Search

Abstract Autologous anti-CD19 chimeric antigen receptor (CAR) T cells are now used in routine practice for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Severe (grade ≥ 3) cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are still the most concerning acute toxicities leading to frequent intensive care unit (ICU) admission, prolonging hospitalization, and adding significant cost to treatment. We report on the incidence of CRS and ICANS and the outcomes in a large cohort of 925 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) in France based on patient data captured through the DESCAR-T registry. CRS of any grade occurred in 778 patients (84.1%), with 74 patients (8.0%) with grade 3 CRS or higher, while ICANS of any grade occurred in 375 patients (40.5%), with 112 patients (12.1%) with grade ≥ 3 ICANS. Based on the parameters selected by multivariable analyses, two independent prognostic scoring systems (PSS) were derived, one for grade ≥ 3 CRS and one for grade ≥ 3 ICANS. CRS-PSS included bulky disease, a platelet count 30 mg/L and no bridging therapy or stable or progressive disease (SD/PD) after bridging. Patients with a CRS-PSS score > 2 had significantly higher risk to develop grade ≥ 3 CRS. ICANS-PSS included female sex, low level of platelets ( 2 had significantly higher risk to develop grade ≥ 3 ICANS. Both scores were externally validated in international cohorts of patients treated with tisa-cel or axi-cel.

Immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant cause of morbidity associated with CD19-targeted chimeric antigen receptor (CAR) T-cell therapy. Early prediction of patients who will develop ICANS would be crucial to better guide individualized management of high-risk patients, but specific predictive markers are still missing. Serum neurofilament light chain (NfL) levels are a sensitive indicator of neuroaxonal injury in neurological diseases. Elevated NfL levels at the time of CAR T-cell infusion have been associated with the severity of ICANS, but their utility for earlier identification of patients with subclinical neurological damage has not been evaluated.We studied all consecutive adult patients who received commercial CAR T cells for relapsed/refractory B-cell lymphomas at Saint-Louis Hospital between January 2019 and February 2023. Patients with pre-existing or current neurological disease were excluded. NfL levels were quantified in frozen serum collected at the time of the decision to treat (ie, the day of leukapheresis) and at the time of treatment (ie, the day of infusion).Of the 150 study patients, 28% developed ICANS of any grade, including 15.3% of grade 2–4. Receiving a CAR construct with a CD28 domain (58% of patients) was the strongest predictor of grade 2–4 ICANS. Serum NfL levels were significantly higher in patients with grade 2–4 ICANS than in those with grade 0–1 ICANS, both at the time of leukapheresis and infusion. In multivariate models, NfL above the cut-off value was independently associated with grade 2–4 ICANS at leukapheresis (NfL>75 pg/mL, OR 4.2, 95% CI 1.2 to 14.2, p=0.022) and infusion (NfL>58 pg/mL, OR 4.3, 95% CI 1.3 to 13.7, p=0.015).In conclusion, high NfL levels at the time of the decision to proceed with CAR T-cell manufacturing may represent an early surrogate of underlying loss of neuroaxonal integrity that increases the risk of subsequent neurotoxicity. Incorporating NfL levels into the decision-making process based on each patient’s risk profile could help determine the appropriate CAR product when possible, and guide the prophylactic or therapeutic management of ICANS.

Limited data are available on breakthrough COVID-19 in patients with hematologic malignancy (HM) after anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Adult patients with HM, ≥1 dose of anti-SARS-CoV-2 vaccine, and breakthrough COVID-19 between January 2021 and March 2022 were analyzed. A total of 1548 cases were included, mainly lymphoid malignancies (1181 cases, 76%). After viral sequencing in 753 cases (49%), the Omicron variant was prevalent (517, 68.7%). Most of the patients received ≤2 vaccine doses before COVID-19 (1419, 91%), mostly mRNA-based (1377, 89%). Overall, 906 patients (59%) received COVID-19-specific treatment. After 30-day follow-up from COVID-19 diagnosis, 143 patients (9%) died. The mortality rate in patients with the Omicron variant was 7.9%, comparable to other variants, with a significantly lower 30-day mortality rate than in the prevaccine era (31%). In the univariable analysis, older age (P < .001), active HM (P < .001), and severe and critical COVID-19 (P = .007 and P < .001, respectively) were associated with mortality. Conversely, patients receiving monoclonal antibodies, even for severe or critical COVID-19, had a lower mortality rate (P < .001). In the multivariable model, older age, active disease, critical COVID-19, and 2-3 comorbidities were correlated with a higher mortality, whereas monoclonal antibody administration, alone (P < .001) or combined with antivirals (P = .009), was protective. Although mortality is significantly lower than in the prevaccination era, breakthrough COVID-19 in HM is still associated with considerable mortality. Death rate was lower in patients who received monoclonal antibodies, alone or in combination with antivirals.

