Статті в журналах з теми "Trajectoire de lanceur"

Résumé Sur la base d'une psychothérapie intensive qu'il a faite avec un adolescent, psychothérapie qui s'est poursuivie durant 15 mois, à raison de 2 à 3 séances par semaine, l'auteur essaie de différencier la problématique d'une crise de la pathologie en évolution en cours de consultation. En alternance avec le matériel clinique, l'auteur utilise diverses notions théoriques qui permettent de comprendre ce matériel.

BackgroundSystemic sclerosis (SSc) is an autoimmune disease that is characterized by systemic vasculopathy and fibrosis. Pulmonary hypertension (PH), defined as elevated pulmonary arterial pressure (PAP), is one of the leading causes of death of SSc1. In recent years, various therapies have been developed to target each of the pathogenesis of SSc – autoimmunity, vasculopathy, and fibrosis. Accordingly, treatment strategies based on risk stratification for PH progression are aspired; however, prediction of changes in PAP in diverse patients with SSc has not been established2.ObjectivesTo visualize the patterns of PAP elevation in SSc and to identify the clinical characteristics of each trajectory, by applying latent trajectory modeling for PAP measured repeatedly by echocardiography.MethodsThis was a multicenter, retrospective cohort study conducted at four referral hospitals in Kyoto, Japan. Patients with SSc who visited the study site between April 2008 and March 2021 and had at least three echocardiographic measurements of systolic pulmonary arterial pressure (sPAP) were included in this study. Follow-up concluded in March 2021. A group-based trajectory model3 was applied to the change in sPAP over time, and individual patients were classified into distinct subgroups that followed similar trajectories. The number and shape of the trajectories were estimated based on adequacy, goodness of fit, parsimony, and interpretability of the model. Clinical plausibility was assessed by comparing PH-free survival, i.e., time to either PH or death, for each trajectory. Multinomial logistic regression analysis was performed for baseline clinical characteristics associated with trajectory assignment.ResultsA total of 236 patients with a total of 1097 sPAP measurements were included. We identified five trajectories following the quadratic function as “rapid progression (n=9, 3.8%)”, “early elevation (n=30, 12.7%)”, “mid elevation (n=54, 22.9%)”, “late elevation (n=24, 10.2%)”, and “low stable (n=119, 50.4%)”. Each trajectory, in this order, showed earlier elevation of sPAP and shorter PH-free survival (Figure 1). In the multinomial logistic regression (with the “low stable” as reference), cardiac involvement was associated with the “rapid progression” (adjusted odds ratio [OR] 28.9, 95% confidence interval [CI] 3.21–259.5), diffuse cutaneous SSc was associated with the “early elevation” (OR 4.08, 95% CI 1.27–13.1), anti-centromere antibody positive was associated with the “mid elevation” (OR 4.50, 95% CI 1.11–18.2), and older age of onset was associated with the above three trajectories.ConclusionThe pattern of changes in pulmonary artery pressure over time in SSc can be classified into five distinct trajectories. Each trajectory differed in baseline clinical characteristics and outcomes.References[1]Pokeerbux MR, et al. Survival and prognosis factors in systemic sclerosis: data of a French multicenter cohort, systematic review, and meta-analysis of the literature. Arthritis Res Ther. 2019;21(1):86.[2]Denton CP, et al. Systemic sclerosis. Lancet. 2017;390(10103):1685-1699.[3]Nagin DS, et al. Group-based trajectory modeling in clinical research. Annu Rev Clin Psychol. 2010;6:109-38.Disclosure of InterestsNone declared

Alexis Danan (1890-1979) est l'une des grandes figures médiatiques de la campagne contre les « bagnes pour enfants » dans la France des années trente. Le reporter n’est pas le premier ni le seul à écrire sur le sujet. Le nom du journaliste est celui que la mémoire de la réforme des établissements de correction a le plus conservé. En pleine période de lutte antifasciste et sous le Front populaire, des hommes et des femmes se mobilisent ; ils interpellent le pouvoir pour dénoncer le scandale et demander des réformes. Après avoir été un homme d'enquête, le journaliste Alexis Danan dénonce et interpelle le pouvoir dans un journal, Paris-Soir, devenu le quotidien le plus lu des Français. En mai 1936, il utilise le média pour lancer la Fédération nationale des comités de vigilance et d’action pour la protection de l’enfance malheureuse. La trajectoire d’un individu – donc une biographie – est un repère pour interroger autrement les processus sociaux et culturels qui, en amont, modifient l’environnement des actions publiques en direction de l’enfance irrégulière. Le journaliste engagé a pu incarner un mode de légitimité bien particulier dans un monde, celui de la protection de l’enfance. Son exemple est à la fois exceptionnel car la norme se trouve ailleurs, et attendu, au regard d’une image, celle d’un « quatrième pouvoir » en démocratie.

BackgroundDuchenne muscular dystrophy (DMD) is an x-linked ultra-rare neuromuscular condition affecting 1 in 3600–6000 live male births.1 Individuals live with an exceptional illness trajectory of prolonged dwindling frailty and high symptom burden.2 While it is recognised that a co-ordinated multidisciplinary team approach may increase the survival of those with DMD and improve their quality of life (QoL)3 adults are receiving less comprehensive and co-ordinated care compared with those in the paediatric service.4AimTo investigate QoL in adults with DMD living in the West of Scotland (WoS).MethodsThe SEIQoL-DW tool was used to assess the five most important elements that contribute to an individual’s QoL – these were then used to guide qualitative interviews with six men in the WoS. A thematic analysis was undertaken.ResultsMen living with DMD in the WoS described living good lives but feel ‘forgotten’ due to perceived gaps in their care: poorly co-ordinated and infrequent health care; lack of multi-disciplinary team input and holistic care; and poor or no access to allied health care professionals for example physiotherapy and psychological support.ConclusionsExisting guidelines rarely seem materialise as person-centred care. There are numerous opportunities to introduce palliative care gently as part of the MDT early in the illness trajectory and continue in a dynamic manner as time elapses and when trigger points arise. Better co-ordinated multi-disciplinary care with the inclusion of a palliative care specialist may be a solution allowing for an early introduction to palliative care and proactive advance care planning.References. Bushby K, et al. Diagnosis and management of duchenne muscular dystrophy part 1: Diagnosis and pharmacological and psychosocial managment. Lancet Neurol2010;9:77–93.. Landfeldt E, et al. The burden of duchenne muscular dystrophy. Neurology2014;83:529–36.. Bushby K, et al. Diagnosis and management of duchenne muscular dystrophy part 2: Implementation of multidisciplinary care. Lancet Neurol2010;9:177–89.. Rodger S, et al. Adult care for duchenne muscular dystrophy in the UK. J Neuro2015;262:629–41.

ObjectiveTo document clinical trial data flow in global clinical trials published in major journals between 2013 and 2021 from Global South to Global North.DesignScoping analysisMethodsWe performed a search in Cochrane Central Register of Controlled Trials (CENTRAL) to retrieve randomised clinical trials published between 2013 and 2021 from The BMJ, BMJ Global Health, the Journal of the American Medical Association, the Lancet, Lancet Global Health and the New England Journal of Medicine. Studies were included if they involved recruitment and author affiliation across different country income groupings using World Bank definitions. The direction of data flow was extracted with a data collection tool using sites of trial recruitment as the starting point and the location of authors conducting statistical analysis as the ending point.ResultsOf 1993 records initially retrieved, 517 studies underwent abstract screening, 348 studies underwent full-text screening and 305 studies were included. Funders from high-income countries were the sole funders of the majority (82%) of clinical trials that recruited across income groupings. In 224 (73.4%) of all assessable studies, data flowed exclusively to authors affiliated with high-income countries or to a majority of authors affiliated with high-income countries for statistical analysis. Only six (3.2%) studies demonstrated data flow to lower middle-income countries and upper middle-income countries for analysis, with only one with data flow to a lower middle-income country.ConclusionsGlobal clinical trial data flow demonstrates a Global South to Global North trajectory. Policies should be re-examined to assess how data sharing across country income groupings can move towards a more equitable model.

The lance is a critical component of the bottom-blowing pool melting process, and its placement has an important impact on the pool?s gas-liquid two-phase flow. In this study, a mathematical model of the bottom-blowing process is established, and the flow pattern, trajectory, wake vortex, and velocity of bubbles under four lance spacings are simulated. Results show that there are three basic bubble flow patterns appear in the flow field: bubbles coalesce before leaving the nozzle (Pattern I), bubbles coalesce after leaving the nozzle (Pattern II), and no coalescence during the rise of bubbles (Pattern III). The bubble pattern varies from Pattern I to Pattern III with the increase in lance spacing. The intensity of the influence of the wake vortex on the bubbles decreases. The Q (The Q is the second Galilean invariant of the velocity gradient tensor ?v.) value of the wake vortex is small, but the vortex structural distribution is complex. Moreover, there is a large velocity difference between gas and liquid at the beginning of gas injection, but the velocity difference between them decreases after gas injection, so the average turbulent kinetic energy in the pool initially increases sharply, and then approaches dynamic equilibrium. The top and bottom velocities of the bubbles are consistent, and the velocity fluctuation is orderly. Moreover, the greater the lance spacing is, the greater the disturbance in the pool is. The mixing effect of D = 0.2 m is the best among the four spacings.

The demographics and communicative disorders which traverse aging, neurocognitive disorders and auditory problems are staggering. Lancet Public Health1 estimates 57 million people globally with dementia in 2019 and by 2050 there will be 153 million cases. People seek counsel from hearing care professionals (HCPs) because of complaints and observations such as they cannot understand speech-in-noise (SIN), and/or they are not sure what someone just said, and/or they cannot recall the details of a recent conversation. For many, the complaints and observations of hearing and listening disorders are the same as, and may overlap with complaints and observations of, mild cognitive impairment and other neurocognitive disorders. In this article we review the current knowledge related to cognition and audition; we explore the practical reasons for incorporating cognitive screening into otolaryngology clinics, with specific regard to patients with hearing and listening problems. We review and explore auditory and cognitive disorders and we specify that these are not silos. That is, they may (and often do) occur in-isolation or in-tandem. We will review multiple studies which demonstrate that for some people, some of the time, early detection of neurocognitive anomalies may help facilitate an improved cognitive trajectory via hearing aid amplification, cochlear implantation, and through attending to modifiable risk factors.

Tous les ans, nombre d’entreprises lancent leur enquête d’engagement et les communicateurs internes sont sommés d’interroger des salariés, confrontés à des questions de sens. Partant du propos qu’« il faut s’engager pour engager », selon les mots d’un praticien, quelle sorte de professionnel engagé est ce praticien ? Celui-ci ne peut-il exercer son métier sans un investissement personnel fort ? De quoi est alors fait cet engagement ? Dans quelle mesure cet engagement influence-t-il la façon d’exercer son métier ? Telle est l’intrigue proposée et trois éclairages nous seront utiles pour la résoudre: sur l’engagement, sur la posture du praticien dans l’organisation, sur la dynamique de sa trajectoire professionnelle. Nous verrons que, engager demande de s’expliquer, de dialoguer, voire de se disputer autour du travail et de son organisation. La dimension communicationnelle du travail apparaît ainsi comme une évidence. Every year, companies launch their commitment survey and internal communicators are asked, as a matter of priority, to interview employees, who are confronted with questions of meaning. Starting from the premise that, in the words of a practitioner, “one must commit oneself to engage others”, we explore the nature of this commitment. Can the practitioner exercise his job without strong personal investment? What is the basis for his commitment? How does this commitment influence the way he does his job? To answer these questions, we will seek to clarify the nature of the practitioner’s commitment, his role within the organization and the dynamics of his career path. We will see that, in order to engage others, internal communicators have to explain, to exchange ideas, to enter into a dialogue and even to argue about the work and its organization and the relations between individual employees. The communication dimension of his work thus seems obvious.

Background: Gastric cancer remains a global malignancy. The role of bibliometric analysis is increasingly valued. It is feasible and necessary to perform a bibliometric analysis to regurgitate studies in the prognosis of gastric cancer. Materials and methods: Web of Science was selected for the dataset resource. Articles published between 2000 and 2020 within the database of Web of Science Core Collection were included with predefined search terms. CiteSpace version 5.7.R1 and R software program version 4.0.3 were used for bibliometric analysis with parameters extrapolated from included studies. Results: A total of 1721 articles were included from 2000 to 2020 with remarkably increasing trends. China (n=1183), Japan (n=218), and South Korea (n=119) showed the most publications. SUN YAT SEN University, FUDAN University, and NANJING MED University were the top institutions with most publications. Keywords with strongest citation bursts between 2000 and 2020 were characterized. Particularly, “statistics”, “resistance”, “mortality”, “lncrna”, “diagnosis”, “outcome”, “migration”, “promote,” and “regulatory t cell” were the latest rising keywords since 2017, indicating possible study trends ahead. Several articles showed strongest citation bursts, including Jemal A. CA-CANCER J CLIN, Van Cutsem E. LANCET, and Japanese Gastric Cancer Association GASTRIC CANCER. Conclusion: This bibliometric analysis provides a thought-provoking, insightful result concerning the trajectory of research development in prognosis of gastric cancer with a future perspective.

Molecular dynamics and free energy simulations have been carried out to elucidate the structural origin of differential protein–protein interactions between the common receptor protein angiotensin converting enzyme 2 (ACE2) and the receptor binding domains of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [A. E. Gorbalenyaet al.,Nat. Microbiol.5, 536–544 (2020)] that causes coronavirus disease 2019 (COVID-19) [P. Zhouet al.,Nature579, 270–273 (2020)] and the SARS coronavirus in the 2002–2003 (SARS-CoV) [T. Kuikenet al., Lancet 362, 263–270 (2003)] outbreak. Analysis of the dynamic trajectories reveals that the binding interface consists of a primarily hydrophobic region and a delicate hydrogen-bonding network in the 2019 novel coronavirus. A key mutation from a hydrophobic residue in the SARS-CoV sequence to Lys417 in SARS-CoV-2 creates a salt bridge across the central hydrophobic contact region, which along with polar residue mutations results in greater electrostatic complementarity than that of the SARS-CoV complex. Furthermore, both electrostatic effects and enhanced hydrophobic packing due to removal of four out of five proline residues in a short 12-residue loop lead to conformation shift toward a more tilted binding groove in the complex in comparison with the SARS-CoV complex. On the other hand, hydrophobic contacts in the complex of the SARS-CoV–neutralizing antibody 80R are disrupted in the SARS-CoV-2 homology complex model, which is attributed to failure of recognition of SARS-CoV-2 by 80R.

BackgroundExercise therapy is recommended as first line treatment for knee osteoarthritis (OA), but it remains to be sub-optimally applied (1). Movement-evoked pain is a potential barrier to exercise adherence, but recent evidence suggests that such pain can be improved by training (2). Walking programs are low-cost, easily adopted and can be performed outdoors which can minimize the risk of SARS-CoV-2 transmission when in a group (3).ObjectivesTo explore the acute pain trajectories of individuals with knee OA during a 24-week outdoor walking intervention. In addition, to explore the effect of pain trajectories and/or baseline characteristics on retention and adherence.MethodsIndividuals with clinical knee OA and bone marrow lesions (BMLs) on magnetic resonance imaging (MRI) were asked to follow a 24-week walking program. Every week consisted of two one hour supervised group sessions at various outdoor locations and one unsupervised session. At the start and end of every supervised group walk, knee pain was self-reported by participants to their trainer using a numerical rating scale (NRS) (0-10). The difference between the NRS pain values was considered as an acute pain change evoked by that walk. At baseline, the most affected knee of each participant was assessed using the Visual Analogue Scale (VAS) pain, the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) pain, stiffness and function, wellbeing (3 questionnaires) and the Osteoarthritis Research Society International (OARSI) recommended strength and performance measures.ResultsIn total, N = 24 participants started the program of whom N = 7 (29%) withdrew. Pain at the start of each walk decreased from NRS 2.5 (SD 1.6) at the first walk (N = 24) to NRS 0.9 (SD 0.8) at the final walk (N = 17). This pain was estimated to decrease on NRS by -0.04 (95% CI -0.05 to -0.02) per supervised session, p < 0.001 during the first 12 weeks and -0.01 (95% CI -0.02 to -0.004), p = 0.004 during the second twelve weeks of the program. The number (%) of participants who experienced an acute increase in pain decreased from 11 (45.8%) at the first walk to 4 (23.5%) at the last walk.At baseline, non-adherent participants (<70% of group sessions) (N = 11) had lower physical performance scores, including the 30s Chair Stand Test (mean 10 (SD 1.7) stands versus mean 12.0 (SD 1.7) stands, p = 0.011), Fast Past Walk Test (1.23 (SD 0.14) meter per seconds (m/s) vs 1.50 (SD 0.20) m/s, p = 0.001), Six Minute Walk Test (418.8 (SD 75.9) m vs 529 (SD 72.6) m, p = 0.002), compared to adherent participants (N = 13). Non-adherent participants also had less severe self-reported symptoms including WOMAC stiffness (90.7 (SD 44.5) mm vs 121.5 (SD 17.0) mm, p = 0.031), compared to adherent participants. During the first two weeks of walking, acute increases in pain on average (mean ≥0.5 NRS) were reported by a greater number of non-adherent (N = 5 (45.5%)) than adherent participants (n = 4 (30.8%)).ConclusionThis was an exploratory study and results need to be interpreted with caution due to the small sample size. The walking program resulted in clinically important improvements (MCIIs) (≥ 1 on NRS) (4) in start pain and acute pain changes. Improvements in start pain during the first 12-weeks were comparable to improvements measured in the NEMEX program (2) and may suggest that 12 weeks of exercise is sufficient to achieve MCIIs in pain. Improvements in acute changes in pain were smaller, which may have been related to a floor effect (5). Lower physical performance scores at baseline and more acute increases in pain during the first two weeks was associated with non-adherence. Participants with these characteristics may benefit from a lighter introduction to exercise.References[1]Bennell KL, et al. The Lancet Regional Health-Western Pacific. 2021;12:100187.[2]Sandal LF, et al. Osteoarthritis and cartilage. 2016;24(4):589-92.[3]Bulfone TC, et al. The Journal of infectious diseases. 2021;223(4):550-61.[4]Perrot S, et al. Pain. 2013;154(2):248-56.[5]McHorney CA, et al. Quality of life research. 1995;4(4):293-307.AcknowledgementsWe thank the participants who made this study possible. We would like to acknowledge the research staff, Kate Probert, Lizzy Reid, Simone Fitzgerald, Claire Roberts, Jasmin Ritchie, Dawn Simpson, and Tim Albion. We also thank Hamish Newsham-West for his contribution to the study design.Disclosure of InterestsStan Drummen: None declared, Saliu Balogun: None declared, Lieke Scheepers Grant/research support from: Competitive Grant Program Inflammation ASPIRE 2020 Rheumatology International Developed Markets from Pfizer, Employee of: previously worked as an Associate Director Epidemiology at the Medical Evidence Observational Research Department at AstraZeneca., Ishanka Munugoda: None declared, aroub lahham: None declared, Kim Bennell: None declared, Rana Hinman: None declared, Michele Callisaya: None declared, Guoqi Cai: None declared, Petr Otahal: None declared, Tania Winzenberg Consultant of: received payment to create educational material by AMGEN, Zhiqiang Wang: None declared, Benny Antony: None declared, Johanne Martel-Pelletier Shareholder of: ArthroLab Inc., Jean-Pierre Pelletier Shareholder of: ArthroLab Inc., François Abram Consultant of: ArthroLab Inc., Employee of: Arthrolab Inc., Graeme Jones Speakers bureau: received payment for a speakers bureau from Novartis, Dawn Aitken: None declared

