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Rajiv Bajracharya,* Kshitis Chandra Baral,* Sang Hoon Lee, Jae Geun Song, Hyo-Kyung Han College of Pharmacy, Dongguk University-Seoul, Goyang, Korea*These authors contributed equally to this workCorrespondence: Hyo-Kyung Han, College of Pharmacy, Dongguk University-Seoul, Dongguk-ro-32, Ilsan-Donggu, Goyang, Korea, Tel +82-31-961-5217, Fax +82-31-961-5206, Email hkhan@dongguk.eduPurpose: Oral administration, although convenient and preferred for treating colorectal cancer (CRC), faces challenges due to limited CRC-related intestinal positioning and a dense mucus barrier. In the present study, a gold-nanoparticle decorated–organometallic phyllosilicate nanocomposite (AC-Au), with a pH-dependent surface coating, was employed for more effective oral delivery of anticancer drugs to treat CRC.Methods: The organometallic AC-Au was synthesized using the in-situ sol-gel method. Subsequently, methotrexate (MTX) was loaded into AC-Au, and the complex (AC-Au/MTX) was surface-coated with poly (methacrylic acid-co-methyl methacrylate) (1:2), a pH-dependent polymer (E/AC-Au /MTX). The in vitro characteristics of nanoparticles were examined using various analytical methods. In vivo efficacy studies were also conducted using an HCT-116 orthotopic colorectal cancer model.Results: AC-Au emerged as a spherical nanoparticle with a mean size of 26.5 ± 0.43 nm, displaying a positive charge over the pH range of 2– 10. Both the uncoated and coated drug–loaded nanocomplexes (AC-Au/MTX and E/AC-Au/MTX) were fabricated with high entrapment efficiency (> 80%). Various analyses, including ultraviolet-visible spectroscopy, X-ray powder diffraction, transmission electron microscopy, and energy dispersive X-ray spectroscopy, confirmed the formation of the nanocomplexes. While AC-Au/MTX achieved rapid and extensive drug release at the pH range of 1.2– 7.4, E/AC-Au/MTX exhibited pH-dependent drug release, with approximately 23% at pH 1.2 and 74% at pH 7.4. Relative to free MTX, the AC-Au-based nanocomplex significantly enhanced the cytotoxicity of MTX in HCT-116 cells. Furthermore, orally administered E/AC-Au/MTX significantly improved the anti-tumor activity of MTX in an HCT-116 orthotopic colorectal cancer model, resulting in approximately 60% suppression of tumor mass compared with the positive control.Conclusion: The organometallic AC-Au nanocomplex coated with a pH-dependent polymer has the potential to be an effective colonic drug delivery system of MTX, enhancing in vivo efficacy against colorectal cancer.Keywords: methotrexate, aminoclay, gold nanoparticle, colonic delivery, cytotoxicity

Le bimekizumab (BKZ), un anticorps monoclonal IgG1 qui inhibe l'IL-17F en plus de l'IL-17A, a démontré son efficacité à la semaine (S)16, qui s'est maintenue jusqu'à S52, chez les patients (pts) atteints de rhumatisme psoriasique (RhuPso) [1,2]. Nous présentons la proportion de pts répondeurs à S16 qui ont maintenu la réponse à 2 ans chez les pts atteints de RhuPso et traités par BKZ. Les essais de phase III BE OPTIMAL (pts naïfs de biologique ; NCT03895203) et BE COMPLETE (pts avec réponse inadéquate ou intolérance aux anti-TNF [anti-TNF-IR] ; NCT03896581) ont évalué le BKZ à 160 mg/4S chez des pts atteints de RhuPso ; les deux essais ont été contrôlés par placebo (PBO) jusqu'à S16. Les pts ayant terminé l'étude BE OPTIMAL à S52/BE COMPLETE à S16 pouvaient entrer dans l'étude d'extension en ouvert BE VITAL (NCT04009499). Les données d'efficacité sont rapportées pour les pts randomisés sous BKZ et celles de tolérance pour tous les pts traités par BKZ. Le maintien de la réponse est indiqué en pourcentage de pts répondeurs à S16 qui ont maintenu cette réponse à S104/100 (BE OPTIMAL/BE COMPLETE) ; ces résultats d'efficacité incluent les scores ACR 20/50/70, PASI 75/90/100, MDA (activité minimale de la maladie)/VLDA (très faible activité de la maladie) et DAPSA (REM (rémission) ≤ 4 ; REM + LDA (faible activité de la maladie) ≤ 14). L'imputation des non-répondeurs (NRI), la méthodologie des cas observés (OC) ou de la catégorie la plus défavorable ont été utilisées. Les taux d'incidence ajustés en fonction de l'exposition pour 100 pts-années (EAIR/100 PA) ont été rapportés à S104 pour les deux études. 359/431 (83,3 %) pts naïfs de biologique et 215/267 (80,5 %) pts anti-TNF-IR randomisés sous BKZ ont terminé la S104/100. Des proportions élevées de pts ayant obtenu une ACR50, un PASI100 et une MDA à S16 ont maintenu leurs réponses à S104/100 (Figure 1, Tableau 1). À S16, 189 (43,9 %) pts naïfs de biologique et 115 (43,1 %) pts anti-TNF-IR ont atteint l'ACR50 ; parmi eux, 150 (79,4 %) pts naïfs de biologique et 87 (75,7 %) pts anti-TNF-IR ont maintenu leur réponse à S104/S100. Chez les pts présentant un psoriasis initial affectant ≥ 3 % de la surface corporelle, 103/217 (47,5 %) pts naïfs de biologique et 103/176 (58,5 %) pts anti-TNF-IR ont atteint le PASI100 à S16 ; parmi eux, 73 (70,9 %) pts naïfs de biologique et 83 (80,6 %) pts anti-TNF-IR ont maintenu leur réponse à S104/S100. La MDA a été atteinte par 194 (45,0 %) pts naïfs de biologique et 117 (43,8 %) pts anti-TNF-IR à la S16 ; parmi eux, 147 (75,8 %) pts naïfs de biologique et 87 (74,4 %) pts anti-TNF-IR ont maintenu leur réponse à S104/S100. Des résultats similaires ont été observés pour les autres critères d'efficacité à S104/S100 (Tableau 1). À S104, le taux d'incidence ajusté en fonction de l'exposition pour 100 pts-années chez les pts traités par BKZ naïfs de biologique ou anti-TNF-IR avec ≥ 1 était de 179,9/100,3. Le BKZ a démontré un maintien robuste de la réponse à 2 ans chez les pts atteints de RhuPso naïfs de biologique ou anti-TNF-IR ayant répondu au traitement par BKZ à S16. Le profil de tolérance était cohérent avec les rapports précédents [1,2]. [ABSTRACT FROM AUTHOR]