Not available.

The Study Demands and Resources Scale (SDRS) has shown promise as a valid and reliable measure for measuring students’ specific study demands and -resources. However, there is no evidence as to its psychometric properties outside of the original context in which it was developed. This study aimed to assess the psychometric properties of the SDRS in a cross-national student population through examining its longitudinal factorial validity, internal consistency, and temporal invariance as well as criterion validity through its association with study engagement and task performance over time. Results showed that a Bifactor Exploratory Structural Equation Model (ESEM) with one general factor (overall study characteristics) and five specific factors (workload, growth opportunities, lecturer support, peer support, information availability) fitted the data, showed strong measurement invariance over time, and was reliable at different time points. The study further established criterion validity for the overall study characteristics factor through its concurrent and predictive associations with study engagement and task performance. However, the specific factors’ concurrent and predictive capacity could only partially be established when controlling for the general study characteristics factor. These findings suggest that study characteristics should be measured as a dynamic interaction between study demands and resources, rather than a hierarchical model.

Summary: Background: The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced. Methods: The EPICOVIDEHA registry (National Clinical Trials Identifier, NCT04733729) gathers COVID-19 data from hematological malignancy patients since the pandemic's start worldwide. It spans various global locations, allowing comprehensive analysis over the first three years (2020–2022). Findings: The EPICOVIDEHA registry collected data from January 2020 to December 2022, involving 8767 COVID-19 cases in hematological malignancy patients from 152 centers across 41 countries, with 42% being female. Over this period, there was a significant reduction in critical infections and an overall decrease in mortality from 29% to 4%. However, hospitalization, particularly in the ICU, remained associated with higher mortality rates. Factors contributing to increased mortality included age, multiple comorbidities, active malignancy at COVID-19 onset, pulmonary symptoms, and hospitalization. On the positive side, vaccination with one to two doses or three or more doses, as well as encountering COVID-19 in 2022, were associated with improved survival. Interpretation: Patients with hematological malignancies still face elevated risks, despite reductions in critical infections and overall mortality rates over time. Hospitalization, especially in ICUs, remains a significant concern. The study underscores the importance of vaccination and the timing of COVID-19 exposure in 2022 for enhanced survival in this patient group. Ongoing monitoring and targeted interventions are essential to support this vulnerable population, emphasizing the critical role of timely diagnosis and prompt treatment in preventing severe COVID-19 cases. Funding: Not applicable.

Abstract Automated and non-invasive mammalian cell analysis is currently lagging behind due to a lack of methods suitable for a variety of cell lines and applications. Here, we report the development of a high throughput non-invasive method for tracking mammalian cell growth and performance based on plate reader measurements. We show the method to be suitable for both suspension and adhesion cell lines, and we demonstrate it can be adopted when cells are grown under different environmental conditions. We establish that the method is suitable to inform on effective drug treatments to be used depending on the cell line considered, and that it can support characterisation of engineered mammalian cells over time. This work provides the scientific community with an innovative approach to mammalian cell screening, also contributing to the current efforts towards high throughput and automated mammalian cell engineering.