BackgroundGuselkumab (GUS), an IL-23p19 inhibitor, has demonstrated efficacy in psoriatic arthritis (PsA) across key Group for Research and Assessment of Psoriasis (PsO) and Psoriatic Arthritis (GRAPPA)-recommended domains[1,2]. Skin disease and enthesitis have been identified as disease manifestations with earlier response times than others[3].ObjectivesIn this analysis we: (a) Determined whether early skin and/or entheseal response predicts future response in other PsA domains; (b) Evaluated the trajectory for achieving skin/entheseal responses by 52 weeks (W) in patients (pts) without early responses.MethodsPts in the DISCOVER-1 and DISCOVER-2 (D1/2) studies were adults with active PsA despite standard therapies. D1 pts had ≥3 swollen and ≥3 tender joints (SJC/TJC) and C-reactive protein (CRP) ≥0.3 mg/dL; D2 pts had SJC ≥5, TJC ≥5, and CRP ≥0.6 mg/dL. 31% of D1 pts received 1-2 prior TNF inhibitors; D2 pts were biologic-naïve. Pts were randomized 1:1:1 to GUS 100 mg every 4 weeks (Q4W); GUS 100 mg at W0, W4, then every 8 weeks (Q8W); or placebo. These post hoc analyses included only pooled GUS Q4W and Q8W pts (N=748). Early skin response was defined as PsO Area and Severity Index (PASI) score ≤1 at W16 or skin visual analogue scale (VAS) ≤15mm at W8 among pts with a baseline (BL) PASI score >1 and skin VAS >15mm (first assessment time for both); early entheseal response was defined as Leeds Enthesitis Index (LEI) score ≤1 at W8; and categories of early response were defined as skin VAS ≤15mm only vs LEI score ≤1 only vs combined skin VAS ≤15mm & LEI score ≤1 vs none at W8. Potential responses at W24 & W52 included achievement of minimal disease activity (MDA), Disease Activity in PsA (DAPSA) low disease activity (LDA) or remission, DAPSA50, and enthesitis/dactylitis resolution. Associations between early skin/entheseal response and W24/W52 response were assessed with crosstabulations and logistic regression.ResultsEarly skin response associated with greater odds of achieving W24 MDA, DAPSA LDA, DAPSA remission, and DAPSA50, but not enthesitis or dactylitis resolution (Figure 1). Early entheseal response associated with greater odds of achieving all W24 outcomes, including resolution of enthesitis or dactylitis, with the exception of DAPSA remission; DAPSA remission was achieved by a greater proportion of early responders, though the association was significant only at W52. In pts with both BL PsO and enthesitis, early responders in both domains were even more likely to subsequently demonstrate MDA, DAPSA LDA, DAPSA50, DAPSA remission only at W52, and dactylitis resolution than pts with individual responses. Among pts who did not achieve early responses, approximately half did so by W52.ConclusionEarly skin and entheseal responses predicted long-term clinical response, including disease remission. A synergistic effect was observed, in which pts with BL PsO and enthesitis exhibiting early response in both domains were more likely to achieve later clinical response. These results highlight the importance of early response in these two domains on the trajectory of long-term pt outcome.References[1]Deodhar A et al. Lancet. 2020;395(10230):1115-25[2]Mease PJ et al. Lancet. 2020;395(10230):1125-36[3]Coates LC et al. A893. EULAR 2022, DenmarkAcknowledgements:NIL.Disclosure of InterestsLaura Coates Speakers bureau: AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Medac, Novartis, Pfizer and UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Julio Ramírez Speakers bureau: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, and UCB, Consultant of: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, and UCB, Dennis McGonagle Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, and UCB, Sibel Aydin Grant/research support from: AbbVie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Miriam Zimmermann Shareholder of: Johnson & Johnson, Employee of: Janssen Scientific Affairs, LLC, Francois Nantel Shareholder of: Johnson & Johnson, Consultant of: Janssen, May Shawi Shareholder of: Johnson & Johnson, Employee of: Janssen Pharmaceutical Companies of Johnson & Johnson, Emmanouil Rampakakis Consultant of: Janssen, Employee of: JSS Medical Research, Peter Nash Grant/research support from: AbbVie, Boehringher-Ingelheim, Eli Lilly, Galapagos, Gilead, GSK, Janssen, MSD, Novartis, Pfizer, Samsung, Sun Pharma, and UCB, Philip J Mease Speakers bureau: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Consultant of: AbbVie, Aclaris, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Inmagene, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Sun Pharma, and UCB.

Background: Analyses of author collaborations and keyword co-occurrences are frequently used in bibliographic research. However, no studies have introduced a straightforward yet effective approach, such as utilizing ChatGPT with Code Interpreter (ChatGPT_CI) or the R language, for creating cluster-oriented networks. This research aims to compare cluster analysis methods in ChatGPT_CI and R, visualize country-specific author collaborations, and then demonstrate the most effective approach. Methods: The research focused on articles and review pieces from Medicine (Baltimore) published in 2023. By August 20, 2023, we had gathered metadata for 1976 articles using the Web of Science core collections. The efficiency and effectiveness of cluster displays between ChatGPT_CI and R were compared by evaluating their time consumption. The best method was then employed to present a series of visualizations of country-specific author collaborations, rooted in social network and cluster analyses. Visualization techniques incorporating network charts, chord diagrams, circle bar plots, circle packing plots, heat dendrograms, dendrograms, and word clouds were demonstrated. We further highlighted the research profiles of 2 prolific authors using timeline visuals. Results: The research findings include that (1) the most active contributors were China, Nanjing Medical University (China), the Medical School Department, and Dr Chou from Taiwan when considering countries, institutions, departments, and individual authors, respectively; (2) the highest cited articles originated from Medicine (Baltimore) accounting for 4.53%: New England Journal of Medicine, PLOS ONE, LANCET, and The Journal of the American Medical Association, with respective contributions of 3.25%, 2.7%, 2.52%, and 1.54%; (3) visual cluster analysis in R proved to be more efficient and effective than ChatGPT_CI, reducing the time taken from 1 hour to just 3 minutes; (4) 7 cluster-focused networks were crafted using R on a custom platform; and (5) the research trajectories of 2 prominent authors (Dr Brin from the United States and Dr Chow from Taiwan) and articles themes in Medicine 2023 were depicted using timeline visuals. Conclusions: This research highlighted the efficient and effective methods for conducting cluster analyses of author collaborations using R. For future related studies, such as keyword co-occurrence analysis, R is recommended as a viable alternative for bibliographic research.

Hydro-gas regularities of liquid combined blowing by gas were studied using cold modeling method at Archimedes criterion for lateral Arl = 12÷120 and bottom blowing Arb = 5÷60 simulating Pobeda bubbling unit. The blowing was performed simultaneously by bottom lance vertically fixed in centre of reactor and by the lateral lance which was attached at an angle 5° to the horizontal axis. The quantitative estimation of instantaneous and average circulation velocities (Vav) of liquid flow elements in different bath areas, depending on the location of blowing zone and Archimedes criterion, was performed. The liquid motion trajectory was determined. A vortex zone was revealed near the liquid surface and the reactor shell, where instantaneous velocity of the liquid flow elements changes from 69.9 to 181.1 mm/s and Vav = 123.8 mm/s. The circulation flows fade in the bulk of liquid and Vav decreases from 123.8 to 47.0 and 54.1 mm/s. It was shown that, in general, circulation velocity depends on the blowing intensity and appears to be higher for the zone of overlapping of lateral and bottom streams. The dynamic blowing conditions, which ensure the direct contact of lateral and bottom jets leading to their interflow and increased spatter formation, were identified. The characteristics of 3 types of surface oscillations for interface phases “pure liquid- gas-liquid layer”, as well as the estimation of the lateral and bottom blowing impact on the type of oscillation were provided. It has been noted that the introduction of the bottom blowing (Arb = 5) causes the wave-like motion of liquid (the 2nd type) along with the transverse oscillations of the 1st type, and at higher values of Arb = 25 the angular oscillations of the 3rd type develop. It has been shown that the presence of a lateral jet at the combined blowing decreases angles of bath swinging to 8–12° to horizontal axis. For the estimation of oscillation intensity, Δhl = (hl )max – (hl )min value, which means the difference between maximum (hl )max and minimum (hl )min height of liquid for the full-wave oscillations (τ), was introduced. The height of liquid (hl ) was plotted as a function of τ, Arl , Arb, Δhl was determined on the basis of obtained graph values, which varied upon modeling over the range of 7.7–69.5 mm. The relation between the liquid circulation velocity and the oscillation value (Δhl ) was established for different bath zones and dynamic conditions of the blowing. The impact of all oscillations types on potential erosive lining wear of Pobeda bubbling unit and the completeness of adoption of charging material nearby the bath surface was investigated.

BackgroundPatients with inflammatory joint conditions have a high prevalence of comorbidities including chronic kidney disease (CKD) [1]. The data pertaining to CKD in rheumatoid arthritis (RA) is limited [2], however and its association with psoriatic arthritis (PsA) remains unclear. Renal disease in RA and PsA is clinically important as it can lead to restrictions in the management of the primary disease, and is also associated with increased all-cause morbidity and mortality [3].ObjectivesTo determine and compare the rate of incident CKD in patients with rheumatoid and psoriatic arthritis and to determine the rate of estimated glomerular filtration rate (eGFR) change over time.MethodsPatients with RA and PsA who were first diagnosed between 1st January 2005 and 31st December 2010 were included in this retrospective, longitudinal analysis. All eGFR values, calculated using the Modification of Diet in Renal Disease equation, for each patient were collected from time of diagnosis until 31stDecember 2020. Demographic details, disease-specific characteristics, the presence of cardiovascular disease at baseline and anti-rheumatic drug use at each appointment were recorded. Generalized additive models (GAMs) were used to smooth the eGFR trajectories for each patient, and mixed-effects models were then used to estimate crude linear trends in eGFR across the period of observation. The primary outcome measure was diagnosis of CKD, defined as patient’s eGFR falling below 60ml/min/m 2 for a period of at least 90 days in their smoothed eGFR trajectory.ResultsThe patient sample (n = 159) included 114 RA and 45 PSA patients. RA patients were less likely to be male (39 vs 51%, p = 0.2) and older (mean age at baseline 52 vs 46 years, p < 0.001) than PsA patients. They also tended to have moderately lower eGFR upon initial observation (78 vs 83 ml/min/m2, p = 0.07). Baseline comorbidity profiles were broadly similar between the two groups. Treatment profiles were also similar, but with RA patients prescribed DMARDs at 69% of their appointments on average vs 56% in PSA patients (p = 0.003). There were 22 incident cases of CKD in the RA patients (19%), vs 7 in the PSA patients (16%, p = 0.6), and 17 RA patients died during the observation period (15%) vs 2 PSA patients (4.4%, p = 0.07). Results from a sex- and age-adjusted mixed effects models suggested that eGFR trajectories tended to slowly decline on average in PSA patients (-0.22 ml/min/m2 per year, p vs no trend = 0.14), but increased on average (0.79 ml/min/m2 per year) among RA patients (p for interaction < 0.001).ConclusionIncident CKD diagnosis was high in both patient populations. While rate of eGFR decline was greater in patients with PsA, overall rates of CKD diagnosis did not differ significantly. Monitoring of kidney function should be an important part of management of inflammatory joint conditions, as the majority of these patients non-steroidal inflammatory drugs and immunosuppressive therapies which may be contraindicated or require dose adjustment if renal impairment is present.References[1] Ziade, N., El Khoury, B., Zoghbi, M. et al. Prevalence and pattern of comorbidities in chronic rheumatic and musculoskeletal diseases: the COMORD study. Sci Rep 10, 7683 (2020).https://doi.org/10.1038/s41598-020-64732-8[2] Raksasuk S, Ungprasert P. Patients with rheumatoid arthritis have an increased risk of incident chronic kidney disease: a systematic review and meta-analysis of cohort studies. Int Urol Nephrol. 2020 Jan;52(1):147-154. doi: 10.1007/s11255-019-02346-4. Epub 2019 Dec 9. PMID: 31820358.[3] GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020 Feb 29;395(10225):709-733. doi: 10.1016/S0140-6736(20)30045-3. Epub 2020 Feb 13. PMID: 32061315; PMCID: PMC7049905Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Abstract Background Responses to ulcerative colitis (UC) treatments vary considerably between individuals, and factors associated with a stable response are not well defined. Filgotinib (FIL) is an oral, Janus kinase 1 preferential inhibitor approved in the EU and the UK as a UC therapy. We aimed to identify factors associated with partial Mayo Clinic Score (pMCS) over time in FIL-treated patients with UC in the phase 2b/3 SELECTION trial (NCT02914522). Methods In SELECTION, adults with moderately to severely active UC received FIL 200 mg (FIL200), FIL 100 mg (FIL100) or placebo once daily for 11 weeks in Induction (IND) Study A (biologic-naive) or B (biologic-experienced).1 Patients in clinical remission or with a Mayo Clinic Score (MCS) response at week 10 could enter the 47-week Maintenance (MNT) Study. To evaluate factors associated with pMCS during MNT this post hoc analysis used a mixed model for repeated measures (MMRM), which included fixed effects of time, IND dose (FIL200 or FIL100), the factor of interest and pMCS at IND baseline, and correlated patient residual errors. For categorical factors, the least-squares mean difference with 95% confidence interval (CI) and the overall type III p value were calculated. For continuous factors, the difference in pMCS for a one-unit change in the factor of interest was estimated with 95% CI. Multiplicity adjustment of p values was not performed. Results Data from 371 patients treated with FIL200 (n=199) or FIL100 (n=172) were included. Previous use of at least one biologic therapy or a tumour necrosis factor antagonist/vedolizumab, and week 10 MCS subscores of ≤1 were associated with higher pMCS over time than their respective reference categories (p&lt;0.0001; Table 1). Over time, pMCS was 0.45 units higher in patients assigned to IND Study A versus IND Study B (p=0.0002). Week 10 endoscopic score ≤1, Geboes histologic remission and Inflammatory Bowel Disease Questionnaire total score &gt;170 were associated with lower pMCS over time than their respective reference categories (p≤0.0001). Change from baseline in pMCS at week 10 and faecal calprotectin levels at week 10 were positively associated with pMCS over time (p&lt;0.0001; Table 2). Patient-reported outcome (PRO) measures at week 10 were negatively associated with pMCS over time (p≤0.0001). Conclusion History of previous biologic therapy, and week 10 assessments (endoscopic, clinical, biomarker and PRO) were among the factors influencing pMCS over the course of 1 year of FIL treatment, consistent with previous findings from trajectory modeling.2 Further MMRM analyses may help to identify patients who benefit most from FIL treatment. 1. Feagan BG et al. Lancet 2021;397:2372–84. 2. Schreiber S et al. MP443 [abstract]. UEGJ 2022;10:459.

