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Background:Rheumatoid arthritis (RA) has a major impact on patients (pts), particularly around quality of life and activity impairment. While the association between clinical manifestations and patient-reported outcomes (PROs) has been demonstrated, the independent effect of specific joint involvement on PROs and their change over time has not been fully elucidated.Objectives:To describe the independent effect of overall and specific joint involvement and their changes over time on PROs in pts with RA treated with abatacept.Methods:This post hoc analysis involved 290 adult RA pts initiated on treatment with abatacept in the Abatacept Best Care (ABC) study (NCT03274141)1. The analysis investigated the association of Tender Joint Count (TJC-28), Swollen Joint Count (SJC-28) and involvement (tender and/or swollen) of five joint groups (shoulder, knee, elbow, wrist, and hand) with changes from baseline (BL) to 12 months (12M) of follow-up in selected PROs: Pt Global Assessment (PtGA), Pt Pain, Pt Fatigue, Health Assessment Questionnaire-Disability Index (HAQ-DI), Routine Assessment of Patient Index Data 3 (RAPID3), Work Productivity and Activity Impairment - Activity Impairment (WPAI-AI) score. Simple linear regression was used to test the association between BL and changes from BL to 12M in TJC and SJC with changes in each PRO at 12M. Multivariate linear regression adjusting for the five available joint groups examined the independent effect of BL and changes from BL to 12M in these joint groups on changes in each PRO at 12M.Results:Among 290 pts, the mean (SD) age was 60.1 (11.6) years, 73.8% were female, and the mean (SD) RA duration was 7.7 (9.0) years. Table 1 describes joint involvement (tender and/or swollen) at BL and the change from BL to 12M for 289 pts with 12M data.Mean (SD) TJC and SJC at BL were 9.6 (6.2) and 7.9 (4.7) and changes in TJC and SJC from BL to 12M were -6.3 (6.6) and -5.9 (5.2), respectively. BL TJC and SJC were not associated with changes in PROs from BL to 12M, whereas changes at 12M in TJC and SJC were significantly (P<0.05) associated with changes in all PROs.Table 2 summarizes the significant (P<0.05) independent associations between BL or change in involvement (tender and/or swollen) of the five available joint groups from BL to 12M with changes in PROs at 12M. Change in hand involvement was significantly associated with changes in all PROs. After adjusting for all available joint groups, changes in elbow, hand, and knee involvement showed the greatest impact on patient function and activity impairment. Elbow was the only joint whose BL involvement was associated with significantly greater improvements in Pt Pain, PtGA, and functional status through 12M.Conclusion:For the majority of pts, specific joint involvement at BL was resolved by 12M of treatment with abatacept. Changes in PROs at 12M were associated with BL elbow involvement and 12M changes in elbow, hand, and knee involvement. These findings have potential implications for clinical practice and research by guiding the focus of evaluations and therapeutic targets.REFERENCES:[1] Bessette, L. et al. Effectiveness of a treat-to-target strategy in patients with moderate to severely active rheumatoid arthritis treated with abatacept. Arthritis Res Ther 25, 183 (2023). https://doi.org:10.1186/s13075-023-03151-2Acknowledgements:NIL.Disclosure of Interests:Janet Pope consultant: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Gilead, Janssen, Medexus, MSD, Novartis, Pfizer, Roche, Sandoz, Sanofi, Teva and UCB, grant/research support: AbbVie, Bristol Myers Squibb, MSD, Pfizer, Roche, Seattle Genetics and UCB, John Sampalis employee of JSS Medical Research, the contract research organization that managed the study, Boulos Haraoui advisory board member and research grants from Abbvie, Amgen, BMS, Fresenius Kabi, Lilly, Pfizer and UCB, Emmanouil Rampakakis employee of JSS Medical Research, the contract research organization that managed the study, Fiona Allum employee of JSS Medical Research, the contract research organization that managed the study, Marc Olivier Trepanier Employee of Bristol Myers Squibb and may hold stock or stock options, Employee of Bristol Myers Squibb, Louis Bessette speaker for Amgen, BMS, Janssen, UCB, AbbVie, Pfizer, Lilly, Novartis, Sanofi, Sandoz, Fresenius Kabi, Teva, Organon and JAMP Pharma, consultant for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Gilead, Janssen, Medexus, MSD, Novartis, Pfizer, Roche, Sandoz, Sanofi, Teva and UCB.