Objectives: Elderly patients with hematologic malignancies face the highest risk of severe COVID-19 outcomes. The infection's impact on different age groups remains unstudied in detail. Methods: We analyzed elderly patients (age groups: 65-70, 71-75, 76-80, and >80 years old) with hematologic malignancies included in the EPICOVIDEHA registry between January 2020 and July 2022. Univariable and multivariable Cox regression models were conducted to identify factors influencing death in COVID-19 patients with hematological malignancy. Results: The study included data from 3,603 elderly patients (aged 65 or older) with hematological malignancy, with a majority being male (58.1%) and a significant proportion having comorbidities. The patients were divided into four age groups, and the analysis assessed COVID-19 outcomes, vaccination status, and other variables in relation to age and pandemic waves. The 90-day survival rate for patients with COVID-19 was 71.2%, with significant differences between groups. The pandemic waves had varying impacts, with the first wave affecting patients over 80 years old, the second being more severe in 65-70, and the third being the least severe in all age groups. Factors contributing to 90-day mortality included age, comorbidities, lymphopenia, active malignancy, acute leukemia, less than three vaccine doses, severe COVID-19, and using only corticosteroids as treatment. Conclusion: These data underscore the heterogeneity of elderly hematological patients, highlight the different impacts of COVID-19 waves and the pivotal importance of vaccination, and may help in planning future healthcare efforts.

The loss of one of the two copies of the 9 bp tandem repeat sequence (CCCCCTCTA) located in the small non-coding region between the cytochrome oxidase II (COII) and the lysine tRNA genes in human mtDNA has been reported to be polymorphic in Asian, Oceanian and Sub-Saharan African populations, but it has rarely been observed in Europe. In this study, we will evaluate the possible association between the MIC9D polymorphism and cognitive disorders. A genetic analysis of unrelated Sicilian patients with cognitive deficits was performed to identify the 9 bp deletion MIC9D polymorphism. The MIC9D polymorphism was found in six patients, whereas this variant was absent in control individuals without cognitive deficits. The patients with the MIC9D polymorphism exhibited more complex clinical presentations; in particular, all had neuromuscular disorders and five also presented with behavioral disorders. The present study suggests a potential association between the MIC9D polymorphism and cognitive impairment with concurrent neuromuscular and behavioral involvement.

The benefits deriving from the coexistence of energy production from a photovoltaic plant and crops growth on the same land have been investigated in Enel Green Power photovoltaic plant of Totana, in the semi-arid region of Murcia, in Spain. In this area, scarcity of water resources and high temperatures can have a major impact on production and agrivoltaic can be relevant for the potential benefits of shading on crops. Pepper “Bola”, aloe vera and thyme have been selected for their economic importance and adaptation to the conditions of the area. The results reported are related to the testing areas in the corridors between two modules rows and to the control area. For pepper, an increase of more than 60% in the agricultural yield and in fresh mean weight and of more than 30% for the fruits number have been observed in the corridors, with respect to the control area. For aloe and thyme in the corridor zone a higher plant biomass (more than 30% and 20%, respectively) has been recorded, compared to the control area. An increase of 11% in weight of the fresh biomass has also been detected for thyme in the corridor after about one year from the implementation. The results obtained in the first year have shown that the intermittent shade and microclimate generated by the photovoltaic panels in the corridor area could benefit pepper, aloe vera and thyme cultivation. These trials will continue in next crop cycles, to confirm the preliminary results.

The EHA-IDWP developed an observational registry collecting data on COVID-19 infection in patients who received CAR T-cell therapy. Prevalence of COVID-19 was 4.8%, and overall mortality was 50%, highlighting the need for prevention of infection in these patients.

Abstract Background in COVID-19 acute respiratory failure, the effects of CPAP and FiO2 on respiratory effort and lung stress are unclear. We hypothesize that, in the compliant lungs of early Sars-CoV-2 pneumonia, the application of positive pressure through Helmet-CPAP may not decrease respiratory effort, and rather worsen lung stress and oxygenation when compared to higher FiO2 delivered via oxygen masks. Methods In this single-center (S.Luigi Gonzaga University-Hospital, Turin, Italy), randomized, crossover study, we included patients receiving Helmet-CPAP for early (