Alvin Toffler once wrote: "The illiterate of the 21st century will not be those who cannot read and write, but those who cannot learn, unlearn, and relearn." This pandemic has proven his statement correct. The global academic community has learned a completely new culture of research, with torrents of data being released daily on preprint servers1,2 and dissected on platforms such as Slack and Twitter before formally peer reviewed. Fifty-five thousand viral genomes sequences of hCoV-19 shared on GISAID platforms to date3 that have been analyzed instantaneously, by a phalanx of evolutionary biologists who share their phylogenetic trees in preprints. Such advances have allowed scientists to trace and monitor the COVID-19 pandemic faster than any previous outbreak. There is still more to learn. The scientist from the fields of epidemiology, virology and biomedical science are struggling to keep this outbreak under control. Estimation of R0, which have been an important part of characterizing pandemics, including the 2003 SARS pandemic, the 2009 H1N1 influenza pandemic and the 2014 Ebola epidemic in West Africa, is something epidemiologists raced to nail down about SARS-CoV-2. There's uncertainty,foranumberofreasons,aboutmanyofthefactorsthatgointoestimatingR0. First,theincubation period of this viral pathogen is uncertain with an average 5-6 days and can be up to 14 days.4 Researchers cannot predict, without sentinel surveillance, the number of mild or asymptomatic cases that have been missed but nevertheless are spreading the disease.5 Secondly, majority of people who get infected, do recover and are likely to be immune. This alters population susceptibility and affects future trajectory of infection spread. Finally, susceptibility to disease in different communities varies based on their demographics, health conditions and different social structures. And hence, mathematical model accuracy, be it Institute for Health Metrics and Evaluation (IHME)6, Ferguson et.al7, Aleta et.al8, Hellewell et.al9 and Kessler et al models10, is constrained by our knowledge of the virus dynamics since many biologic features of transmission are hard to measure and remain unknown. Another aspect of the Covid-19, which is reshaping the world of bioscience publishing, is the tension between rapid speed of research publication verses scientific rigor. This has raised serious issues regarding data integrity. The Lancet and NEMJ had had to retract some publication on this account for example, Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis11 and Cardiovascular Disease, Drug Therapy, and Mortality in Covid-1912, because independent auditors were unable to validate the primary data sources. This is of concern in the middle of a global health emergency.13 Finally, this crisis has also altered our perspective. An important feature of our ongoing experience is what anthropologist Jane Guyer termed “enforced presentism”, a feeling of being stuck in the present, combined with an inability to plan ahead.14 The question is how do we reclaim our future? The past has provided us a prologue for discussion, whether it is the biological origins of a potential pandemic or its social repercussions, it is up to us to reorder the society in dramatic ways, for better or worse. Editor-in-Chief doi: http://doi.org/10.37185/LnS.1.1.127

BackgroundCD19 is a membrane glycoprotein interacting with different surface molecules like the B cell receptor (BCR) and is crucial for antigen-independent development as well as immunoglobulin-induced activation of B cells.[1] Alterations in this signalling pathway can incline autoantibody production and systemic autoimmunity in humans. Rituximab (RTX), a CD20 antagonist appears to be an effective candidate in the treatment of different autoimmune diseases that are partly driven by autoreactive B cells, such as systemic sclerosis (SSc).[2] It has been speculated that RTX might work not only by depleting B cells but also to down regulate activation markers, such as CD19.ObjectivesIn-depth analysis of CD19 abundancy and activation on B cells in SSc patients with and without RTX treatmentMethodsPeripheral blood samples from 41 patients suffering from SSc (median ± standard deviation SD, age: 54.3 ± 10.6 years, female ratio: 0.8) and 45 age- and sex-matched healthy controls (HC) (age: 51.0 ± 13.9 years, female ratio: 0.8) were drawn and PBMCs were isolated on-site. We performed flow cytometry analysis on a standardized BD LSRFortessa platform to identify B cell (CD19+CD20+) subpopulations. The geometric mean fluorescence intensity (gMFI) for CD19 in all B cell subtypes was extracted from the data set and used for further statistical analysis. Additionally, a quantitative flow cytometric bead-based assay (QuantiBRITE PE kit from Becton Dickinson) was used for the estimation of CD19 antibodies bound per cell.Results3 out of 41 SSc patients were in high disease activity at the time of blood drawal. 23 SSc patients were under RTX therapy of whom 5 patients still displayed measurable B cells frequencies. Naïve B cells made up the most abundant B cell population in SSc patients. Thus, the frequency of IgM+/IgD+/CD27- B cells was 67.9% ±13.2 (mean ±SD), followed by class-switched memory B cells (IgM-/IgD-/CD27+, 10.5 ± 4.9), non-switched memory B cells (IgM+/IgD+/CD27+, 4.0 ± 3.6) and plasmablasts (0.3 ± 4.4). Pairwise Wilcoxon Tests (Bonferroni-corrected for multiple testing) showed significant differences (p < 0.001) between frequencies of naïve B cells and all other cell types. In contrast, naïve B cells displayed the second lowest CD19 gMFI levels (7601.0 ± 1912.0) in the dataset. Non-switched memory B cells in SSc patients showed the highest CD19 gMFI (10620.0 ± 15689.8), followed by class-switched (9388 ± 3048.6). As expected, Plasmablasts displayed the lowest CD19 gMFI levels (4799.0 ± 4185.7). The decrease in CD19 gMFI was again highly significant. This trajectory in decreasing CD19 gMFI was found in both HCs and SSc patients. We saw a significant reduction in percentages of non-switch B cells and class-switched B cells in SSc patients compared to HCs (4.0 ± 3.6 vs 6.5 ± 4.2, p = 0.029, 10.5 ± 4.9 vs 13.2 ± 7.2 p = 0.04) but an increase in CD19 gMFI in non-switched B cells (HC: 9204.5 ± 2116.8, p = 0.05). Interestingly, SSc patients under RTX treatment had significantly lower class-switched memory B cell frequencies compared to HCs (6.4 ± 4.2 vs. 13.2 ± 7.2, p = 0.015). However, RTX did not affect CD19 gMFI or bound CD19 in SSc.ConclusionRTX treatment in SSc is not associated with downregulation of the co-stimulation marker CD19. Thus, the main effect of this drug is the reduction of B cells, especially class-swtched memory B cells that might have a high capacity to activate other cells involved in the pathogenesis of SSc.References[1]M. Wang et al., “Identification and Validation of Predictive Biomarkers to CD19- and BCMA-Specific CAR T-Cell Responses in CAR T-Cell Precursors,” Blood, vol. 134, no. Supplement_1, pp. 622–622, Nov. 2019, doi: 10.1182/blood-2019-122513.[2]S. Ebata et al., “Safety and efficacy of rituximab in systemic sclerosis (DESIRES): a double-blind, investigator-initiated, randomised, placebo-controlled trial,” Lancet Rheumatol., 2021.AcknowledgementsThis work was funded by a grant from JDRF, LRA and NMSS (grant key: 2-SRA-2021-1043-S-B) and the Austrian Federal Government within the COMET K1 Centre Program, Land Steiermark and Land Wien.Disclosure of InterestsBarbara Dreo: None declared, Barbara Prietl: None declared, Selina Kofler: None declared, Verena Pfeifer: None declared, Harald Sourij: None declared, Florentine Moazedi-Fürst: None declared, Sonja Kielhauser: None declared, Monica D’Orazio: None declared, Sabine Zenz: None declared, Jens Thiel Speakers bureau: Novartis, GSK, Vifor, BMS, Consultant of: Novartis, GSK, Vifor, Grant/research support from: BMS, Martin Stradner: None declared, Hans-Peter Brezinsek: None declared

Abstract Background: Treatment-related financial burden, or financial toxicity, can detract from mental health and quality of life and can lead patients to alter their care to offset treatment costs. In doing so, these patients compromise adherence which can contribute to disparities (Zafar Oncologist 2013). Among cancers, multiple myeloma treatment is particularly costly due to use of expensive, novel agents, often in combination, and for extended durations. One study found that patients with myeloma frequently reported financial toxicity and used coping strategies, including borrowing money or prematurely stopping treatment (Huntington Lancet Haematology 2015). In this study, we aim to measure financial toxicity in a cohort of patients with myeloma and examine relationships between financial toxicity and demographic, socioeconomic, and clinical factors. We further aim to follow this cohort longitudinally to examine the course of financial toxicity. Methods: We contacted individuals with multiple myeloma who had participated in our institutional banking study between 2018 and 2021. Patients who agreed to participate were sent a questionnaire which included the 11-item Comprehensive Score for financial Toxicity (COST). Scores range from 0-44 with lower scores indicating higher financial toxicity. Follow-up surveys will be completed after 3 and 6 months. This analysis included data from the initial survey only; follow-up survey data will be available at time of presentation. Results: At time of analysis, 234 patients were contacted and 122 (52%) had returned the survey. Ninety-four completed the COST at least 6 months following myeloma diagnosis and were included in the analysis. The median age at time of survey was 68 (range 37-88). The majority were Caucasian (95%), male (70%), college-educated (62%), and had left the workforce (70%). Seventy-two percent of patients were receiving first-line treatment for MM while 28% had relapsed or refractory disease. The median time from myeloma diagnosis to survey completion was 29 months (range 7-159 months). The median COST score was 28 (range 7-44); those below the median were considered to have higher financial toxicity. Patient characteristics are detailed in Table 1. Notably, 4 of the 5 African-American participants were in the higher financial toxicity group. The mean COST score for African-Americans was 18.4 (SD 8.0) compared to 27.7 (SD 9.2) for Caucasians (p = 0.03). In addition, those in the higher financial toxicity group were less likely to be college educated (52% versus 72%; p &lt;0.05) and the mean COST score for college educated patients was 28.9 (SD 9.3) compared to 24.1 (SD 8.7) for those without (p = 0.02). Interestingly, patients off treatment (n =11) had lower COST scores than patients receiving treatment (mean 21.5 [SD 9.6] compared to 27.9 [SD 9.1]; p = 0.03). Eighty-four patients had complete data and were included in the outcome analysis. Many trends were observed although none were statistically significant. Those with private insurance were more likely to be in the higher financial toxicity group. Those with college degrees or with higher socioeconomic status, approximated using the median household income from each patient's home census tract from the 2019 American Community Survey, were less likely to be in the higher financial toxicity group. Those receiving intravenous myeloma treatment were less likely to be in the higher financial toxicity group compared to those on oral only regimens or no treatment. Results from the analysis are detailed in Table 2. Conclusion: In this study, we observed relationships between demographics, socioeconomic status, and myeloma clinical characteristics with scores on the COST. However, none were independently associated with having a score below the median. Our findings are limited by sample composition, which was skewed toward patients who were Caucasian, college educated, and retired. In addition, because there is no established threshold for financial toxicity on the COST measure, we used our sample's median score; however, our median was higher than that of prior studies and this may have impacted the results. Nevertheless, these preliminary results show financial toxicity is a complex outcome that is difficult to predict. Our longitudinal data, which will be available at time of presentation, will build on these findings to assess the trajectory of financial toxicity over time. Figure 1 Figure 1. Disclosures Vij: BMS: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; BMS: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria; Karyopharm: Honoraria; CareDx: Honoraria; Legend: Honoraria; Biegene: Honoraria; Adaptive: Honoraria; Harpoon: Honoraria.

BackgroundA growing number of studies indicate the considerable mental health impacts of the prolonged COVID-19 pandemic in the general population as chronic stress is a risk factor for the development of depression and anxiety. Mood disorders are more prevalent in RA and a history of anxiety or depressive disorders increases the risk of recurrence in the future.ObjectivesTo compare trends in prevalence of anxiety and depressive symptoms, prior to and during the COVID-19 pandemic in RA patients with and without a lifetime history of mood disorders.MethodsData were from RA patients diagnosed and treated for RA in rheumatology clinics across Canada enrolled in the Canadian Early Arthritis Cohort (CATCH) Study. We estimated monthly trends in prevalence of clinically significant levels of anxiety and depression (PROMIS Depression and Anxiety 4a score 55+) from all visits between Mar 2019 and Jan 2022 and compared monthly trends in anxiety and depression in the year prior to (Mar 2019- Feb 2020) and during the pandemic (Mar 2020 to Jan 2022) stratified by lifetime history of mood disorders.Results4,148 visits were completed from Mar 2019 to Jan 2022 in 1,644 RA patients with a mean (SD) age of 60 (14) and disease duration of 6 (4) years. 73% were women, 84% white, 60% had completed some post-secondary education, and 77% were in CDAI REM/LDA at the visit closest to the start of pandemic. 253 (15%) reported a lifetime history of depression and 217 (13%) a lifetime history of anxiety; 8% reported prior treatment for either.Patients with a history of mood disorders had higher levels of depression and anxiety prior-to and during the pandemic compared with patients without a history of mood disorders (Table 1). Proportions were highest during COVID waves in all and were substantially higher and more variable in people with a previous history of mood disorders as compared to those without a history (Figure 1). While depressive symptoms peaked early in the pandemic, anxiety increased with each wave, peaking in Wave 3 (May-Jun 2021).Table 1.Prevalence of depression and anxiety symptoms prior to and during the COVID-19 pandemic in RA patients with and without a history of mood disorders.Period Prevalence (monthly range)DepressionAnxietyNo historyPrior HistoryNo HistoryPrior HistoryN observations35276213610538Prepandemic (3/19 - 2/20)21%(14%-30%)51%(29%-64%)27%(20%-35%)58%(31%-89%)Pandemic (3/20 - 1/22)22%(15%-29%)53%(33%-78%)28%(20%-43%)59%(33%-80%)Figure 1.During the first 22 months of the COVID-19 pandemic, the proportion of patients with depression and anxiety increased in all groups. More than half of those with a history of emotional distress had clinically significant levels of depression and anxiety; proportions were highest during COVID waves in all and were substantially higher in people with previous history as compared to those without a history (see Figure 1). Whereas depressive symptoms peaked early in the pandemic, anxiety increased with each wave, peaking in Wave 3 (May-Jun 2021).ConclusionSymptoms of anxiety and depression were common in Canadian adults with RA prior to and after the onset of the COVID-19 pandemic. Whereas others have found that high levels of depression and anxiety occurred early in the pandemic but declined fairly rapidly in the general population1, emotional distress was not attenuated over time in this large cohort of RA patients. Individuals reporting lifetime history of mood disorders were more than twice as likely to report anxiety and depression, with depression peaking early in the pandemic and anxiety growing with each successive wave in the first year. The results demonstrate the importance of applying a lifetime perspective as previous episodes of anxiety and depression may be an important marker of increased vulnerability and recurrence in RA patients, particularly during the pandemic.References[1]Fancourt D et al. Trajectories of anxiety and depressive symptoms during enforced isolation due to COVID-19 in England. Lancet Psychiatry. 2021;8:141-9.AcknowledgementsCATCH is supported through unrestricted research grants from: Amgen and Pfizer Canada since 2007; AbbVie Corporation since 2011; Medexus since 2013; Sandoz Canada since 2019; Fresenius Kabi Canada since 2021 and; Organon Canada since 2021. Previous funding from Janssen Canada (2011-16); UCB Canada and Bristol-Myers Squibb Canada (2011-18); Hoffman La Roche Limited (2011-21); Sanofi Genzyme (2016-17); Eli Lilly Canada (2016-20); Merck Canada (2017-21) and; Gilead Sciences Canada (2020-21)Disclosure of InterestsNone declared

Background: Mutations in the Nucleophosmin 1 gene ( NPM1 mut ) represent one of the most common genetic lesions in acute myeloid leukemia (AML).Based on its characteristic clinico-pathologic features, NPM1 mutAML has been recognized as a distinct entity among the category “AML with recurrent genetic abnormalities”. According to the ELN 2022 genetic risk-stratification, NPM1 mut AML, in the absence of FLT3-ITD mutation, is associated with a favorable prognosis. However, a significant proportion of these patients (pts) relapse after intensive therapy suggesting that other co-mutations may have an impact on outcome. Aims: To comprehensively characterize the genomic landscape and leukemogenic trajectoriesin a large cohort of NPM1 mut AML pts and to investigate its prognostic and predictive impact on outcome. Methods: Targeted DNA sequencing (mean read depth: 1817) on the entire coding region of 263 genes was performed in 568 NPM1 mut AML pts (median age: 58.7 years; 18-60 years, n=317; &gt;60 years, n=251). All pts were enrolled in the randomized open-label Phase 3 AMLSG 09-09 trial [NCT00893399; Döhner H et al. Lancet Haematol 2023]. In this trial, pts were assigned to intensive chemotherapy plus all- trans retinoic acid with or without gemtuzumab ozogamicin; none of the pts received midostaurin. Results: In total n=3,058 variants (variant allele frequency of ≥1%) were identified in 195/263 genes. The median number of co-mutations was 3 (range 0-11). The most common co-mutated genes were DNMT3A (49.5%), FLT3-TKD (42.8%) PTPN11 (24.8%), NRAS (22.7%) TET2 (21.7%), IDH2 (21.3%), IDH1 (18%), and FLT3-ITD (17.3%). DNMT3AR882 hotspot mutations occurred more frequently in younger pts (36.6% vs 17.1%), while there was no difference for DNMT3AnonR882 mutations between the two age groups (21.8% and 21.9%). An age-dependent difference was also identified for mutations in myelodysplasia-related genes ( ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2) as defined by the ICC, occurring with a higher incidence in older pts (30.3% vs 12.3% in younger pts). Analyzing the mutational pattern of co-mutations, we found statistically significant tertiary gene-gene interactions: e.g., NPM1- NFE2- STAG2 (p&lt;.001), NPM1- IDH2- SRSF2 (p&lt;.001), NPM1- CEBPA- TET2 (p&lt;.001), NPM1- DNMT3AR882- NRAS (p=.002), and NPM1- ASXL1- SRSF2 (p=.004); mutual exclusivities were identified for NPM1- DNMT3AR882- DNMT3AnonR882 (p&lt;.001), NPM1- IDH2- TET2 (p&lt;.001), NPM1- DNMT3AR882- SRSF2 (p&lt;.001), NPM1- IDH1- TET2 (p&lt;.001), and NPM1- FLT3-ITD- KRAS (p&lt;.002). Correlating co-mutation data with outcome, we found that DNMT3AR882 hotspot mutations confer inferior event-free (EFS) and overall survival (OS) only in younger pts (EFS, p&lt;.001 vs p=.11, Figure 1a; OS, p=.003 vs p=.8), whereas DNMT3AnonR882 mutations did not impact prognosis within the two age groups. We also found a negative prognostic impact of IDH1 mutations which was restricted to younger pts (EFS, p=.05), whereas IDH2 mutations were associated with superior EFS in older pts (p=.04) and superior OS in both groups (p=.05 and p=.03). Of note, co-mutations occurring in one or more of the myelodysplasia-related genes did not impact EFS or OS (Figure 1b). In multivariable analysis (all pts) including age, WBC, LDH, allogeneic transplantation in CR1, and mutations with an incidence of at least 3% as covariables, age (HR,1.03; p&lt;.001), DNMT3AR882 (HR, 1.86; p&lt;.001), FLT3-ITD (HR, 1.54; p=.012), IDH1 (HR, 1.48; p=.009), MYC (HR, 1.83; p=.032), and WT1 (HR, 1.73; p=.012), were associated with an inferior EFS, while SMC3 mutation showed favorable EFS (HR, 0.44; p=.019). To further study the leukemogenic trajectories, we used an oncogenetic tree modeling algorithm, which yielded a tree with several main branches including DNMT3AR882, DNMT3AnonR882, FLT3-TKD , IDH1, IDH2, PTPN11, and TET2. These mutations might represent initiating events which predispose to additional events with further distinct branches. Conclusions: Our study provides comprehensive data on the genomic landscape and its clinical impact in pts with NPM1mut AML fit for intensive chemotherapy. The co-mutational pattern clearly differs between younger and older NPM1 mutAML pts. Using this large dataset allowed the identification of secondary and tertiary gene-gene interactions with significant impact on outcome. Further data analysis is ongoing and will be presented at the meeting.