Le bimekizumab (BKZ), un anticorps monoclonal IgG1 qui inhibe de manière sélective l'IL-17F en plus de l'IL-17A, a montré une efficacité supérieure au placebo (PBO) à 16 semaines (S) et une meilleure tolérance chez les patients (pts) atteints de rhumatisme psoriasique (RhuPso) actif qui n'avaient jamais reçu de biologique ou qui avaient déjà présenté une intolérance ou une réponse inadéquate aux anti-TNF (anti-TNF-IR). [1,2] L'obtention d'une réponse rapide au traitement est un facteur prédictif important du contrôle à long terme de la maladie et de l'amélioration de la qualité de vie. [3,4] Nous présentons ici la rapidité de la réponse au traitement par BKZ chez des pts atteints de RhuPso, en utilisant les données sur les articulations, la peau et les résultats composites regroupés dans deux essais. Les essais de phase III BE OPTIMAL (NCT03895203 ; pts naïfs de biologique) et BE COMPLETE (NCT03896581 ; pts anti-TNF-IR) ont évalué BKZ à la dose de 160 mg/4S chez des pts atteints de RhuPso actif. Les deux essais étaient en double-aveugle, contrôlés par PBO jusqu'à S16. Nous présentons les données regroupées de l'étude jusqu'à S16 pour les bras de traitement BKZ et PBO, ainsi que les analyses Kaplan-Meier des scores ACR50 pour chaque étude. L'imputation des non-répondeurs et l'imputation multiple ont été utilisées pour les variables binaires et continues manquantes. Sur 1112 pts randomisés sous KZ ou PBO, 1074 (96,6 %) ont terminé la S16 de BE OPTIMAL et BE COMPLETE, parmi lesquels 1 pt n'a pas reçu le traitement randomisé. Les caractéristiques à l'inclusion étaient généralement similaires entre les groupes de traitement. Les analyses de Kaplan-Meier ont montré une séparation précoce entre les pts traités par BKZ et ceux traités par PBO atteignant une réponse ACR50 dans les deux groupes de traitement (Figure 1). Dans l'analyse groupée, la proportion de pts ayant obtenu des améliorations au niveau des articulations était numériquement plus importante sous BKZ que sous PBO à S4 pour l'ACR20 et l'ACR50 (p nominal < 0,001 dans les deux cas) et pour l'ACR70 (p nominal = 0,001) ; les améliorations sont restées plus importantes à chaque visite jusqu'à S16 (p < 0,001 dans les deux cas ; Tableau 1). Des résultats similaires ont été observés pour l'amélioration du nombre d'articulations gonflées et douloureuses et de la douleur. Chez les pts présentant un psoriasis cutané important à l'inclusion (≥ 3 % de la surface corporelle), une plus grande proportion de pts a atteint des seuils stricts d'amélioration du PASI sous BKZ vs PBO à S4, y compris un blanchiment complet (PASI100 ; p nominal < 0,001 ; Figure 1). Cette amélioration s'est maintenue à S16 (p nominal < 0,001). De même, la proportion de pts ayant atteint la MDA était plus importante sous BKZ que sous PBO à la S4 et est restée plus importante à S16 (p < 0,001). Les pts traités par BKZ ont obtenu des réponses rapides sous traitement, avec une différence précoce par rapport au PBO, au niveau des articulations, de la peau et des résultats composites. [ABSTRACT FROM AUTHOR]

Nous présentons ici une mise à jour jusqu'en juillet 2023 des données groupées de tolérance à long terme concernant le bimekizumab (BKZ) lors des études de phase IIb/III chez les patients (pts) atteints de spondyloarthrite axiale (axSpA) ou de rhumatisme psoriasique (RhuPso). Les données de tolérance sont rapportées pour les 2 groupes séparément, chacun comprenant 3 études de phase IIb/III et leurs études d'extension en ouvert chez des pts atteints d'axSpA active non radiographique (nr-axSpA) ou radiographique (r-axSpA) et de RhuPso actif (Figure 1). Nous présentons les évènements indésirables apparus sous traitement (EIAT) chez les pts ayant reçu ≥ 1 dose de BKZ 160 mg/4S en nombre n (%) et en taux d'incidence ajustés en fonction de l'exposition pour 100 pts-années (EAIR/100 PA). Toutes les études étaient terminées au moment de la clôture des données, à l'exception des études BE MOVING et BE VITAL ; les pts toujours en cours d'étude avaient atteint ∼104S de participation au total (Figure 1). Les groupes de traitement pour l'axSpA et le RhuPso comprenaient respectivement 848 pts (2,513,8 PA) et 1,409 pts (3,655,9 PA). Depuis l'analyse précédente des données [1] , les EAIR pour la majorité des EIAT sont restés stables avec une exposition plus longue au BKZ. Les 3 événements indésirables les plus fréquemment rapportés chez les patients atteints d'axSpA et de RhuPso étaient l'infection par le SARS-CoV-2 (COVID-19), les rhinopharyngites et es infections des voies respiratoires supérieures (Tableau 1). Les événements indésirables d'intérêt particulier sont présentés dans le tableau. L'EAIR/100 PA des infections graves était de 1,4 dans l'axSpA et de 1,3 dans le RhuPso. Pour les infections fongiques, l'EAIR/100 PA était de 8,4 dans l'axSpA et de 7,9 dans le RhuPso. La plupart des infections fongiques étaient cutanéomuqueuses et de sévérité légère/modérée, y compris les candidoses orales. L'arrêt définitif du BKZ en raison d'une candidose orale a été peu fréquent (axSpA : 0,2/100 PA ; RhuPso : 0,4/100 PA). Aucune infection fongique systémique n'a été signalée. L'EAIR/100 PA des événements hépatiques était de 5,3 dans l'axSpA et de 5,0 dans le RhuPso ; la plupart étaient des anomalies transitoires des enzymes hépatiques (Tableau 1 ; aucun cas confirmé de loi de Hy). Pour les MICI évaluées (certaines ou probables), l'EAIR/100 AP était de 0,7 dans l'axSpA) et de 0,2 dans le RhuPso, ce qui est cohérent avec la comorbidité des MICI plus fréquente au cours de l'axSpA que du RhuPso [2]. Une uvéite s'est produite avec un EAIR/100 PA de 1,3 dans l'axSpA et de 0,1 dans le RhuPso. Aucun cas de tuberculose active ou de suicide n'ont été signalés ; les taux d'idées/comportements suicidaires et d'événements cardiaques indésirables majeurs sont indiqués dans le tableau. 3 et 5 décès ont été signalés respectivement chez les pts atteints d'axSpA et de RhuPso, (voir Tableau 1). Aucun décès n'a été considéré comme lié au médicament par les investigateurs. Le profil de tolérance à long terme du BKZ chez les pts souffrant d'axSpA et de RhuPso est cohérent avec les études précédentes ; aucun nouveau signal de tolérance n'a été mis en évidence. [3] [ABSTRACT FROM AUTHOR]

Objective: To assess the longer-term impact of bimekizumab to 1 year on patient-reported symptoms, health-related quality of life (HRQoL), and work productivity in patients with active PsA who were biologic disease-modifying antirheumatic drug (bDMARD)-naïve or had inadequate response/intolerance to tumor necrosis factor inhibitors (TNFi-IR) up to 1 year., Methods: BE OPTIMAL (NCT03895203; bDMARD-naïve) and BE COMPLETE (NCT03896581; TNFi-IR) are phase 3 studies of subcutaneous bimekizumab 160 mg every 4 weeks; both were double-blind and placebo-controlled to 16 weeks. Patients who completed Week 52 of BE OPTIMAL or Week 16 of BE COMPLETE were eligible for the open-label extension, BE VITAL (NCT04009499), during which all patients received bimekizumab. Patient-reported pain, fatigue, physical function, HRQoL, and work productivity are reported to Week 52/40 using individual study data for bimekizumab and placebo treatment arms., Results: Bimekizumab-randomized patients demonstrated sustained mean improvements from baseline in patient-reported outcomes to Week 52/40, including pain (Pain VAS [0-100]: bDMARD-naïve -30.5; TNFi-IR -31.8), fatigue (FACIT-Fatigue [0-52]: bDMARD-naïve 5.3; TNFi-IR 6.0), physical function (HAQ-DI [0-3]: bDMARD-naïve -0.34; TNFi-IR -0.39), and HRQoL (SF-36 PCS: bDMARD-naïve 8.1; TNFi-IR 8.4); placebo patients who switched to bimekizumab at Week 16 demonstrated comparable levels of improvement from Week 16 to 52/40. Improvements in overall work impairment were sustained among bimekizumab-randomized patients to Week 52. Similar trends were observed for absenteeism, presenteeism, and activity impairment., Conclusion: Bimekizumab treatment resulted in sustained improvements in patient-reported symptoms, HRQoL, and work productivity up to 1 year in bDMARD-naïve and TNFi-IR patients with active PsA.

