Immunotherapy: ALLOGENEIC UMBILICAL CORD BLOOD REGULATORY T CELLS DECREASE INFLAMMATION AND PRESERVE ANTI-TUMOR ACTIVITY OF CAR T CELLS

Background & Aim: With larger accessibility and increased number of patients being treated with CART cell therapy, real-world toxicity continues to remain a significant challenge to its widespread adoption. We have previously shown that allogeneic umbilical cord blood derived (UCB) regulatory T cells (Tregs) can resolve uncontrolled inflammation and can treat acute and immune mediated lung injury in a xenogenic model as well as in patients suffering from COVID-19 acute respiratory distress syndrome. The unique properties of UCB Tregs including: i) lack of plasticity when exposed to inflammatory micro-environments;ii) no requirement for HLA matching;iii) long shelf life of cryopreserved Tregs;and iv) immediate product availability for on demand treatment, makes them an attractive source for treating acute inflammatory syndromes. Therefore, we hypothesized that add-on therapy with UCB derived Tregs may resolve uncontrolled inflammation responsible for CART cell therapy associated toxicity. Methods, Results & Conclusion(s): UCB Tregs were added in 1:1 ratio to CART cells, where no interference in their ability to kill CD19+ Raji cells, was detected at different ratios : 8:1 (80.4% vs. 81.5%);4:1 (62.0% vs. 66.2%);2:1 (50.1% vs. 54.7%);1:1 (35.4% vs. 44.1%) (Fig 1A). In a xenogenic B cell lymphoma model, multiple injections of Tregs were administered after CART injection (Fig 1B), which did not impact distribution of CD8+ T effector cells (Fig 1C) or CART cells cells (Fig 1D) in different organs. No decline in the CAR T levels was observed in the Tregs recipients (Fig 1E). Specifically, no difference in tumor burden was detected between the two arms (Fig 2A). No tumor was detected in CART+Tregs in liver (Fig 2B) or bone marrow (Fig 2C). A corresponding decrease in multiple inflammatory cytokines in peripheral blood was observed in CART+Tregs when compared to CART alone (Fig 2D). Here we show "proof of concept" for add-on therapy with Tregs to mitigate hyper-inflammatory state induced by CART cells without interference in their on-target anti-tumor activity. The timing of Tregs administration after CART cells have had sufficient time for forming synapse with tumor cells allows for preservation of their anti-tumor cytotoxicity, such that the infused Tregs home to the areas of tissue damage to bind to the resident antigen presenting cells which in turn collaborate with Tregs to resolve inflammation. Such differential distribution of cells allow for a Treg "cooling blanket" and lays ground for clinical study. [Figure presented]Copyright © 2023 International Society for Cell & Gene Therapy

Breaking the exascale barrier for the electronic structure problem in ab-initio molecular dynamics

The non-orthogonal local submatrix method applied to electronic structure–based molecular dynamics simulations is shown to exceed 1.1 EFLOP/s in FP16/FP32-mixed floating-point arithmetic when using 4400 NVIDIA A100 GPUs of the Perlmutter system. This is enabled by a modification of the original method that pushes the sustained fraction of the peak performance to about 80%. Example calculations are performed for SARS-CoV-2 spike proteins with up to 83 million atoms. [ FROM AUTHOR] Copyright of International Journal of High Performance Computing Applications is the property of Sage Publications, Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Assessing perceptions of pedestrian-focused intervention in a car-dependent European island