Abstract Background: Real-world data (RWD) derived from electronic health records are becoming increasingly important for deriving insights from clinical practice to complement findings from clinical trials. Response to treatment in multiple myeloma (MM) is assessed using the International Myeloma Working Group (IMWG) response criteria based on MM-specific laboratory measures (i.e. monoclonal [M] protein in serum and urine, free light chain [FLC] levels), as well as radiological images and bone marrow (BM) investigations when appropriate. As healthcare providers do not routinely collect all the information required by the IMWG response criteria, RWD data are often incomplete. Here, we present a derived real-world response (dR) algorithm based on IMWG criteria that accounts for lab measures routinely collected in the clinical care of MM patients and evaluate its ability to accurately assess response to treatment using clinical trial patient-level data. Methods: Treatment response is assessed using a rule-based algorithm integrating longitudinal laboratory measures routinely captured in RWD (Xu et al. Pharmacoepidemiol Drug Saf 2021) as e.g. by the Flatiron MM database. The rules are based on 'relaxed' IMWG criteria, which entail exclusion of BM biopsies data and of imaging results, and reduction in either serum or urine M protein levels (rather than both) to assign partial response. This algorithm was applied to patient-level clinical trial data from the Bellini trial (Kumar et al. Lancet Oncol 2020) with response assignment made by an independent review committee (IRC) in the trial used as the 'ground truth'. Agreement between the IRC's and algorithm's assignments of response was estimated using Cohen's Kappa statistic. Differences in overall response rate (ORR) between treatment and placebo arms were calculated using stratified Cochran-Mantel-Haenszel tests based on strata at randomization with number of prior lines of therapy and previous proteasome inhibitor treatment status variables used for stratification. Results: The Bellini trial is a Phase 3 clinical trial with 2:1 design enrolling 194 and 97 patients in its treatment and placebo arms, respectively (291 patients in total). Regular assessments of M protein and FLC levels were performed (median 13 or 14 measurements), providing detailed trajectory of patient response (Table 1). Comparison between the IRC's and algorithm's assignments of responders classified as Partial Response or better (PR+) resulted in almost perfect agreement with Cohen's Kappa 0.82 (274/291 assignments in agreement). It is worth noting that the Cohen's Kappa between the IRC's and Investigator's assessments is 0.85, indicating that the algorithm's error is within some expected uncertainty. Due to the exclusion of BM information, agreement decreased to 0.56 when depths of response were considered separately as opposed to grouping PR+ patients together with most cases being overestimated as complete response (CR) or stringent CR. In assessing treatment effect, differences in ORR between the intervention and placebo arms in the trial based on IRC's assessment could be accurately recapitulated (68% [66/97] vs 71% [69/97] responders in the placebo arm and 82% [159/194] vs 87% [169/194] in the intervention arm for IRC's and algorithm's assessment, respectively). Based on these results, algorithm response assignment led to consistent conclusions about treatment efficacy in the Bellini trial. Implementation of criteria to characterize very good partial response or better (VGPR+) also led to a conclusion consistent with the Bellini trial IRC's assessment, while implementation of criteria of CR+ resulted in estimates of treatment efficacy that were higher, but directionally consonant (Table 2). Conclusions: We present a fully automated rule-based algorithm for response assessment in MM relying on longitudinal lab measurements during treatment. The algorithm uses 'relaxed' IMWG criteria to account for routine clinical practice settings and demonstrates very high agreement with the assessment of trained clinicians, while reliably reproducing the efficacy analysis in the Bellini trial when ORR and VGPR+ are considered. We envision that, if the concordance observed here is confirmed in other independent cohorts, this algorithm can be used in the assessment of response in RWD and can facilitate response assessment when suboptimal amounts of data are available. Figure 1 Figure 1. Disclosures Tyanova: F. Hoffmann-La Roche: Current Employment. Xu: F. Hoffmann-La Roche AG: Current Employment. Williamson: Amgen: Current equity holder in publicly-traded company; Genentech: Current Employment, Current equity holder in publicly-traded company. Rocci: Novartis: Other: Wife is and employee of Novartis and holds Novartis stocks; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Received travel sponsorship ; Janssen-Cilag Ltd: Honoraria, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Other: Received travel sponsorship ; Owner of 100% stocks of Harlock Healthcare Consulting Ltd (UK privately-held company currently not active).: Current holder of individual stocks in a privately-held company; Roche: Current equity holder in publicly-traded company; Takeda: Consultancy, Honoraria, Other: Received travel sponsorship , Speakers Bureau; Sanofi: Consultancy; NHS: Ended employment in the past 24 months; F. Hoffmann-La Roche Ltd.: Current Employment; AbbVie: Other: Received travel sponsorship . Hong: Imago BioSciences: Current Employment; Genentech, Inc.: Ended employment in the past 24 months; Stock options in Imago BioSciences: Current equity holder in publicly-traded company. Jin: Genentech Inc: Current Employment; Roche: Current equity holder in publicly-traded company. Karve: AbbVie: Current Employment, Current equity holder in publicly-traded company. Roose: Flatiron Health, Inc.: Current Employment; Roche: Current equity holder in publicly-traded company. Sawas: Seattle Genetics: Honoraria; Affimed: Research Funding; Roche: Current equity holder in publicly-traded company; Flat Iron Health: Current Employment; Acrotech: Honoraria; Daiichi-Sankyo: Speakers Bureau; Seattle Genetics: Speakers Bureau; Gilead: Speakers Bureau. Kumar: Antengene: Consultancy, Honoraria; Novartis: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Tenebio: Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Bluebird Bio: Consultancy; Roche-Genentech: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

Abstract Background: Bortezomib has efficacy in follicular lymphoma (FL). Though generally well tolerated, it is associated with a few known toxicities, including neurotoxicity. As a chronically administered agent, it is important to investigate the tolerability of bortezomib over time as a single agent and in combination with chemotherapy. The current method of summarizing adverse events (AEs) -focusing on the maximum grade and reporting only grade 3 or higher incidences- fails to capture toxicity that evolves over time or chronic low grade AEs that may occur at significant expense to patients' quality of life. In this study, we applied the Toxicity over Time (ToxT) analytic approach (Thanarajasingam et al, Lancet Oncol 2016), which graphically and analytically depicts AEs longitudinally, to a randomized Phase 2 ECOG-ACRIN sponsored study, E2408, to characterize chronic toxicity of bortezomib (V) when added to standard bendamustine-rituximab (BR) induction in previously untreated high risk FL. Methods: In E2408, patients (pts) were randomized to one of 3 arms at a 1:2:2 ratio: A) BR x 6 followed by maintenance rituximab (MR) x 2 years (yrs) vs B) BVR x 6 (bortezomib 1.3 mg/m2 IV/SQ days 1, 4, 8, 11) then MR x 2 yrs vs C) BR x 6 then MR x 2 yrs + lenalidomide 20mg/day x 1 yr. Pts enrolled 1/2011-5/2015. This analysis focuses on the 6 cycles of induction only, with arms A and C combined. Six AEs of interests were selected, 4 symptomatic (subjective) AEs (peripheral sensory neuropathy (PSN), diarrhea, febrile neutropenia, fatigue); and 2 non-symptomatic (objective) AEs (neutropenia and thrombocytopenia). Treatment-related post baseline AEs of any grade were investigated by conventional maximum grade toxicity analysis (ToxC) and ToxT methods. The mean AE grades over cycles were analyzed by repeated measures models, time to grade 2 or higher (gr2+)AE were analyzed with time-to-event analysis; and AE profile over the entire course of the study was summarized by area under the curve (AUC) analyses. Comparisons were performed between treatment arms (BVR vs. BR). Results: All 280 randomized treated pts (187 on BR, 93 on BVR) were included in the analysis regardless of eligibility status; 87% (163/187 BR, 81/93 BVR) completed all 6 cycles. Analyzing the symptomatic AEs,ToxC indicates that the overall incidence of grade 3+ PSN was significantly higher in BVR (12%) than BR (1%) (p<.0001). Additional, ToxT captures the trajectory, demonstrating a rapid, rising incidence and worsening grade of PSN on BVR vs BR over 6 cycles in a steam plot of mean gr. by cycle (Fig 1a) and bar chart of incidence and grade per cycle (c1: 13% gr1 3% gr2, c6: 36% gr1 12% gr2 6% gr3 on BVR; c1: 3% gr1, c6: 10% gr1 1% gr2 on BR, Fig. 1b). Risk of developing gr2+ PSN was significantly higher in BVR than BR with 28% vs 0.5% by day 100 (HR=0.01, p<.0001, Fig. 1c). ToxC captures a higher incidence of grade 3+ diarrhea on BVR (7% vs. 1% , p=.01) while AUC from ToxT includes chronic lower grade diarrhea, that is substantial over time on BVR vs. BR (p<.0001), but is not cumulative. Furthermore, the risk of developing gr2+ diarrhea affecting drug tolerability is significantly higher on BVR than BR(13% vs 5% by day 100) (HR=0.3, p=.05). Febrile neutropenia appeared to be similar, and fatigue was marginally more severe under BVR (p=.06 by AUC). For objective AEs, ToxC reveals no significant difference in neutropenia or thrombocytopenia BVR vs BR (neutropenia gr 3+: 36% vs 31%, p=.4; thrombocytopenia gr3+: 10% vs. 5%, p=.12). However, ToxT illustrates that neutropenia is cumulative, worsening over repeated exposure to drug (c1: 2% gr1 5% gr2 5% gr 3+ , c6: 7% gr1 10% gr2 12% gr3+ both arms combined; p<.0001) on mean grade over time (Fig. 2a). In contrast, thrombocytopenia does not worsen with continued treatment (Fig 2b, p=.73). Conclusions: Compared with conventional toxicity analysis (ToxC), ToxT delineated important additional and clinically relevant depictions of both symptomatic and laboratory AEs over time for bortezomib added to BR in FL pts. In patients receiving BVR, close monitoring is suggested for PSN, diarrhea and neutropenia for reassessment of risks and benefits, symptom interventions and dose modification. Longitudinal toxicity analyses such as ToxT can guide AE interventions as well as patient and clinician education, and provide a more patient-centered toxicity assessment of chronically administered therapies for lymphoma. Disclosures Hong: Merck: Consultancy. Evens:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy; Abbvie: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Tesaro: Research Funding; Affimed: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees. Advani:Kura: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Celgene: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Infinity: Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Janssen: Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Forty Seven Inc.: Research Funding; Merck: Research Funding; Millenium: Research Funding; Agensys: Research Funding; Celgene: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dueck:Bayer: Employment; Pfizer: Honoraria; Phytogine: Employment. Kahl:Genentech: Consultancy; Acerta: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy; Abbvie: Consultancy; Juno: Consultancy; Gilead: Consultancy; Celgene: Consultancy; CTI: Consultancy; AstraZeneca: Consultancy.

Background The time to treatment initiation is determined by tumour burden in patients with follicular lymphoma (FL). The Groupe d'Etude des Lymphomes Folliculaires ('GELF') criteria, defined in the pre-rituximab era, are commonly used to assess tumour burden.2 Patients must meet ≥1 of the following criteria to be considered "high" tumour burden according to GELF: any tumour mass >7 cm; ≥ 3 nodal sites (each >3 cm); B symptoms; splenomegaly; compression syndrome; pleural/peritoneal effusion; leukemic phase or cytopenias. Low tumour burden FL is often excluded from clinical trials, based on data from initial retrospective studies and later randomised trials, demonstrating no survival advantage with chemotherapy compared with observation alone. 1-3 Conversely, it is recommended those with high burden disease receive immediate therapy. The use of GELF in therapeutic decision-making outside of clinical trials is not well described. Methods Cases of newly diagnosed Grade 1-3a FL were retrospectively identified from the Australian Lymphoma and Related Diseases Registry (LaRDR), and 2 additional institutional databases from 2002-2019. Additional data was obtained from electronic hospital records. The primary aim of the study was to determine the utilisation of GELF criteria in guiding therapeutic decisions in FL. The secondary aims were to document frequency of GELF according to stage and treatment and to determine the impact of the number of GELF criteria on PFS. Survival analysis was calculated according to the Kaplan-Meier method. Results 385 cases were identified. Patient characteristics are in table 1. The median follow-up was 2 years (range 0.1-18) with 2-year PFS and OS of 89% (95% CI 85-92%) and 96% (95% CI 92-98%) respectively. 94 (24%) patients underwent a 'watch and wait' approach (W&W), 54 (14%) received radiotherapy alone and 237 (62%) received chemotherapy +/- radiotherapy. 118 (31%) patients had stage I/II disease at diagnosis, of these 36 (30%) underwent a W&W approach, 41 (35%) had radiotherapy alone and 41 (35%) received chemotherapy +/- radiotherapy (with only 3 patients in the latter group being enrolled on clinical trial). 260 (69%) had advanced stage disease, of these 56 (22%) underwent a W&W approach, 13 (5%) had radiotherapy alone and 191(73%) received chemotherapy +/- radiotherapy. In the W&W group, 23% of patients had ≥1 GELF criteria, of these, 38% had limited stage disease. Of the patients who received chemotherapy +/-radiotherapy and radiation therapy, 36% and 57% respectively had no GELF criteria identified with 25% and 80% having limited stage disease respectively (table 2) Where available the reasons for commencing chemotherapy +/- radiotherapy in GELF negative patients were examined and included pain associated with lymph nodes, concerns regarding high-grade transformation (secondary to high SUVmax, size of nodal mass or trajectory of growth), cosmesis, nausea and fatigue. In both the W&W and treated cohorts, the number of GELF criteria did not predict outcome (Figure 1A & B). In a subgroup analysis by treatment modality, patients with no GELF criteria versus those with ≥1 GELF criteria, no statistically significant difference in PFS in the W&W group (PFS: HR 0.69 95% CI 0.14-3.27, P=0.63), the chemotherapy +/- radiotherapy group (PFS: HR 1.66 95% CI 0.79-3.52, P=0.18) and the radiotherapy alone group (PFS: HR 4.53 95% CI 0.51-40.71, P=0.13) was demonstrated. Conclusion One fifth of W&W FL patients had ≥ 1 GELF criteria and 36% of those receiving chemotherapy +/-radiotherapy had no GELF criteria at baseline, suggesting clinicians are using other measures to make therapeutic decisions. By restricting eligibility for clinical trials to those with high tumour burden, using GELF, a significant proportion of patients being treated in the 'real world' are not represented. In our cohort of both treated and untreated patients with FL, the presence of ≥1 GELF criteria did not influence prognosis. References 1. Young RC, et al. The treatment of indolent lymphomas: watchful waiting v aggressive combined modality treatment. Semin Hematol 1988. 2. Brice P, et al. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the GELF. J Clin Oncol 1997. 3. Ardeshna KM, et al; Long-term effect of a W & W policy versus immediate systemic treatment for asymptomatic advanced-stage NHL. Lancet 2003. Disclosures Cheah: Roche: Other: Travel expenses; Celgene, Roche, Abbvie: Research Funding; Roche, Janssen, MSD, Gilead, Loxo Oncology, Acerta, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Keane:Roche: Consultancy, Other: Travel Grant; Celgene: Consultancy; MSD: Consultancy; Gilead: Consultancy; BMS: Research Funding. Johnston:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen, Roche: Membership on an entity's Board of Directors or advisory committees. Dickinson:Merck Sharpe and Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Opat:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy. McQuilten:CSL Biotherapies: Research Funding; Celgene: Research Funding; Gilead Sciences: Research Funding; Takeda Pharmaceuticals: Research Funding; AbbVie: Research Funding; Janssen-Cilag: Research Funding. Wood:Abbvie, Alexion, Amgen, Bristol-Myers Squibb, Celgene, CSL Behring, Gilead, Janssen, Novartis, Roche,, Sanofi, Takeda: Research Funding. Hawkes:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Merck KgA: Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Research Funding; Takeda: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Mundi pharma: Research Funding; Astra Zeneca: Research Funding; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees.

