Identification and quantification of flavor compounds in smoked tuna fish based on GC-Orbitrap volatolomics approach.

Cold smoking enhances the appeal of fish products, offering consumers a smooth texture and a delicate smoky flavor. This study aims to explore variations in the volatile profile from different exposure times during cold smoking processing (light, moderate, and full-cure) in tune samples. An innovative untargeted analytical approach, headspace solid-phase microextraction combined with gas chromatography and a hybrid quadrupole-orbitrap mass analyzer, was employed to identify 86 volatiles associated with the cold smoking process. Most of these compounds, including phenols, furan derivates, aldehydes, cyclic ketones, and different aromatic species, were found to contribute to the smoke odor. The development of a QuEChERS-based extraction and clean-up method facilitated the quantification of 25 relevant smoky markers across all smoking degrees, revealing significant concentration differences after 15 h of smoking. This research sheds light on the dynamics of cold smoking impact and its on the flavor profile and safety quality of processed fish products.

Incorporating photosynthetic acclimation improves stomatal optimisation models.

Stomatal opening in plant leaves is regulated through a balance of carbon and water exchange under different environmental conditions. Accurate estimation of stomatal regulation is crucial for understanding how plants respond to changing environmental conditions, particularly under climate change. A new generation of optimality-based modelling schemes determines instantaneous stomatal responses from a balance of trade-offs between carbon gains and hydraulic costs, but most such schemes do not account for biochemical acclimation in response to drought. Here, we compare the performance of six instantaneous stomatal optimisation models with and without accounting for photosynthetic acclimation. Using experimental data from 37 plant species, we found that accounting for photosynthetic acclimation improves the prediction of carbon assimilation in a majority of the tested models. Photosynthetic acclimation contributed significantly to the reduction of photosynthesis under drought conditions in all tested models. Drought effects on photosynthesis could not accurately be explained by the hydraulic impairment functions embedded in the stomatal models alone, indicating that photosynthetic acclimation must be considered to improve estimates of carbon assimilation during drought.

Correlating concerted cations with oxygen redox in rechargeable batteries.

Rechargeable batteries currently power much of our world, but with the increased demand for electric vehicles (EVs) capable of traveling hundreds of miles on a single charge, new paradigms are necessary for overcoming the limits of energy density, particularly in rechargeable batteries. The emergence of reversible anionic redox reactions presents a promising direction toward achieving this goal; however this process has both positive and negative effects on battery performance. While it often leads to higher capacity, anionic redox also causes several unfavorable effects such as voltage fade, voltage hysteresis, sluggish kinetics, and oxygen loss. However, the introduction of cations with topological chemistry tendencies has created an efficient pathway for achieving long-term oxygen redox with improved kinetics. The cations serve as pillars in the crystal structure and meanwhile can interact with oxygen in ways that affect the oxygen redox process through their impact on the electronic structure. This review delves into a detailed examination of the fundamental physical and chemical characteristics of oxygen redox and elucidates the crucial role that cations play in this process at the atomic and electronic scales. Furthermore, we present a systematic summary of polycationic systems, with an emphasis on their electrochemical performance, in order to provide perspectives on the development of next-generation cathode materials.

The effect of ixekizumab on axial manifestations in patients with psoriatic arthritis from two phase III clinical trials: SPIRIT-P1 and SPIRIT-P2.

Background: Psoriatic arthritis (PsA) is a chronic inflammatory condition predominantly affecting the peripheral joints. However, some patients with PsA can experience axial involvement which is manifested with back pain and associated with increased burden of illness. Objectives: The aim of this post hoc analysis was to determine the efficacy of ixekizumab (IXE) up to 52 weeks in reducing axial symptoms in PsA patients, presenting with axial manifestations. Design: This was a post hoc analysis of two pooled phase III clinical trials. Methods: Patients with axial manifestations, from two placebo-controlled, randomized, double-blind, phase III trials (SPIRIT-P1 and SPIRIT-P2), were defined as Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Question 2 (Q2; back pain)] total score ⩾4 and average of BASDAI Q5 + Q6 (morning stiffness) ⩾4 at baseline. For this post hoc analysis, the efficacy of IXE was evaluated at weeks 16, 24, and 52 using separate BASDAI questions (including back pain and morning stiffness), total BASDAI and modified BASDAI (mBASDAI; without Q3), Ankylosing Spondylitis Disease Activity Score (ASDAS), and 50% improvement in BASDAI (BASDAI50) response. Treatment comparisons were performed using logistic regression and analysis of covariance model for categorical and continuous end points, respectively. Results: In the post hoc analysis among PsA patients with axial manifestations at baseline (N = 313), improvements in back pain and morning stiffness at weeks 16 and 24 were significantly greater in patients receiving IXE versus placebo (both p < 0.001). Improvements in BASDAI individual scores and total scores, mBASDAI, and ASDAS were significantly greater in patients receiving IXE compared with placebo. Similarly, significantly more IXE-treated patients achieved BASDAI50 at weeks 16 and 24 versus placebo. The effect of IXE was sustained at week 52. Similar effects were observed in sensitivity analyses subgroups. Conclusion: IXE is effective in improving axial symptoms in patients with active PsA presenting with axial manifestations.

