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Abstract Bendamustine has been retrospectively shown to be an effective and safe lymphodepletion regimen prior to the anti-CD19 chimeric antigen receptor T cell (CART) products tisagenlecleucel and axicabtagene ciloleucel, as well as the anti-BCMA CART products idecabtagene vicleucel and ciltacabtagene autoleucel. However, bendamustine as lymphodepletion prior to lisocabtagene maraleucel (liso-cel), a 4-1BB co-stimulated, fixed CD4:CD8 ratio anti-CD19 CART product, has not been described yet. Thus, we studied a cohort of sequentially-treated patients with large B-cell lymphomas who received bendamustine lymphodepletion before liso-cel at the University of Pennsylvania between 5/2021 and 12/2023 (n = 31). Patients were evaluated for toxicities and responses. Of note, 7 patients (22.6%) would have dnot met the inclusion criteria for the registrational liso-cel clinical trials, mostly due to older age. Overall and complete response rates were 76.9% and 73.1%, respectively. At a median follow-up of 6.3 months, the 6-month progression-free and overall survival were 59.9% and 91.1%, respectively. Rates of cytokine-release syndrome (CRS) and neurotoxicity (ICANS) of any grade were 9.7% and 9.7%, respectively, with no grade ≥ 3 events. No infections were reported during the first 30 days following liso-cel infusion. Neutropenia ≥ grade 3 was observed in 29.0% of patients; thrombocytopenia ≥ grade 3 occurred in 9.7%. In conclusion, bendamustine lymphodepletion before liso-cel appears to be a strategy that can drive tumor responses while ensuring a mild toxicity profile.

Abstract Ants are key ecosystem service providers and can serve as important biological control agents in pest management. However, the effects of insecticides on common farmland ant species are poorly understood. We tested the effects of three commonly used insecticides on ants (Hymenoptera, Formicidae). The tested insecticides were acetamiprid (neonicotinoid; formulated as Mospilan 20 SP), deltamethrin (pyrethroid; formulated as Sanium Ultra), and sulfoxaflor (sulfilimine; formulated as Gondola). We tested two ant (Hymenoptera: Formicidae) species with different colony founding strategies, Lasius niger (Linnaeus, 1758) and Myrmica rubra (Linnaeus, 1758). We sprayed their queens with insecticides at concentrations recommended for use in foliar applications in agriculture, i.e., at 1.25 g L−1 (acetamiprid), 0.6 g L−1 (sulfoxaflor), and 0.875 g L−1 (deltamethrin). Further, we diluted the compounds in distilled water and tested them at 10%, 1%, and 0.1% of the field-recommended concentrations, and used distilled water as a control. We monitored the survival of the queens and the number of eggs laid. All three tested insecticides caused severe lethal and sublethal concentration-dependent effects. Even at concentrations three orders of magnitudes lower than recommended for field applications, significantly lower numbers of eggs were found in the queens’ nests. The extent of the sublethal effects of acetamiprid and sulfoxaflor was concentration-dependent and differed between the two ant species. Besides bees and bumblebees, ants represent an important group of hymenopterans that are severely affected even by low concentrations of the tested compounds and therefore should be included in risk assessment schemes.

Populations evolve by accumulating advantageous mutations. Every population has some spatial structure that can be modeled by an underlying network. The network then influences the probability that new advantageous mutations fixate. Amplifiers of selection are networks that increase the fixation probability of advantageous mutants, as compared to the unstructured fully-connected network. Whether or not a network is an amplifier depends on the choice of the random process that governs the evolutionary dynamics. Two popular choices are Moran process with Birth-death updating and Moran process with death-Birth updating. Interestingly, while some networks are amplifiers under Birth-death updating and other networks are amplifiers under death-Birth updating, so far no spatial structures have been found that function as an amplifier under both types of updating simultaneously. In this work, we identify networks that act as amplifiers of selection under both versions of the Moran process. The amplifiers are robust, modular, and increase fixation probability for any mutant fitness advantage in a range r ∈ (1, 1.2). To complement this positive result, we also prove that for certain quantities closely related to fixation probability, it is impossible to improve them simultaneously for both versions of the Moran process. Together, our results highlight how the two versions of the Moran process differ and what they have in common.