While apoptosis dismantles the cell to enforce immunological silence, pyroptotic cell death provokes inflammation. Little is known of the structural architecture of cells undergoing pyroptosis, and whether pyroptotic corpses are immunogenic. Here we report that inflammasomes trigger the Gasdermin-D- and calcium-dependent eruption of filopodia from the plasma membrane minutes before pyroptotic cell rupture, to crown the resultant corpse with filopodia. As a rich store of F-actin, pyroptotic filopodia are recognized by dendritic cells through the F-actin receptor, CLEC9A (DNGR1). We propose that cells assemble filopodia before cell rupture to serve as a posthumous mark for a cell that has died by gasdermin-induced pyroptosis, or MLKL-induced necroptosis, for recognition by dendritic cells. This study reveals the spectacular morphology of pyroptosis and identifies a mechanism by which inflammasomes induce pyroptotic cells to construct a de novo alarmin that activates dendritic cells via CLEC9A, which coordinates the transition from innate to adaptive immunity 1,2 ., Competing Interests: Competing interests: K.S., M.H.L. and J.C.K. declare the following competing interests: K.S. is a coinventor on patent applications for NLRP3 inhibitors that have been licensed to Inflazome Ltd. K.S. served on the Scientific Advisory Board of Inflazome (2016–2017) and Quench Bio, USA (2018–2021) and serves on a Scientific Advisory Board for Novartis, Switzerland (since 2020). M.H.L. is an inventor on patents relating to CLEC9A antibodies. J.C.K. consults and holds equity in Corner Therapeutics, Larkspur Biosciences, MindImmune Therapeutics and Neumora Therapeutics; none of these relationships affected this study. The other authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Observational studies have shown that more educated people are at lower risk of developing type 2 diabetes (T2D). However, robust study designs are needed to investigate the likelihood that such a relationship is causal. This study used genetic instruments for education to estimate the effect of education on T2D using the Mendelian randomisation (MR) approach., Methods: Analyses have been conducted in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study (more than 20 000 individuals), a case-cohort study of T2D nested in the EPIC cohort. Education was measured as Years of Education and Relative Index of Inequality. Prentice-weighted Cox models were performed to estimate the association between education and T2D. One-sample MR analyses investigated whether genetic predisposition towards longer education was associated with risk of T2D and investigated potential mediators of the association., Results: MR estimates indicated a risk reduction of about 15% for each year of longer education on the risk of developing T2D, confirming the protective role estimated by observational models (HR 0.96, 95% CI 0.95 to 0.96). MR analyses on putative mediators showed a significant role of education on body mass index, alcohol consumption, adherence to the Mediterranean diet and smoking habits., Conclusion: The results supported the hypothesis that higher education is a protective factor for the risk of developing T2D. Based on its position in the causal chain, education may be antecedent of other known risk factors for T2D including unhealthy behaviours. These findings reinforce evidence obtained through observational study designs and bridge the gap between correlation and causation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Psoriatic arthritis (PsA) is a chronic inflammatory disease that causes pain and fatigue, reduces physical function, and negatively impacts health-related quality of life (HRQoL). In the phase III BE OPTIMAL and BE COMPLETE studies, bimekizumab demonstrated clinical efficacy and meaningful improvements in patient-reported outcome (PRO) measures in biologic disease-modifying antirheumatic drug (bDMARD)-naïve patients, and those who had prior inadequate response/intolerance to tumor necrosis factor inhibitors (TNFi-IR)., Objectives: To examine the association between achieving increasingly stringent clinical disease control criteria and improvements in PRO measures in patients with active PsA receiving bimekizumab., Design: Post hoc analysis of two phase III studies., Methods: BE OPTIMAL and BE COMPLETE assessed subcutaneous bimekizumab 160 mg every 4 weeks in bDMARD-naïve and TNFi-IR patients with active PsA. Disease control was assessed using American College of Rheumatology (ACR) response criteria, Minimal Disease Activity, Disease Activity Index for Psoriatic Arthritis, and the composite outcome of ACR50 and 100% improvement in Psoriasis Area and Severity Index. Associations between clinical disease control criteria and PRO measures of pain, fatigue, physical function, and HRQoL were assessed at week 16 and week 52/40 (BE OPTIMAL/BE COMPLETE)., Results: Achievement of increasingly stringent clinical disease control criteria was generally associated with sequentially greater improvements in all PRO measures, including pain. At week 52/40, 94.7% of bDMARD-naïve and 97.6% of TNFi-IR patients achieving ACR70 reported ⩾50% improvements in pain from baseline, and the greatest numerical improvements (-48.5 bDMARD-naïve; -54.7 TNFi-IR). This pattern was evident as early as week 16 and sustained when assessed at week 52/40 across the majority of clinical disease control criteria and PRO measures reported., Conclusion: The achievement of increasingly stringent thresholds of disease control was associated with corresponding greater improvements in PROs, for patients receiving bimekizumab