Apart from the numerous social, economic, and environmental impacts of car dependence, the time people spend sitting in motorised vehicles has been identified as a sedentary behaviour that can negatively impact people's physical and psychological health. The climate breakdown and the COVID-19 pandemic have continued to expose the fragility and vulnerability of the urban environment and the imminent need for response, management, and radical re-thinking through innovation, especially within the transport sector. The incidence of the COVID-19 pandemic has also reiterated the need for urban centres to re-establish a sense of community, extend the benefits reaped from reduced motorised transport usage and boost small/medium-size businesses through the provision of active travel spaces. This paper investigates the role of pedestrian-focused intervention to encourage walking rather than car use for short-distance trips, within the context of the car-dependent small island state of Malta. The research includes the use of semi-structured interviews with a broad range of stakeholders to develop a virtual platform for citizen participation. The platform is an interactive space for participants to identify barriers that discourage walking and explore and evaluate options that encourage walking as a mode of transport. A discussion of preliminary findings sheds light on the impact of pedestrian interventions that encourage active travel and contribute policy-relevant outcomes based on the perceptions and direct feedback from citizens and stakeholders alike. © 2023 The Authors. Published by ELSEVIER B.V.

Covid-19 disruption, resilience and industrial policy: the automotive sector in the West Midlands

The Covid-19 pandemic and Brexit have focused attention on the resilience of key sectors and firms. This paper explores the financial resilience of the 50 largest automotive firms in the West Midlands region of the UK in their response to disruption and economic shocks. The findings demonstrate that 22 firms are at high risk due to poor current liquidity ratios, with Coventry and Birmingham emerging as locations most susceptible to firm closures. High-risk firms include key flagship original equipment manufacturers operating at the downstream end of supply chains. If these firms were to fail, there would be a significant destructive impact on both the industry and the local economy. We assert an effective subnational industrial policy is required in order to support economic resilience in regions such as the West Midlands where a few firms account for a disproportionate share of employment and value-added.

Trip generation models for Tikrit city

Urban transportation planning has become a matter of urgency in small cities and, in particular, the need to develop planning models for Tikrit city has become pressing. Questionnaire forms and household interviews were used among families in the city, with 22% asked to complete a full interview, 68% offered paper questionnaires to be retrieved on completion, and the rest contacted electronically due to the restrictions of the COVID-19 pandemic. The data from the 4,150 questionnaires collected showed that the characteristics of the community are compatible with those found in other studies and official statistics, with the community of Tikrit being youthful society, with an average of 88.3% of residents not exceeding 60 years of age. After statistical checks were performed on the obtained data, trip generation models were developed using various methods of cross-classification to match vehicle ownership with both income and family size. Using the developed models, the total number of trips by purpose across four sectors were extracted. A comparison of the results across models showed significant difference between the methods, suggesting that the family size variable should be adopted for such modelling as an easily obtainable and relevant variable. © 2023 AIP Publishing LLC.

ANALYSIS OF THE EFFECT OF MACROPRUDENTIAL AND MACROPRUDENTIAL INDICATORS ON THE STOCK PRICE INDEX OF ISLAMIC BANKS IN INDONESIA USING THE ERROR CORRECTION MODEL

The experience of various crises that have occurred, including the impact of the Covid-19 pandemic, presents a challenge to implement macroprudential policies to ensure the financial system survives and continues to carry out its function in driving the economy. The existing macroprudential policies tend to be individual and focus on prudent banking and other financial institutions. Economic fluctuations that occur on the macro side will greatly impact, either directly or indirectly, the stock price index, as well as the company's internal indicators which are considered to have a major influence on the decisions of investors and potential investors to take action on the stock exchange. The type of research used in this research is quantitative research. The nature of this research is descriptive with a quantitative approach. The data collection technique in this research is Literature Study. The test carried out in this study is the multiple linear regression analysis test (multiple linear regression method), this study uses the ECM model to obtain the best model which includes the classical assumption test. The results of this study based on the partial short-term relationship test, it can be concluded that the Exchange Rate, Inflation, and TPF in the short term have no significant effect on the PNBS Stock Price Index. Meanwhile, short-term CAR has a significant positive effect on the PNBS Stock Price Index. Based on the results of the partial long-term relationship test, it can be concluded that in the long term, the Exchange Rate has a significant negative effect and TPF and CAR have a significant positive effect on the PNBS Stock Price Index while Inflation has no significant effect on the PNBS Stock Price Index. Based on the output results of the simultaneous short-term and long-term F test, it shows that all independent variables simultaneously have a significant effect on the PNBS Stock Price Index in the short term. Based on the provisions of the MUI DSN through the issued fatwas related to the Sharia capital market and Sharia shares, it is explained that Sharia stock investment to invest according to the perspective of Sharia economic law is allowed. [ FROM AUTHOR] Copyright of Jurnal Syntax Admiration is the property of Ridwan Institute and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Shocks, resilience and regional industry policy: Brexit and the automotive sector in two Midlands regions