Ants are a large group of animals that also live in orchards and gardens. Their presence on fruit trees is often associated with presence of aphids, and their perception by the public is therefore rather negative. The article below describes the importance of ants in nature and their role in orchards. Furthermore, as part of this study, the first results are published with an evaluation of the effect of selected insecticides on Lasius niger queens and L. niger and Lasius brunneus workers. Laboratory experiments show that none of the tested products had a significant effect on queens or workers of L. niger within 72 hours. In contrast, increased mortality was observed in L. brunneus workers with all tested products, often even at very low concentrations. The most significant effect was observed with Sivanto Prime, when the mortality of L. brunneus workers was determined to be 53% after 24 hours of application and 70% after 72 hours.

Abstract Motivated by COVID-19, we develop and analyze a simple stochastic model for the spread of disease in human population. We track how the number of infected and critically ill people develops over time in order to estimate the demand that is imposed on the hospital system. To keep this demand under control, we consider a class of simple policies for slowing down and reopening society and we compare their efficiency in mitigating the spread of the virus from several different points of view. We find that in order to avoid overwhelming of the hospital system, a policy must impose a harsh lockdown or it must react swiftly (or both). While reacting swiftly is universally beneficial, being harsh pays off only when the country is patient about reopening and when the neighboring countries coordinate their mitigation efforts. Our work highlights the importance of acting decisively when closing down and the importance of patience and coordination between neighboring countries when reopening.

Background and purpose: CD19-targeting chimeric antigen receptor T-cell (CART) therapy is a promising treatment for relapsed/refractory non-Hodgkin lymphoma, but most patients experience post-CART progression. We describe our institutional experience of salvage radiotherapy (SRT) in this setting. Materials and methods: Of 94 patients who received CART therapy from 2018 to 2020, 21 received SRT for post-CART progression. Patients were divided into two groups: locoregional disease (n = 9 [43 %], all disease encompassable within an RT field) and advanced disease (n = 12 [57 %]). Patterns of failure, progression-free survival (PFS), overall survival (OS), and toxicity were assessed. Results: Median time from CART infusion to SRT was 4.0 months (range, 0.6–11.5 months). In the locoregional disease group, 8/9 patients (89 %) were treated with comprehensive SRT to a median dose of 37.5 Gy in a median of 15 fractions. In the advanced disease group, all patients (n = 12) were treated with focal SRT to a median dose of 20.8 Gy in a median of 5 fractions. Median follow-up post-SRT was 15.2 months. In-field response was observed in 8/9 (89 %) in the locoregional disease and 8/9 (89 %) evaluable patients in the advanced disease groups. 17/18 evaluable patients (94 %) patients experienced post-SRT progression, all with a distant component. Median OS was 7.4 months; 21 months for locoregional disease versus 2.4 months for advanced disease (p = 0.0002). Median PFS was 1.1 month, and similarly poor regardless of group. No grade ≥ 3 toxicities occurred. Conclusions: SRT post-CART therapy appears safe with encouraging in-field response but high rates of out-of-field progression, even for those presenting with locoregional disease, highlighting the need for integration of novel systemic agents.