treatment, irrespective of prior TNFi use., Trial Registration Clinicaltrialsgov: NCT03895203, NCT03896581, and NCT04009499., Competing Interests: L.E.K.: At the time of manuscript preparation. L.E.K. was at The Parker Institute, Copenhagen University Hospital, L.E.K. is now an employee of LEO Pharma; Consulting and speaking fees from AbbVie, Amgen, BMS, Biogen, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer and UCB; IIT research grants from AbbVie, Eli Lilly Novartis, Novo, and UCB. W.T.: Research grants, consulting fees, speaking fees, and/or honoraria from AbbVie, Amgen, BMS, Celgene, Eli Lilly, GSK, Janssen, MSD, Novartis, Ono Pharma, Pfizer, and UCB. P.N.: Grants for research and clinical trials and honoraria for advice and lectures from AbbVie, BMS, Boehringer Ingelheim, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Novartis, Pfizer, Samsung, Sanofi, and UCB. L.C.C.: Grants/research support from AbbVie, Amgen, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, and UCB; consultant for AbbVie, Amgen, BMS, Boehringer Ingelheim, Celgene, Domain, Eli Lilly, Galapagos, Gilead, Janssen, Moonlake Pharma, Novartis, Pfizer, and UCB; speaking fees from AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Galapagos, Gilead, GSK, Janssen, medac, Novartis, Pfizer, and UCB. P.J.M.: Research grants from AbbVie, Acelyrin, Amgen, BMS, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sun Pharma, and UCB; consultancy fees from AbbVie, Acelyrin, Aclaris, Amgen, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Moonlake Pharma, Novartis, Pfizer, Sun Pharma, Takeda, UCB, and Ventyx; speakers’ bureau for AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer and, UCB. A.O.: Grant/research support from AbbVie, Amgen, Janssen, Novartis, and Pfizer; consultancy fees from AbbVie, Amgen, BMS, Celgene, CorEvitas, Eli Lilly, GSK, Gilead, Janssen, Novartis, Pfizer, Takeda, and UCB. P.G.: Consultancy fees from AbbVie, Abiogen, Almirall, Celgene, Eli Lilly, Janssen, LEO Pharma, Merck, MSD, Novartis, Otsuka, Pfizer, Pierre Fabre, Sanofi, and UCB. B.I.: Employee of UCB; shareholder of AbbVie, GSK, and UCB. A.R.P., R.B., V.T., N.L., and J.L.: Employees and shareholders of UCB. J.A.W.: Consultant for/grant support from AbbVie, Amgen, Eli Lilly, Janssen, Merck, Novartis, Pfizer, and UCB., (© The Author(s), 2024.)

Objective: The objective of this study was to assess 52-week efficacy and safety of bimekizumab in patients with active psoriatic arthritis (PsA) with or without concomitant methotrexate (+/-MTX) treatment at baseline., Methods: We conducted a post hoc analysis of patients in BE OPTIMAL (NCT03895203; biologic disease-modifying antirheumatic drug [bDMARD]-naïve), BE COMPLETE (NCT03896581; prior inadequate response or intolerance to tumor necrosis factor inhibitors [TNFi-IR]), and the BE VITAL open-label extension (NCT04009499) study. Patients were randomized to one of the following treatment groups: bimekizumab 160 mg every four weeks, placebo, or a reference drug (adalimumab 40 mg every two weeks; BE OPTIMAL only). From Week 16, placebo-randomized patients received bimekizumab. Missing data were imputed using non-responder imputation, multiple imputation, or worst-category imputation., Results: Through Week 52, similar proportions of bimekizumab-treated patients achieved American College of Rheumatology 50% (ACR50) response criteria for both +MTX and -MTX (BE OPTIMAL: 54.4% +MTX, 54.7% -MTX; BE COMPLETE: 56.3% +MTX, 48.0% -MTX). Similar proportions of bimekizumab-treated patients achieved complete skin clearance (Psoriasis Area and Severity Index 100% [PASI100] response) and minimal disease activity in both +MTX and -MTX groups. Similar trends were seen in placebo/bimekizumab-treated patients. Through Week 52, the proportion of bimekizumab-treated patients with ≥1 treatment-emergent adverse event were similar between the +MTX and -MTX groups (BE OPTIMAL 325 of 410 [79.3%] vs 230 of 292 [78.8%], BE COMPLETE 105 of 168 [62.5%] vs 138 of 220 [62.7%]). The safety profile was comparable between subgroups and consistent with the prior safety profile of bimekizumab., Conclusion: Treatment with bimekizumab demonstrated consistent, sustained efficacy to 52 weeks in bDMARD-naïve and TNFi-IR patients with PsA and was well tolerated, irrespective of concomitant MTX., (© 2024 UCB Pharma and The Author(s). ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Introduction: Psoriatic arthritis (PsA) is a chronic inflammatory disease requiring long-term treatment. Bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A, has demonstrated tolerability and sustained clinical efficacy for up to 1 year for patients with PsA. Here, we report the longer-‍term safety and efficacy of bimekizumab up to 2 years., Methods: BE OPTIMAL (biologic disease-modifying antirheumatic drug [bDMARD]-naïve) and BE COMPLETE (prior inadequate response/intolerance to tumor necrosis factor inhibitors [TNFi-IR]) assessed subcutaneous bimekizumab 160 mg every 4 weeks in patients with PsA. BE OPTIMAL included a reference arm (adalimumab 40 mg every 2 weeks); patients switched to bimekizumab at week 52 with no washout between treatments. BE OPTIMAL week 52 and BE COMPLETE week 16 completers were eligible for the BE VITAL open-label extension. Efficacy outcomes are reported to week 104/100 (BE OPTIMAL/BE COMPLETE)., Results: A total of 710/852 (83.3%) bDMARD-naïve and 322/400 (80.5%) TNFi-IR patients completed week 104/100. Up to 104 weeks, patients treated with bimekizumab in BE OPTIMAL and BE COMPLETE had treatment-emergent adverse event incidence rates (exposure-adjusted incidence rate/100 patient-years) of 179.9 (95% CI 166.9, 193.7) and 100.3 (89.2, ‍112.4), respectively. The proportion of patients achieving efficacy outcomes (≥ 50% improvement from baseline in American College of Rheumatology [ACR] response criteria, 100% improvement from baseline in Psorisis Area and Severity Index [PASI], minimal disease activity [MDA]) was sustained in all patients from week 52 to week 104/100., Conclusions: Bimekizumab was well tolerated for up to 2 years of treatment and no new safety signals were observed. Sustained clinical efficacy was observed up to 2 years in bDMARD-naïve and TNFi-IR patients with active PsA. Patients switching from adalimumab to bimekizumab demonstrated further improvement in skin and nail symptoms, and sustained efficacy in joint symptoms., Trial Registration: BE OPTIMAL (NCT03895203), BE COMPLETE (NCT03896581), BE VITAL (NCT04009499)., (© 2024. The Author(s).)

