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Objectives: The persistence in therapy of rheumatoid arthritis drugs and particularly bDMARD is a limiting factor for their long-term use. The randomized controlled trials (RCTs) may not reflect real-world contexts due to strict inclusion and exclusion criteria. Baricitinib, which targets both JAK1 and JAK2, has been used in Italy for several years. The aim of this multi-center study is to assess the real world persistence on therapy of baricitinib in RA patients and to identify predictive factors of baricitinib's survival rate. Methods: This is a retrospective, multicentric, Italian, longitudinal study. All patients were enrolled according to the following criteria: a) age ≥ 18 years old; b) diagnosed with RA according 2010 ACR/EULAR classification criteria; c) treated with baricitinib. In order to describe baricitinib clinical efficacy, the survival rate was evaluated by The Kaplan–Meier curve. Then, predictive factors of drug retention rate were assessed by performing the Cox analysis, identifying which risk factors influenced treatment persistence. Results: Overall, we included 478 patients treated with baricitinib. Among them, 380 (79.5%) were females. Baricitinib's survival rate was 94.6% at 6 months, 87.9% at 12 months, 81.7% at 24 months and 53.4% at 48 months. The Cox analysis regression showed that a higher bDMARDs/tsDMARD line of therapy seems to be a negative prognostic factor for the drug retention rate (HR 1.26 CI 95% 1.07–1.49, p = 0.006. Conclusion: Real-life study confirms baricitinib effectiveness up to 4 years, but previous treatment with bDMARDs was a negative prognostic factor for its survival rate.

A hybrid organic monolithic column made of poly(lauryl methacrylate-co-1,6-hexanediol dimethacrylate) and the metal-organic framework MIL-68(Al) was prepared for the first time. The column was used in capillary liquid chromatography, both in isocratic and gradient elution modes. Separation performance towards small molecules of different chemical nature (polycyclic aromatic hydrocarbons, alkylbenzenes, phenols, etc.) was studied. Monte Carlo simulations were made to both select the proper precursors to obtain empty metal-organic framework micropores in the monolithic polymer and also, to analyze the potential free access of the studied analytes into the micropores (necessary to improve mass transfer and column efficiency). The hereby synthesized metal-organic framework microcrystals allowed obtaining homogeneous hybrid monolithic columns. Adding of MIL-68(Al) (1030 m 2 g -1 BET specific surface area) increased the surface area from 3.9 m 2 g -1 for the parent monolith to 18.2 m 2 g -1 for the hybrid column containing 8 mg mL -1 of the microcrystals. Chromatographic performance of this new column was evaluated by studying retention factors, resolution, and plate counts at room temperature. Different compounds, not completely resolved in the parent monolith, were partially or completely separated after metal-organic framework addition. Using the monolithic column with only 2 mg mL -1 of MIL-68(Al), five alkylbenzenes were completely separated with very symmetrical peak shapes, resolution factors up to 3.60 and plate counts of 4300 plates m -1 for n-hexylbenzene. This value is higher than those obtained by other authors who used organic monolithic columns with embedded metal-organic frameworks to perform separations at room temperature. Additionally, nine polycyclic aromatic hydrocarbons were partially or completely resolved in gradient elution mode. The hybrid monolithic columns exhibited very good intra-day (%RSD=1.9), inter-day (%RSD=2.6), and column-to-column (%RSD=4.3) reproducibility values. Easy and fast column preparation, and versatility to efficiently separate several compounds of different chemical nature in isocratic and gradient mode, makes this new hybrid column a very good option for the analysis of small molecules in capillary (or nano) HPLC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Upadacitinib (UPA) is a selective, reversible Janus kinase inhibitor (JAKi) approved for the treatment of RA. However, there is still no solid evidence on the long-term efficacy of UPA in treated patients. The purpose of this study was to determine the efficacy of UPA to obtain remission or low disease activity (LDA) in a series of UPA patients in patients with RA after 6 and 12 months of treatment in a real-world setting., Methods: A series of 111 consecutive patients treated with UPA in 23 rheumatology centers were enrolled. Personal history, treatment history and disease activity at baseline, after 6 and 12 months were recorded. Intention-to-treat (ITT) and per-protocol (PP) analyses assessed achievement of remission or LDA or defined as DAS28 <2.6 and ≤3.2, respectively. Logistic regression analysis examined the role of several independent factors on the reduction of disease activity after 6 months of treatment., Results: Of the initial group of 111 subjects at baseline, 86 and 29 participants completed clinical assessments at 6 and 12 months. According to ITT analysis, the rates of remission and LDA were 18% and 18% at 6 months and 31.5% and 12.5% at 12 months, respectively. PP analysis showed higher rates of remission and LDA at 6 (23.3% and 19.8%) and 12 months (55.2% and 20.7%). Results of multivariate logistic regression analysis indicated that a low DAS28 score (P=0.045) was the only predictor of achieving remission at 6 months. None of the baseline factors predicted remission/LDA at 6 months., Conclusions: RA patients treated with UPA achieved a significant rate of disease remission or LDA in a real-world setting. The 6-month response was found to depend only on the baseline value of DAS28, while it was not influenced by other factors such as disease duration, line of treatment or concomitant therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or corticosteroids.