Ixekizumab improves symptoms of back pain and morning stiffness in patients with psoriatic arthritis Background: Psoriatic arthritis is a chronic, immune-mediated condition with heterogeneous manifestations including peripheral arthritis, axial arthritis, enthesitis, dactylitis, and skin and nail psoriasis. Some patients with psoriatic arthritis also experience symptoms relating to the spine and sacroiliac joint. These symptoms are referred to as axial manifestations of the psoriatic arthritis. Ixekizumab is a monoclonal antibody that targets IL-17A with high affinity. IL-17A has been implicated in the pathogenesis of PsA. Aim: The aim is to investigate the effects of ixekizumab in controlling symptoms suggestive of axial involvement in patients with active psoriatic arthritis. Methods: This post hoc analysis included patients with psoriatic arthritis from two phase III clinical trials. Only patients with psoriatic arthritis who had back pain and morning stiffness at baseline were included. In the second analysis, we assessed the effect of ixekizumab in a subset of patients with psoriatic arthritis with back pain who were aged less than 45 years. A third analysis included a subset of patients with increased CRP. Results: Our results show that patients with psoriatic arthritis and back pain suggestive of axial involvement experience a greater disease burden than patients without back pain. This post hoc analysis showed that ixekizumab was significantly better compared with placebo in improving inflammatory back pain, morning stiffness, and disease activity at weeks 16 and 24. Disease activity was also significantly improved in ixekizumab-treated patients compared with placebo. Conclusion: Axial manifestations in patients with psoriatic arthritis were significantly improved following ixekizumab treatment. These improvements were noted regardless of whether the patients were less than 45 years and regardless of the level of inflammation.

LC-IMS-HRMS for identification of biomarkers in untargeted metabolomics: The effects of pterostilbene and resveratrol consumption in liver steatosis, animal model.

Untargeted metabolomics with the combination of ion mobility separation coupled to high resolution mass spectrometry (IMS-HRMS) was applied to investigate the impact of resveratrol and pterostilbene supplementation on the metabolic fingerprint of the Wistar rats liver with induced liver steatosis. RP-LC and HILIC in both ionisation modes were employed to analyse the liver samples (n = 40) from Wistar rats fed with a high-fat and high-fructose diet, supplemented or not with resveratrol and pterostilbene. After univariate and multivariate statistical analysis, 34 metabolites were highlighted in the different diets and elucidated. Despite the structural similarity, different alterations in liver metabolism were observed by the supplementations. Resveratrol treatment was characterised by the alteration in metabolism of 17 lysophospholipids, while pterostilbene affected some vitamins and derivatives, among others. IMS has demonstrated great potential in the elucidation process thanks to the additional structural descriptor the CCS (Å2), providing more confidence in the identification.

Discovery of Food Intake Biomarkers Using Metabolomics.

Due to the high impact of diet exposure on health, it is crucial the generation of robust data of regular dietary intake, hence improving the accuracy of dietary assessment. The metabolites derived from individual food or group of food have great potential to become biomarkers of food intake (BFIs) and provide more objective food consumption measurements.Herein, it is presented an untargeted metabolomic workflow for the discovery BFIs in blood and urine samples, from the study design to the biomarker identification. Samples are analyzed by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). A wide variety of compounds are covered by separate analyses of medium to nonpolar molecules and polar metabolites based on two LC separations as well as both positive and negative electrospray ionization. The main steps of data treatment of the comprehensive data sets and statistical analysis are described, as well as the principal considerations for the BFI identification.

A Comparison between Three Tuning Strategies for Gaussian Kernels in the Context of Univariate Genomic Prediction.