The Channichthyidae, a monophyletic fish group belonging to the suborder Notothenioidei, are uniquely adapted to the polar environment. However, while their physiology has been extensively studied, studies on their ecology are relatively rare. Here, we investigated the trophic ecology of seven icefish species (Chaenodraco wilsoni, Chionobathyscus dewitti, Chionodraco hamatus, Dacodraco hunteri, Neopagetopis ionah, Pagetodes antarcticus and Pagetopsis macropterus) by using the traditional morphometric approach to assess the relationship between form and feeding function. The suction index (SI), the mechanical advantage in jaw closing (MA) and nine morphological traits related to feeding structures have been analysed. Icefish species are characterised by non-protractible, elongate jaws and a wide gape; such morphological features influence the low values of both MA and SI, supporting their ram-feeding habit. The ecomorphological differences among species resulted mainly determined by the anatomical structures related to SI. Such differences do not seem to be determined primarily by the type of prey, as is the case in other taxonomic groups of Notothenioidei, but rather by phylogenetic proximity. A 3D animation was developed to visualise the different feeding modes of two icefish species (C. hamatus and P. macropterus) which are characterised by different approaches to prey.

Abstract Resource competition can be the cause of unintended coupling between co-expressed genetic constructs. Here we report the quantification of the resource load imposed by different mammalian genetic components and identify construct designs with increased performance and reduced resource footprint. We use these to generate improved synthetic circuits and optimise the co-expression of transfected cassettes, shedding light on how this can be useful for bioproduction and biotherapeutic applications. This work provides the scientific community with a framework to consider resource demand when designing mammalian constructs to achieve robust and optimised gene expression.

PurposeSavouring interventions aim to amplify the intensity and duration of positive feelings and positive affect. Research has shown that the potential benefits of savouring include the promotion of psychological well-being and diminution of negative affective states. Savouring strategies may be particularly useful amongst clinical populations in changing biobehavioural processes which can strengthen an individual's propensity to exert control over how to develop, intensify and promote psychological well-being, while simultaneously mitigating negative affective states. This paper outlines a protocol for a systematic review that will be used to identify, critically appraise and synthesise findings of studies examining the effectiveness of savouring interventions in adult clinical populations. Savouring interventions will be defined broadly, operationalised as any savouring strategy focusing on past, present or future events or experiences whereby participants are instructed to attend to and amplify positive affect relating to same. The goal of our review is to include the extent of the literature on this topic and contribute to the overall evidence to support savouring interventions.MethodsThis protocol is carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Protocols Guidelines. The protocol has been registered with PROSPERO (CRD42023404857). The databases PsycINFO, PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and Scopus will be searched alongside a search of grey literature. An examination of the first 200 papers on Google Scholar will also be done to identify relevant papers. Studies describing randomised controlled trials evaluating the effects of savouring interventions as described within this article on adult clinical populations will be included in the review. Outcomes will include well-being, quality of life, depression, anxiety or stress. Study selection and data extraction will be completed by three independent reviewers to reduce risk of bias. Interrater percentage agreement and interrater reliability will be reported on same. The quality of studies will be assessed using criteria based on the Cochrane Collaboration's tool for assessing risk of bias and the Jadad scale. A narrative synthesis with tables of study characteristics will be provided. Separate considerations of the three time perspectives of savouring interventions (past-focused, present-focused, and future-focused) will also be described.ConclusionsThis systematic review will provide important clinical insights into the potential efficacy of savouring interventions when working with adult clinical samples.

BackgroundPoor employee mental health and wellbeing are highly prevalent and costly. Time-related factors such as work intensification and perceptions of time poverty or pressure pose risks to employee health and wellbeing. While reviews suggest that there are positive associations between time management behavior and wellbeing, there is limited rigorous and systematic research examining the effectiveness of time management interventions on wellbeing in the workplace. A thorough review is needed to synthesize time management interventions and their effectiveness to promote employee mental health and wellbeing.MethodA systematic search will be conducted using the following databases: PsychINFO via OVID (1806-Present), Web of Science, Scopus via Elsevier (1976-Present), Academic Search Complete (EBSCO), Cochrane Library via Wiley (1992-Present), and MEDLINE via OVID (1946-Present). The review will include experimental and quasi-experimental studies that evaluate the effects of time management interventions on wellbeing outcomes on healthy adults in a workplace context. Only studies in English will be included. Two authors will independently perform the literature search, record screening, data extraction, and quality assessment of each study included in the systematic review and meta-analysis. Data will be critically appraised using the Cochrane risk-of-bias tools. Depending on the data, a meta-analysis or a narrative synthesis will be conducted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed in the development of this protocol. The protocol has been registered in PROSPERO (CRD4202125715).DiscussionThis review will provide systematic evidence on the effects of time management interventions on wellbeing outcomes in the workplace. It will contribute to our understanding of how time management approaches may help to address growing concerns for employee mental health and wellbeing.