This article draws upon novel survey evidence to examine the possible regional impacts of Brexit as a ‘disruptive process' to manufacturing operations and logistics in the automotive industry, in the context of the regional resilience literature. The current Brexit (and Covid-19) context, along with the sector's need to re-orientate towards electrification, provides renewed urgency to reconsider industrial policy in spatial terms. The findings have salience not only in the context of anticipating and reacting to Brexit-induced economic shocks at a regional level, but also over the role of decentralized regional bodies. In this regard, the UK government's agenda of ‘levelling up' will be challenging, especially in the context of the place-based shocks likely to arise from Brexit as well as the impact of Covid-19. The article concludes that a more place-based regional industrial policy is required both to anticipate and to respond to shocks and also to reposition the sector in the region going forward.

Immune Reconstitution and Vaccinations in Multiple Myeloma: A Report From the 19th International Myeloma Society Annual Workshop.

Given the significance of the immune system and the important role of therapies within the context of the immune system in plasma cell disorders, the International Myeloma Society annual workshop convened a session dedicated to this topic. A panel of experts covered various aspects of immune reconstitution and vaccination. The top oral presentations were highlighted and discussed. This is a report of the proceedings.

Respiratory Viral Infections in Recipients of Cellular Therapies: A Review of Incidence, Outcomes, Treatment, and Prevention.

Respiratory viral infections (RVIs) are of major clinical importance in immunocompromised patients and represent a substantial cause of morbidity and mortality in patients with hematologic malignancies and those who have undergone hematopoietic cell transplantation. Similarly, patients receiving immunotherapy with CD19-targeted chimeric antigen receptor-modified T cells, natural killer cells, and genetically modified T-cell receptors are susceptible to RVIs and progression to lower respiratory tract infections. In adoptive cellular therapy recipients, this enhanced susceptibility to RVIs results from previous chemotherapy regimens such as lymphocyte-depleting chemotherapy conditioning regimens, underlying B-cell malignancies, immune-related toxicities, and secondary prolonged, profound hypogammaglobulinemia. The aggregated risk factors for RVIs have both immediate and long-term consequences. This review summarizes the current literature on the pathogenesis, epidemiology, and clinical aspects of RVIs that are unique to recipients of adoptive cellular therapy, the preventive and therapeutic options for common RVIs, and appropriate infection control and preventive strategies.

Modeling the Tumor Microenvironment and Cancer Immunotherapy in Next-Generation Humanized Mice.

Cancer immunotherapy has brought significant clinical benefits to numerous patients with malignant disease. However, only a fraction of patients experiences complete and durable responses to currently available immunotherapies. This highlights the need for more effective immunotherapies, combination treatments and predictive biomarkers. The molecular properties of a tumor, intratumor heterogeneity and the tumor immune microenvironment decisively shape tumor evolution, metastasis and therapy resistance and are therefore key targets for precision cancer medicine. Humanized mice that support the engraftment of patient-derived tumors and recapitulate the human tumor immune microenvironment of patients represent a promising preclinical model to address fundamental questions in precision immuno-oncology and cancer immunotherapy. In this review, we provide an overview of next-generation humanized mouse models suitable for the establishment and study of patient-derived tumors. Furthermore, we discuss the opportunities and challenges of modeling the tumor immune microenvironment and testing a variety of immunotherapeutic approaches using human immune system mouse models.

