Quantifying the available capacity and resource needs for provision of CAR-T therapies in the National Health Service in Spain: a survey-based study

Leukaemia; Organisation of health services; TherapeuticsLeucemia; Organización de servicios de salud; TerapéuticaLeucèmia; Organització dels serveis sanitaris; TerapèuticaObjectives To estimate the readiness of Spanish National Health Service (NHS) hospitals to provide chimeric antigen receptor T cell (CAR-T), and to identify and quantify the different resources needed to provide CAR-T considering three scenarios defined by 10, 25 and 50 patients per centre per year. Design Targeted literature review and quantitative study using a questionnaire and telephone interviews. An algorithm was created to determine hospitals’ readiness based on their capacity and capability. All the requirements for quantification were assessed and validated by the steering committee, formed by members of the Spanish Group of Haematopoietic Transplantation and Cell Therapy. A weighting system (from 0 to 1) was established for capability quantification. For resources quantification, a scoring system was established, with 0 points representing the minimum and 3 points the maximum of additional resources that a hospital indicated necessary. Setting 40 Spanish hospital centres that perform allogeneic haematopoietic stem cell transplantation were invited to complete the questionnaire for capacity quantification, 28 of which provided valid responses. Nine hospitals participated in the interviews for resource quantification, eight of which had previously been designated by the Ministry of Health (MoH) to provide CAR-T. Outcome measure Current capacity of NHS Spanish sites to administer CAR-T under different theoretical scenarios with varying numbers of procedures, and the potential healthcare resources that would be needed to realise the theoretical capacity requirements. Results Four hospitals were optimally ready, 17 were somewhat ready and 7 were not ready. The actual extrapolated capacity of the currently designated MoH CAR-T sites would allow treatment of approximately 250 patients per year. Regarding healthcare resource needs, the numbers of haematologists, nurses and beds were the most important limiting factors, and those requiring further growth as patient numbers increased. Conclusions Increasing the number of CAR-T-qualified centres and/or increasing resources in the current designated sites are two potential strategies that should be considered to treat CAR-T-eligible patients in Spain.This study was conducted with a grant from GETH-TC (grant number: N/A)

Drying and rewetting conditions differentially affect the mineralization of fresh plant litter and extant soil organic matter

Drought is becoming more common globally and has the potential to alter patterns of soil carbon (C) storage in terrestrial ecosystems. After an extended dry period, a pulse of soil CO2 release is commonly observed upon rewetting (the so-called ‘Birch effect’), the magnitude of which depends on soil rewetting frequency. But the source and implications of this CO2 efflux are unclear. We used a mesocosm field experiment to subject agricultural topsoil to two distinct drying and rewetting frequencies, measuring Birch effects (as 3-day cumulative CO2 efflux upon rewetting) and the overall CO2 efflux over the entire drying-rewetting cycle. We used 14C-labelled wheat straw to determine the contribution of fresh (recently incorporated) plant litter or extant soil organic matter (SOM) to these fluxes, and assessed the extent to which the amount of soil microbial biomass + K2SO4-extractable organic C (fumigated-extracted C, FEC) before rewetting determined the magnitude of Birch effect CO2 pulses. Our results showed a gradual increase in SOM-derived organic solutes within the FEC fraction, and a decrease in soil microbial biomass, under more extreme drying and rewetting conditions. But, contrary to our hypothesis, pre-wetting levels of FEC were not related to the magnitude of the Birch effects. In the longer term, rewetting frequency and temperature influenced the overall (31-day cumulative) amount of CO2–C released from SOM upon rewetting, but the overall 14CO2–C respired from fresh straw was only influenced by the rewetting frequency, with no effect of seasonal temperature differences of ∼15 °C. We conclude that the mineralization of fresh plant litter in soils is more sensitive to water limitations than extant SOM in soils under drying-rewetting conditions. Moreover, we found little evidence to support the hypothesis that the availability of microbial and soluble organic C before rewetting determined the magnitude of the Birch effects, and suggest that future work should investigate whether these short-term CO2 pulses are predominantly derived from substrate-supply mechanisms resulting from the disruption of the soil organo-mineral matrix