Dicarbonyl compounds are highly reactive precursors of advanced glycation end products (AGE), produced endogenously, present in certain foods and formed during food processing. AGE contribute to the development of adverse metabolic outcomes, but health effects of dietary dicarbonyls are largely unexplored. We investigated associations between three dietary dicarbonyl compounds, methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG), and body weight changes in European adults. Dicarbonyl intakes were estimated using food composition database from 263 095 European Prospective Investigation into Cancer and Nutrition-Physical Activity, Nutrition, Alcohol, Cessation of Smoking, Eating Out of Home in Relation to Anthropometry participants with two body weight assessments (median follow-up time = 5·4 years). Associations between dicarbonyls and 5-year body-weight changes were estimated using mixed linear regression models. Stratified analyses by sex, age and baseline BMI were performed. Risk of becoming overweight/obese was assessed using multivariable-adjusted logistic regression. MGO intake was associated with 5-year body-weight gain of 0·089 kg (per 1-sd increase, 95 % CI 0·072, 0·107). 3-DG was inversely associated with body-weight change (-0·076 kg, -0·094, -0·058). No significant association was observed for GO (0·018 kg, -0·002, 0·037). In stratified analyses, GO was associated with body-weight gain among women and older participants (above median of 52·4 years). MGO was associated with higher body-weight gain among older participants. 3-DG was inversely associated with body-weight gain among younger and normal-weight participants. MGO was associated with a higher risk of becoming overweight/obese, while inverse associations were observed for 3-DG. No associations were observed for GO with overweight/obesity. Dietary dicarbonyls are inconsistently associated with body weight change among European adults. Further research is needed to clarify the role of these food components in overweight and obesity, their underlying mechanisms and potential public health implications.

Background: Epidemiological evidence suggests that a potential association between dietary protein intake and cardiovascular disease (CVD) may depend on the protein source, that is, plant- or animal-derived, but past research was limited and inconclusive., Objectives: To evaluate the association of dietary plant- or animal-derived protein consumption with risk of CVD, and its components ischemic heart disease (IHD) and stroke., Methods: This analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD case-cohort study included 16,244 incident CVD cases (10,784 IHD and 6423 stroke cases) and 15,141 subcohort members from 7 European countries. We investigated the association of estimated dietary protein intake with CVD, IHD, and stroke (total, fatal, and nonfatal) using multivariable-adjusted Prentice-weighted Cox regression. We estimated isocaloric substitutions of replacing fats and carbohydrates with plant- or animal-derived protein and replacing food-specific animal protein with plant protein. Multiplicative interactions between dietary protein and prespecified variables were tested., Results: Neither plant- nor animal-derived protein intake was associated with incident CVD, IHD, or stroke in adjusted analyses without or with macronutrient-specified substitution analyses. Higher plant-derived protein intake was associated with 22% lower total stroke incidence among never smokers [HR 0.78, 95% confidence intervals (CI): 0.62, 0.99], but not among current smokers (HR 1.08, 95% CI: 0.83, 1.40, P-interaction = 0.004). Moreover, higher plant-derived protein (per 3% total energy) when replacing red meat protein (HR 0.52, 95% CI: 0.31, 0.88), processed meat protein (HR 0.39, 95% CI: 0.17, 0.90), and dairy protein (HR 0.54, 95% CI: 0.30, 0.98) was associated with lower incidence of fatal stroke., Conclusion: Plant- or animal-derived protein intake was not associated with overall CVD. However, the association of plant-derived protein consumption with lower total stroke incidence among nonsmokers, and with lower incidence of fatal stroke highlights the importance of investigating CVD subtypes and potential interactions. These observations warrant further investigation in diverse populations with varying macronutrient intakes and dietary patterns., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Fibrolamellar carcinoma (FLC) is a liver tumor with a high mortality burden and few treatment options. A promising therapeutic vulnerability in FLC is its driver mutation, a conserved DNAJB1-PRKACA gene fusion that could be an ideal target neoantigen for immunotherapy. In this study, we aim to define endogenous CD8 T cell responses to this fusion in FLC patients and evaluate fusion-specific T cell receptors (TCRs) for use in cellular immunotherapies. We observe that fusion-specific CD8 T cells are rare and that FLC patient TCR repertoires lack large clusters of related TCR sequences characteristic of potent antigen-specific responses, potentially explaining why endogenous immune responses are insufficient to clear FLC tumors. Nevertheless, we define two functional fusion-specific TCRs, one of which has strong anti-tumor activity in vivo. Together, our results provide insights into the fragmented nature of neoantigen-specific repertoires in humans and indicate routes for clinical development of successful immunotherapies for FLC., Competing Interests: Declaration of interests J.C.C., A.M.K., A.E.Z., S.E.S., and P.G.T. have a patent application for TCRs for treating FLC. J.C.C. has additional patent applications in the field of immunotherapy. A.W.P. is a member of the scientific advisory board (SAB) of Bioinformatics Solutions Inc. (Canada), shareholder and SAB member of Evaxion Biotech (Denmark), consultant for Grey Wolf Therapeutics (UK), and cofounder of Resseptor Therapeutics (Melbourne). S.G. is a co-inventor on patent applications in the fields of cell/gene therapy for cancer, consultant of TESSA Therapeutics, member of the Data and Safety Monitoring Board of Immatics, and SAB member of Be Biopharma and has received honoraria from Tidal, Catamaran Bio, and Sanofi within the last 2 years. S.E.S. is a cofounder, stockholder, and paid consultant for Gliknik Inc., serves on the SAB and holds stock options for Virion Inc., and receives royalties from the Mayo Clinic for licensed IP surrounding manipulation of the PD-1:PD-L1 pathway for cancer treatment. P.G.T. is on the SAB of Immunoscape and Shennon Bio, received personal fees and research support from Elevate Bio, and consulted for 10×, Illumina, Pfizer, Cytoagents, and JNJ., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the role of adiposity in the associations between ultra-processed food (UPF) consumption and head and neck cancer (HNC) and oesophageal adenocarcinoma (OAC) in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort., Methods: Our study included 450,111 EPIC participants. We used Cox regressions to investigate the associations between the consumption of UPFs and HNC and OAC risk. A mediation analysis was performed to assess the role of body mass index (BMI) and waist-to-hip ratio (WHR) in these associations. In sensitivity analyses, we investigated accidental death as a negative control outcome., Results: During a mean follow-up of 14.13 ± 3.98 years, 910 and 215 participants developed HNC and OAC, respectively. A 10% g/d higher consumption of UPFs was associated with an increased risk of HNC (hazard ratio [HR] = 1.23, 95% confidence interval [CI] 1.14-1.34) and OAC (HR = 1.24, 95% CI 1.05-1.47). WHR mediated 5% (95% CI 3-10%) of the association between the consumption of UPFs and HNC risk, while BMI and WHR, respectively, mediated 13% (95% CI 6-53%) and 15% (95% CI 8-72%) of the association between the consumption of UPFs and OAC risk. UPF consumption was positively associated with accidental death in the negative control analysis., Conclusions: We reaffirmed that higher UPF consumption is associated with greater risk of HNC and OAC in EPIC. The proportion mediated via adiposity was small. Further research is required to investigate other mechanisms that may be at play (if there is indeed any causal effect of UPF consumption on these cancers)., (© 2023. The Author(s).)