Genomic prediction is revolutionizing plant breeding since candidate genotypes can be selected without the need to measure their trait in the field. When a reference population contains both phenotypic and genotypic information, it is trained by a statistical machine learning method that is subsequently used for making predictions of breeding or phenotypic values of candidate genotypes that were only genotyped. Nevertheless, the successful implementation of the genomic selection (GS) methodology depends on many factors. One key factor is the type of statistical machine learning method used since some are unable to capture nonlinear patterns available in the data. While kernel methods are powerful statistical machine learning algorithms that capture complex nonlinear patterns in the data, their successful implementation strongly depends on the careful tuning process of the involved hyperparameters. As such, in this paper we compare three methods of tuning (manual tuning, grid search, and Bayesian optimization) for the Gaussian kernel under a Bayesian best linear unbiased predictor model. We used six real datasets of wheat (Triticum aestivum L.) to compare the three strategies of tuning. We found that if we want to obtain the major benefits of using Gaussian kernels, it is very important to perform a careful tuning process. The best prediction performance was observed when the tuning process was performed with grid search and Bayesian optimization. However, we did not observe relevant differences between the grid search and Bayesian optimization approach. The observed gains in terms of prediction performance were between 2.1% and 27.8% across the six datasets under study.

Multi-trait genome prediction of new environments with partial least squares.

The genomic selection (GS) methodology proposed over 20 years ago by Meuwissen et al. (Genetics, 2001) has revolutionized plant breeding. A predictive methodology that trains statistical machine learning algorithms with phenotypic and genotypic data of a reference population and makes predictions for genotyped candidate lines, GS saves significant resources in the selection of candidate individuals. However, its practical implementation is still challenging when the plant breeder is interested in the prediction of future seasons or new locations and/or environments, which is called the "leave one environment out" issue. Furthermore, because the distributions of the training and testing set do not match, most statistical machine learning methods struggle to produce moderate or reasonable prediction accuracies. For this reason, the main objective of this study was to explore the use of the multi-trait partial least square (MT-PLS) regression methodology for this specific task, benchmarking its performance with the Bayesian Multi-trait Genomic Best Linear Unbiased Predictor (MT-GBLUP) method. The benchmarking process was performed with five actual data sets. We found that in all data sets the MT-PLS method outperformed the popular MT-GBLUP method by 349.8% (under predictor E + G), 484.4% (under predictor E + G + GE; where E denotes environments, G genotypes and GE the genotype by environment interaction) and 15.9% (under predictor G + GE) across traits. Our results provide empirical evidence of the power of the MT-PLS methodology for the prediction of future seasons or new environments. Furthermore, the comparison between single univariate-trait (UT) versus MT for GBLUP and PLS gave an increase in prediction accuracy of MT-GBLUP versus UT-GBLUP, but not for MT-PLS versus UT-PLS.

Efficacy and safety of ixekizumab treatment in patients with axial spondyloarthritis: 2-year results from COAST.

OBJECTIVES: To study the efficacy and safety of ixekizumab (IXE) in patients with radiographic (r-) and non-radiographic (nr-)axial spondyloarthritis (axSpA) for up to 116 weeks. METHODS: COAST-Y (NCT03129100) is the 2-year extension study following COAST-V, COAST-W and COAST-X. Patients were treated with either 80 mg IXE every 4 weeks or 2 weeks, as assigned in the originating studies. Efficacy was assessed in all participants continuously treated with IXE through week 116 and in subgroups based on disease subtype and dosing. Missing data were handled by non-responder imputation for categorical variables and modified baseline observation carried forward for continuous variables. Safety data were analysed in all patients having received ≥1 IXE dose. RESULTS: Of 932 patients who received ≥1 IXE dose, 773 enrolled in COAST-Y (82.9%); 665 of which (86.0%) completed week 116. Of 352 continuously treated patients, the proportion achieving Assessment of Spondyloarthritis International Society (ASAS40) at week 52 was 51.4%, which increased to 56.0% at week 116. The proportion of patients achieving ASAS40 at week 116 was 64.9% and 57.7% for biological disease-modifying antirheumatic drug (bDMARD)-naïve patients with r-axSpA and nr-axSpA, respectively, and 47.0% for TNFi-experienced patients. The proportion of patients achieving Ankylosing Spondylitis Disease Activity Score <2.1 through week 116 was 57.0% and 52.9% for bDMARD-naïve patients with r-axSpA and nr-axSpA, respectively, and 33.6% for TNFi-experienced patients. Incidences of treatment-emergent adverse events and serious adverse events were consistent with previous reports. CONCLUSION: IXE treatment led to sustained long-term improvements in patients with axSpA, with similar efficacy for r-axSpA and nr-axSpA, and for patients receiving the approved every 4 weeks dose. The safety profile of IXE was consistent with previous reports. No new safety signals were identified.