Introduction: With the expanding use of CAR-T cell therapy, which is associated with serious adverse effects (AEs), there is a need to characterize the patient's experience over time to guide patient/provider education, and help optimize symptom management. This study reports on longitudinal evaluation of patient-reported quality of life (QOL) and symptom burden of CAR-T cell therapy compared with established forms of cellular therapy i.e autologous stem cell transplant (autoSCT) and allogeneic SCT (alloSCT). Methods: Patients with hematologic malignancies were prospectively recruited in three cohorts: CAR-T, autoSCT and alloSCT. The primary endpoint was change in QOL from baseline, using the FACT-G questionnaire. Secondary endpoints were patient-reported AEs (PRO-AEs) using 7 items from the PRO-CTCAE and assessment of cognition/memory using the NeuroQOLv2 questionnaire. PRO-CTCAE data was graded using a composite score (combining frequency, severity, and interference) and rates, using a method adjusting for pre-existing baseline symptoms, were compared using Fisher's exact test. We also evaluated the time profile of PRO-AEs using the Toxicity over Time (ToxT) approach, a longitudinal approach to AE analysis (Thanarajasingam Lancet Onc 2016). Patients completed questionnaires at baseline, week 2 and monthly thereafter. Results: From 07/2018 to 06/2019, 93 patients were recruited (CAR-T: 20; autoSCT: 37; alloSCT: 36). At data cut-off, week 2 and months 1, 2 and 3 data were available in 74, 62, 46 and 35 patients, respectively. There was no difference in patient age across the 3 groups (median age 63, range 23-77; p=0.26). Baseline QOL by FACT-G total score (mean=83.4, SD=14.7; p=0.77), side effect bother by FACT-G GP5 (66/93 [71%] a little bit or less; p=0.72), activities and function (70/93 [75%] fairly normal activities or no limitations; p=0.68) and cognition by NeuroQOL t-score (mean=52.2, SD=8.13; p=0.39) were similar across 3 groups at baseline. The CAR-T group experienced significantly less worsening in QOL (FACT-G) than both autoSCT and alloSCT groups (Fig. 1a). Worsening in overall QOL nadired at week 2, after which QOL gradually returned to baseline in all groups. When comparing changes from baseline in overall QOL, statistically significant differences between groups were evident at week 2 (CAR-T vs autoSCT p&lt;0.001; vs alloSCT p&lt;0.001), month 1 (CAR-T vs autoSCT p=0.02; vs alloSCT p=0.003), month 2 (CAR-T vs autoSCT p=0.02; vs alloSCT p=0.001) and month 3 (CAR-T vs autoSCT p=NS; vs alloSCT p=0.03). Results for physical (Fig. 1b) and functional well-being (WB) were similar, with significantly less QOL worsening at week 2 in CAR-T vs autoSCT and alloSCT groups. The most common PRO-AEs (Table 1) in the CAR-T group were decreased appetite (59%), diarrhea (53%) and fatigue (44%). There was no statistically significant difference in the PRO-AEs between CAR-T and autoSCT groups. However, patients undergoing alloSCT had significantly higher proportion of PRO-AEs vs the CAR-T group, except for neuropathy and sad feelings. AutoSCT and alloSCT groups had significant worsening of FACT-G side effect bother (GP5) at week 2, which was significantly different from that of the CAR-T group, following which the side effect bother gradually returned to baseline. (Fig. 1c) This was the first application of ToxT to PRO-CTCAE data (graphs not shown). Bar charts of maximum grade frequency and stream plots of mean grade over time demonstrate that mouth sores, fatigue, diarrhea and decreased appetite peak at week 2 and improve by month 3, and are of lesser severity in the CAR-T vs autoSCT and alloSCT groups. The trajectory of maximum grade across all PRO-AEs was similar by group as overall side effect burden by FACT-G GP5. Heatmap visualization demonstrated significant intra-patient variability and allowed inspection of data completeness. No difference in cognition and memory was observed across the three groups over the first three months. (Fig. 1d) Conclusion: This study is the first to our knowledge to provide comprehensive PRO data comparing QOL, patient-reported AEs and cognition in CAR-T cell therapy vs. auto- and alloSCT, and the first application of ToxT to PRO-CTCAE data. Short-term QOL, including physical and functional WB domains was better in the CAR-T group vs. SCT groups. These data can serve as a guide for patient education and symptom management in CAR-T cell therapy. Co-senior authors: SKK & ACD Disclosures Paludo: Celgene: Research Funding; Celgene: Research Funding; Verily Life Sciences: Research Funding; Verily Life Sciences: Research Funding. Gertz:Johnson and Johnson: Speakers Bureau; Celgene: Consultancy; Appellis: Consultancy; Amyloidosis Foundation: Research Funding; DAVA oncology: Speakers Bureau; Physicians Education Resource: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Medscape: Consultancy, Speakers Bureau; Prothena Biosciences Inc: Consultancy; Teva: Speakers Bureau; Research to Practice: Consultancy; Annexon: Consultancy; Alnylam: Consultancy; International Waldenstrom Foundation: Research Funding; Ionis/Akcea: Consultancy; Spectrum: Consultancy, Research Funding; i3Health: Other: Development of educational programs and materials; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Springer Publishing: Patents & Royalties. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Ansell:Trillium: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding. Bennani:Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

The age period of 0-8 years is the most important moment for every human being to develop all the developmental features supported by parents at home and teachers / tutors at the Early Childhood Education Institute (ECE). In parenting, six main aspects must be known and applied by each parent. Lack of education, nutritional knowledge, care and care, and aspects of clean-living habits in the family can have an impact on children's growth and development processes. This study aims to develop a module 6 aspects of child development for parental guidance. This study uses a research and development approach to test the effectiveness of the posttest design. Respondents in this study are parents who have children up to 5 years and early childhood educators. The findings show that from these six main aspects, it seems that parents and ECE tutors do not yet understand the ECE concept. In another perspective, there is still a lack of knowledge about these 6 main aspects which require training and parenting modules to develop the 6 aspects of child development. Keywords: Early Childhood Education, Child Development Aspect, Parenting Training Module References: Arikunto, S. (2010). Prosedur Penelitian Suatu Pendekatan Praktik. Jakarta: Asdi Mahasatya. Britto, P. R., Lye, S. J., Proulx, K., Yousafzai, A. K., Matthews, S. G., Vaivada, T., … Bhutta, Z. A. (2017). Nurturing care: promoting early childhood development. The Lancet, 389(10064), 91–102. https://doi.org/10.1016/S0140-6736(16)31390-3 Coore Desai, C., Reece, J. A., & Shakespeare-Pellington, S. (2017). The prevention of violence in childhood through parenting programmes: a global review. Psychology, Health and Medicine, 22(February), 166–186. https://doi.org/10.1080/13548506.2016.1271952 Darling-Churchill, K. E., & Lippman, L. (2016). Early childhood social and emotional development: Advancing the field of measurement. Journal of Applied Developmental Psychology, 45, 1–7. https://doi.org/10.1016/j.appdev.2016.02.002 Davis, S., Votruba-Drzal, E., & Silk, J. S. (2015). Trajectories of Internalizing Symptoms From Early Childhood to Adolescence: Associations With Temperament and Parenting. Social Development, 24(3), 501–520. https://doi.org/10.1111/sode.12105 Đorđić, V., Tubić, T., & Jakšić, D. (2016). The Relationship between Physical, Motor, and Intellectual Development of Preschool Children. Procedia - Social and Behavioral Sciences, 233(May), 3–7. https://doi.org/10.1016/j.sbspro.2016.10.114 Eisenberg, N., Taylor, Z. E., Widaman, K. F., & Spinrad, T. L. (2015). Externalizing symptoms, effortful control, and intrusive parenting: A test of bidirectional longitudinal relations during early childhood. Development and Psychopathology, 27(4), 953–968. https://doi.org/10.1017/S0954579415000620 Gall, M. D., Gall, J. P., & Borg, W. R. (2007). Educational Research: An Introduction (4th ed.). New York: Longman Inc. Gardner, F., Montgomery, P., & Knerr, W. (2016). Transporting Evidence-Based Parenting Programs for Child Problem Behavior (Age 3–10) Between Countries: Systematic Review and Meta-Analysis. Journal of Clinical Child and Adolescent Psychology, 45(6), 749–762. https://doi.org/10.1080/15374416.2015.1015134 Gilmer, C., Buchan, J. L., Letourneau, N., Bennett, C. T., Shanker, S. G., Fenwick, A., & Smith-Chant, B. (2016). Parent education interventions designed to support the transition to parenthood: A realist review. International Journal of Nursing Studies, 59, 118–133. https://doi.org/10.1016/j.ijnurstu.2016.03.015 Grindal, T., Bowne, J. B., Yoshikawa, H., Schindler, H. S., Duncan, G. J., Magnuson, K., & Shonkoff, J. P. (2016a). The added impact of parenting education in early childhood education programs: A meta-analysis. Children and Youth Services Review, 70, 238–249. https://doi.org/10.1016/j.childyouth.2016.09.018 Guyer, A. E., Jarcho, J. M., Pérez-Edgar, K., Degnan, K. A., Pine, D. S., Fox, N. A., & Nelson, E. E. (2015). Temperament and Parenting Styles in Early Childhood Differentially Influence Neural Response to Peer Evaluation in Adolescence. Journal of Abnormal Child Psychology, 43(5), 863–874. https://doi.org/10.1007/s10802-015-9973-2 Jones, D. E., Feinberg, M. E., Hostetler, M. L., Roettger, M. E., Paul, I. M., & Ehrenthal, D. B. (2018). Family and Child Outcomes 2 Years After a Transition to Parenthood Intervention. Family Relations, 67(2), 270–286. https://doi.org/10.1111/fare.12309 Jürges, H., Schwarz, A., Cahan, S., & Abdeen, Z. (2019). Child mental health and cognitive development: evidence from the West Bank. Empirica, 46(3), 423–442. https://doi.org/10.1007/s10663-019-09438-5 Kalland, M., Fagerlund, Å., Von Koskull, M., & Pajulo, M. (2016). Families First: The development of a new mentalization-based group intervention for first-Time parents to promote child development and family health. Primary Health Care Research and Development, 17(1), 3–17. https://doi.org/10.1017/S146342361500016X Knauer, H. A., Ozer, E. J., Dow, W. H., & Fernald, L. C. H. (2019). Parenting quality at two developmental periods in early childhood and their association with child development. Early Childhood Research Quarterly, 47, 396–404. https://doi.org/10.1016/j.ecresq.2018.08.009 Kopala-Sibley, D. C., Cyr, M., Finsaas, M. C., Orawe, J., Huang, A., Tottenham, N., & Klein, D. N. (2018). Early Childhood Parenting Predicts Late Childhood Brain Functional Connectivity During Emotion Perception and Reward Processing. Child Development, 00(0), 1–19. https://doi.org/10.1111/cdev.13126 Kurniah, N., Andreswari, D., & Kusumah, R. G. T. (2019). Achievement of Development on Early Childhood Based on National Education Standard. 295(ICETeP 2018), 351–354. https://doi.org/10.2991/icetep-18.2019.82 Leijten, P., Raaijmakers, M. A. J., Orobio de Castro, B., van den Ban, E., & Matthys, W. (2017). Effectiveness of the Incredible Years Parenting Program for Families with Socioeconomically Disadvantaged and Ethnic Minority Backgrounds. Journal of Clinical Child and Adolescent Psychology, 46(1), 59–73. https://doi.org/10.1080/15374416.2015.1038823 Lomanowska, A. M., Boivin, M., Hertzman, C., & Fleming, A. S. (2017). Parenting begets parenting: A neurobiological perspective on early adversity and the transmission of parenting styles across generations. Neuroscience, 342, 120–139. https://doi.org/10.1016/j.neuroscience.2015.09.029 Lucassen, N., Kok, R., Bakermans-Kranenburg, M. J., Van Ijzendoorn, M. H., Jaddoe, V. W. V., Hofman, A., … Tiemeier, H. (2015). Executive functions in early childhood: The role of maternal and paternal parenting practices. British Journal of Developmental Psychology, 33(4), 489–505. https://doi.org/10.1111/bjdp.12112 Molchanov, S. V. (2013). The Moral Development in Childhood. Procedia - Social and Behavioral Sciences, 86, 615–620. https://doi.org/10.1016/j.sbspro.2013.08.623 Morris, A. S., & Williamson, A. C. (2019). Building early social and emotional relationships with infants and toddlers: Integrating research and practice. Building Early Social and Emotional Relationships with Infants and Toddlers: Integrating Research and Practice, 1–351. https://doi.org/10.1007/978-3-030-03110-7 Parhomenko, K. (2014). Diagnostic Methods of Socio – Emotional Competence in Children. Procedia - Social and Behavioral Sciences, 146, 329–333. https://doi.org/10.1016/j.sbspro.2014.08.142 Rutherford, H. J. V., Wallace, N. S., Laurent, H. K., & Mayes, L. C. (2015). Emotion regulation in parenthood. Developmental Review, 36, 1–14. https://doi.org/10.1016/j.dr.2014.12.008 Sheedy, A., & Gambrel, L. E. (2019). Coparenting Negotiation During the Transition to Parenthood: A Qualitative Study of Couples’ Experiences as New Parents. American Journal of Family Therapy, 47(2), 67–86. https://doi.org/10.1080/01926187.2019.1586593 Sitnick, S. L., Shaw, D. S., Gill, A., Dishion, T., Winter, C., Waller, R., … Wilson, M. (2015). Parenting and the Family Check-Up: Changes in Observed Parent-Child Interaction Following Early Childhood Intervention. Journal of Clinical Child and Adolescent Psychology, 44(6), 970–984. https://doi.org/10.1080/15374416.2014.940623 Sulik, M. J., Blair, C., Mills-Koonce, R., Berry, D., & Greenberg, M. (2015). Early Parenting and the Development of Externalizing Behavior Problems: Longitudinal Mediation Through Children’s Executive Function. Child Development, 86(5), 1588–1603. https://doi.org/10.1111/cdev.12386 Theise, R., Huang, K. Y., Kamboukos, D., Doctoroff, G. L., Dawson-McClure, S., Palamar, J. J., & Brotman, L. M. (2014). Moderators of Intervention Effects on Parenting Practices in a Randomized Controlled Trial in Early Childhood. Journal of Clinical Child and Adolescent Psychology, 43(3), 501–509. https://doi.org/10.1080/15374416.2013.833095 UNDP. (2018). Human Development Indices and Indicators. 2018 Statistical Update. United Nations Development Programme, 27(4), 123. Retrieved from http://hdr.undp.org/sites/default/files/2018_human_development_statistical_update.pdf%0Ahttp://www.hdr.undp.org/sites/default/files/2018_human_development_statistical_update.pdf%0Ahttp://hdr.undp.org/en/2018-update

Abstract Background: Checkpoint blockade therapies (CBT) have substantially improved outcomes for patients in a variety of cancers. However, they are associated with a unique spectrum of immune-related adverse events (AEs). Additionally, unlike standard chemotherapy, many patients (pts) remain on CBT for prolonged periods of time, thus immune-related symptomatic AEs may be chronic or low grade therefore important to capture long term tolerability when used as a single agent or in combination with chemotherapy. In this study, we applied the Toxicity over Time (ToxT) analytic approach (Thanarajasingam et al, Lancet Oncol 2016), which incorporates the dimension of time and includes chronic lower grade events, to the first 6 cohorts (A-F) of a Phase 1/2 ECOG-ACRIN sponsored study of the combinations of Brentuximab Vedotin (BV) and the CBT therapies ipilimumab (Ipi) and nivolumab (Nivo) in pts with relapsed or refractory Hodgkin lymphoma (R/R HL). Methods: Pts with confirmed R/R HL were treated with BV 1.8mg/kg + Ipi 1or 3 mg/kg (n=23); or Nivo 3mg/kg + BV: 1.2 or 1.8 mg/kg (n=19). BV was administered every 21 days for 16 cycles; Ipi every 21 days x 4 and then every 3 months for one year and Nivo every 21 days for up to 2 years. Seven symptomatic (subjective) AEs were selected: fatigue, peripheral sensory neuropathy (PSN), nausea/vomiting (NV), rash/skin (RS), diarrhea, ocular-all types, and hair loss. Treatment-related AEs of any grade were investigated by conventional maximum grade toxicity analysis (ToxC) and ToxT methods up to 12 cycles. Using ToxT, mean AE grades over cycles were analyzed for time trend with repeated measures models, time to grade 2 or higher AE (gr2+) was analyzed with time-to-event analysis; AE profile over the entire course of the study was summarized by area under the curve (AUC) analyses. Comparisons were performed between treatment groups: BV/Ipi(A-C arms) and BV/Nivo (D-F arms). Results: 9/23 (BV/Ipi) and 6/19 (BV/Nivo) pts completed 10 cycles. For BV/Ipi vs. BV/nivo, ToxC provides overall incidence rates (any grade): fatigue 52% vs 26% (p=0.09); PSN 61% vs 53%; NV 70% vs 53% ; RS 65% vs. 37% (p=0.07); diarrhea 57% vs. 21% (p=0.02); ocular 17% vs. 21% ; and hair loss 17% vs. 0% (p=0.06), respectively. Gr3 AE occurred in 1 pt (2.4%) each for PSN, NV, diarrhea, and 6 pts (14.3%) for RS, and were similar between BV/ipi and BV/nivo. AUC from ToxT which captures chronic lower grade AEs suggested for BV/Ipi: diarrhea (p=0.02) and NV (p=0.03) are significantly more substantial over time with a trend seen for fatigue (p=0.07), RS (p=0.07) and hair loss (p=0.07) . Additionally, ToxT captures the trajectory of AEs, demonstrated a rising incidence and worsening grade of PSN (BV-related) on BV/Ipi (c1: 9% gr1, c2: 21% gr1 5% gr2, c5: 11% gr1 and c10: 22% gr2 [p=0.005], Fig 1a). In contrast there was a slow but significant decreasing incidence of NV on both combinations; for BV/Nivo (c1:52% gr1, c5: 26% gr1 and c10: 22% gr1) and BV/Ipi (c1: 47% gr1 ,c5: 0% and c10 1% gr1) with p=0.006 (Fig 1b). RS and diarrhea appear early on treatment and are not cumulative (Fig1c and 1d). There is no significant difference in the time to gr 2+ toxicities in any of the 7 AE. Combining all 7 AEs and using the maximum grade as a pilot measure of overall AE burden , ToxC indicates no difference in any grade (100% vs 100%) but a significantly higher gr 3+ incidence (35% vs. 11%) for BV/Ipi. Additionally, ToxT further elucidates that BV/Ipi is associated with significantly higher overall AE over time (Fig 2a, p=0.02) and compared to BV/Nivo a significantly higher risk of developing gr 2+ toxicity ( 57% vs 16% gr2 + event by day 50) (HR=0.41, p=0.02, Fig 2b). Conclusions: The CBT therapies Ipi and Nivo, in combination with BV, are overall both well tolerated over time, although BV/Ipi has a higher overall AE burden. Neither regimen has significant cumulative immune toxicity. Results of this analysis should be interpreted in the context of limited number of pts in both cohorts. A larger scale examination of this analysis is planned to incorporate both phase 1 and the ongoing phase 2 components of E4412. Compared with conventional tox analysis, ToxT delineated important additional and clinically relevant depictions of AEs over time and adds a more comprehensive assessment of the tolerability of chronically administered immune therapies for lymphoma. Disclosures Hong: Merck: Consultancy. Ansell:Regeneron: Research Funding; Merck & Co: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding. Cohen:Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; BioInvent: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding. Advani:Kura: Research Funding; Janssen: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Millenium: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Celgene: Research Funding; Agensys: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Forty Seven Inc.: Research Funding; Celgene: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Regeneron: Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Svoboda:Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; KITE: Consultancy; TG Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Regeneron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Kyowa: Consultancy. Karmali:AstraZeneca: Speakers Bureau; Gilead: Speakers Bureau. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dueck:Bayer: Employment; Phytogine: Employment; Pfizer: Honoraria. Kahl:Genentech: Consultancy; Acerta: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; Juno: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; ADC Therapeutics: Consultancy; CTI: Consultancy; Gilead: Consultancy. Diefenbach:Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Acerta: Research Funding; Millenium/Takeda: Research Funding; Genentech: Consultancy; Denovo: Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Research Funding.