Objectives: To assess 52-week safety and efficacy of bimekizumab in patients with active psoriatic arthritis (PsA) and prior inadequate response/intolerance to tumour necrosis factor inhibitors., Methods: Patients completing the 16-week phase III double-blind, placebo-controlled BE COMPLETE (NCT03896581) study entered the open-label extension, BE VITAL (NCT04009499). All patients in BE VITAL received 160 mg bimekizumab every 4 weeks. Safety and efficacy are reported to week 52., Results: A total of 347/400 (86.8%) patients completed week 52. To week 52, the exposure-adjusted incidence rate/100 patient-years for ≥1 treatment-emergent adverse event (TEAE) was 126.0, and was 7.0 for serious TEAEs. The most frequent TEAEs were SARS-CoV-2 (COVID-19), oral candidiasis, nasopharyngitis and urinary tract infection. All fungal infections were mild or moderate in severity and localised; two patients discontinued the study due to oral candidiasis. No cases of active tuberculosis, uveitis or inflammatory bowel disease were reported. One sudden death occurred. Sustained efficacy was observed with bimekizumab from week 16 to ‍52 across clinical and patient-reported outcomes. At week 52, 51.7% bimekizumab-randomised and 40.6% placebo/bimekizumab patients (receiving bimekizumab from week 16 to 52) had ≥50% improvement in the American College of Rheumatology criteria. Complete skin clearance (Psoriasis Area and Severity Index 100) was achieved by 65.9% bimekizumab and 60.2% placebo/bimekizumab patients at week 52. Minimal disease activity was achieved by 47.2% bimekizumab and 33.1% placebo/bimekizumab patients at week 52., Conclusions: Bimekizumab demonstrated a safety profile consistent with previous reports; no new safety signals were identified. Sustained efficacy was observed from week 16 to 52., Competing Interests: Competing interests: LCC: Grants/research support from AbbVie, Amgen, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer and UCB Pharma; consultant for AbbVie, Amgen, BMS, Boehringer Ingelheim, Celgene, Domain, Eli Lilly, Galapagos, Gilead, Janssen, Moonlake Pharma, Novartis, Pfizer and UCB Pharma; speaking fees from AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Galapagos, Gilead, GSK, Janssen, medac, Novartis, Pfizer and UCB Pharma. Associate Editor of RMD Open. RL: Consultancy fees from AbbVie, AstraZeneca, BMS, Eli Lilly, Novartis, Pfizer and UCB Pharma; research grants from AbbVie, Pfizer, Novartis, and UCB Pharma; owner of Rheumatology Consultancy BV, an AMS company under Dutch law. On the Editorial Board of RMD Open. IBM: Consulting fees and honoraria from AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Cabaletta, Causeway Therapeutics, Celgene, Eli Lilly, Evelo, Janssen, Moonlake Pharma, Novartis and UCB Pharma; research support from BMS, Boehringer Ingelheim, Celgene, Janssen, Novartis and UCB Pharma. On the Editorial Board of RMD Open. PJM: Research grants from AbbVie, Amgen, BMS, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sun Pharma and UCB Pharma; consultancy fees from AbbVie, Acelyrin, Aclaris, Amgen, BMS, Boehringer Ingelheim, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Moonlake Pharma, Novartis, Pfizer, Sun Pharma and UCB Pharma; speakers’ bureau for AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer and UCB Pharma. CTR: Research for AbbVie; consultant for AbbVie, Amgen, Eli Lilly, Gilead, Janssen, Novartis, Pfizer and UCB Pharma. YT: Speaking fees and/or honoraria from AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Eisai, Eli Lilly, Gilead, GSK, Pfizer, Taiho and Taisho; received grants from Chugai, Eisai, Mitsubishi-Tanabe and Taisho. On the Editorial Board of RMD Open. AA: Honoraria and/or research grants from AbbVie, Amgen, BMS, Boehringer Ingelheim, Eisai, Eli Lilly, Janssen, Kyowa Kirin, LEO Pharma, Maruho, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Sun Pharma, Taiho Pharma, Torii Pharmaceutical Co. and UCB Pharma. FB: Consultant and/or speaker and/or investigator for AbbVie, Affibody, Amgen, BMS, Boehringer Ingelheim, Celgene, Chugai, Eli Lilly, Genzyme, GSK, Janssen, MoonLake Pharma, MSD, Novartis, Pfizer, Roche, Sandoz and Sanofi. DDG: Consultant and/or received grant support from AbbVie, Amgen, BMS, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer and UCB Pharma. LG: Grants from AbbVie, Biogen, Eli Lilly, Novartis, Sandoz and UCB Pharma; personal fees from AbbVie, Amgen, BMS, Celltrion, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, Sandoz and UCB Pharma. AMO: Research grants to Johns Hopkins University from AbbVie, Amgen, and Janssen; consulting fees from BMS, Janssen, Sanofi and UCB Pharma. ABG: Received research/educational grants from AnaptypsBio, BMS, Highlights Therapeutics, Janssen, Moonlake Immunotherapeutics AG, Novartis and UCB Pharma, (all paid to Mount Sinai School of Medicine); Received honoraria as an advisory board member and consultant for Amgen, AnaptypsBio, Avotres Therapeutics, BMS, Boehringer Ingelheim, Dice Therapeutics, Eli Lilly, Highlights Therapeutics, Janssen, Novartis, Sanofi, UCB and Xbiotech. RBW: Consulting fees from AbbVie, Almirall, Amgen, Arena, Astellas, Avillion, Biogen, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, GSK, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi and UCB Pharma; research grants to his institution from AbbVie, Almirall, Janssen, LEO Pharma, Novartis and UCB Pharma; honoraria from Astellas, DICE Therapeutics, GSK and Union Therapeutics. BI: Shareholder of AbbVie, GSK and UCB Pharma; employee of UCB Pharma. RB and JC: Employees and shareholders of UCB Pharma. VS: Employee of UCB Pharma. JFM: Consultant and/or investigator for AbbVie, Amgen, Biogen, BMS, Dermavant, Eli Lilly, Janssen, LEO Pharma, Pfizer, Novartis, Regeneron, Sanofi, Sun Pharma and UCB Pharma., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In