Benefits of Ion Mobility Separation in GC-APCI-HRMS Screening: From the Construction of a CCS Library to the Application to Real-World Samples.

The performance of gas chromatography (GC) combined with the improved identification properties of ion mobility separation coupled to high-resolution mass spectrometry (IMS-HRMS) is presented as a promising approach for the monitoring of (semi)volatile compounds in complex matrices. The soft ionization promoted by an atmospheric pressure chemical ionization (APCI) source designed for GC preserves the molecular and/or quasi-molecular ion information enabling a rapid, sensitive, and efficient wide-scope screening. Additionally, ion mobility separation (IMS) separates species of interest from coeluting matrix interferences and/or resolves isomers based on their charge, shape, and size, making IMS-derived collision cross section (CCS) a robust and matrix-independent parameter comparable between instruments. In this way, GC-APCI-IMS-HRMS becomes a powerful approach for both target and suspect screening due to the improvements in (tentative) identifications. In this work, mobility data for 264 relevant multiclass organic pollutants in environmental and food-safety fields were collected by coupling GC-APCI with IMS-HRMS, generating CCS information for molecular ion and/or protonated molecules and some in-source fragments. The identification power of GC-APCI-IMS-HRMS for the studied compounds was assessed in complex-matrix samples, including fish feed extracts, surface waters, and different fruit and vegetable samples.

Efficacy and safety of ixekizumab in patients with active psoriatic arthritis with and without concomitant conventional disease-modifying antirheumatic drugs: SPIRIT-P1 and SPIRIT-P2 3-year results.

INTRODUCTION/OBJECTIVES: To evaluate the three-year efficacy and safety of ixekizumab with and without concomitant conventional synthetic disease-modifying antirheumatic drug (csDMARD) use in patients with active psoriatic arthritis (PsA). METHOD: Patients with PsA who were biologic-naïve (SPIRIT-P1, NCT01695239) or had prior inadequate response to tumor necrosis factor inhibitors (SPIRIT-P2, NCT02349295) were randomized to receive 80-mg ixekizumab every four weeks after receiving 160-mg ixekizumab at baseline. Efficacy, safety, and immunogenicity were evaluated in this post-hoc analysis in three subgroups: (1) ixekizumab monotherapy, (2) ixekizumab and methotrexate (MTX), (3) ixekizumab and any csDMARD (including MTX). Missing data were imputed using multiple imputation for continuous variables and modified non-responder imputation for categorical variables. RESULTS: Efficacy was similar across the three subgroups with 59.1%, 67.0%, and 66.1% of ixekizumab-treated patients achieving 20% improvement in the American College of Rheumatology scale score at week 156. Radiographic progression of structural joint damage (SPIRIT-P1 only) was similarly inhibited across the three subgroups with several outliers. No new safety signals were reported, and 91.0%, 84.1%, and 83.2% in the three subgroups reported ≥ 1 treatment-emergent adverse event. At week 156, 15.9%, 13.1%, and 11.0% in the three subgroups had antidrug antibodies; most had low titer status. CONCLUSIONS: Ixekizumab showed sustained efficacy in treating patients with PsA for up to three years in monotherapy or in combination with MTX or any csDMARD. The three subgroups had similar safety and immunogenicity profiles, which supports that the use of concomitant MTX or csDMARDs does not seem to impact the benefit/risk profile of ixekizumab. Key Points • Ixekizumab treatment led to improved clinical responses over time when used as monotherapy or in combination with concomitant MTX or any concomitant csDMARD (including MTX) in patients with active PsA. • Ixekizumab monotherapy has similar radiographic efficacy as ixekizumab with MTX or ixekizumab with other csDMARDs (including MTX); similar inhibition of radiographic progression was observed between the subgroups of patients receiving ixekizumab monotherapy or ixekizumab with MTX or other csDMARDs. • The long-term safety profile of ixekizumab used as monotherapy or in combination with MTX or any other csDMARDs is consistent with what has been previously reported. The addition of MTX or any csDMARD to ixekizumab treatment did not negatively impact the favorable long-term safety profile of ixekizumab.

Baseline Characteristics and Treatment Response to Ixekizumab Categorised by Sex in Radiographic and Non-radiographic Axial Spondylarthritis Through 52 Weeks: Data from Three Phase III Randomised Controlled Trials.