The present article involves a qualitative study of the framing of dementia in ‘Alzheimer’s and Dementia’, the Journal of the Alzheimer’s Association, published in 2016. The aim of this study is to elucidate how dementia is framed qualitatively in the corpus consisting of scientific articles involving dementia published in ‘Alzheimer’s and Dementia’. The results of the qualitative analysis indicate that dementia is represented in ‘Alzheimer’s and Dementia’ in 2016 as the frames associated with gender, age, costs, caregiver and care-recipients, disability and death, health policy, spatial orientation, medical condition, and ethnic groups. These findings are further discussed in the article. References Andrews, J. (2011). We need to talk about dementia. Journal of Research in Nursing, 16(5),397–399. Aronowitz, R. (2008). Framing Disease: An Underappreciated Mechanism for the SocialPatterning Health. Social Science & Medicine, 67, 1–9. Bayles, K. A. (1982). 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Abstract Background Evidence is limited regarding the cumulative effect of risk factors on cognitive decline and the added value of physical function for cognitive function trajectory stratification. We operationalize 13 modifiable dementia risk factors in a scoring system and investigate the relationship between this brain health score, combined with simple measures of physical function, and risk of cognitive decline. Methods Population-based cohort study of persons aged 50 and older from the Irish Longitudinal Study on Ageing without a history of dementia at baseline who underwent repeated neuropsychological tests (8.08 ± 0.3-year follow-up) were included in the analyses. Exposures were the number of brain health metrics (defined by the Lancet Commission on Dementia Prevention, Intervention, and Care report) at recommended optimal levels. Physical function exposures included Timed Up and Go, dual-task walking speed, and grip strength. Each health metric and physical function measure at the recommended level was assigned a value of 1 and combined to generate brain health scores. Relationship with group-based trajectories of global cognitive function (multidomains composite score), estimated using K-means for longitudinal data, was assessed via ordinal logistic regressions. Results Among 2 327 participants (mean age, 61 years; 54% women), each additional optimal metric on the brain health score (odds 0.67 [0.62, 0.73]) was associated with reduced odds of cognitive decline. Adding Timed Up and Go (odds 0.71 [0.59, 0.84]) and dual-task walking speed (odds 0.74 [0.63, 0.89]) further improved model fit (ΔAIC = 14.8). Conclusion These findings support the promotion and maintenance of physical function in addition to brain health strategies to reduce the risk of cognitive decline.

En 2009 était lancée l’étude préalable à la fermeture de la décharge de Penn ar Roc’h située en contexte de pelouse et de lande de hauts de falaises littorales. Des échanges entre le bureau d’étude en charge de l’étude environnementale et des universitaires de l’Université de Bretagne occidentale menant des travaux de recherche sur la restauration écologique permettent de lancer une réflexion pour une expérimentation d’ingénierie écologique (transferts de litière de lande et de fauche de pelouse). Lors des journées REVER 2 à Brest en 2010, une visite du site de la décharge est réalisée juste avant les travaux, permettant de bénéficier de l’expertise des chercheurs et praticiens présents. Un partenariat se noue avec le Muséum national d’Histoire naturelle et l’Université de Brest pour mettre en place un suivi écologique de cette opération. Celui-ci est par la suite repris par le Parc naturel régional d’Armorique, gestionnaire du site Natura 2000 – sur lequel se situe l’ancienne décharge – et le Centre d’étude du milieu d’Ouessant. La dynamique de la végétation montre de fortes variations dans l’espace et dans le temps. Si les résultats des premières années étaient encourageants, avec l’apparition d’espèces cibles de lande (ajonc et bruyère), un coup d’arrêt de la dynamique a été observé ces dernières années en lien probable avec des perturbations (tempêtes, pâturage par un troupeau de chèvres). La question d’une nouvelle intervention d’ingénierie écologique est donc posée sur ce site, même si la lenteur du processus écologique est plutôt un bon signe sur ce type de milieu naturellement contraint. Ces résultats, mis en perspective avec ceux d’autres opérations de restauration menées en Bretagne, confirment l’existence possible de dynamiques particulières de la végétation sur des sites de hauts de falaises perturbés par d’anciennes infrastructures : les trajectoires de successions sont alors plus aléatoires que sur des sites uniquement dégradés par la fréquentation.

Resume :Lorsqu’il part pour l’Afrique en 1931, Michel Leiris quitte très explicitement le surréalisme pour l’ethnologie : c’est un adieu à la poésie. A son retour en 1933, déçu par une discipline qui n’a pas tenu ses promesses de renouvellement, il revient à la création littéraire et entre dans une oscillation qui perdurera toute sa vie : les écrits professionnels et savants d’un côté, la littérature de l’autre. Du moins, c’est ainsi que rétrospectivement il présente sa propre trajectoire. Mais ce récit, qui oppose ethnologie et littérature comme deux « carrières » et deux modes d’écriture, est sans doute un peu trop simple, car ce n’est pas la même littérature que Leiris quitte et qu’il retrouve : il abandonne la poésie surréaliste pour, deux ans plus tard, se lancer dans une vaste entreprise autobiographique qui l’occupera quarante ans. Et surtout en 1958, il revient à la poésie après une longue éclipse, en même temps qu’il fait paraître La Possession et ses Aspects théâtraux chez les Éthiopiens de Gondar à partir de notes de terrain vieilles de vingt‑cinq ans — comme si de part et d’autre et simultanément, un blocage avait été levé. Peut‑on établir un lien entre ces deux événements ? Et si oui lequel ? Quelle articulation réelle, véritable y a‑t‑il entre le travail de Leiris sur la transe et son retour au poème à partir de la fin des années 1950 ?When Leiris leaves Paris for Africa in 1931, he is also leaving surrealism for anthropology: it is an explicit farewell to poetry. He then returns home, disillusioned by a discipline which did not hold its promises of renewal, and comes back to literary creation, entering an oscillation which will last his whole life: professional and scholarly writings on the one hand, literature on the other. At least, this is how he describes his own trajectory. However, this narrative, opposing anthropology and literature as two careers and two modes of writing, is probably slightly oversimplifying, since it is not the same literature that Leiris forsakes and goes back to: he leaves surrealist poetry and, two years later, starts an ambitious and four-decade long autobiography. Above all, in 1958, he comes back to poetry after a long eclipse, while at the same time he publishes La Possession et ses Aspects théâtraux chez les Éthiopiens de Gondar, a monograph based on old ethnographic notes dating back to his fieldwork in Ethiopia — as if, on both ends and simultaneously, a generic writing block had been overcome. Is there a connection between these two events? And if yes, what is it? What is the true articulation between Leiris’s anthropological work on possession trance and his return to poetry at the end of the 1950’s?

AbstractBackgroundSocial isolation is a recently documented modifiable risk factors for dementia but little is known about its prevalence in low and middle income countries (LMICs).1 Older adults in Nepal are increasingly at for risk for social isolation given trends of adult child migration to other communities. The resultant social isolation increases risk for depression, psychological distress, and dementia2‐3. This study aimed to estimate the prevalence of social isolation among older adults of Nepal and its associated factors.MethodsA quantitative cross‐sectional study in Dhulikhel municipality of Nepal. Two geographical regions within the city were randomly selected. Systematic random sampling was used for the selection of respondents. We employed the Lubben Social Network Scale (LSNS‐18), a brief tool validated in LMIC, to quantify social isolation.4 Data were analyzed with Statistical Package for Social Sciences (SPSS) v25.ResultsMore than half of respondents (52.3%) were age 60‐70 years, 56.1% were male, 55.1% were illiterate, and 59.8% were living in a nuclear family. More than one third (37.4%) met criteria for socially isolation. Social isolation associated with age (p = 0.026), being a widow (p = 0.002), living in a nuclear family (p = 0.001), and the presence of chronic diseases (p = 0.014). Whereas gender and education were not significantly associated with social isolation.ConclusionMore than one third of older adults in this representative community met criteria for social isolation despite the family‐based societal norms that are typical of Nepal. Addressing this issue may promote brain health among older adults. Further research is recommended to examine the cognitive health of this isolated population.References1. Livingston et al, Dementia prevention, intervention, and care. The Lancet. 20172. Xiang X, et al Trajectories of Social Isolation and Dementia in Older Adults J Aging Health. 20213. Taylor HO, et al. Social Isolation, Depression, and Psychological Distress Among Older Adults. J Aging Health. 20184. Bincy, K. et al. Validation of Expanded form of Lubben Social Network Scale among Community‐Dwelling Geriatric Population in India. Indian Journal of Community Medicine 2022. Keywords:Older adults, Social isolation, Dementia

Construction projects require unwavering commitment from workers. In large-scale endeavors like mosque construction, timely progress is crucial. Motivation within the construction sector plays a pivotal role, determining their willingness to deploy skills and time towards project objectives. This study explores the influence of worker motivation on the progress of the KRS Mosque project. The findings emphasize that salaries and benefits positively impact motivation levels. Work conditions and physical environments affect morale, although some hold negative perceptions. Most workers feel secure, which has a positive impact on project progress. Strong relationships among coworkers enhance motivation for contributions. Recognition and appreciation for contributions further boostmotivation. Opportunities for career advancement carry significant motivational weight. The entire project team take spride in their contributions. Project progress data demonstrates a continuous upward trajectory, underscoring thecritical role of motivation in timely project completion. Understanding worker motivation is essential for efficient project management, ensuring that projects run smoothly and meet their goals within budget and schedule constraints. Abstrak Proyek konstruksi menuntut komitmen yang teguh dari para pekerja. Dalam proyek-proyek besar seperti pembangunan masjid, kemajuan yang tepat waktu menjadi sangat penting. Motivasi dalam sektor konstruksi memainkan peran penting, menentukan sejauh mana mereka bersedia mengaplikasikan keterampilan dan waktu untuk mencapai tujuan proyek. Penelitian ini mengeksplorasi pengaruh motivasi pekerja terhadap kemajuan proyek Masjid KRS. Temuan penelitian menekankan bahwa gaji dan manfaat tambahan memiliki dampak positif terhadap tingkat motivasi. Kondisi kerja dan lingkungan fisik memengaruhi semangat, meskipun beberapa pekerja memiliki pandangan negatif. Sebagian besar pekerja merasa aman, yang berdampak positif pada kemajuan proyek. Hubungan yang kuat di antara rekan kerja meningkatkan motivasi untuk berkontribusi. Pengakuan dan apresiasi atas kontribusi lebih lanjut meningkatkan motivasi. Peluang untuk kemajuan karier memiliki bobot motivasi yang signifikan. Seluruh tim proyek dengan bangga merasa memiliki kontribusi besar. Data kemajuan proyek menunjukkan tren positif yang berkelanjutan, menggarisbawahi peran krusial motivasi dalam penyelesaian proyek tepat waktu. Memahami motivasi pekerja adalah kunci untuk manajemen proyek yang efisien, memastikan bahwa proyek berjalan lancar dan mencapai tujuannya dalam batas anggaran dan jadwal yang ditetapkan.