this study, we aimed to provide novel evidence on the impact of changing lifestyle habits on cancer risk. In the EPIC cohort, 295,865 middle-aged participants returned a lifestyle questionnaire at baseline and during follow-up. At both timepoints, we calculated a healthy lifestyle index (HLI) score based on cigarette smoking, alcohol consumption, body mass index and physical activity. HLI ranged from 0 (most unfavourable) to 16 (most favourable). We estimated the association between HLI change and risk of lifestyle-related cancers-including cancer of the breast, lung, colorectum, stomach, liver, cervix, oesophagus, bladder, and others-using Cox regression models. We reported hazard ratios (HR) with 95% confidence intervals (CI). Median time between the two questionnaires was 5.7 years, median age at follow-up questionnaire was 59 years. After the follow-up questionnaire, we observed 14,933 lifestyle-related cancers over a median follow-up of 7.8 years. Each unit increase in the HLI score was associated with 4% lower risk of lifestyle-related cancers (HR 0.96; 95%CI 0.95-0.97). Among participants in the top HLI third at baseline (HLI > 11), those in the bottom third at follow-up (HLI ≤ 9) had 21% higher risk of lifestyle-related cancers (HR 1.21; 95%CI 1.07-1.37) than those remaining in the top third. Among participants in the bottom HLI third at baseline, those in the top third at follow-up had 25% lower risk of lifestyle-related cancers (HR 0.75; 95%CI 0.65-0.86) than those remaining in the bottom third. These results indicate that lifestyle changes in middle age may have a significant impact on cancer risk., (© 2023. Springer Nature B.V.)

The number of prescribed medications might be used as proxy indicator for general health status, in models to predict mortality risk. To estimate the time-varying association between active pharmaceutical ingredient (API) count and all-cause mortality, we analyzed data from a population cohort in Heidelberg (Germany), including 25,546 participants with information on medication use collected at 3-yearly intervals from baseline recruitment (1994-1998) until end of 2014. A total of 4548 deaths were recorded until May 2019. Time-dependent modeling was used to estimate hazard ratios (HR) and their 95% confidence intervals (CI) for all-cause mortality in relation to number of APIs used, within three strata of age (≤ 60, > 60 to  ≤ 70 and > 70 years) and adjusting for lifestyle-related risk factors. For participants reporting commonly used APIs only (i.e., API types accounting for up to 80% of medication time in the population) total API counts showed no association with mortality risk within any age stratum. However, when at least one of the APIs was less common, the total API count showed a strong relationship with all-cause mortality especially up to age ≤ 60, with HR up to 3.70 (95% CI 2.30-5.94) with 5 or 6 medications and 8.19 (5.61-11.97) for 7 or more APIs (versus none). Between > 60 and 70 years of age this risk association was weaker, with HR up to 3.96 (3.14-4.98) for 7 or more APIs, and above 70 years it was weakened further (HR up to 1.54 (1.34-1.79)). Multiple API-use may predict mortality risk in middle-aged and women and men ≤ 70 years, but only if it includes at least one less frequently used API type. With advancing age, and multiple medication becomes increasingly prevalent, the association of API count with risk of death progressively attenuates, suggesting an increasing complexity with age of underlying mortality determinants., (© 2024. The Author(s).)

Recent epidemiological studies have suggested a positive association between ultra-processed food consumption and breast cancer risk, although some studies also reported no association. Furthermore, the evidence regarding the associations between intake of food with lower degrees of processing and breast cancer risk is limited. Thus, we investigated the associations between dietary intake by degree of food processing and breast cancer risk, overall and by breast cancer subtypes in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Dietary intake of EPIC participants was assessed via questionnaires at baseline. More than 11,000 food ingredients were classified into four groups of food processing levels using the NOVA classification system: unprocessed/minimally processed (NOVA 1), culinary ingredients (NOVA 2), processed (NOVA 3) and ultra-processed (NOVA 4). Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer per standard deviation increase in daily consumption (grams) of foods from each NOVA group. The current analysis included 14,933 breast cancer cases, diagnosed among the 318,686 EPIC female participants, (median follow-up of 14.9 years). No associations were found between breast cancer risk and the level of dietary intake from NOVA 1 [HR per 1 SD =0.99 (95% CI 0.97 - 1.01)], NOVA 2 [HR per 1 SD =1.01 (95% CI 0.98 - 1.03)] and NOVA 4 [HR per 1 SD =1.01 (95% CI 0.99 - 1.03)] foods. However, a positive association was found between NOVA 3 and breast cancer risk [HR per 1 SD =1.05 (95% CI 1.03 - 1.07)] which became non-significant after adjustment for alcohol intake [HR per 1 SD =1.01 (95% CI 0.98 - 1.05)] or when beer and wine were excluded from this group [HR per 1 SD =0.99 (95% CI 0.97 - 1.01)]. The associations did not differ by breast cancer subtype, menopausal status or body mass index. Findings from this large-scale prospective study suggest that the positive association between processed food intake and breast cancer risk was likely driven by alcoholic beverage consumption., Supplementary Information: The online version contains supplementary material available at 10.1186/s43014-024-00264-2., Competing Interests: Competing interestsThe authors declare no potential conflicts of interest., (© The Author(s) 2024.)