OBJECTIVES: Assess baseline characteristics and treatment response to ixekizumab (IXE) categorised by sex in patients with radiographic axial spondyloarthritis (r-axSpA) and non-radiographic axSpA (nr-axSpA) up to 52 weeks. METHODS: Data were analysed from three randomised controlled trials of IXE through 52 weeks. Patients fulfilled ASAS classification criteria for r-axSpA or nr-axSpA and were randomised to receive 80 mg subcutaneous administration of IXE every 2 weeks (Q2W) or 4 weeks (Q4W), or placebo (16 weeks COAST-V/W; 52 weeks COAST-X). Baseline characteristics and treatment outcomes were assessed. Patients were categorised by sex; methods included non-responder imputation for categorical variables, and modified baseline observation carried forward for continuous efficacy variables. RESULTS: At presentation, female patients had higher disease burden as reflected by significantly higher spinal pain at night, fatigue scores and pain/swelling in joints other than the neck, back or hip. ASAS40 response rate with the approved label dose, IXEQ4W, was achieved in 39% of male patients with r-axSpA by week 16, and 44% by week 52. For female patients, 16.7% and 33.3% achieved ASAS40 at week 16 and 52, respectively. In nr-axSpA, 46% of male patients achieved ASAS40 at week 16 and 30% at week 52. In total, 23.9% of female patients achieved ASAS40 at week 16, and 30.4% at week 52. CONCLUSIONS: This analysis demonstrates that for the axSpA disease spectrum, female patients present with higher disease burden. Following treatment with IXE, there is a higher proportion of male responders up to 16 weeks, while female patients show less robust responses for the first 16 weeks but larger responses from weeks 16 through 52. TRIAL REGISTRATION NUMBERS: NCT02696785, NCT02696798 and NCT02757352.

Ixekizumab in radiographic axial spondyloarthritis with and without elevated C-reactive protein or positive magnetic resonance imaging.

OBJECTIVE: To evaluate response rates at week 16 with ixekizumab in patients with radiographic axial SpA (r-axSpA) and elevated or normal/low baseline inflammation measured by serum CRP or spinal MRI using data from two randomized, double-blind, placebo (PBO)-controlled phase III trials. METHODS: Biologic-naïve (COAST-V) or TNF inhibitor-experienced (COAST-W) adults with active r-axSpA received 80 mg ixekizumab every 2 weeks (IXEQ2W) or 4 weeks (IXEQ4W) or PBO or active reference [40 mg adalimumab every 2 weeks (ADAQ2W) in COAST-V. At week 16, patients receiving ixekizumab continued as assigned and patients receiving PBO or ADA were rerandomized 1:1 to IXEQ2W or IXEQ4W through week 52. Assessment of SpondyloArthritis international Society 40% (ASAS40) response rates were examined by baseline CRP (≤5 or >5 mg/l) and Spondyloarthritis Research Consortium of Canada (SPARCC) MRI spine inflammation score (<2 or ≥2). RESULTS: In the COAST-V/W integrated dataset (N = 567), significantly more patients treated with ixekizumab achieved ASAS40 response at week 16 by CRP ≤5 mg/l (27% IXEQ4W, P < 0.05; 35% IXEQ2W, P < 0.01 vs 12% PBO), CRP >5 mg/l (39% IXEQ4W, P < 0.001; 43% IXEQ2W, P < 0.001 vs 17% PBO), SPARCC MRI spine score <2 (40% IXEQ4W P < 0.01, 52% IXEQ2W P < 0.001 vs 16% PBO), and SPARCC MRI spine score ≥2 (44% IXEQ4W P < 0.001, 47% IXEQ2W P < 0.001 vs 19% PBO). ASAS40 response was observed with CRP ≤5 mg/l and SPARCC MRI spine score <2 with IXEQ4W (29%) and was significant with IXEQ2W (48%; P < 0.05) vs PBO (13%). CONCLUSION: Ixekizumab demonstrated efficacy in the treatment of AS/r-axSpA in patients with and without elevated CRP or evidence of spinal inflammation on MRI. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov): NCT02696785, NCT02696798.

Spinal Radiographic Progression and Predictors of Progression in Patients With Radiographic Axial Spondyloarthritis Receiving Ixekizumab Over 2 Years.