IntroductionSand flies (Diptera: Phlebotominae) belonging to the Lutzomyia genus transmit Leishmania infantum parasites. To understand the complex interaction between the vector and the parasite, we have been investigating the sand fly immune responses during the Leishmania infection. Our previous studies showed that genes involved in the IMD, Toll, and Jak-STAT immunity pathways are regulated upon Leishmania and bacterial challenges. Nevertheless, the parasite can thrive in the vectors’ gut, indicating the existence of mechanisms capable of modulating the vector defenses, as was already seen in mammalian Leishmania infections.Methods, results, and discussionIn this study, we investigated the expression of Lutzomyia longipalpis genes involved in regulating the Toll pathway under parasitic infection. Leishmania infantum infection upregulated the expression of two L. longipalpis genes coding for the putative repressors cactus and protein tyrosine phosphatase SHP. These findings suggest that the parasite can modulate the vectors’ immune response. In mammalian infections, the Leishmania surface glycoprotein GP63 is one of the inducers of host immune depression, and one of the known effectors is SHP. In L. longipalpis we found a similar effect: a genetically modified strain of Leishmania amazonensis over-expressing the metalloprotease GP63 induced a higher expression of the sand fly SHP indicating that the L. longipalpis SHP and parasite GP63 increased expressions are connected. Immuno-stained microscopy of L. longipalpis LL5 embryonic cells cultured with Leishmania strains or parasite conditioned medium showed cells internalization of parasite GP63. A similar internalization of GP63 was observed in the sand fly gut tissue after feeding on parasites, parasite exosomes, or parasite conditioned medium, indicating that GP63 can travel through cells in vitro or in vivo. When the sand fly SHP gene was silenced by RNAi and females infected by L. infantum, parasite loads decreased in the early phase of infection as expected, although no significant differences were seen in late infections of the stomodeal valve.ConclusionsOur findings show the possible role of a pathway repressor involved in regulating the L. longipalpis immune response during Leishmania infections inside the insect. In addition, they point out a conserved immunosuppressive effect of GP63 between mammals and sand flies in the early stage of parasite infection.

The effects of the co-location of energy production from a photovoltaic (PV) plant and aromatic crops (thyme, oregano, and Greek mountain tea) in a hot and dry environment have been investigated in Enel Green Power PV plant located in Kourtesi (Greece). The study was aimed at evaluating the influence of the PV plant on microclimate, on soil temperature and water potential, and on the crops’ growth in a testing area (the corridors between two modules rows) compared to a full sunlight control area. The net radiation and of the wind speed recorded in the testing area showed a 44% and 38% reduction respectively, compared to the control area, while air temperature and relative humidity did not show any difference. Among crop/soil monitored parameters, cumulative reference evapotranspiration (ET0) and the average soil temperature were found 29% and 8% lower in the testing area, conversely the soil water potential (SWP) was 34% higher compared to control area. No significant differences in the plant growth have been detected between testing and control areas, except for oregano whose weight was higher in testing area. The results suggest that in hot and dry climatic conditions, the reduction of climatic stress could compensate the decrease of photosynthesis due to the shading effect of the PV modules, thus not damaging crops’ growth.

Recurrent gene fusions (GFs) in translocated sarcomas are recognized as major oncogenic drivers of the disease, as well as diagnostic markers whose identification is necessary for differential diagnosis. EWSR1 is a ‘promiscuous’ gene that can fuse with many different partner genes, defining different entities among a broad range of mesenchymal neoplasms. Molecular testing of EWSR1 translocation traditionally relies on FISH assays with break-apart probes, which are unable to identify the fusion partner. Therefore, other ancillary molecular diagnostic modalities are being increasingly adopted for accurate classification of these neoplasms. Herein, we report three cases with rare GFs involving EWSR1 in undifferentiated mesenchymal neoplasms with uncertain differential diagnoses, using targeted RNA-seq and confirming with RT-PCR and Sanger sequencing. Two GFs involved hormone nuclear receptors as 3′ partners, NR4A2 and RORB, which have not been previously reported. NR4A2 may functionally replace NR4A3, the usual 3′ partner in extraskeletal myxoid chondrosarcoma. The third GF, EWSR1::BEND2, has previously been reported in a subtype of astroblastoma and other rare entities, including a single case of a soft-tissue tumor that we discuss in this work. In conclusion, our findings indicate that the catalogue of mesenchymal neoplasm-bearing EWSR1 fusions continues to grow, underscoring the value of using molecular ancillary techniques with higher diagnostic abilities in the routine clinical setting.

