The Effect of Guselkumab on Work Productivity in Biologic-Naïve Patients with Active Psoriatic Arthritis Through Week 52 of the Phase 3, Randomized, Placebo-Controlled DISCOVER-2 Trial

Introduction: The phase 3 DISCOVER-2 trial evaluated the effect of guselkumab on impaired work productivity and nonwork activity in biologic-naïve patients with psoriatic arthritis (PsA). Methods: Adults with active PsA were randomized (1:1:1) to guselkumab 100 mg every 4 weeks (Q4W), guselkumab 100 mg at weeks 0 and 4 and then every 8 weeks (Q8W), or placebo (with crossover to guselkumab Q4W at week 24). Least squares mean change from baseline in Work Productivity and Activity Impairment Questionnaire for PsA (WPAI-PsA) domains and employment were assessed by treatment group. Multivariate analysis of data from weeks 0 through 24 assessed independent associations between PsA clinical features and WPAI-PsA domains. Results: In total, 738 patients were evaluated (guselkumab Q4W n = 245; guselkumab Q8W n = 248; placebo n = 245). At week 24, improvements (reduced impairment) in presenteeism (Q4W −20.1%, Q8W −19.6%, placebo −10.5%), work productivity (Q4W −20.1%, Q8W −19.2%, placebo −10.6%), and nonwork activity (Q4W −20.5%, Q8W −21.2%, placebo −9.9%) were greater in guselkumab-treated versus placebo-treated patients. At week 52, following placebo crossover at week 24, improvements were similar among groups. Baseline absenteeism was minimal and did not change in any group. By week 52, 23.1–25.9% of guselkumab-treated patients who were unemployed at baseline were employed. All WPAI-PsA domains were positively associated with C-reactive protein level, fatigue, and pain. All domains except absenteeism were positively associated with enthesitis and Psoriasis Area and Severity Index score. Age was negatively associated with presenteeism and work productivity loss, female sex and tender joint count were positively associated with nonwork activity impairment, and dactylitis was positively associated with presenteeism. Conclusion: Both guselkumab regimens reduced work productivity loss and nonwork activity impairment in patients with active PsA. Association of work productivity loss and nonwork activity impairment with PsA joint and skin features suggests that improvement in both features is beneficial for optimizing improved work productivity loss and nonwork activity impairment. Trial registration: ClinicalTrials.gov identifier, NCT03158285

IGF1 Is a Common Target Gene of Ewing's Sarcoma Fusion Proteins in Mesenchymal Progenitor Cells

The EWS-FLI-1 fusion protein is associated with 85-90% of Ewing's sarcoma family tumors (ESFT), the remaining 10-15% of cases expressing chimeric genes encoding EWS or FUS fused to one of several ets transcription factor family members, including ERG-1, FEV, ETV1 and ETV6. ESFT are dependent on insulin-like growth factor-1 (IGF-1) for growth and survival and recent evidence suggests that mesenchymal progenitor/stem cells constitute a candidate ESFT origin. To address the functional relatedness between ESFT-associated fusion proteins, we compared mouse progenitor cell (MPC) permissiveness for EWS-FLI-1, EWS-ERG and FUS-ERG expression and assessed the corresponding expression profile changes. Whereas all MPC isolates tested could stably express EWS-FLI-1, only some sustained stable EWS-ERG expression and none could express FUS-ERG for more than 3-5 days. Only 14% and 4% of the total number of genes that were respectively induced and repressed in MPCs by the three fusion proteins were shared. However, all three fusion proteins, but neither FLI-1 nor ERG-1 alone, activated the IGF1 promoter and induced IGF1 expression. Whereas expression of different ESFT-associated fusion proteins may require distinct cellular microenvironments and induce transcriptome changes of limited similarity, IGF1 induction may provide one common mechanism for their implication in ESFT pathogenesis

JWST-TST DREAMS: Quartz Clouds in the Atmosphere of WASP-17b

Clouds are prevalent in many of the exoplanet atmospheres that have been observed to date. For transiting exoplanets, we know if clouds are present because they mute spectral features and cause wavelength-dependent scattering. While the exact composition of these clouds is largely unknown, this information is vital to understanding the chemistry and energy budget of planetary atmospheres. In this work, we observe one transit of the hot Jupiter WASP-17b with JWST's MIRI LRS and generate a transmission spectrum from 5-12 $\rm{\mu}$m. These wavelengths allow us to probe absorption due to the vibrational modes of various predicted cloud species. Our transmission spectrum shows additional opacity centered at 8.6 $\rm{\mu}$m, and detailed atmospheric modeling and retrievals identify this feature as SiO$_2$(s) (quartz) clouds. The SiO$_2$(s) clouds model is preferred at 3.5-4.2$\sigma$ versus a cloud-free model and at 2.6$\sigma$ versus a generic aerosol prescription. We find the SiO$_2$(s) clouds are comprised of small ${\sim}0.01$ $\rm{\mu}$m particles, which extend to high altitudes in the atmosphere. The atmosphere also shows a depletion of H$_2$O, a finding consistent with the formation of high-temperature aerosols from oxygen-rich species. This work is part of a series of studies by our JWST Telescope Scientist Team (JWST-TST), in which we will use Guaranteed Time Observations to perform Deep Reconnaissance of Exoplanet Atmospheres through Multi-instrument Spectroscopy (DREAMS).Comment: 19 pages, 7 figures, accepted for publication in ApJ