OBJECTIVE: To evaluate the long-term effect of ixekizumab (IXE) on radiographic changes in the spine in patients with radiographic axial spondyloarthritis (r-axSpA) by measuring change from baseline through 2 years in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS), and to identify potential predictors of progression. METHODS: This study evaluates patients from COAST-V (ClinicalTrials.gov: NCT02696785, biologic disease-modifying antirheumatic drug-naïve) and COAST-W (NCT02696798, tumor necrosis factor inhibitor-experienced) who had mSASSS data at baseline in the originating studies and 108 weeks after baseline in the extension study COAST-Y (NCT03129100). We examined the proportion of patients who did not have spinal radiographic progression through 2 years (108 weeks) of treatment with IXE (80 mg every 2 or 4 weeks) and the change from baseline to year 2 in mSASSS. Potential predictors of spinal radiographic progression were also evaluated. RESULTS: Among patients with evaluable radiographs who were originally assigned to IXE (n = 230), mean (SD) change in mSASSS from baseline at year 2 was 0.3 (1.8). The proportion of nonprogressors over 2 years was 89.6% if defined as mSASSS change from baseline < 2 and 75.7% if defined as mSASSS change from baseline ≤ 0. Predictors of structural progression at year 2 (mSASSS change > 0) were age ≥ 40, baseline syndesmophytes, HLA-B27 positivity, and male sex. Week 52 inflammation in Spondyloarthritis Research Consortium of Canada spine was also a predictor of radiographic progression at year 2 in patients with magnetic resonance imaging data in COAST-V (n = 109). CONCLUSION: The majority of patients with r-axSpA receiving IXE had no radiographic progression in the spine through 2 years of treatment. Predictors were generally consistent with previous studies.

Effects of ixekizumab treatment on structural changes in the sacroiliac joint: MRI assessments at 16 weeks in patients with non-radiographic axial spondyloarthritis.

BACKGROUND: There is limited understanding regarding the inhibition of structural damage in the sacroiliac joint of patients with non-radiographic axial spondyloarthritis. This study evaluated the effect of the interleukin-17A inhibitor ixekizumab versus placebo on structural lesions in the sacroiliac joints as assessed by MRI at week 16 in patients with non-radiographic axial spondyloarthritis from the COAST-X study. METHODS: COAST-X was a 52-week, randomised, double-blind, placebo-controlled, parallel-group study done at 107 sites in 15 countries in Europe, Asia, North America, and South America. Eligible participants were adults (aged ≥18 years) with active axial spondyloarthritis without definite radiographic sacroiliitis (non-radiographic axial spondyloarthritis), objective signs of inflammation (via MRI or C-reactive protein), and an inadequate response or intolerance to non-steroidal anti-inflammatory drugs. Patients were randomly allocated to placebo or double-blind ixekizumab 80 mg every 4 weeks (Q4W) or 2 weeks (Q2W), with an 80 mg or 160 mg starting dose. We report a post-hoc analysis of 266 patients with available MRI scans from baseline and week 16. MRI scans were scored using the Spondyloarthritis Research Consortium of Canada (SPARCC) sacroiliac joint structural score (SSS) method independently by two masked readers. Treatment comparisons used analysis of covariance based on observed cases. Correlations were evaluated among changes in SPARCC SSS for erosion, fat lesions, and backfill, and between changes in SPARCC SSS and sacroiliac joint inflammation scores and clinical measures. COAST-X was registered with ClinicalTrials.gov, NCT02757352. FINDINGS: Between Aug 2, 2016, and Jan 29, 2018, 303 patients were enrolled to the COAST-X study. 290 (96%) of 303 participants completed the week 16 visit (95 in the ixekizumab Q4W group, 98 in the ixekizumab Q2W group, and 97 in the placebo group), and MRI scans were available for 266 patients at baseline and week 16 (85 in the ixekizumab Q4W group, 91 in the ixekizumab Q2W group, and 90 in the placebo group). Changes from baseline to week 16 in mean SPARCC SSS for erosion were -0·39 for ixekizumab Q4W (p=0·003 vs placebo), -0·40 for ixekizumab Q2W (p=0·002), and 0·16 for placebo; for fat lesions: 0·16 for ixekizumab Q4W (p=0·013), 0·10 for ixekizumab Q2W (p=0·067), and -0·04 for placebo; and for backfill: 0·21 for ixekizumab Q4W (p=0·011), 0·22 for ixekizumab Q2W (p=0·006), and -0·10 for placebo. Ankylosis did not change. Effects of ixekizumab versus placebo on structural changes were most pronounced in patients with baseline inflammation in the sacroiliac joints. Changes from baseline at week 16 in erosion, fat lesions, and backfill were correlated. INTERPRETATION: Although the clinical relevance is not yet clear, patients with non-radiographic axial spondyloarthritis receiving ixekizumab had significant reductions in erosions and increases in fat lesions and backfill in the sacroiliac joints versus placebo at week 16, suggesting an early repair process with ixekizumab treatment. FUNDING: Eli Lilly and Company.