Investigating changes in longitudinal associations between declining bus ridership, bus service, and neighborhood characteristics

Amid the recent transit ridership decline, gaining an understanding of the factors affecting ridership becomes crucial for transit agencies to utilize limited resources effectively. I use generalized linear multilevel negative binomial models to investigate the longitudinal relationship and changes in the associations between neigh-borhood-level bus ridership and a series of socio-economic and bus service factors in Philadelphia between 2014 and 2018. Data come from passenger boarding at bus stops in Philadelphia. Results show that the associations between bus ridership, population and the number of jobs, and the percent of zero-car households are positive, but weakened over time. The associations between ridership and bus service supply are inelastic. The findings have implications on transit agencies' resource allocation and service adjustments as they recover from the ridership and revenue losses during the COVID-19 pandemic while facing competition from new travel options such as Uber and Lyft.

The power of telemedicine to improve CAR-T cell therapy programs: lessons learned from COVID-19 pandemic.

PURPOSE: CAR-T programs will burden increasingly on healthcare systems, since the implementation of these therapies involves: multidisciplinary team collaboration, post-infusion hospitalization with risk of life-threatening toxicities, frequent in hospital visits and prolonged follow-up which heavily influence patients' quality of life. In this review we propose an innovative, telehealth-based, model for monitoring CAR-T patients: this method was used for managing a case of COVID-19 infection occurred two weeks after CAR-T cell infusion. METHODS: Several benefits for management of all these aspects of CAR-T programs could be made using telemedicine: for example, telemedicine real-time clinical monitoring could reduce the COVID-19 contagion risks for CAR-T patients. RESULTS: Our experience confirmed feasibility and utility of this approach in a real-life case. We believe that use of telemedicine for CAR-T patients could improve: the logistics of toxicity monitoring (frequent vital sign checks and neurologic assessments), the multidisciplinary team communication (patient selection, specialists consulting, coordination with pharmacists, etc.), the decrease in hospitalization time and the reduction of ambulatory visits. CONCLUSIONS: This approach will be fundamental for future CAR-T cell program development, enhancing patients' quality of life and cost-effectiveness for healthcare systems.

Infectious complications following CAR-t cell therapy for B cell non-Hodgkin lymphoma: a single-center experience and review of the literature.

Chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 has significantly improved outcomes in the treatment of refractory or relapsed (R/R) B-cell non-Hodgkin lymphoma (NHL). Several risk factors including CAR-T cell-related toxicities and their treatments often lead to infectious complications (ICs); however, the pattern and timeline is not well established. We evaluated ICs in 48 patients with R/R B-cell NHL following CAR-T cell therapy at our institution. Overall, 15 patients experienced 22 infection events. Eight infections (4 bacterial, 3 viral and 1 fungal) occurred within the first 30 days and 14 infections (7 bacterial, 6 viral, 1 fungal) between days 31 to 180 following CAR-T infusion. Most infections were mild-to-moderate and fifteen infections involved the respiratory tract. Two patients developed mild-to-moderate COVID-19 infection and one patient a cytomegalovirus reactivation after CAR-T infusion. Two patients developed IFIs: one case each of fatal disseminated candidiasis and invasive pulmonary aspergillosis at day 16 and 77, respectively. Patients with more than 4 prior antitumor regimens and patient's ≥ 65 years had a higher infection rate. Infections in patients with relapsed/refractory B-cell NHL are common after CAR-T despite the use of infection prophylaxis. Age ≥ 65 years and having > 4 prior antitumor treatments were identified as risk factors for infection. Fungal infections carried significant impact in morbidity and mortality, suggesting a role for increase fungal surveillance and/or anti-mold prophylaxis following high-dose steroids and tocilizumab. Four of ten patients developed an antibody response following two doses of SARS-CoV-2 mRNA vaccine.