(Position Paper) Characterizing the Behavior of Small Producers in Smart Grids:A Data Sanity Analysis

Renewable energy production throughout low-voltage grids has gradually increased in electrical distribution systems, therefore introducing small energy producers - prosumers. This paradigm challenges the traditional unidirectional energy distribution flow to include disperse power production from renewables. To understand how energy usage can be optimized in the dynamic electrical grid, it is important to understand the behavior of prosumers and their impact on the grid’s operational procedures. The main focus of this study is to investigate how grid operators can obtain an automatic data-driven system for the low-voltage electrical grid management, by analyzing the available grid topology and time-series consumption data from a real-life test area. The aim is to argue for how different consumer profiles, clustering and prediction methods contribute to the grid-related operations. Ultimately, this work is intended for future research directions that can contribute to improving the trade-off between systematic and scalable data models and software computational challenges.This work is financially supported by the Danish project RemoteGRID, which is a ForskEL program under Energinet.dk with grant agreement no. 2016-1-12399.Peer ReviewedPostprint (published version

Live synthesis of selective carbon dots as fluorescent probes for cobalt determination in water with an automatic microanalyzer

Altres ajuts: acords transformatius de la UABA new strategy integrating the straight synthesis of carbon dots (CDs) and their direct use for the determination of heavy metals by means of fuorescence quenching is presented. The proposal consists of a modular analyzer, which includes a low temperature co-fred ceramics (LTCC) microreactor for the synthesis of CDs and a cyclic olefn copolymer (COC) microfuidic platform, which automatically performs a reverse fow injection analysis (rFIA) protocol for the determination of heavy metal ions in water by CD fuorescence quenching. As a proof of concept, nitrogen-doped CDs were synthesized from acrylic acid and ethylenediamine (ED) with quantum yields (QYs) of up to 44%, which are selective to cobalt. With the described system, we synthesized homogeneous CDs without the need for further purifcation and with the minimum consumption of reagents, and optimized fuorescence measurements can be performed with freshly obtained luminescent nanomaterials that have not undergone decomposition processes. They have an averagehydrodynamic diameter of 4.2±0.9 nm and maximum excitation and emission wavelengths at 358 nm and 452 nm, respectively. The system allows the automatic dilution and bufering of the synthesized CDs and the sample prior to the determination of cobalt. The concentration of cobalt was determined with good sensitivity and a limit of detection of 7 μg·L−1 with a linear range of 0.02-1 mg·L−1 of Co2+. Spiked tap water and river water samples were analyzed, obtaining recovery from 98 to 104%. This demonstrates the potential of the equipment as an efcient on-site control system for heavy metal monitoring in water

Identifying Early Infections in the Setting of CRS With Routine and Exploratory Serum Proteomics and the HT10 Score Following CD19 CAR-T for Relapsed/Refractory B-NHL