Purpose: To report objective response rates (ORR), time to local failure (TTLF), and overall survival (OS) among patients with relapsed or refractory diffuse large B-cell lymphoma after salvage- or palliative-intent radiation therapy (RT) and to investigate whether outcomes differed with conventional versus hypofractionated (≥2.5 Gy/fraction) RT. Methods and Materials: A single-institution observational cohort study was performed for patients who completed a course of RT for relapsed or refractory diffuse large B-cell lymphoma between January 1, 2008, and April 1, 2020. Predictors of ORR, TTLF, and OS were calculated using univariable and multivariable regression models. The Kaplan-Meier method was used to estimate TTLF and OS, and log-rank analysis was used to compare outcomes. Equivalent dose in 2 Gy fractions (EQD2) was calculated using an α/β of 10. Results: One-hundred and sixty-nine patients were treated with 205 RT courses (73 [36%] salvage, 132 [64%] palliative), and hypofractionated RT was used in 100 RT courses (49%). Median RT dose was 30 Gy (range, 8-60 Gy). ORR was 60% for the total cohort (53% and 69% for palliative and salvage cohorts, respectively). Over a median follow-up time of 4 months, median OS in all patients was 5 months (3 and 22 months for palliative and salvage cohorts, respectively). No statistically significant differences in ORR, TTLF, and OS were observed with hypofractionation compared with conventional fractionation. EQD2 ≥35 Gy was associated with improved ORR (odds ratio, 3.79 [1.19-12.03]; P = .024) and prolonged TTLF (0.39 [0.18-0.87]; P = .022), while double-hit receptor status (8.18 [1.08-62.05]; P = .042), cell of origin (3.87 [1.17-8.74]; P = .0012), and bulky disease (≥7.5 cm; 2.12 [1.18-3.81]; P = .012) were associated with inferior TTLF. In the palliative-only cohort, a low-dose regimen of 8 Gy in 2 fractions was associated with similar ORR compared with other fractionation schema but trended towards inferior TTLF (P = .36). Conclusions: Hypofractionation is not associated with differences in disease outcomes for patients with relapsed or refractory diffuse large B-cell lymphoma, while higher RT dose (EQD2 ≥35 Gy) may improve ORR and TTLF. Future work is warranted to elucidate the ideal dose and fractionation schema for such patients who will likely also undergo novel systemic agents and cellular therapies.

This article presents the results of a study dealing with the use of a combination of recycled rubber from waste tires as a 100% substitute in the production of cement composites. Aggregate was replaced with recycled rubber in two ratios, namely the ratio of 50/50 and the ratio of 40/60 of the share of fraction 0/1 mm and fraction 1/3 mm. The designed formulas of cement composites were subjected to the tests of their physical and mechanical properties in order to determine the properties of the used recycled rubber combination. The tests included the consistency of the grain curve, mixing water properties, consistency of cement mortar, and strength characteristics (tensile flexural strength and compressive strength). The study presents results that are fundamentally different from the comparative samples and their use in the building industry; however, at the same time, they open up new possibilities of their utilization as a building material.

We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850).

Idiopathic acquired aplastic anemia (AA) is a rare lymphocyte-mediated bone marrow aplasia. No specific mechanisms or triggers of AA have been identified. We recently observed several patients who developed AA after Hodgkin lymphoma (HL). We hypothesized that the co-occurrence of HL and AA is not random and may be etiologically significant. To test this hypothesis, we determined the incidence of AA in HL patients at our institution. We identified four patients with co-occurring HL and AA, with the incidence of AA in HL patients >20-fold higher compared to the general population. We identified 12 additional patients with AA and HL through a systematic literature review. Of the 16 total patients,15 (93.8%) developed AA after or concurrent with a HL diagnosis. None of the patients had marrow involvement by HL. Five of 15 patients were in complete remission from HL at the time of AA diagnosis, and six had a concurrent presentation with no prior cytotoxic therapy, with diagnostic timeframe information unavailable for four patients. The median interval between HL diagnosis and AA onset was 16 months, ranging from concurrent to 14 years after a HL diagnosis. The median survival after AA diagnosis was 14 months (range: 1 month to 20 years). Our results show that patients with HL have a higher incidence of AA compared to the general population and suggest that HL-related immune dysregulation may be a risk factor for AA. Better recognition and management of AA in HL patients is needed to improve outcomes in this population.

This article describes an experimental study aimed at investigating the potential use of recycled rubber granulate from waste tires of fractions 0/1 and 1/3 mm in cement composites as a 100% replacement for natural aggregates. The use of waste in the development and production of new building materials represents an important aspect for the sustainability and protection of the environment. This article is focused on the sound-absorbing and thermal-insulating properties of experimental cement composites based on recycled rubber from waste tires. The article describes the grain characteristics of recycled rubber, sound absorption capacity, thermal conductivity and strength characteristics. The results of this research show that the total replacement of natural aggregate with recycled rubber in cement composites is possible. Replacing natural aggregate with recycled rubber has significantly improved the thermal and acoustic properties of the prepared cement composites, however, at the same time; there was also the expected decrease in the strength characteristics due to the elasticity of rubber.

Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated IGHV, 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients, the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study.

Clinical trials that led to ibrutinib’s approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58 versus 61 years, P=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85 versus 87 months, P=0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure.