Ixekizumab improves sleep and work productivity in patients with non-radiographic axial spondyloarthritis: results from the COAST-X trial at 52 weeks.

BACKGROUND: Patients with non-radiographic axial spondyloarthritis experience negative impacts on sleep, work productivity, and activity impairment. Ixekizumab, a monoclonal antibody selectively targeting interleukin-17A, has shown efficacy in treating the signs and symptoms of non-radiographic axial spondyloarthritis. This analysis evaluated the effect of ixekizumab treatment on sleep, work productivity, and activity impairment in patients with non-radiographic axial spondyloarthritis. METHODS: COAST-X ( NCT02757352 ) was a 52-week, phase 3, multicenter, randomised placebo-controlled trial evaluating 80-mg ixekizumab every 2 weeks and every 4 weeks in patients with active non-radiographic axial spondyloarthritis. Sleep disturbance was measured with the Jenkins Sleep Evaluation Questionnaire (JSEQ) and analysed using mixed-effects models for repeated measures. Work productivity and activity impairment were measured using the Work Productivity and Activity Impairment Questionnaire for Spondyloarthritis and analysed using analysis of covariance. Absenteeism, presenteeism, and overall work impairment were assessed for patients reporting paid work; activity impairment was assessed regardless of work status. RESULTS: Overall, patients treated with both dosing regimens of ixekizumab reported numerically greater improvements in sleep than placebo through Week 52. At Weeks 16 and 52, patients treated with ixekizumab every 4 weeks had significantly greater improvements in presenteeism (p = 0.007 and p = 0.003, respectively) and overall work impairment (p = 0.014 and p = 0.005, respectively) and numeric improvements in absenteeism than placebo. Patients treated with ixekizumab every 2 weeks had numerically greater improvements in absenteeism, presenteeism, and overall work impairment than placebo. Both dosing regimens of ixekizumab were associated with significantly greater improvements in activity impairment than placebo (ixekizumab every 4 weeks: p = 0.003 at Week 16 and p = 0.004 at Week 52; ixekizumab every 2 weeks: p = 0.007 at Week 16 and p = 0.006 at Week 52). CONCLUSIONS: Treatment with ixekizumab improved sleep, work productivity, and activity impairment in patients with nr-axSpA. Improvements in presenteeism and overall work impairment were sustained and consistent in the patients treated with ixekizumab every 4 weeks from Week 16 to Week 52. Improvements in activity impairment were sustained and consistent in both ixekizumab-treated groups from Week 16 to Week 52. TRIAL REGISTRATION: NCT02757352 , May 2, 2016.

Comparing symptoms, treatment patterns, and quality of life of ankylosing spondylitis and non-radiographic axial spondyloarthritis patients in the USA: findings from a patient and rheumatologist Survey.

OBJECTIVES: The aim of this study was to compare the symptoms, treatment patterns, and quality of life (QoL) of ankylosing spondylitis (AS) patients to non-radiographic axial spondyloarthritis (nr-axSpA) patients in the USA. METHOD: A cross-sectional survey was conducted with rheumatologists and their consulting patients in the USA from June through August 2018. Patients who had a rheumatologist confirmed diagnosis of AS and nr-axSpA were eligible to participate. Patient demographics, symptoms, and medication use were reported by the rheumatologist, while work disability and QoL measures were reported by the patient. Patient demographics, symptoms, QoL and treatment patterns of AS and nr-axSpA patients were compared using parametric tests and non-parametric tests when appropriate. RESULTS: A total of 515 AS patients and 495 nr-axSpA patients were included in this analysis. A higher proportion of AS patients were male (p < 0.001), older (p = 0.014), and more likely to be prescribed a biologic (p < 0.0001). On average, AS patients experienced slightly more symptoms at diagnosis (p = 0.023); however, nr-axSpA patients were more likely to experience enthesitis (p = 0.048) and synovitis (p = 0.003). Patient reported outcomes such as the ASAS Health Index (p = 0.171), ASQoL (p = 0.296), BASDAI (p = 0.124), and WPAI (p = 0.183) were similar between AS and nr-axSpA patients after adjusting for confounding variables such as medication use. CONCLUSIONS: AS and nr-axSpA patients share the same clinical features. The burden of the disease, as assessed by QoL measurements, is also similar in AS and nr-axSpA patients; however, despite these similarities, patients with nr-axSpA are less likely to be treated with a biologic. KEY POINTS: • Ankylosing spondylitis and non • radiographic axial spondyloarthritis patients share similar clinical features and burden of disease. • Quality of life is similar among ankylosing spondylitis and non • radiographic axial spondyloarthritis after adjusting for current treatment patterns.