Omega-3 fatty acids and genome-wide interaction analyses reveal DPP10-pulmonary function association

Rationale: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health. Objective: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility. Methods: Associations of n-3 PUFA biomarkers (a-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (FEV1, FVC, and FEV1/FVC) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N=16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N=11,962) and replicated in one cohort (N=1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of SNPassociations and their interactions with n-3PUFAs. Results: DPA and DHA were positively associated with FEV1 and FVC (P < 0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P-2df = 9.4 x 10(-9) across discovery and replication cohorts). The rs11693320-A allele (frequency, similar to 80%) was associated with lower FVC (P-SNP = 2.1 x 10(-9); beta(SNP) = 2161.0 ml), and the association was attenuated by higher DHA levels (P-SNPxDHA interaction = 2.1x10(-7); beta(SNPxDHA interaction) = 36.2 ml). Conclusions: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction

The case for developing a cohesive systems approach to research across unhealthy commodity industries.

OBJECTIVES: Most non-communicable diseases are preventable and largely driven by the consumption of harmful products, such as tobacco, alcohol, gambling and ultra-processed food and drink products, collectively termed unhealthy commodities. This paper explores the links between unhealthy commodity industries (UCIs), analyses the extent of alignment across their corporate political strategies, and proposes a cohesive systems approach to research across UCIs. METHODS: We held an expert consultation on analysing the involvement of UCIs in public health policy, conducted an analysis of business links across UCIs, and employed taxonomies of corporate political activity to collate, compare and illustrate strategies employed by the alcohol, ultra-processed food and drink products, tobacco and gambling industries. RESULTS: There are clear commonalities across UCIs' strategies in shaping evidence, employing narratives and framing techniques, constituency building and policy substitution. There is also consistent evidence of business links between UCIs, as well as complex relationships with government agencies, often allowing UCIs to engage in policy-making forums. This knowledge indicates that the role of all UCIs in public health policy would benefit from a common approach to analysis. This enables the development of a theoretical framework for understanding how UCIs influence the policy process. It highlights the need for a deeper and broader understanding of conflicts of interests and how to avoid them; and a broader conception of what constitutes strong evidence generated by a wider range of research types. CONCLUSION: UCIs employ shared strategies to shape public health policy, protecting business interests, and thereby contributing to the perpetuation of non-communicable diseases. A cohesive systems approach to research across UCIs is required to deepen shared understanding of this complex and interconnected area and also to inform a more effective and coherent response

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Type 2 Diabetes Modifies the association of Cad Genomic Risk Variants With Subclinical atherosclerosis

BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D. METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test. RESULTS: Using a Bonferroni-corrected significance threshold of CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC

Early Release Science of the Exoplanet WASP-39b with JWST NIRSpec G395H

Measuring the abundances of carbon and oxygen in exoplanet atmospheres is considered a crucial avenue for unlocking the formation and evolution of exoplanetary systems. Access to an exoplanet's chemical inventory requires high-precision observations, often inferred from individual molecular detections with low-resolution space-based and high-resolution ground-based facilities. Here we report the medium-resolution (R$\sim$600) transmission spectrum of an exoplanet atmosphere between 3-5 $\mu$m covering multiple absorption features for the Saturn-mass exoplanet WASP-39b, obtained with JWST NIRSpec G395H. Our observations achieve 1.46x photon precision, providing an average transit depth uncertainty of 221 ppm per spectroscopic bin, and present minimal impacts from systematic effects. We detect significant absorption from CO$_2$ (28.5$\sigma$) and H$_2$O (21.5$\sigma$), and identify SO$_2$ as the source of absorption at 4.1 $\mu$m (4.8$\sigma$). Best-fit atmospheric models range between 3 and 10x solar metallicity, with sub-solar to solar C/O ratios. These results, including the detection of SO$_2$, underscore the importance of characterising the chemistry in exoplanet atmospheres, and showcase NIRSpec G395H as an excellent mode for time series observations over this critical wavelength range.Comment: 44 pages, 11 figures, 3 tables. Resubmitted after revision to Natur