes (BTCP-AE-FMs) for bone regeneration under in vitro and in vivo conditions. The mesh physicochemical properties included a 147 ± 50 nm fibrous structure, in aqueous media the contact angles were 64.1 ± 1.7°, and it released Ca, P, and Si. The viability of dental pulp stem cells on the BTCP-AE-FM was proven by an alamarBlue assay and with a scanning electron microscope. Critical-size calvarial defects in rats were performed as in vivo experiments to investigate the influence of meshes on bone regeneration. PET imaging using
F-sodium fluoride standardized uptake values (SUVs) detected 7.40 ± 1.03 using polyvinyl alcohol/chitosan fibrous meshes (FMs) while 10.72 ± 1.11 with BTCP-AE-FMs after 6 months. New bone formations were confirmed by histological analysis. Despite a slight change in the morphology of the mesh because of cross-linking, the BTCP-AE-FM basically retained its fibrous, porous structure and hydrophilic and biocompatible character. Our experiments proved that hybrid nanospun scaffold composite mesh could be a new experimental bone substitute bioactive material in future medical practice.
We study the atomic embeddability testing problem, which is a common generalization of clustered planarity (c-planarity, for short) and thickenability testing, and present a polynomial-time algorithm ...for this problem, thereby giving the first polynomial-time algorithm for c-planarity. C-planarity was introduced in 1995 by Feng, Cohen, and Eades as a variant of graph planarity, in which the vertex set of the input graph is endowed with a hierarchical clustering and we seek an embedding (crossing free drawing) of the graph in the plane that respects the clustering in a certain natural sense. Until now, it has been an open problem whether c-planarity can be tested efficiently. The thickenability problem for simplicial complexes emerged in the topology of manifolds in the 1960s. A 2-dimensional simplicial complex is thickenable if it embeds in some orientable 3-dimensional manifold. Recently, Carmesin announced that thickenability can be tested in polynomial time. Our algorithm for atomic embeddability combines ideas from Carmesin’s work with algorithmic tools previously developed for weak embeddability testing. We express our results purely in terms of graphs on surfaces, and rely on the machinery of topological graph theory. Finally, we give a polynomial-time reduction from atomic embeddability to thickenability thereby showing that both problems are polynomially equivalent, and show that a slight generalization of atomic embeddability to the setting in which clusters are toroidal graphs is NP-complete.
The Cloud Aerosol Lidar and Infrared Pathfinder Satellite
Observations (CALIPSO) mission released version 4.00 of their lidar level 1
data set in April of 2014, and subsequently updated this to ...version 4.10 in
November of 2016. The primary difference in the newly released version 4
(V4) data is a suite of updated calibration coefficients calculated using
substantially revised calibration algorithms. This paper describes the
revisions to the V4 daytime calibration procedure for the 532 nm parallel
channel. As in earlier releases, the V4 daytime calibration coefficients are
derived by scaling the raw daytime signals to the calibrated nighttime
signals acquired within a calibration transfer region, and thus the new V4
daytime calibration benefits from improvements made to the V4 532 nm
nighttime calibration. The V4 calibration transfer region has been moved
upward from the upper troposphere to the more stable lower stratosphere. The
identification of clear-air columns by an iterative thresholding scheme,
crucial to selecting the observation regions used for calibration, now uses
uncalibrated 1064 nm data rather than recursively using the calibrated 532 nm data, as was done in version 3 (V3). A detailed account of the rationale
and methodology for this new calibration approach is provided, along with
results demonstrating the improvement of this calibration over the previous
version. Extensive validation data acquired by NASA's airborne high spectral
resolution lidar (HSRL) shows that during the daytime the average difference
between collocated CALIPSO and HSRL measurements of 532 nm attenuated
backscatter coefficients is reduced from 3.3 %±3.1 % in V3 to
1.0 %±3.5 % in V4.
In a companion paper (Xian et al., 2022, part 1 of the study), we present an Arctic aerosol optical depth (AOD) climatology and trend analysis for 2003-2019 spring and summertime periods derived from ...a combination of aerosol reanalyses, remote-sensing retrievals, and ground observations. Continued from the previous discussion and as the second part of the study, we report the statistics and trends of Arctic AOD extreme events using the U.S. Navy Aerosol Analysis and Prediction System ReAnalysis version 1 (NAAPS-RA v1), the sun photometer data from the AErosol RObotic NETwork (AERONET) sites, and the oceanic Maritime Aerosol Network (MAN) measurements. Here, extreme AOD events are defined as events with AOD exceeding the 95th percentile (denoted "AOD.sub.95 ") of AOD distributions for given locations using 6-hourly or daily AOD data. While AERONET and MAN data estimate the Arctic median 550 nm AOD value to be 0.07, the 95th percentile value is 0.24. Such extreme events are dominated by fine-mode aerosol particles, largely attributable to biomass burning (BB) smoke events for the North American Arctic, the Asian Arctic, and most areas of the Arctic Ocean. However, extreme AOD events for the lower European Arctic are more attributable to anthropogenic and biogenic fine particles. The extreme-event occurrence dominance of sea salt is largely limited to the North Atlantic and Norwegian Sea. The extreme AOD amplitudes of anthropogenic and biogenic fine-mode and sea salt AOD are, however, significantly lower than those regions where extreme smoke AOD is dominant. Even for sites distant from BB source regions, BB smoke is the principal driver of AOD variation above the AOD.sub.95 threshold.
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