Engineering living cells for production of chemicals, enzymes and therapeutics can burden cells due to use of limited native co-factor availability and/or expression burdens, totalling a fitness deficit compared to parental cells encoded through long evolutionary trajectories to maximise fitness. Ultimately, this discrepancy puts a selective pressure against fitness-burdened engineered cells under prolonged bioprocesses, and potentially leads to complete eradication of high-performing engineered cells at the population level. Here we present the mutation landscapes of fitness-burdened yeast cells engineered for vanillin-β-glucoside production. Next, we design synthetic control circuits based on transcriptome analysis and biosensors responsive to vanillin-β-glucoside pathway intermediates in order to stabilize vanillin-β-glucoside production over ~55 generations in sequential passage experiments. Furthermore, using biosensors with two different modes of action we identify control circuits linking vanillin-β-glucoside pathway flux to various essential cellular functions, and demonstrate control circuits robustness and almost 2-fold higher vanillin-β-glucoside production, including 5-fold increase in total vanillin-β-glucoside pathway metabolite accumulation, in a fed-batch fermentation compared to vanillin-β-glucoside producing cells without control circuits.

Small-molecule binding allosteric transcription factors (aTFs) derived from bacteria enable real-time monitoring of metabolite abundances, high-throughput screening of genetic designs, and dynamic control of metabolism. Yet, engineering of reporter promoter designs of prokaryotic aTF biosensors in eukaryotic cells is complex. Here we investigate the impact of aTF binding site positions at single-nucleotide resolution in >300 reporter promoter designs in Saccharomyces cerevisiae. From this we identify biosensor output landscapes with transient and distinct aTF binding site position effects for aTF repressors and activators, respectively. Next, we present positions for tunable reporter promoter outputs enabling metabolite-responsive designs for a total of four repressor-type and three activator-type aTF biosensors with dynamic output ranges up to 8- and 26-fold, respectively. This study highlights aTF binding site positions in reporter promoters as key for successful biosensor engineering and that repressor-type aTF biosensors allows for more flexibility in terms of choice of binding site positioning compared to activator-type aTF biosensors.

La Seconda guerra mondiale rappresenta un evento cruciale nella storia dell’umanità e, in particolar modo, del nostro continente. La vittoria degli Alleati non solo sancisce la fine del nazifascismo, ma inaugura un lungo periodo di pace in Europa Occidentale e crea i presupposti per il processo di integrazione, che prenderà forma coi trattati di Parigi e Roma del 1951 e del 1957. L’assalto alla “Festung Europa” comincia con lo Sbarco in Sicilia: è per questo che la creazione di un itinerario turistico-culturale nella parte orientale dell’isola ha un valore anche ideologico. Non sarebbe solamente un’opera di valorizzazione di un territorio che già ha una forte vocazione turistica, ma avrebbe altresì un profondo significato etico ed educativo in un’epoca in cui i valori della nostra civiltà occidentale sembrano sgretolarsi, schiacciati tra le tendenze sovraniste e la globalizzazione. World War II represents a crucial event in the history of humanity and, in particular, of our Continent. The victory of the Allies does not determine only the end of Nazi-fascism, but inaugurates a long period of peace in Western Europe and creates the conditions for the integration process, which will take shape with the treaties of Paris and Rome of 1951 and 1957. The assault at “Festung Europa” begins with the invasion of Sicily: this is why the creation of a tourist and cultural route in the eastern part of the island has a high ideological value too. It would not only be a work of enhancement of a territory that already has a strong tourist vocation, but would also have a profound ethical and educational significance in an era in which the values of our western civilization seem to crumble, crushed between sovereignist tendencies and globalization.