Background/Objectives: The Janus kinase inhibitors (JAKi) tofacitinib (TOFA), baricitinib (BARI), upadacitinib (UPA), and filgotinib (FILGO) are effective drugs for the treatment of rheumatoid arthritis. However, the US Food and Drug Administration (FDA) raised concerns about the safety of TOFA after its approval. This prompted the European Medicines Agency (EMA) to issue two safety warnings for limiting TOFA use, then extended a third warning to all JAKi in patients at high risk of developing serious adverse effects (SAE). These include thrombosis, major adverse cardiac events (MACE), and cancer. The purpose of this work was to analyze how the first two safety warnings from the EMA affected the prescribing of JAKi by rheumatologists in Italy. Methods: All patients with rheumatoid arthritis who had been prescribed JAKi for the first time in a 36-month period from 1 July 2019, to 30 June 2022 were considered. Data were obtained from the medical records of 29 Italian tertiary referral rheumatology centers. Patients were divided into three groups of 4 months each, depending on whether the JAKi prescription had occurred before the EMA's first safety alert (1 July-31 October 2019, Group 1), between the first and second alerts (1 November 2019-29 February 2020, Group 2), or between the second and third alerts (1 March 2021-30 June 2021, Group 3). The percentages and absolute changes in the patients prescribed the individual JAKi were analyzed. Differences among the three groups of patients regarding demographic and clinical characteristics were also assessed. Results: A total of 864 patients were prescribed a JAKi during the entire period considered. Of these, 343 were identified in Group 1, 233 in Group 2, and 288 in Group 3. An absolute reduction of 32% was observed in the number of patients prescribed a JAKi between Group 1 and Group 2 and 16% between Group 1 and Group 3. In contrast, there was a 19% increase in the prescription of a JAKi in patients between Group 2 and Group 3. In the first group, BARI was the most prescribed drug (227 prescriptions, 66.2% of the total), followed by TOFA (115, 33.5%) and UPA (1, 0.3%). In the second group, the most prescribed JAKi was BARI (147, 63.1%), followed by TOFA (65, 27.9%) and UPA (33, 11.5%). In the third group, BARI was still the most prescribed JAKi (104 prescriptions, 36.1%), followed by UPA (89, 30.9%), FILGO (89, 21.5%), and TOFA (33, 11.5%). The number of patients prescribed TOFA decreased significantly between Group 1 and Group 2 and between Group 2 and Group 3 ( p ˂ 0.01). The number of patients who were prescribed BARI decreased significantly between Group 1 and Group 2 and between Group 2 and Group 3 ( p ˂ 0.01). In contrast, the number of patients prescribed UPA increased between Group 2 and Group 3 ( p ˂ 0.01). Conclusions : These data suggest that the warnings issued for TOFA were followed by a reduction in total JAKi prescriptions. However, the more selective JAKi (UPA and FILGO) were perceived by prescribers as favorable in terms of the risk/benefit ratio, and their use gradually increased at the expense of the other molecules.

Dogs bring many benefits to our society but, if not properly managed, they can be detrimental for humans, livestock and wildlife. We highlight the increasing problems associated with free-ranging dogs using examples from two regions of the world where this issue is pervasive, India and South America. In these regions, free-ranging dogs spread diseases, injure people, harm biodiversity, and negatively impact human livelihoods. We discuss why mitigating these deleterious effects can be extremely complicated because there are diverse challenges such as: (a) a lack of or inappropriate legislations concerning free-ranging dog management and human-dog interactions, (b) unregulated intentional and unintentional feeding of free-ranging dogs, (c) limitations of animal shelters, (d) non-responsible ownership, and (e) uncontrolled dog populations. As the management of animal species is usually shaped by differing interests, existing policies and regulations, views and social influence of stakeholders, power asymmetries between interested parties is yet another challenge in this regard. We need evidence-based legislations and strong institutions (e.g., public health and conservation institutions) that are capable of implementing governance principles and managing the complexities of this socio-ecological system by taking science-based decisions, and balancing power asymmetries to promote consensus., (© 2023. The Author(s) under exclusive licence to Royal Swedish Academy of Sciences.)