Polycyclic aromatic hydrocarbons (PAHs) play an important role in interstellar chemistry and are subject to high energy photons that can induce excitation, ionization, and fragmentation. Previous studies have demonstrated electronic relaxation of parent PAH monocations over 10–100 femtoseconds as a result of beyond-Born-Oppenheimer coupling between the electronic and nuclear dynamics. Here, we investigate three PAH molecules: fluorene, phenanthrene, and pyrene, using ultrafast XUV and IR laser pulses. Simultaneous measurements of the ion yields, ion momenta, and electron momenta as a function of laser pulse delay allow a detailed insight into the various molecular processes. We report relaxation times for the electronically excited PAH * , PAH +* and PAH 2+* states, and show the time-dependent conversion between fragmentation pathways. Additionally, using recoil-frame covariance analysis between ion images, we demonstrate that the dissociation of the PAH 2+ ions favors reaction pathways involving two-body breakup and/or loss of neutral fragments totaling an even number of carbon atoms. Polycyclic aromatic hydrocarbons play an important role in interstellar chemistry, where interaction with high energy photons can induce ionization and fragmentation reactions. Here the authors, with XUV-IR pump-probe experiments, investigate the ultrafast photoinduced dynamics of fluorene, phenanthrene and pyrene, providing insight into their preferred reaction channels.

Chromosome doubling was induced in vitro in a diploid hybrid of Rosa rugosa Thunb. using oryzalin as the spindle inhibitor. Nodal sections, 2 mm long, were exposed to 2.5 or 5 microM oryzalin and 10 mm nodal sections were exposed to 5 microM oryzalin for 0 (controls), 6, 12, 24 and 48 h. The ploidy of the emergent shoots was determined by flow cytometry. The frequency of tetraploid and mixoploid leaves that developed from 2 mm nodal sections exposed to 5 microM oryzalin peaked at 12 h exposure, when 35% of the leaves were tetraploid, but fell after longer exposures. Fewer tetraploid and mixoploid leaves were found when 2 mm nodes were exposed to 2.5 microM oryzalin for 6 and 12 h, indicating that it took longer for a spindle inhibiting concentration of oryzalin to build up in the meristem. However, the frequencies of tetraploid and mixoploid leaves continued to rise after 12 h and were highest at 48 h, when 44% were tetraploid. In treatments with 5 microM oryzalin, the frequencies of tetraploid and mixoploid leaves were lower, at equivalent exposure times, in 10 mm nodes than 2 mm nodes. This suggests that oryzalin diffused to the meristem mainly via the cut surfaces and that access via the epidermis and cuticle was impeded.

Synopsis (X-ray) free-electron lasers are employed to site specifically interrogate atomic fragments during ultra-fast photolysis of chiral molecules via time-resolved photoelectron circular dichroism.

Synopsis In the interstellar medium polycyclic aromatic hydrocarbon molecules (PAH) are exposed to strong ionizing radation leading to complex organic photochemistry. We investigated these ultrafast fragmentation reactions after ionization of the PAHs phenanthrene, fluorene and pyrene at a wavelength of 30.3 nm using pump probe spectroscopy at a free electron laser. We observe double ionization and afterwards hydrogen abstraction and acetylene loss with characteristic time scales for the reaction processes below one hundred femtoseconds.

Sparse profiling of CpG methylation in blood by microarrays has identified epigenetic links to common diseases. Here we apply methylC-capture sequencing (MCC-Seq) in a clinical population of ~200 adipose tissue and matched blood samples (N total ~400), providing high-resolution methylation profiling (>1.3 M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in ~800 independent adipose tissue and blood samples from the general population. We follow-up on adipose-specific regulatory regions under (1) genetic and (2) epigenetic (environmental) regulation via integrational studies. Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits. Obesity and related metabolic complications represent an important health burden. Here the authors carry out a methylC-capture sequencing-based epigenome-wide association study to link circulating plasma lipid levels, CpG methylation and cardiometabolic risk across adipose and blood tissues.