Abstract Background CAR-T cell (chimeric antigen receptor T) therapy has emerged as an effective treatment of refractory hematological malignancies. Intensive care management is intrinsic to CAR-T cell therapy. We aim to describe and to assess outcomes in critically ill CAR-T cell recipients. Study design and methods Hospital-wide retrospective study. Consecutive CAR-T cell recipients requiring ICU admission from July 2017 and December 2020 were included. Results 71 patients (median age 60 years [37–68]) were admitted to the ICU 6 days [4–7] after CAR-T cell infusion. Underlying malignancies included diffuse large B cell lymphoma (n = 53, 75%), acute lymphoblastic leukemia (17 patients, 24%) and multiple myeloma (n = 1, 1.45%). Performance status (PS) was 1 [1–2]. Shock was the main reason for ICU admission (n = 40, 48%). Isolated cytokine release syndrome (CRS) was the most common complication (n = 33, 46%), while 21 patients (30%) had microbiologically documented bacterial infection (chiefly catheter-related infection). Immune effector cell-associated neurotoxicity syndrome was reported in 26 (37%) patients. At ICU admission, vasopressors were required in 18 patients (25%) and invasive mechanical ventilation in two. Overall, 49 (69%) and 40 patients (56%) received tocilizumab or steroids, respectively. Determinant of mortality were the reason for ICU admission (disease progression vs. sepsis or CRS (HR 4.02 [95%CI 1.10–14.65]), Performance status (HR 1.97/point [95%CI 1.14–3.41]) and SOFA score (HR 1.16/point [95%CI 1.01–1.33]). Conclusions Meaningful survival could be achieved in up to half the CAR-T cell recipients. The severity of organ dysfunction is a major determinant of death, especially in patients with altered performance status or disease progression.

This paper presents a code-to-code verification of the SPERT-III reactor in its E-core configuration using the Monte Carlo codes TRIPOLI-4®, TRIPOLI-5® and OpenMC. A SPERT-III E-core model was originally developed for the Monte Carlo code TRIPOLI-4® and will be the baseline of our analysis The simulation results obtained for the main reactor physics parameters (neutron effective multiplication factor, rod worth, reactivity coefficients and kinetics parameters) with TRIPOLI-4®and OpenMC using different nuclear data libraries are compared and analyzed. Additional verifications are carried out with the next-generation Monte Carlo code TRIPOLI-5®, which is currently under development by CEA and IRSN (France). This paper summarizes a joint study that was conducted within an international research collaboration between CEA Paris-Saclay (France) and the Nuclear Research Center Negev (NRCN, Israel), and is a stepping stone towards future multi-physics simulations exploring the SPERT-III reactor power excursions, including thermal-hydraulics feedback.

Parkinson’s disease (PD) is a multisystem and multifactorial disorder and, therefore, the application of modern genetic techniques may assist in unraveling its complex pathophysiology. We conducted a clinical–demographic evaluation of 126 patients with PD, all of whom were Caucasian and of Sicilian ancestry. DNA was extracted from the peripheral blood for each patient, followed by sequencing using a Next-Generation Sequencing system. This system was based on a custom gene panel comprising 162 genes. The sample underwent further filtering, taking into account the allele frequencies of genetic variants, their presence in the Human Gene Mutation Database, and their association in the literature with PD or other movement/neurodegenerative disorders. The largest number of variants was identified in the leucine-rich repeat kinase 2 (LRRK2) gene. However, variants in other genes, such as acid beta-glucosidase (GBA), DNA polymerase gamma catalytic subunit (POLG), and parkin RBR E3 ubiquitin protein ligase (PRKN), were also discovered. Interestingly, some of these variants had not been previously associated with PD. Enhancing our understanding of the genetic basis of PD and identifying new variants possibly linked to the disease will contribute to improved diagnostic accuracy, therapeutic developments, and prognostic insights for affected individuals.