Infections; Serum proteomicsInfeccions; Proteòmica sèricaInfecciones; Proteómica séricaEarly fever after chimeric antigen receptor T-cell (CAR-T) therapy can reflect both an infection or cytokine release syndrome (CRS). Identifying early infections in the setting of CRS and neutropenia represents an unresolved clinical challenge. In this retrospective observational analysis, early fever events (day 0–30) were characterized as infection versus CRS in 62 patients treated with standard-of-care CD19.CAR-T for relapsed/refractory B-cell non-Hodgkin lymphoma. Routine serum inflammatory markers (C-reactive protein [CRP], interleukin-6 [IL-6], procalcitonin [PCT]) were recorded daily. Exploratory plasma proteomics were performed longitudinally in 52 patients using a multiplex proximity extension assay (Olink proteomics). Compared with the CRSonly cohort, we noted increased event-day IL-6 (median 2243 versus 64 pg/mL, P = 0.03) and particularly high PCT levels (median 1.6 versus 0.3 µg/L, P < 0.0001) in the patients that developed severe infections. For PCT, an optimal discriminatory threshold of 1.5 µg/L was established (area under the receiver operating characteristic curve [AUCROC] = 0.78). Next, we incorporated day-of-fever PCT levels with the patient-individual CAR-HEMATOTOX score. In a multicenter validation cohort (n = 125), we confirmed the discriminatory capacity of this so-called HT10 score for early infections at first fever (AUCROC = 0.87, P < 0.0001, sens. 86%, spec. 86%). Additionally, Olink proteomics revealed pronounced immune dysregulation and endothelial dysfunction in patients with severe infections as evidenced by an increased ANGPT2/1 ratio and an altered CD40/CD40L-axis. In conclusion, the high discriminatory capacity of the HT10 score for infections highlights the advantage of dynamic risk assessment and supports the incorporation of PCT into routine inflammatory panels. Candidate markers from Olink proteomics may further refine risk-stratification. If validated prospectively, the score will enable risk-adapted decisions on antibiotic use.This work was supported by a grant within the Gilead Research Scholar Program (to KR, MS). Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) research grant provided within the Sonderforschungbereich SFB-TRR 388/1 2021 – 452881907, and DFG research grant 451580403 (to MS). The work was further supported by the Bavarian Elite Graduate Training Network (to MS), the Wilhelm-Sander Stiftung (to MS, project no. 2018.087.1), the Else-Kröner-Fresenius Stiftung (to MS), and the Bavarian Center for Cancer Research (BZKF). KR received a fellowship from the School of Oncology of the German Cancer Consortium (DKTK). KR, VB, and VLB were funded by the Else Kröner Forschungskolleg (EKFK) within the Munich Clinician Scientist Program (MCSP)

Effect of Sodium Hydroxide Treatments on the Tensile Strength and the Interphase Quality of Hemp Core Fiber-Reinforced Polypropylene Composites

[EN] The formulation of greener composite materials by substituting glass fibers with natural fibers is a current field of research. If such natural fiber reinforcements come from industrial side streams, as hemp core fibers (HCFs) come from the extraction of hemp strands for the textile industry, an additional advantage can be identified. Nonetheless, such by-product fibers show some drawbacks, such as high lignin contents, which can make it difficult to obtain a good interphase between the fibers and the matrix and to obtain a good fiber individualization. A digestion treatment at different NaOH contents is proposed to eliminate soluble lignin and extractives from the surface of the fibers. At the same time, the use of a coupling agent solves incompatibilities between the fibers and the matrix. The composites were tensile tested and the impact of the proposed treatments is evaluated and discussed. Later, the Kelly-Tyson modified equation and a modified rule of mixtures¿the micro-mechanic models¿is used to study the impact of such treatments on the quality of the interphase between the polymer and the reinforcement. Both treatments showed a high impact on the tensile strength and the quality of the interphase, obtaining competitive composite materials reinforced with HCFs derived from a by-product.S1159

Best Treatment Option for Patients With Refractory Aggressive B-Cell Lymphoma in the CAR-T Cell Era: Real-World Evidence From GELTAMO/GETH Spanish Groups

CAR-T cell therapy; Real world evidence; B cell lymphomaTerapia con células CAR-T; Evidencia del mundo real; Linfoma de células BTeràpia amb cèl·lules CAR-T; Evidència del món real; Limfoma de cèl·lules BReal-world evidence comparing the efficacy of chimeric antigen receptor (CAR) T-cell therapy against that of the previous standard of care (SOC) for refractory large B-cell lymphoma (LBCL) is scarce. We retrospectively collected data from patients with LBCL according to SCHOLAR-1 criteria treated with commercial CAR T-cell therapy in Spain (204 patients included and 192 treated, 101 with axicabtagene ciloleucel [axi-cel], and 91 with tisagenlecleucel [tisa-cel]) and compared the results with a historical refractory population of patients (n = 81) obtained from the GELTAMO-IPI study. We observed superior efficacy for CAR-T therapy (for both axi-cel and tisa-cel) over pSOC, with longer progression-free survival (PFS) (median of 5.6 vs. 4–6 months, p ≤ 0.001) and overall survival (OS) (median of 15 vs. 8 months, p < 0.001), independently of other prognostic factors (HR: 0.59 (95% CI: 0.44–0.80); p < 0.001] for PFS, and 0.45 [(95% CI: 0.31–0.64)] for OS). Within the CAR-T cohort, axi-cel showed longer PFS (median of 7.3 versus 2.8 months, respectively, p = 0.027) and OS (58% versus 42% at 12 months, respectively, p = 0.048) than tisa-cel. These differences were maintained in the multivariable analysis. On the other hand, axi-cel was independently associated with a higher risk of severe cytokine release syndrome and neurotoxicity. Our results suggest that the efficacy of CAR-T cell therapy is superior to pSOC in the real-world setting. Furthermore, axi-cel could be superior in efficacy to tisa-cel, although more toxic, in this group of refractory patients according to SCHOLAR-1 criteria