Over the last 35 years, the acclaimed American political economist, Thomas C. Schelling, has asserted his belief that organized crime is purely monopoly enterprise. His definition of the phenomenon remains highly influential & continues to form the basis of many definitions of organized crime today. This article outlines Schelling's economic definition of organized crime & then applies it to an analysis of the major organized crime groups operating in the states of the European Union. It concludes that a purely economic definition is inadequate to define organized crime in Europe in the 21st century & that, in order to understand the phenomenon fully, other variables need to be introduced & appreciated. 40 References. Adapted from the source document.

Inner-shell photoelectron spectroscopy provides an element-specific probe of molecular structure, as core-electron binding energies are sensitive to the chemical environment. Short-wavelength femtosecond light sources, such as Free-Electron Lasers (FELs), even enable time-resolved site-specific investigations of molecular photochemistry. Here, we study the ultraviolet photodissociation of the prototypical chiral molecule 1-iodo-2-methylbutane, probed by extreme-ultraviolet (XUV) pulses from the Free-electron LASer in Hamburg (FLASH) through the ultrafast evolution of the iodine 4d binding energy. Methodologically, we employ electron-ion partial covariance imaging as a technique to isolate otherwise elusive features in a two-dimensional photoelectron spectrum arising from different photofragmentation pathways. The experimental and theoretical results for the time-resolved electron spectra of the 4d 3/2 and 4d 5/2 atomic and molecular levels that are disentangled by this method provide a key step towards studying structural and chemical changes from a specific spectator site. Coincidence experiments at free-electron lasers enable time resolved site-specific investigations of molecular photochemistry at high signal rates, but isolating individual dissociation processes still poses a considerable technical challenge. Here, the authors use electron-ion partial covariance imaging to isolate otherwise elusive chemical shifts in UV-induced photofragmentation pathways of the prototypical chiral molecule 1-iodo-2-methylbutane.

Polycyclic aromatic hydrocarbons (PAHs) play an important role in interstellar chemistry and are subject to high energy photons that can induce excitation, ionization, and fragmentation. Previous studies have demonstrated electronic relaxation of parent PAH monocations over 10–100 femtoseconds as a result of beyond-Born-Oppenheimer coupling between the electronic and nuclear dynamics. Here, we investigate three PAH molecules: fluorene, phenanthrene, and pyrene, using ultrafast XUV and IR laser pulses. Simultaneous measurements of the ion yields, ion momenta, and electron momenta as a function of laser pulse delay allow a detailed insight into the various molecular processes. We report relaxation times for the electronically excited PAH*, PAH+*and PAH2+*states, and show the time-dependent conversion between fragmentation pathways. Additionally, using recoil-frame covariance analysis between ion images, we demonstrate that the dissociation of the PAH2+ions favors reaction pathways involving two-body breakup and/or loss of neutral fragments totaling an even number of carbon atoms.

We investigated the ultrafast structural dynamics of cyclobutanone following photoexcitation at \\(\\lambda=200\\) nm using gas-phase megaelectronvolt ultrafast electron diffraction. Our investigation complements the simulation studies of the same process within this special issue. It provides information about both electronic state population and structural dynamics through well-separable inelastic and elastic electron scattering signatures. We observe the depopulation of the photoexcited S\\(_2\\) state of cyclobutanone with n3s Rydberg character through its inelastic electron scattering signature with a time constant of \\((0.29 \\pm 0.2)\\) ps towards the S\\(_1\\) state. The S\\(_1\\) state population undergoes ring-opening via a Norrish Type-I reaction, likely while passing through a conical intersection with S\\(_0\\). The corresponding structural changes can be tracked by elastic electron scattering signatures. These changes appear with a delay of \\((0.14 \\pm 0.05)\\) ps with respect the initial photoexcitation, which is less than the S\\(_2\\) depopulation time constant. This behavior provides evidence for the ballistic nature of the ring-opening once the S\\(_1\\) state is reached. The resulting biradical species react further within \\((1.2 \\pm 0.2)\\) ps via two rival fragmentation channels yielding ketene and ethylene, or propene and carbon monoxide. Our study showcases both the value of gas-phase ultrafast diffraction studies as an experimental benchmark for nonadiabatic dynamics simulation methods and the limits in the interpretation of such experimental data without comparison to such simulations.