The copyrighting of digital augmentations (our data-flesh), their privatization and ownership by others from a vast distance that is simultaneously instantly telematically surmountable started simply enough. It was the initially innocuous corporatization of language and semiotics that started the deeper ontological flip, which placed the posthuman bits and parts over the posthuman that thought that it was running things. The posthumans in question, myself included, didn't help things much when, for instance, we all clicked an unthinking or unconcerned "yes" to Facebook® or Gmail®'s "terms and conditions of use" policies that gives them the real ownership and final say over those data based augments of sociality, speech, and memory. Today there is growing popular concern (or at least acknowledgement) over the surveillance of these augmentations by government, especially after the Edward Snowden NSA leaks. The same holds true for the dataveillance of data-flesh (i.e. Gmail® or Facebook® accounts) by private corporations for reasons of profit and/or at the behest of governments for reasons of "national security." While drawing a picture of this (bodily) state, of the intrusion through language of brands into our being and their coterminous policing of intelligible and iterative body boundaries and extensions, I want to address the next step in copyrighted augmentation, one that is current practice in professional sport, and part of the bourgeoning "anti-aging" industry, with rewriting of cellular structure and hormonal levels, for a price, on the open market. What I want to problematize is the contradiction between the rhetorical moralizing against upgrading the analogue-flesh, especially with respect to celebrity sports stars like Lance Armstrong and Alex Rodriquez, all the while the "anti-aging" industry does the same without censor. Indeed, it does so within the context of the contradictory social messaging and norms that our data-flesh and electric augmentations receive to constantly upgrade. I pose the question of the contradiction between the messages given to our analogue-flesh and data-flesh in order to examine the specific site of commentary on professional sports stars and their practices, but also to point to the ethical gap that exists not just for (legal) performance enhancing drugs (PED), but also to show the link to privatized and copyrighted genomic testing, the dataveillance of this information, and subsequent augmentations that may be undertaken because of the results. Copyrighted Language and Semiotics as Gateway Drug The corporatization of language and semiotics came about with an intrusion of exclusively held signs from the capitalist economy into language. This makes sense if one want to make surplus value greater: stamp a name onto something, especially a base commodity like a food product, and build up the name of that stamp, however one will, so that that name has perceived value in and of itself, and then charge as much as one can for it. Such is the story of the lack of real correlation between the price of Starbucks Coffee® and coffee as a commodity, set by Starbucks® on the basis of the cultural worth of the symbols and signs associated with it, rather than by what they pay for the labor and production costs prior to its branding. But what happens to these legally protected stamps once they start acting as more than just a sign and referent to a subsection of a specific commodity or thing? Once the stamp has worth and a life that is socially determined? What happens when these stamps get verbed, adjectived, and nouned? Naomi Klein, in the book that the New York Times referred to as a "movement bible" for the anti-globalization forces of the late 1990s said "logos, by the force of ubiquity, have become the closest thing we have to an international language, recognized and understood in many more places than English" (xxxvi). But there is an inherent built-in tension of copyrighted language and semiotics that illustrates the coterminous problems with data- and analogue-flesh augments. "We have almost two centuries' worth of brand-name history under our collective belt, coalescing to create a sort of global pop-cultural Morse code. But there is just one catch: while we may all have the code implanted in our brains, we're not really allowed to use it" (Klein 176). Companies want their "brands to be the air you breathe in - but don't dare exhale" or otherwise try to engage in a two-way dialogue that alters the intended meaning (Klein 182). Private signs power first-world and BRIC capitalism, language, and bodies. I do not have a coffee in the morning; I have Starbucks®. I do not speak on a cellular phone; I speak iPhone®. I am not using my computer right now; I am writing MacBook Air®. I do not look something up, search it, or research it; I Google® it. Klein was writing before the everyday uptake of sophisticated miniaturized and mobile computing and communication devices. With the digitalization of our senses and electronic limbs this viral invasion of language became material, effecting both our data- and analogue-flesh. The trajectory? First we used it; then we wore it as culturally and socially demarcating clothing; and finally we no longer used copyrighted speech terms: it became an always-present augmentation, an adjective to the lexicon body of language, and thereby out of democratic semiotic control. Today Twitter® is our (140 character limited) medium of speech. Skype® is our sense of sight, the way we have "real" face-to-face communication. Yelp® has extended our sense of taste and smell through restaurant reviews. The iPhone® is our sense of hearing. And OkCupid® and/or Grindr® and other sites and apps have become the skin of our sexual organs (and the site where they first meet). Today, love at first sight happens through .jpeg extensions; our first sexual experience ranked on a scale of risk determined by the type of video feed file format used: was it "protected" enough to stop its "spread"? In this sense the corporatization of language and semiotics acted as the gateway drug to corporatized digital-flesh; from use of something that is external to us to an augmentation that is part of us and indeed may be in excess of us or any notion of a singular liberal subject.Replacement of Analogue-Flesh? Arguably, this could be viewed as the coming to be of the full replacement of the fleshy analogue body by what are, or started as digital augmentations. Is this what Marshall McLuhan meant when he spoke of the "electronic exteriorization of the central nervous system" through the growing complexity of our "electric extensions"? McLuhan's work that spoke of the "global village" enabled by new technologies is usually read as a euphoric celebration of the utopic possibilities of interconnectivity. What these misreadings overlook is the darker side of his thought, where the "cultural probe" picks up the warning signals of the change to come, so that a Christian inspired project, a cultural Noah’s Ark, can be created to save the past from the future to come (Coupland). Jean Baudrillard, Paul Virilio, and Guy Debord have analyzed this replacement of the real and the changes to the relations between people—one I am arguing is branded/restricted—by offering us the terms simulacrum (Baudrillard), substitution (Virilio), and spectacle (Debord). The commonality which links Baudrillard and Virilio, but not Debord, is that the former two do not explicitly situate their critique as being within the loss of the real that they then describe. Baudrillard expresses that he can have a 'cool detachment' from his subject (Forget Foucault/Forget Baudrillard), while Virilio's is a Catholic moralist's cry lamenting the disappearance of the heterogeneous experiential dimensions in transit along the various axes of space and time. What differentiates Debord is that he had no qualms positioning his own person and his text, The Society of the Spectacle (SotS), as within its own subject matter - a critique that is limited, and acknowledged as such, by the blindness of its own inescapable horizon.This Revolt Will Be Copyrighted Yet today the analogue - at the least - performs a revolt in or possibly in excess of the spectacle that seeks its containment. How and at what site is the revolt by the analogue-flesh most viewable? Ironically, in the actions of celebrity professional sports stars and the Celebrity Class in general. Today it revolts against copyrighted data-flesh with copyrighted analogue-flesh. This is even the case when the specific site of contestation is (at least the illusion of) immortality, where the runaway digital always felt it held the trump card. A regimen of Human Growth Hormone (HGH) and other PEDs purports to do the same thing, if not better, at the cellular level, than the endless youth paraded in the unaging photo employed by the Facebook or Grindr Bodies®. But with the everyday use and popularization of drugs and enhancement supplements like HGH and related PEDs there is something more fundamental at play than the economic juggernaut that is the Body Beautiful; more than fleshy jealousy of Photoshopped® electronic skins. This drug use represents the logical extension of the ethics that drive our tech-wired lives. We are told daily to upgrade: our sexual organs (OkCupid® or Grindr®) for a better, more accurate match; our memory (Google® services) for largeness and safe portability; and our hearing and sight (iPhone® or Skype®) for increase connectivity, engaging the "real" (that we have lost). These upgrades are controlled and copyrighted, but that which grows the economy is an especially favored moral act in an age of austerity. Why should it be surprising, then, that with the economic backing of key players of Google®—kingpin of the global for-profit dataveillance racket—that for $99.95 23andMe® will send one a home DNA test kit, which once returned will be analyzed for genetic issues, with a personalized web-interface, including "featured links." Analogue-flesh fights back with willing copyrighted dataveillance of its genetic code. The test and the personalized results allow for augmentations of the Angelina Jolie type: private testing for genetic markers, a double mastectomy provided by private healthcare, followed by copyrighted replacement flesh. This is where we find the biopolitics of data- and analogue-flesh, lead forth, in an ironic turn, by the Celebrity Class, whom depend for their income on the lives of their posthuman bodies. This is a complete reversal of the course Debord charts out for them: The celebrity, the spectacular representation of a living human being, embodies this banality by embodying the image of a possible role. Being a star means specializing in the seemingly lived; the star is the object of identification with the shallow seeming life that has to compensate for the fragmented productive specializations which are actually lived. (SotS) While the electronic global village was to have left the flesh-and-blood as waste, today there is resistance by the analogue from where we would least expect it - attempts to catch up and replant itself as ontologically prior to the digital through legal medical supplementation; to make the posthuman the posthuman. We find the Celebrity Class at the forefront of the resistance, of making our posthuman bodies as controlled augmentations of a posthuman. But there is a definite contradiction as well, specifically in the press coverage of professional sports. The axiomatic ethical and moral sentiment of our age to always upgrade data-flesh and analogue-flesh is contradicted in professional sports by the recent suspensions of Lance Armstrong and Alex Rodriguez and the political and pundit critical commentary on their actions. Nancy Reagan to the Curbside: An Argument for Lance Armstrong and Alex Rodriguez's "Just Say Yes to Drugs" Campaign Probably to the complete shock of most of my family, friends, students, and former lovers who may be reading this, I actually follow sports reporting with great detail and have done so for years. That I never speak of any sports in my everyday interactions, haven't played a team or individual sport since I could speak (and thereby use my voice to inform my parents that I was refusing to participate), and even decline amateur or minor league play, like throwing a ball of any kind at a family BBQ, leaves me to, like Judith Butler, "give an account of oneself." And this accounting for my sports addiction is not incidental or insignificant with respect either to how the posthuman present can move from a state of posthumanism to one of posthumanism, nor my specific interpellation into (and excess) in either of those worlds. Recognizing that I will not overcome my addiction without admitting my problem, this paper is thus a first-step public acknowledgement: I have been seeing "Dr. C" for a period of three years, and together, through weekly appointments, we have been working through this issue of mine. (Now for the sake of avoiding the cycle of lying that often accompanies addiction I should probably add that Dr. C is a chiropractor who I see for back and nerve damage issues, and the talk therapy portion, a safe space to deal with the sports addiction, was an organic outgrowth of the original therapy structure). My data-flesh that had me wired in and sitting all the time had done havoc to the analogue-flesh. My copyrighted augments were demanding that I do something to remedy a situation where I was unable to be sitting and wired in all the time. Part of the treatment involved the insertion of many acupuncture needles in various parts of my body, and then having an electric current run through them for a sustained period of time. Ironically, as it was the wired augmentations that demanded this, due to my immobility at this time - one doesn't move with acupuncture needles deep within the body - I was forced away from my devices and into unmediated conversation with Dr. C about sports, celebrity sports stars, and the recent (argued) infractions by Armstrong and Rodriguez. Now I say "argued" because in the first place are what A-Rod and Armstrong did, or are accused of doing, the use of PEDs, HGH, and all the rest (cf. Lupica; Thompson, and Vinton) really a crime? Are they on their way, or are there real threats of jail and criminal prosecution? And in the most important sense, and despite all the rhetoric, are they really going against prevailing social norms with respect to medical enhancement? No, no, and no. What is peculiar about the "witch-hunt" of A-Rod and Armstrong - their words - is that we are undertaking it in the first place, while high-end boutique medical clinics (and internet pharmacies) offer the same treatment for analogue-flesh. Fixes for the human in posthuman; ways of keeping the human up to speed; arguably the moral equivalent, if done so with free will, of upgrading the software for ones iOS device. If the critiques of Baudrillard and Virilio are right, we seem to find nothing wrong with crippling our physical bodies and social skills by living through computers and telematic technologies, and obsess over the next upgrade that will make us (more) faster and quicker (than the other or others), while we righteously deny the same process to the flesh for those who, in Debord's description, are the most complicit in the spectacle, to the supposedly most posthuman of us - those that have become pure spectacle (Debord), pure simulation (Baudrillard), a total substitution (Virilio). But it seems that celebrities, and sports celebrities in specific haven't gone along for the ride of never-ending play of their own signifiers at the expense of doing away with the real; they were not, in Debord's words, content with "specializing in the seemingly lived"; they wanted, conversely, to specialize in the most maximally lived flesh, right down to cellular regeneration towards genetic youth, which is the strongest claim in favor of taking HGH. It looks like they were prepared to, in the case of Armstrong, engage in the "most sophisticated, professionalized and successful doping program that sport has ever seen" in the name of the flesh (BBC). But a doping program that can, for the most part, be legally obtained as treatment, and in the same city as A-Rod plays in and is now suspended for his "crimes" to boot (NY Vitality). This total incongruence between what is desired, sought, and obtained legally by members of their socioeconomic class, and many classes below as well, and is a direct outgrowth of the moral and ethical axiomatic of the day is why A-Rod and Armstrong are so bemused, indignant, and angry, if not in a state of outright denial that they did anything that was wrong, even while they admit, explicitly, that yes, they did what they are accused of doing: taking the drugs. Perhaps another way is needed to look at the unprecedentedly "harsh" and "long" sentences of punishment handed out to A-Rod and Armstrong. The posthuman governing bodies of the sports of the society of the spectacle in question realize that their spectacle machines are being pushed back at. A real threat because it goes with the grain of where the rest of us, or those that can buy in at the moment, are going. And this is where the talk therapy for my sports addiction with Dr. C falls into the story. I realized that the electrified needles were telling me that I too should put the posthuman back in control of my damaged flesh; engage in a (medically copyrighted) piece of performance philosophy and offset some of the areas of possible risk that through restricted techne 23andMe® had (arguably) found. Dr. C and I were peeved with A-Rod and Armstrong not for what they did, but what they didn't tell us. We wanted better details than half-baked admissions of moral culpability. We wanted exact details on what they'd done to keep up to their digital-flesh. Their media bodies were cultural probes, full in view, while their flesh bodies, priceless lab rats, are hidden from view (and likely to remain so due to ongoing litigation). These were, after all, big money cover-ups of (likely) the peak of posthuman science, and the lab results are now hidden behind an army of sports federations lawyers, and agents (and A-Rod's own army since he still plays); posthuman progress covered up by posthuman rules, sages, and agents of manipulation. Massive posthuman economies of spectacle, simulation, or substitution of the real putting as much force as they can bare on resurgent posthuman flesh - a celebrity flesh those economies, posthuman economies, want to see as utterly passive like Debord, but whose actions are showing unexpected posthuman alignment with the flesh. Why are the centers of posthumanist power concerned? Because once one sees that A-Rod and Armstrong did it, once one sees that others are doing the same legally without a fuss being made, then one can see that one can do the same; make flesh-and-blood keep up, or regrow and become more organically youthful, while OkCupid® or Grindr® data-flesh gets stuck with the now lagging Photoshopped® touchups. Which just adds to my desire to get "pumped up"; add a little of A-Rod and Armstrong's concoction to my own routine; and one of a long list of reasons to throw Nancy Reagan under the bus: to "just say yes to drugs." A desire that is tempered by the recognition that the current limits of intelligibility and iteration of subjects, the work of defining the bodies that matter that is now set by copyrighted language and copyrighted electric extensions is only being challenged within this society of the spectacle by an act that may give a feeling of unease for cause. This is because it is copyrighted genetic testing and its dataveillance and manipulation through copyrighted medical technology - the various branded PEDs, HGH treatments, and their providers - that is the tool through which the flesh enacts this biopolitical "rebellion."References Baudrillard, Jean. Forget Foucault/Forget Baudrillard. Trans Nicole Dufresne. Los Angeles: Semiotext(e), 2007. ————. Simulations. Trans. Paul Foss, Paul Patton and Philip Beitchman. Cambridge: Semiotext(e), 1983. BBC. "Lance Armstong: Usada Report Labels Him 'a Serial Cheat.'" BBC Online 11 Oct. 2012. 1 Dec. 2013 ‹http://www.bbc.co.uk/sport/0/cycling/19903716›. Butler, Judith. Giving an Account of Oneself. New York: Fordham University Press, 2005. Clark, Taylor. Starbucked: A Double Tall Tale of Caffeine, Commerce, and Culture. New York: Back Bay, 2008. Coupland, Douglas. Marshall McLuhan. Toronto: Penguin Books, 2009. Debord, Guy. Society of the Spectacle. Detroit: Black & Red: 1977. Klein, Naomi. No Logo: Taking Aim at the Brand Bullies. Toronto: Knopf Canada, 1999. Lupica, Mike. "Alex Rodriguez Beginning to Look a Lot like Lance Armstrong." NY Daily News. 6 Oct. 2013. 1 Dec. 2013 ‹http://www.nydailynews.com/sports/baseball/lupica-a-rod-tour-de-lance-article-1.1477544›. McLuhan, Marshall. Understanding Media: The Extensions of Man. New York: McGraw-Hill Book Company, 1964. NY Vitality. "Testosterone Treatment." NY Vitality. 1 Dec. 2013 ‹http://vitalityhrt.com/hgh.html›. Thompson, Teri, and Nathaniel Vinton. "What Does Alex Rodriguez Hope to Accomplish by Following Lance Armstrong's Legal Blueprint?" NY Daily News 5 Oct. 2013. 1 Dec. 2013 ‹http://www.nydailynews.com/sports/i-team/a-rod-hope-accomplish-lance-blueprint-article-1.1477280›. Virilio, Paul. Speed and Politics. Trans. Mark Polizzotti. New York: Semiotext(e), 1986.

Photo by Tim Mossholder on Unsplash INTRODUCTION “Precision psychiatry” is one aspect of the growing field of precision medicine. Precision psychiatry will provide individualized care tailored to certain biomarkers. The patient’s unique mental health profile is at the core of advancing machine learning models for clinical practice. Traditionally psychiatrists used a “trial-and-error” approach to standardized drugs, whereas precision psychiatry integrates objectivity with the diagnosis and treatment.[1] The long-term benefits of precision psychiatry include generating effective therapeutic plans for a person, eliminating the emotional burden of the trial-and-error process, and optimizing medications currently on the market for sustained use. To take advantage of the many benefits of precision psychiatry, more mental health practitioners, an effective allocation plan, and the continuation of traditional psychiatry are necessary. Precision psychiatry should not supplant traditional psychiatry as not all practitioners and patients will have access to it. ANALYSIS The National Institute of Mental Health is working on the Research Domain Criteria (RDoC) project intending to establish an updated classification system for mental health disorders based on a combination of observational and neurobiological findings.[2] While this effort is working toward the goal of providing a research-based classification system, the technological tools necessary to arm a physician with a well-endowed toolbox may not be cost-effective in the initial phase.[3] To reap the rewards of precision psychiatry, physicians should eventually circumvent the trial-and-error approach to psychiatric care, with its hefty financial burden often thrust upon the patient and family. a. Emotional and Financial Benefits The usual course of diagnosis for mental health disorders involves analyzing symptoms according to the Statistical Manual of Mental Disorders (DSM) and the International Classification of Diseases (ICD) developed by the World Health Organization.[4] The promising advances in the accuracy of neuroimaging will prove to be an asset to the field of precision psychiatry. For example, several studies showcase the increased responsiveness to lithium therapy as a predictor of the efficacy of bipolar disorder treatment.[5] Ultimately, one of the greatest benefits of precision psychiatry is the ability to predict whether a particular person with major depressive disorder will develop antidepressant resistance by the course of their proposed treatment. 5 For 30 percent of people diagnosed with major depressive disorder, the treatment trajectory often ends with treatment resistance.[6] By circumventing the trial-and-error algorithm to psychiatric care, the patient’s emotional and financial burden may be reduced. b. Justice and Access Successfully implementing precision psychiatry is no easy feat; it requires interconnectedness, including “big data” storage, research analyzing molecular biosignatures, “computational psychiatry,” communication with experts in the field of neuroimaging and neuroscience, and electronic health records.[7] The success of precision psychiatry would revolutionize the field altogether, with the goal being “to improve the diagnostic process and the choice of a specific treatment using biomarkers derived from peripheral blood, imaging…or neuropsychological tests.”[8] However, the success of precision psychiatry is contingent on modifying the healthcare infrastructure, which cannot currently provide equitable access to basic mental health care.[9] For example, mental health disorders are the leading cause of lost productivity and disability, with the US incurring an economic cost of $42-53 billion per year.[10] One goal of the Affordable Care Act (ACA) was to increase insurance coverage for mental health care. However, the US still possesses “one of the highest mental health burdens among high-income countries.”[11] Access and affordability of psychiatric care in the US is already of utmost concern as one in six adults seeks out care; however, due to the lack of affordability, such required care is unattainable.[12] The mismatch between the volume of individuals requiring mental health care and the number receiving it may be due to the relatively low workforce capacity in comparison to other high-income countries.[13] The US has a staggeringly low number of mental healthcare professionals compared to Canada, including nurses, psychiatrists, psychologists, and social workers, with 105 and 277 professionals per 100,000 individuals, respectively.[14] The gap in mental health care is prominent in the US, where one-third of the indigenous population diagnosed with a mental health disorder does not receive any treatment.[15] Inequity in access to mental health care is still of paramount concern, with basic mental health care needs remaining unmet for many Americans.[16] Precision psychiatry involving advanced technology and interdisciplinary care teams provides individualized psychiatric care, which could prove beneficial. However, the inability to guarantee equitable access to such care calls into question distributive justice and whether the benefits will accrue to those in need. c. Saves Time Precision psychiatry is costly, and communities with limited psychiatric resources may potentially become further disadvantaged. If precision psychiatry is readily available to the masses and is used instead of trial and error, the willingness of people to seek mental health care may rise. A faster route to the discovery of medication combinations optimized for the patient would contribute to building trust and rapport. Targeting both the biological and physical manifestations of mental illness not only provide rapid improvement but also decreases the risk of losing patients due to frustration over lack of improvement with pharmacological intervention. Providing precision psychiatry decreases the time required for each person to achieve a successful therapeutic regimen, ultimately allowing the physician to invest time in a greater number of patients. The redistribution of mental health care and eliminating mental healthcare deserts are necessary to reap the benefits. d. A Humanistic Approach Establishing rigorous evidence-based criteria for precision psychiatry will not only involve decades of research but may also impact the humanistic aspects of psychiatry. Psychiatry involves a humanistic approach to medical care. Building a trustworthy patient-physician relationship is the foundation of exemplary care. Precision psychiatry provides the crucial benefit of tailoring medical treatments to the predicted response rate of the person.[17] However, one must be wary of falling into the trap that precision psychiatry is the answer for mental health disorders. Without active intercommunication between varying healthcare disciplines, including social work, the person may be “reduced to an object of big data.”[18] A humanistic approach will properly include the ongoing relationship with the psychiatrist and may include some trial and error as well to reflect patient preferences based on side effect profile rather than efficacy alone. CONCLUSION Reducing people to either their brain or their computed contribution to “big data” will not benefit precision psychiatry. While it is helpful to understand the root of a patient’s mental illness through neuroimaging and neurological biomarkers, such intrinsically evidence-based medicine must coexist with traditional psychiatric care. Precision psychiatry could benefit people with treatment-resistant mental illness by integrating neurological biomarkers as a tool for retrofitting existing medications to the person. Used under ethical standards, precision psychiatry is a positive development. Distributive justice should be included in the goals of all health care, especially in the distribution of precision psychiatry as it becomes more finetuned and garners broad appeal. During the phasing-in period of precision psychiatry, the gap in equitable access to standard mental health care should be resolved. The US needs to better its mental health diagnosis and treatment options to offer both traditional and precision psychiatry to people in need. Although it may take several years, even decades for a rigorous set of tools capable of foreseeing medication responsiveness to come to fruition for physicians, such precision psychiatry will be a game-changer. [1] Evers, Kathinka. “Personalized medicine in psychiatry: ethical challenges and opportunities.” Dialogues in Clinical Neuroscience vol. 11,4 (2009): 427-34. [2] Menke, Andreas. “Precision pharmacotherapy: psychiatry's future direction in preventing, diagnosing, and treating mental disorders.” Pharmacogenomics and Personalized Medicine vol. 11 211-222. 19 Nov. 2018, doi:10.2147/PGPM.S146110. [3] Manchia, et al., p131 [4] Menke, p 211 [5] Manchia, Mirko et al. “Challenges and Future Prospects of Precision Medicine in Psychiatry.” Pharmacogenomics and Personalized Medicine vol. 13 127-140. 23 Apr. 2020, doi:10.2147/PGPM.S198225. [6] Manchia, et al., p 131 [7] Fernandes, Brisa S et al. “The new field of 'precision psychiatry'.” BMC Medicine vol. 15,1 80. 13 Apr. 2017, doi:10.1186/s12916-017-0849-x. [8] Menke, p211 [9] Fernandes, p80 [10] Williams, Leanne M. “Precision psychiatry: a neural circuit taxonomy for depression and anxiety.” The Lancet. Psychiatry vol. 3,5 (2016): 472-80. doi:10.1016/S2215-0366(15)00579-9. [11] Tikkanen, Roosa et al. “Mental Health Conditions and Substance Use: Comparing U.S. Needs and Treatment Capacity with Those in Other High-Income Countries.” Commonwealth Fund. 21 May. 2020, doi:10.26099/09ht-rj07. [12] Fernandes, p 80 [13] Fernandes, p 80 [14] Fernandes, p 80 [15] Kohn, Robert et al. “Mental health in the Americas: an overview of the treatment gap.” Revista panamericana de salud publica = Pan American Journal of Public Health vol. 42 e165. 10 Oct. 2018, doi:10.26633/RPSP.2018.165 [16] Kohn et al., p 165 [17] Fernandes, p 80 [18] Stiefel, Friedrich et al. “Precision psychiatry: Promises made-Promises to be kept?.” The Australian and New Zealand Journal of Psychiatry vol. 53,9 (2019): 841-843. doi:10.1177/0004867419849482.