The COVID-19 pandemic, a period of uncertainty and risk, has presented a threat to people’s physical and mental health worldwide. Previous research has shown that pandemic-related uncertainty can contribute to individuals’ psychological distress and coping responses. Therefore, the aim of this study was to investigate the relationship between intolerance of uncertainty and risk perception (i.e., individual’s perceived likelihood of becoming infected both for themselves and people in one’s own country and perceived severity of the infection), and the mediating role of fear of COVID-19. This two-wave longitudinal study (T1 = April 2020; T2 = May 2020) involved 486 young adults (age range = 18–29 years; Mage = 23.84 ± 2.94). Participants provided demographic data as well as measures of intolerance of uncertainty, fear of COVID-19, and risk perception. Structural equation modeling showed that intolerance of uncertainty was indirectly related to risk perception through fear of COVID-19. The study confirms the central role of IU in fear management and, consequently, in determining individuals’ risk estimates.

Summary: Background: Nirmatrelvir/ritonavir treatment decreases the hospitalisation rate in immunocompetent patients with COVID-19, but data on efficacy in patients with haematological malignancy are scarce. Here, we describe the outcome of nirmatrelvir/ritonavir treatment in a large cohort of the latter patients. Methods: This is a retrospective cohort study from the multicentre EPICOVIDEHA registry (NCT04733729) on patients with haematological malignancy, who were diagnosed with COVID-19 between January and September 2022. Patients receiving nirmatrelvir/ritonavir were compared to those who did not. A logistic regression was run to determine factors associated with nirmatrelvir/ritonavir administration in our sample. Mortality between treatment groups was assessed with Kaplan–Meier survival plots after matching all the patients with a propensity score. Additionally, a Cox regression was modelled to detect factors associated with mortality in patients receiving nirmatrelvir/ritonavir. Findings: A total of 1859 patients were analysed, 117 (6%) were treated with nirmatrelvir/ritonavir, 1742 (94%) were treated otherwise. Of 117 patients receiving nirmatrelvir/ritonavir, 80% had received ≥1 anti-SARS-CoV-2 vaccine dose before COVID-19 onset, 13% of which received a 2nd vaccine booster. 5% were admitted to ICU. Nirmatrelvir/ritonavir treatment was associated with the presence of extrapulmonary symptoms at COVID-19 onset, for example anosmia, fever, rhinitis, or sinusitis (aOR 2.509, 95%CI 1.448–4.347) and 2nd vaccine booster (aOR 3.624, 95%CI 1.619–8.109). Chronic pulmonary disease (aOR 0.261, 95%CI 0.093–0.732) and obesity (aOR 0.105, 95%CI 0.014–0.776) were not associated with nirmatrelvir/ritonavir use. After propensity score matching, day-30 mortality rate in patients treated with nirmatrelvir/ritonavir was 2%, significantly lower than in patients with SARS-CoV-2 directed treatment other than nirmatrelvir/ritonavir (11%, p = 0.036). No factor was observed explaining the mortality difference in patients after nirmatrelvir/ritonavir administration. Interpretation: Haematological malignancy patients were more likely to receive nirmatrelvir/ritonavir when reporting extrapulmonary symptoms or 2nd vaccine booster at COVID-19 onset, as opposed to chronic pulmonary disease and obesity. The mortality rate in patients treated with nirmatrelvir/ritonavir was lower than in patients with targeted drugs other than nirmatrelvir/ritonavir. Funding: EPICOVIDEHA has received funds from Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223).

The loss of one of the two copies of the 9 bp tandem repeat sequence (CCCCCTCTA) located in the small non-coding region between the cytochrome oxidase II (COII) and the lysine tRNA genes in human mtDNA has been reported to be polymorphic in Asian, Oceanian and Sub-Saharan African populations, but it has rarely been observed in Europe. In this study, we will evaluate the possible association between the MIC9D polymorphism and cognitive disorders. A genetic analysis of unrelated Sicilian patients with cognitive deficits was performed to identify the 9 bp deletion MIC9D polymorphism. The MIC9D polymorphism was found in six patients, whereas this variant was absent in control individuals without cognitive deficits. The patients with the MIC9D polymorphism exhibited more complex clinical presentations; in particular, all had neuromuscular disorders and five also presented with behavioral disorders. The present study suggests a potential association between the MIC9D polymorphism and cognitive impairment with concurrent neuromuscular and behavioral involvement. [ABSTRACT FROM AUTHOR]