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Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .

Diversity in the quality of organic manure produced on farms in West Africa: what impact on recommendations for the use of manure?. The maintenance of humus balance in cultivated soils is a guarantee of the sustainability of production systems. In West Africa, the advice regarding application of organic manure to fields remains unique and independent of the quality of organic manures available on farms. Some studies show that West African farms produce a diversity of organic manure. Should the advice for organic manure application be reformulated to reflect this diversity of farm-produced organic manure? We propose to analyze the diversity of organic manure produced on certain farms and estimate the optimal amount of organic fertilizer that should be applied to the fields to ensure the renewal of organic matter. The analysis distinguishes a great heterogeneity of farm-produced organic manure. Farm-produced manure with a high amendment value provides a reference for the quality of the manure, but this is also the case for farm-produced manure with an average quality and for farm-produced composts with a high or average amendment value. Depending on the quality of the manure, with these types of organic fertilizer, it would be necessary to apply between 2.4 and 5.1 t·ha-1 per year on sandy soils and 2.1 to 4.4 t·ha-1 per year for clay. Depending on the quality of the compost, it would be necessary to apply between 4.1 and 5.4 t·ha-1 per year for sandy soils and between 3.5 and 4.6 t·ha-1 per year for clay. Taking into account the heterogeneity of the quality of farm-produced organic manure, we can adapt the current technical advice to ensure a renewal of soil organic matter. However, the quantities of organic manure needed are beyond the current capacity of farms. It would be necessary to increase the amount of organic manure produced on farms, to improve its quality and to integrate other modes of soil fertility management at farm level.

Introduction The fragility and sensitivity of the skin in people with albinism (PWA) have necessitated extensive research across molecular genetics, dermatology, and cosmetology. These efforts aim to address the increased susceptibility of albino skin to sun damage and dermatological conditions. Purpose This study investigates the dermatological efficacy of two galenic formulations, one based on Mathesia and the other on Curcuma longa L. (Zingiberaceae) oil, assessing their antimicrobial, anti-inflammatory, and photoprotective properties for the skin of PWA. Methods Using freeze-drying techniques for Mathesia and slight modifications of Sahouli et al.'s method for extracting Curcuma longa L. oil, we developed two creams. Their macroscopic properties, pH levels, and tyrosine concentrations were analyzed. UV-visible spectrophotometry determined their sun protection factor (SPF). An antibiogram test assessed their antimicrobial activity, and a clinical test evaluated their efficacy on PWA with and without skin conditions. Results The study revealed that both creams had good texture and appropriate pH levels. However, neither cream provided sufficient photoprotection for the sensitive skin of PWA. The Mathesia-based cream demonstrated a higher antimicrobial efficacy compared to the turmeric oil-based and neutral creams. Clinical tests showed 75% of participants had very satisfactory results, with the turmeric oil-based cream showing the most significant overall efficacy. Conclusion The creams exhibited beneficial antimicrobial and anti-inflammatory properties but were inadequate for UV protection of albino skin. Future research should focus on increasing active ingredient concentrations or exploring alternative plants to enhance tyrosine content and SPF values, potentially offering better protection and therapeutic effects for PWA.

Parental burnout results from chronic stress in parenting, and it can be accompanied by harmful behaviors such as parental neglect and violence (Mikolajczak & Roskam, 2018). Network analysis examines psychological phenomena within a system of its constituents, and thus it is promising for understanding the distinct features of parental burnout and behaviors related to it. Recently, Blanchard et al. (2021) conducted the first network analysis of parental burnout and related harmful behaviors in the family context, but did so using an outdated measure and conceptualization of parental burnout. In the present study, in a sample of French-speaking parents (N = 3144, from five different previous studies), we aimed to investigate how each of the four features in the new conceptualization of parental burnout (i.e., emotional exhaustion, feeling fed up, emotional distance, and contrast with the previous parental self) interact with one another and with parental neglect and violence in a network system. In this preregistered reanalysis, we generated two network models commonly used with cross-sectional data: a Graphical Gaussian Model and a Directed Acyclic Graph. Our results point to emotional exhaustion and feeling fed up as key driving forces of the network structure, while emotional distance appears as a critical feature tying parental burnout with parental neglect and violence., Author(s): Rana Begum Kalkan [sup.1] [sup.2] , M. Annelise Blanchard [sup.2] [sup.3] , Moïra Mikolajczak [sup.2] , Isabelle Roskam [sup.2] , Alexandre Heeren [sup.2] [sup.3] [sup.4] Author Affiliations: (1) grid.5596.f, [...]