Photo ID 279661800 © Sidewaypics|Dreamstime.com ABSTRACT Decolonization is complex, vast, and the subject of an ongoing academic debate. While the many efforts to decolonize or dismantle the vestiges of colonialism that remain are laudable, they can also reinforce what they seek to end. For decolonization to be impactful, it must be done with epistemic and cultural humility, requiring decolonial scholars, project leaders, and well-meaning people to be more sensitive to those impacted by colonization and not regularly included in the discourse. INTRODUCTION Decolonization is complex. To successfully achieve decolonization, projects should incorporate the voices of those subjugated or silenced. Including such voices requires sincerely exploring who has been affected by colonialism or neocolonialism and how, as well as cultural sensitivity. In its basic use, decolonization refers to countries under colonial rule gaining independence or freedom from forms of subjugation. Additionally, scholars use the term to refer to efforts to dismantle neocolonialism and vestiges of colonialism. The process includes de-silencing subjugated voices.[1] I use decolonization in the latter way to refer to countries with technical independence. While arguably colonization ended formally with independence from colonizing powers, neocolonialism is the indirect, informal, and sometimes subtle control of the people, their economy, and political life despite formal independence from colonizing authorities. I conceptualize neocolonialism as a system that involves direct and involuntary control of another’s political, economic, or social life, impacting their worldview and ways of encountering the world. Decolonization may target actions, places, or systems like health care or AI to overcome the ills of colonialism and neocolonialism. It also may target knowledge and require rethinking how people develop their knowledge base. For example, if people grew up seeing an outside colonizer as superior, they would need to change their knowledge of superiority. Decolonization may target power, for example, changing who owns and distributes COVID-19 vaccines and who distributors exclude in the distribution of vaccines. Decolonization could require looking at those disempowered in the distribution process. Additionally, decolonization may target autonomy of persons by freeing people, ensuring human and individual rights, and respecting cultural traditions. Decolonization projects that try to de-silence by including the voices of those affected by colonialism and neocolonialism must examine inclusiveness in the context of the culture of the subrogated individuals. Examples of decolonization projects include making datasets inclusive of diverse peoples and places, returning to traditional food and eating practices, making sure hospitals in developing countries are led by locals and respectful of cultural traditions, returning unethically obtained artefacts or objects. Another project would be laying the groundwork for equality in formerly colonized countries to ensure that business ownership, education, and financial success will flow fairly to those previously victimized by colonization. Summarily, there are many strategies for decolonizing. However, it is worth asking whether the strategies have risks that undermine the goal of decolonization. I. Understanding Decolonization Discourses Many fields, from AI to politics, economics, health care, aviation, and academia, discuss decolonization. The content of the discourse on decolonization depends on the region and field discussing it. Rather than just reporting on decolonization, the discussions may be calls to action. For example, decolonization discourses reflect activism for cognitive justice, such as equal consideration of Indian or African knowledge systems in global health discourses.[2] In politics and political science, some scholars frame decolonization as an anti-western, anti-colonial movement by Africans to emancipate Africa/ns from subjugation or shift the continent to postcolonialism and post-neo-colonialism. This framing walls off non-African participants and may undermine their capacity to benefit the conversation.[3] There are other political scientists who actively support decolonization and see it as a field of activism in support of anyone and countries where colonization harmed people and development.[4] The point is that two ways of conceptualizing decolonization in politics and political science are discernible. One conceptualization is less inclusive since it alienates scholars and professionals from Western, high-income, or developed countries. The other is more inclusive. In humanitarian studies, including philosophy, some decolonization articles and conversations are efforts to end the destructive force of colonization. They focus on either the form, such as ecocide, genocide, and many others, or the geographic location, such as Africa, Asia, Latin America, and Oceania.[5] Finally, the feelings one brings into this conversation can adversely impact how one engages in them and who they listen to or are willing to hear from. For example, anger, rage, bitterness, and hatred are emotions that are not uncommon in spaces of decolonization conversations. Decolonization conversations that originate from a place of negativity risk deepening the psychological state of victimhood and prevent people from disrupting constructively or critically engaging in the conversation.[6] II. Understanding Decolonization Strategies Decolonization strategies mainly aim to de-silence victims of domination or subjugation. People have proposed many strategies for decolonizing. These strategies may be informed by what the target is for decolonization. Decolonization can target power relations in global health. For example, during the COVID-19 pandemic, public health organizations noted the power imbalance in vaccine distribution. Decolonization could involve de-silencing those affected by neocolonialism to bring about a more balanced distribution of power and a more fair distribution of the vaccine. By analyzing who was adversely impacted by the distribution and who ought to wield power, those engaged in decolonizing advocated for positive change and equitable power relations. Equally, when being is the target of decolonization, the language of unlearning or relearning and mental decolonization take centre stage in the decolonization discourse. For example, the quest to decolonize colonized minds aims to demythologize African inferiority and Western superiority. Demythologizing African inferiority enables those engaged in the decolonization discourse to cultivate and foster African agency.[7] Finally, when knowledge production is the target of decolonization, scholars use inclusion and cognitive justice. For example, they try to alter the knowledge that underlies global health ethics.[8] “[D]decolonizing researchers aim to respectfully understand and integrate theory from Other(ed) perspectives, while also critically examining the underlying assumptions that inform their Western research framework.”[9] One common strategy that scholars use in decolonization is inclusion. It is worth asking, does including people who have been subrogated foster decolonization? Whether that is effective depends on whether included people are more heard or whether the strategies to include them create new forms of silencing. III. Inclusion and the Quest to Decolonize Evaluating how effective inclusion is in the quest to de-silence subjugated voices is important. First, inclusive strategies are not neutral. They are epistemically situated. This situatedness constrains meaning-making in different ways: how and what questions are asked, how social roles are constructed, organized or assigned, and who is admitted to the room where these conversations occur.[10] Inclusion strategies may reinforce (unchallenged) assumptions. For example, to address prejudices and stereotypes in global health images, Arsenii Alenichev and his colleagues[11] successfully inverted “one stereotypical global health image” by prompting a generative AI to produce “an image of a traditional Indian or African healer healing a White Child.” Although there were some problems with the image of the White child, this innovation is a significant, useful effort to de-embed or strip global health images of problematic pictures that mythologize White superiority and Black inferiority. Yet it is possible that using categories like traditional Indian or African reinforces unchallenged assumptions, raising key questions regarding how language and words create new stereotypes. It is common to define traditional as non-conventional, unorthodox, and informal. Yet studies continue to reveal that non-scientifically appraised healing approaches in India or Africa are not only effective but also real, meaningful, fundamental, and primary care-seeking behaviours in many communities in these regions.[12] Suppose inclusive strategies are not un-situated. These conversations may be had within the structures, language, and spaces built by or connected to colonialism. The spaces, language, places, and structures in which these conversations occur can limit who can participate and how they participate. Importantly, some conditions are not conducive to participation as equals. The allocated time for the discussion could also constrain how individuals express themselves. It is unclear who is ultimately heard. Furthermore, epistemic situatedness of inclusion can impact decolonization conversations when participants are beneficiaries of, products of, and trained by structures and systems they seek to dismantle. To enhance the decolonization project and its goals, a pressing task is to unveil and question how the circumstances may inhibit activism. If the vestiges of colonialism continue to structure the decolonization discourse invisibly, the vestiges may undermine decolonization. For example, a public health discussion that includes white Western doctors and Western pharmaceutical executives in Africa may have many local Africans at the table but could still effectively devalue their input based on built-in assumptions and biases that are vestiges of colonialism. Second, exclusion and inclusion are also not binary. Individuals may experience exclusion, even while included (the phenomenon called internal exclusion). In other words, inclusion can fail to be substantial or become a means of enhancing optics, “a way of (un)consciously weakening the radical claims being pursued.”[13] For example, in South Africa, many institutions have made significant efforts to diversify their faculties due to the promulgation of the Employment Equity Act 55.[14] The act requires South African institutions to implement employment equity that redresses the history of harmful discrimination in the country. The act further requires transforming departments and institutional administrations. Although many recognize and support the need to transform departments in South Africa, the rhetoric of transformation departs sharply from the lived experiences.[15] This misalignment between the plan and practice is evident in the underrepresentation of black people and females in senior management teams, professorships in many universities and health departments, and positions of power in some South African institutions. Those selected in the transformation of the departments have also complained of being overworked. The burden of extra work undermines their ability to develop agency and voice in the space they now occupy or fulfil key requirements that have implications for their career trajectory.[16] This is called the minority tax. Notably, "the minority tax… is the burden of extra responsibilities [placed] on faculty of colour to achieve diversity and inclusion and contributes to attrition and impedes academic promotion."[17] One challenge for decolonializing projects will be for decolonial scholars and those selected for decolonization objectives to have the humility to decline invitations, requests, roles, and platforms for which they are either unqualified or lack the capacity to fulfil. At its heart, decolonization strategies must empower those included rather than weaken them. Finally, inclusion can lead to a phenomenon known as elite capture.[18] Elite capture occurs when socially advantaged individuals in a group monopolize or exploit activism to their own benefit at the expense of the larger, struggling group. Elite capture weakens decolonization efforts from within, revealing that those likely to benefit from global inclusive efforts are those who fulfil globally constructed standards, those “already present in the room.” There is no better strategy to weaken decolonial movements than weakening the project from within by strategically positioning individuals who share physical properties with the victims of exclusion and silencing but intellectually, behaviourally, psychologically, and emotionally share more common ground with the colonizer. Such insiders may be unaware they are furthering neocolonial conditions rather than decolonizing. In relation to decolonization, particularly in global health, elite capture reveals that those whose voices are loudest in the room are not necessarily those more impacted by colonialism. They may benefit more from reinforcing colonialism. Opportunism weakens meaningful activism from within, preventing good initiatives and strategies from having their intended impact or taking substantive root.[19] This paper cannot do justice to elite capture, but it is worth noting its negative impacts. IV. Improving the Impact of Decolonization To end neo-colonialism, it is important to understand how it manifests and what to do at each level. Beyond the academic discourse, many tangible efforts exist to decolonize through de-silencing. Examples of these efforts include the ME2 movement that seeks to centre the concerns and experiences of sexually abused or harassed victims in the public discourse. At the funding level, many grant-awarding agencies like Wellcome Trust have dedicated huge budgets to studies that help them understand how they may have perpetrated colonialism or neocolonialism and what they can do differently going forward.[20] In South Africa, promulgating the Employment Equity Act 55 was a tangible attempt to entrench decolonization concerns in a country's regulatory framework. Yet, these decolonization efforts could fail to be substantive if they do not reflect cultural sensitivity. Two key components of cultural sensitivity are worth highlighting here: epistemic and cultural humility. Epistemic humility is an intellectual virtue described as knowing one’s limitations and the limitations of the learning methods employed. At its simplest, it is the ability to admit when one is wrong. Cultural humility includes genuine attempts to learn about and embrace other cultures. Epistemic and cultural humility are signs of academic excellence and strength. Epistemic and cultural humility seriously acknowledge how the state of our knowledge, cognitive limitations, experiences, and backgrounds, while constraining us, also invite us to listen, learn, grow, and change. The limitations-owing account of epistemic and cultural humility suggests that “a person who is aware of her cognitive limitations and owns them is much better positioned to achieve such epistemic goods as true beliefs and understanding than someone who… simply has insight into the epistemic status of her beliefs.”[21] Epistemic and cultural humility may help prevent decolonization projects that unintentionally reinforce what they seek to dismantle. Epistemic humility calls on decolonizers to defer tasks for which they are not qualified to suitably qualified persons. Beyond this, humility supports brave scholarship that imagines and reimagines how featuring the same voices, faces, and perspectives possibly introduces new forms of domination or silencing. Cultural knowledge can lead to a more intentional way of seeking out the right people or a more diverse group than those frequently featured in decolonization conversations. This would give others more opportunities to navigate these spaces and should do so in ways that are familiar to them. One ought to be more sensitive to those who would ordinarily not be included in these conversations. Unless we radically and boldly reimagine these discussions, we risk alienating those most negatively impacted by neocolonialism. CONCLUSION Decolonization conversations are complex and the subject of academic debate. The strategies employed to decolonize can harm or help the victims of neo-colonialism. Inclusion of previously silenced individuals may not be enough to overcome the vestiges of colonialism, leading to a false inclusion, where those included feel excluded or contribute in ways reflecting their own biases and circumstances. Inclusion of an elite or people who do not truly represent the subjugated can lead to elite capture. For decolonization strategies to be impactful, for example, in the context of global health, project leaders and participants must engage in conversations employing epistemic and cultural humility. In many ways, epistemic and cultural humility can help us demythologize our assumptions of any cultural superiority or cognitive authority, allowing for diverse voices, cultures, and perspectives to emerge without domination. - [1] Caesar Atuire & Olivia Rutazibwa. 2021. An African Reading of the Covid-19 Pandemic and the Stakes of Decolonization. An African Reading of the Covid-19 Pandemic and the Stakes of Decolonization [Online]. Available from: https://law.yale.edu/yls-today/news/african-reading-covid-19-pandemic-and-stakes-decolonization [Accessed July 29, 2021 2021]. [2] Bridget Pratt & Jantina De Vries 2023. Where is knowledge from the Global South? An account of epistemic justice for a global bioethics. Journal of Medical Ethics, medethics-2022-108291. [3] Anye-Nkwenti Nyamnjoh 2023. Is decolonisation Africanisation? The politics of belonging in the truly African university. Social Dynamics, 1-20. [4] Rianna Oelofsen 2015. Decolonisation of the African mind and intellectual landscape. Phronimon, 16, 130-146. [5] Caesar Atuire & Olivia Rutazibwa. 2021. An African Reading of the Covid-19 Pandemic and the Stakes of Decolonization. An African Reading of the Covid-19 Pandemic and the Stakes of Decolonization [Online]. Available from: https://law.yale.edu/yls-today/news/african-reading-covid-19-pandemic-and-stakes-decolonization [Accessed July 29, 2021 2021]. [6] Pedro Alexis Tabensky 2008. The Postcolonial Heart of African Philosophy. South African Journal of Philosophy, 27, 285-295. [7] Nicholas M. Creary 2012. African Intellectuals and Decolonization, Ohio, Ohio University Press. [8] Bridget Pratt & Jantina De Vries 2023. Where is knowledge from the Global South? An account of epistemic justice for a global bioethics. Journal of Medical Ethics, medethics-2022-108291. [9] Vivetha Thambinathan & Elizabeth Anne Kinsella 2021. Decolonizing Methodologies in Qualitative Research: Creating Spaces for Transformative Praxis. International Journal of Qualitative Methods, 20, 16094069211014766. [10] Abimbola Seye 2023. Knowledge from the global South is in the global South. Journal of Medical Ethics, 49, 337. [11] A. Alenichev, P. Kingori & K. P. Grietens 2023. Reflections before the storm: the AI reproduction of biased imagery in global health visuals. Lancet Glob Health. [12] Jonathan K. Burns & Andrew Tomita 2015. Traditional and religious healers in the pathway to care for people with mental disorders in Africa: a systematic review and meta-analysis. Social Psychiatry and Psychiatric Epidemiology, 50, 867-877. [13] Anye-Nkwenti Nyamnjoh & Cornelius Ewuoso 2023. What type of inclusion does epistemic injustice require? Journal of Medical Ethics, jme-2023-109091. [14] 1998. Employment Equity Act. In: GOVERNMENT, S. A. (ed.) 19370. [15] Dina Zoe Belluigi & Gladman Thondhlana 2019. ‘Why mouth all the pieties?’ Black and women academics’ revelations about discourses of ‘transformation’ at an historically white South African university. Higher Education, 78, 947-963. [16] Juliet Ramohai & Khomotso Marumo 2016. Women in Senior Positions in South African Higher Education: A Reflection on Voice and Agency. 231, 135-157. [17] J. Trejo 2020. The burden of service for faculty of color to achieve diversity and inclusion: the minority tax. Mol Biol Cell, 31, 2752-2754. [18] Olufemi Taiwo 2020. Being-in-the-Room Privilege: Elite Capture and Epistemic Deference. The Philosopher, 108, 7. [19] Margarita Kurbatova & Elena Kagan 2016. Opportunism of University Lecturers As a Way to Adaptate the External Control Activities Strengthening. Journal of Institutional Studies, 8, 116-136. [20] Jeremy Farrar. 2022. An update on Wellcome's anti-racist programme. An update on Wellcome's anti-racist programme [Online]. Available from: https://wellcome.org/news/update-wellcomes-anti-racism-programme [Accessed August 10, 2022 2022]. [21] Katherine Dormandy 2018. Does Epistemic Humility Threaten Religious Beliefs? Journal of Psychology and Theology, 46, 292-304.