Background: Dramaturgy is a specific method of course design and conduct used in experiential education in the Czech Republic. However, little is known about how the application of dramaturgy affects participants in experiential education. This paper explores dramaturgy in a winter expeditionary course organized by Vacation School Lipnice and participants' experience. Objective: Firstly, to explicate how the dramaturgy was used to design and conduct a winter expeditionary course by Vacation School Lipnice. Secondly, to explore the participants' experience. Methods: Content analysis was employed, using data from twelve unstructured interviews made with the course participants. Results: Four main themes representing participants' experience emerged from the interviews: a) inner self-experience, reflecting on life; b) relationships with others; c) nature; and d) embodiment and physical demands. These four underlying aspects have turned out to be relevant to the course dramaturgy in a number of ways. Considering the dramaturgy of the course, the main theme of the course was a pilgrimage not only to certain goal, but also to oneself. This theme was transformed into a practical programme of a long winter journey on snowshoes. Conclusions: The dramaturgy approach was found useful in the design of the experiential education course, positively contributing to the participants' experience.

This paper presents the results of research dealing with the use of recycled waste sludge water from a concrete plant (CP) as partial or complete replacement of mixing water in cement mixtures. The need to recycle waste sludge water generated as a by-product (waste sludge water) during the production of fresh concrete in the concrete plant results from the environmental and economic problems associated with the operation of the concrete plant. Mixing water was replaced with recycled waste sludge water in the amount of 25%, 50%, 75%, and 100%. In order to determine the effect of partial or complete replacement of mixing water with waste sludge water from the concrete plant in the production of cement composites, laboratory tests of waste sludge water were carried out to determine whether the waste sludge water complies with the requirements for mixing water defined in CSN EN 1008. The tests also determined the properties of fresh cement mortar and hardened cement composites. These were tests of the beginning and end of cement mortar setting, and the strength characteristics (flexural strength, compressive strength). The results of these tests show that it is possible to replace the mixing water by waste sludge water from the concrete plant in the amount of up to 25% without significantly affecting the tested properties, in comparison with the formula containing pure mixing water.

This article presents the results of a study dealing with the utilization of sludge water from a concrete plant as a partial replacement for mixing water in the production of cement composites. The replacement of mixing water with sludge water from a concrete plant was carried out in the amounts of 20% and 50%. The following tests were carried out in order to determine the effect of the replacement of mixing water with sludge water from a concrete plant on the physical and mechanical properties of the cement composites: cement mortar consistency, beginning and end of setting, strength characteristics (compressive strength and flexural strength), and thermal properties. The measured values of the strength characteristics of the test specimens after 28 days of age confirm the possibility of replacing mixing water with sludge water from a concrete plant without significantly reducing the compressive and flexural strength.

Nezisková organizace Prázdninová škola Lipnice (PŠL) navazuje na poměrně bohatou tradici české výchovy v přírodě (skauting, woodcraft, Foglar, tramping atd.), již po několik desetiletí pořádá vícedenní projekty (kurzy) využívající metod zážitkové pedagogiky a touto svou činností zapadá do konceptu neformálního vzdělávání. Na těchto kurzech instruktoři usilují o všestranný rozvoj osobnosti účastníka. Tato studie se zaměřuje konkrétně na projekt Život je gotickej pes 2011 (ŽGP 2011), tedy putovní kurz odehrávající se v zimní přírodě. Tento kurz je specifický blízkým sepětím s přírodou, společenstvím lidí a možností zamyslet se nad svým životem z nadhledu. Studie se zabývá individuální zkušeností účastníka kurzu ŽGP 2011, kterým je hlavní autor studie sám. Pro účely výzkumu je využit kvalitativní přístup, metoda interpretativní fenomenologické analýzy (IPA) je použita pro kvalitativní analýzu několika typů dat: rozhovor, zpětnovazební esej z kurzu, účastnický deník. Z analýzy vyplývá několik hlavních kategorií, které jsou jádrem účastnické zkušenosti. Těmito hlavními kategoriemi jsou: bytí v přítomnosti, autenticita, sebepřekonání, otevřenost ve vztahu k lidem, hledání smyslu a přenos do pokurzovního života. Diskuze se věnuje objasnění těchto kategorií v kontextu zážitkové pedagogiky a v kontrastu turistiky a poutnictví.