Network science has allowed varied scientific fields to investigate and visualize complex relations between many variables, and psychology research has begun to adopt a network perspective. In this paper, we consider how leaving behind reductionist approaches and instead embracing a network perspective can advance the field of parental burnout. Although research into parental burnout is in its early stages, we argue that a network approach to parental burnout could set the scene for radically new vistas in parental burnout research. We claim that such an approach can allow simultaneous investigations (and clear visualizations) of many variables related to parental burnout and their interactions, integrates smoothly with prior family systems theories, and prioritizes dynamic research questions. We likewise discuss potential future clinical applications, such as interventions targeting central nodes and treatment personalized to a specific family's network system. We also review practical considerations, limitations, and future directions for researchers interested in applying a network approach to parental burnout research.

Simon Fifer,1 Andrea Puig,2 Vanessa Sequeira,3 Mustafa Acar,2 Chee H Ng,4 Michelle Blanchard,5 Ariana Cabrera,6 James Freemantle,7 Jennifer Grunfeld8 1Research and Innovation, Community and Patient Preference Research, Sydney, New South Wales, Australia; 2Real World Evidence, Janssen Australia, Macquarie Park, New South Wales, Australia; 3Medical Affairs, Janssen Australia, Macquarie Park, New South Wales, Australia; 4Professorial Unit, The Melbourne Clinic, Department of Psychiatry, University of Melbourne, Richmond, Victoria, Australia; 5Melbourne School of Psychological Sciences, University of Melbourne, Parkville, Victoria, Australia; 6Data Analytics and Visualisation, Community and Patient Preference Research, Sydney, New South Wales, Australia; 7People Measures, South Melbourne, Victoria, Australia; 8Peninsula Therapeutic & Research Group, Frankston, Victoria, AustraliaCorrespondence: Andrea PuigReal World Evidence, Janssen Australia, 66 Waterloo Road, Macquarie Park, NSW, 2113, AustraliaTel +61-4-2912-8695Fax +61 2 9815 3200Email apuig@ITS.JNJ.comBackground: There is evidence of improved adherence and treatment outcomes when patients’ treatment preferences are considered, and shared decision making is utilized.Purpose: We aimed to better understand treatment preferences among Australians with treatment-resistant depression (TRD), focusing on the specific treatment attributes that people value (such as effectiveness, risk of side effects and cost) and their relative importance. The risk-benefit trade-offs that characterize treatment choices were also examined.Patients and Methods: An online survey of 75 patients with experience of TRD was conducted, consisting of two discrete choice experiment (DCE) components – a medication DCE and a treatment plan DCE. Participants were able to prioritize and trade off different features of medications and treatment plans. Additional questions aimed to better define this population group, which in Australia is poorly understood.Results: In both DCEs, two distinct latent classes were identified. In the medication DCE, the classes were distinguished by willingness to consider new treatment alternatives. Participants in class 1 were reluctant to give up current treatment, while those in the slightly larger class 2 preferred new treatment options. In both classes, treatment effectiveness and cost were the greatest contributors to preference. Similar behavior was seen in the treatment plan DCE, with the larger class more likely to choose a new plan over their current treatment arrangement. Participants preferred medications that were low-cost, taken orally, had a high percentage improvement in mood symptoms, high rate of remission and low risk of weight gain. A similar result was found in preferences for treatment plans such that plans with the greatest effectiveness and lowest cost were most favorable.Conclusion: Patient preferences should routinely be considered and discussed to guide informed decisions regarding the value of new and existing medications for TRD and how they sit in the context of treatment plans.Keywords: patient preferences, patient value mapping, behavioral economics, major depressive disorder, quantitative research, patient centricity

Myxobacteria are single-celled, but social, eubacterial predators. Upon starvation they build multicellular fruiting bodies using a developmental program that progressively changes the pattern of cell movement and the repertoire of genes expressed. Development terminates with spore differentiation and is coordinated by both diffusible and cell-bound signals. The growth and development of Myxococcus xanthus is regulated by the integration of multiple signals from outside the cells with physiological signals from within. A collection of M. xanthus cells behaves, in many respects, like a multicellular organism. For these reasons M. xanthus offers unparalleled access to a regulatory network that controls development and that organizes cell movement on surfaces. The genome of M. xanthus is large (9.14 Mb), considerably larger than the other sequenced delta-proteobacteria. We suggest that gene duplication and divergence were major contributors to genomic expansion from its progenitor. More than 1,500 duplications specific to the myxobacterial lineage were identified, representing >15% of the total genes. Genes were not duplicated at random; rather, genes for cell-cell signaling, small molecule sensing, and integrative transcription control were amplified selectively. Families of genes encoding the production of secondary metabolites are overrepresented in the genome but may have been received by horizontal gene transfer and are likely to be important for predation.