Preoperative diagnostic uncertainty in T2-T3 rectal adenomas and T1-T2 adenocarcinomas and a therapeutic dilemma : Transanal endoscopic surgery, or total mesorectal excision?

Background: Endorectal ultrasound and rectal magnetic resonance are sometimes unable to differentiate between stages T2 and T3 in rectal adenomas that are possible adenocarcinomas, or between stages T1 and T2 in rectal adenocarcinomas. These cases of diagnostic uncertainty raise a therapeutic dilemma: transanal endoscopic surgery (TES) or total mesorectal excision (TME)? Methods: An observational study of a cohort of 803 patients who underwent TES from 2004 to 2021. Patients operated on for adenoma (group I) and low-grade T1 adenocarcinoma (group II) were included. The variables related to uncertain diagnosis, and to the definitive pathological diagnosis of adenocarcinoma stage higher than T1, were analyzed. Results: A total of 638 patients were included. Group I comprised 529 patients, 113 (21.4%) with uncertain diagnosis. Seventeen (15%) eventually had a pathological diagnosis of adenocarcinoma higher than T1. However, the variable diagnostic uncertainty was a risk factor for adenocarcinoma above T1 (OR 2.3, 95% CI 1.1-4.7). Group II included 109 patients, eight with uncertain diagnosis (7.3%). Two patients presented a definitive pathological diagnosis of adenocarcinoma above T1. Conclusions: On the strength of these data, we recommend TES as the initial indication in cases of diagnostic uncertainty. Multicenter studies with larger samples for both groups should now be performed to further assess this strategy of initiating treatment with TES

The development and characterisation of a bacterial artificial chromosome library for Fragaria vesca

<p>Abstract</p> <p>Background</p> <p>The cultivated strawberry <it>Fragaria ×ananassa </it>is one of the most economically-important soft-fruit species. Few structural genomic resources have been reported for <it>Fragaria </it>and there exists an urgent need for the development of physical mapping resources for the genus. The first stage in the development of a physical map for <it>Fragaria </it>is the construction and characterisation of a high molecular weight bacterial artificial chromosome (BAC) library.</p> <p>Methods</p> <p>A BAC library, consisting of 18,432 clones was constructed from <it>Fragaria vesca </it>f. <it>semperflorens </it>accession 'Ali Baba'. BAC DNA from individual library clones was pooled to create a PCR-based screening assay for the library, whereby individual clones could be identified with just 34 PCR reactions. These pools were used to screen the BAC library and anchor individual clones to the diploid <it>Fragaria </it>reference map (FV×FN).</p> <p>Findings</p> <p>Clones from the BAC library developed contained an average insert size of 85 kb, representing over seven genome equivalents. The pools and superpools developed were used to identify a set of BAC clones containing 70 molecular markers previously mapped to the diploid <it>Fragaria </it>FV×FN reference map. The number of positive colonies identified for each marker suggests the library represents between 4× and 10× coverage of the diploid <it>Fragaria </it>genome, which is in accordance with the estimate of library coverage based on average insert size.</p> <p>Conclusion</p> <p>This BAC library will be used for the construction of a physical map for <it>F. vesca </it>and the superpools will permit physical anchoring of molecular markers using PCR.</p