Ixekizumab Improves Patient-Reported Outcomes in Non-Radiographic Axial Spondyloarthritis: Results from the Coast-X Trial.

INTRODUCTION: Ixekizumab, an interleukin-17A antibody, has shown efficacy in non-radiographic axial spondyloarthritis (nr-axSpA). The objectives of this analysis were (a) to measure improvement in ixekizumab-treated patients in Assessment of Spondyloarthritis International Society (ASAS) response domains and other patient-reported outcomes (PROs) and (b) to determine how ASAS responses were associated with changes in patient global disease activity (PtGA), spinal pain, function, stiffness, fatigue, and spinal pain at night. METHODS: COAST-X was a phase 3, 52-week multicenter, randomized, controlled trial investigating the efficacy and safety of 80-mg ixekizumab every 2 weeks (Q2W) and every 4 weeks (Q4W) in patients with active nr-axSpA. Changes from baseline in PROs were analyzed via mixed-effects models for repeated measures. Association analyses for ASAS responses used analysis of covariance with Scheffé's method. RESULTS: Patients treated with ixekizumab Q2W and Q4W reported significantly greater improvements in PtGA, spinal pain, function, and stiffness at week 1, when these measures were first assessed, compared with placebo (p < 0.05). ASAS40 responders, in comparison to ASAS20 non-responders, had the highest correlations with improvements in all response domains (PtGA, spinal pain, function, and stiffness) as well as fatigue and spinal pain at night (p < 0.001). ASAS40 responses were associated with 3.5- to 48.0-fold greater improvements in these PROs, with the highest values for PtGA and function, compared to ASAS20 non-achievement. CONCLUSIONS: As early as week 1, patients with nr-axSpA treated with ixekizumab reported significant improvements in PtGA, spinal pain, function, and stiffness compared with those taking placebo. ASAS40 responders reported significantly greater improvements in all ASAS response domains (PtGA, spinal pain, function, and stiffness) as well as fatigue and spinal pain at night than ASAS20 non-responders. Improvements in PtGA and function appear to be major drivers in achieving ASAS40 response in patients with nr-axSpA. TRIAL REGISTRATION: NCT02757352.

Impacts of soil water stress on the acclimated stomatal limitation of photosynthesis: Insights from stable carbon isotope data.

Atmospheric aridity and drought both influence physiological function in plant leaves, but their relative contributions to changes in the ratio of leaf internal to ambient partial pressure of CO2 (χ) - an index of adjustments in both stomatal conductance and photosynthetic rate to environmental conditions - are difficult to disentangle. Many stomatal models predicting χ include the influence of only one of these drivers. In particular, the least-cost optimality hypothesis considers the effect of atmospheric demand for water on χ but does not predict how soils with reduced water further influence χ, potentially leading to an overestimation of χ under dry conditions. Here, we use a large network of stable carbon isotope measurements in C3 woody plants to examine the acclimated response of χ to soil water stress. We estimate the ratio of cost factors for carboxylation and transpiration (ß) expected from the theory to explain the variance in the data, and investigate the responses of ß (and thus χ) to soil water content and suction across seed plant groups, leaf phenological types and regions. Overall, ß decreases linearly with soil drying, implying that the cost of water transport along the soil-plant-atmosphere continuum increases as water available in the soil decreases. However, despite contrasting hydraulic strategies, the stomatal responses of angiosperms and gymnosperms to soil water tend to converge, consistent with the optimality theory. The prediction of ß as a simple, empirical function of soil water significantly improves χ predictions by up to 6.3 ± 2.3% (mean ± SD of adjusted-R2 ) over 1980-2018 and results in a reduction of around 2% of mean χ values across the globe. Our results highlight the importance of soil water status on stomatal functions and plant water-use efficiency, and suggest the implementation of trait-based hydraulic functions into the model to account for soil water stress.