Introduction: Despite the rise of post-COVID care centers, few studies exist that quantify the burden of patient healthcare usage and hospital costs after COVID-19 hospitalization. It is essential to target post-COVID follow-up care to the individuals who need it most, such that costs and emergencies are minimized and health and appointment attendance are optimized., Methods: This was a retrospective cohort comparison among four groups of 50 patients (200 total). Post-discharge healthcare utilization metrics were collected for individuals hospitalized with COVID-19 during the first four surges of the pandemic to compare how patients receive and seek care in the year after they contract COVID-19. A brief cost analysis was done to identify high-usage groups that could be targeted for intervention to decrease post-COVID hospitalization emergencies and burden., Results: Patients hospitalized during the Omicron surge were scheduled for the most specialist visits on average, significantly higher than average specialist visits in the Delta surge (p<0.05). The Delta surge had significantly less specialty care and missed visits than all other surges (p<0.05) and less primary care than the first two surges of the pandemic (p<0.05). Patients with type 2 diabetes and asthma had the highest overall costs (p<0.05). Females and Hispanic patients had the highest specialty and ED costs (p<0.05)., Conclusion: Each surge reflects a different approach to post-COVID care, with the Omicron surge demonstrating the heaviest usage overall, particularly with specialty visits. Increased specialty referrals may exacerbate rates of missed appointments, while primary care may lower emergency visits. Future approaches to post-COVID care design should identify patients at risk for emergencies and reinstate them with primary care., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Leahy et al.)

Background: Combating COVID-19 by frontline nurses is highly concerned to manage and maintain the health care delivery system through qualitative services to the infected people. If nurses do not agree to the frontline role to combat COVID-19, it might create massive crisis in health sectors. The purpose of this study was to explore the learning experiences of frontline nurses combating COVID-19 in the public hospitals of Kathmandu valley. Furthermore, this study has explored their stories of combating COVID-19., Methods: Philosophically, this study is guided by interpretive paradigm utilizing the qualitative design with narrative inquiry. Stories were collected using face to face interview with six frontline nurses (seniors and juniors) working at COVID special units in three different public hospitals of Kathmandu valley. I have interpreted shared stories of combating experiences and learning, using self-efficacy theory and resilience theory., Results: This study revealed that the participants faced many challenges related to physical, mental, emotional and psychological and various managerial issues. However, they were able to cope due to their self-willingness, nursing education, altruistic nature and support system. Likewise, they acquired various skills: patient care, managerial and leadership, similarly understanding philosophy of life., Conclusions: Frontline nurses were able to combat COVID-19 successfully. Nowadays, they are happy, satisfied and proud with their roles that they had during the health emergency of COVID-19 pandemic and the commitment they fulfilled.

Objective: To quantify the effect of 2 home-based 16-week multi-component physical therapy interventions on functional recovery compared to usual care after hip fracture., Design: Cross-study comparison using participants from the Community Ambulation Project (CAP; a randomized controlled trial) were compared to the Baltimore Hip Studies-seventh cohort (BHS-7; an observational cohort study) at 3 different time points (CAP: 15, 31, 55 weeks; BHS-7: 8, 26, and 52 weeks)., Setting: General community PARTICIPANTS: Combined convenience sample of hip-fracture patients 8-26 weeks post admission from a prospective cohort study and randomized controlled trial. (N=549) INTERVENTIONS: CAP participants were randomized to one of 2 interventions (PUSH: specific multi-component intervention; PULSE: non-specific multi-component intervention) after standard rehabilitation; BHS-7 participants received usual care., Main Outcome Measures: Mean function (as measured by Short Physical Performance Battery (SPPB) and gait speed) was estimated in each cohort as quadratic functions of time using data from 3 post-fracture assessments in both studies (CAP: 15, 31, 55 weeks; BHS-7: 8, 26, and 52 weeks)., Results: The harmonized samples included 101 PUSH, 100 PULSE, and 128 BHS-7 participants that had different demographic and clinical characteristics. Mean baseline SPPB scores (meters per second) were PUSH: 5.5 (SD=2.2), PULSE: 5.5 (SD=2.4), and BHS-7: 4.6 (SD=2.5); and mean gait speeds were 0.60 m/s (SD=0.20) for PUSH, 0.59 m/s (SD=0.17) for PULSE, and 0.46 m/s SD=(0.21) for BHS-7, respectively. Estimated between-group differences for SPPB improvement from 75 days to 1-year post admission were 0.7 (P=.04) in PUSH vs BHS-7; and 0.9 (P=.01) in PULSE vs BHS-7. Mean differences in change in gait speed were 0.08 (P=.002) for PUSH vs BHS-7; and 0.06 (P=.02) PULSE vs BHS-7 (P=.02)., Conclusions: Findings from this cross-study comparison that combined participants from 2 separate studies, with different designs and samples, suggest that home-based multi-component physical therapy programs were associated with greater functional improvement after hip fracture compared to usual care., (Copyright © 2023 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Background: It is currently unknown whether ultra-processed foods (UPFs) consumption is associated with a higher incidence of multimorbidity. We examined the relationship of total and subgroup consumption of UPFs with the risk of multimorbidity defined as the co-occurrence of at least two chronic diseases in an individual among first cancer at any site, cardiovascular disease, and type 2 diabetes., Methods: This was a prospective cohort study including 266,666 participants (60% women) free of cancer, cardiovascular disease, and type 2 diabetes at recruitment from seven European countries in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Foods and drinks consumed over the previous 12 months were assessed at baseline by food-frequency questionnaires and classified according to their degree of processing using Nova classification. We used multistate modelling based on Cox regression to estimate cause-specific hazard ratios (HR) and their 95% confidence intervals (CI) for associations of total and subgroups of UPFs with the risk of multimorbidity of cancer and cardiometabolic diseases., Findings: After a median of 11.2 years of follow-up, 4461 participants (39% women) developed multimorbidity of cancer and cardiometabolic diseases. Higher UPF consumption (per 1 standard deviation increment, ∼260 g/day without alcoholic drinks) was associated with an increased risk of multimorbidity of cancer and cardiometabolic diseases (HR: 1.09, 95% CI: 1.05, 1.12). Among UPF subgroups, associations were most notable for animal-based products (HR: 1.09, 95% CI: 1.05, 1.12), and artificially and sugar-sweetened beverages (HR: 1.09, 95% CI: 1.06, 1.12). Other subgroups such as ultra-processed breads and cereals (HR: 0.97, 95% CI: 0.94, 1.00) or plant-based alternatives (HR: 0.97, 95% CI: 0.91, 1.02) were not associated with risk., Interpretation: Our findings suggest that higher consumption of UPFs increases the risk of cancer and cardiometabolic multimorbidity., Funding: Austrian Academy of Sciences, Fondation de France, Cancer Research UK, World Cancer Research Fund International, and the Institut National du Cancer., Competing Interests: None of the authors declared a competing interest., (© 2023 Published by Elsevier Ltd.)