Hunger and prices in Brazil: a spatial analysis of the increase in the price of the basic food basket in times of the covid-19 pandemic

The advent of the Covid-19 pandemic worsened trade relations in Brazil and in the world, causing enormous social, economic and health instabilities. As a country of continental dimensions, the five macro-regions of the country are unique, some more industrialized and others not so much. And through the Global and Local Moran Index, it was possible to map and identify clusters of high and low prices of the basic food basket in the Southeast and Northeast regions, respectively. Using the SAR and CAR models, it was estimated that, with the increase of one thousand of the employed population, there was an increase in the prices of the basic food basket by R$ 0.10. The Covid-19 Pandemic triggered an increase in the prices of the basic food basket in a spatial way, as for every 1000 infected with the SarsCov2 virus in a given state, it was estimated that there was an increase in prices by R$ 1.31 (SAR) and R$ 1.21 ( CAR) in its neighbours, increasing the disheartened population in the country.

The French automotive industry faces the challenge of the ecological transition

[...]the vehicle of the future must be considered within the broader framework of the mobility of the future, taking into account the entire value chain. Transforming our future into a sustainable future: planning for the automotive transition Didier Sepulchre de Condé, Mechanical industry The automotive industry is in turmoil, firstly because of the economic situation, with a market deeply affected by Covid, shortages of materials and components and disoriented customers;and secondly because of the structural situation, with the forced transition to electrification. The four paradoxes of the ecological transition of the European car industry Alois Kirchner, Former Director of Cabinet of the Minister for Industry The energy transition in the automotive sector is essential for achieving French and European climate objectives. [...]the actions implemented come up against four paradoxes, which must be overcome if this transition is to succeed: * the regulation on the reduction of CO2 emissions from the tank to the wheel, to the exclusion of other sources which now represent the majority of emissions from new vehicles;* the steering of vehicle traffic restrictions based on Crit'air stickers, leading to the prohibition of access to certain cities for vehicles that are more virtuous than others that are still allowed to enter;* the inability to implement policies to support the production of vehicles on European soil that are sufficiently powerful to halt the fall in associated jobs;a situation that benefits production sites that are not subject to the same environmental standards;* and the rising price of "green" vehicles, leading to a slowdown in the renewal of the fleet and the maintenance of a high level of pollution and carbon emissions.

Car Ownership and Post-COVID Urban Mobility across European Cities

The COVID-19 pandemic has greatly affected households' mobility habits and choices in the past two years. Scarce evidence is available concerning medium term decisions such as the purchase or sale of a private vehicle. This work aims to explore the factors that have influenced households' decisions to buy or sell a private car due to the pandemic and foresee how these decisions might influence their travel behaviour in the next few years. To achieve this goal, an EU-wide survey gathering information from 21 European cities was carried out during the second term of 2021, when lockdowns were no longer in place, but some mobility and sanitary restrictions were still maintained. The survey focuses on the impact of the pandemic and the consequent mobility restrictions on the transport habits and preferences of the respondents. The questionnaire collected socio-economic characteristics and mobility habits of 10,152 individuals. Interestingly, the analysis of the survey does not provide any evidence of a reduction of motorization rates for teleworkers. On the contrary, both partial and full-time teleworkers have bought significantly more cars than the rest of the groups. These findings greatly contrast with the fact that changes in daily habits resulting from the adoption of teleworking regimes are the main cause of reductions in car use among car buyers. This result suggests that further incentives for car ownership reduction are needed to harness the full potential of teleworking for decreasing car dependency. A positive relation between number of cars owned before COVID and car purchases has been found, pointing out that these purchases are probably not solving accessibility limitations for car-less households. Finally, a positive relation is also observed between car purchases and increased use of shared mobility services. © 2023 The Authors. Published by ELSEVIER B.V.

Assessing perceptions of pedestrian-focused intervention in a car-dependent European island

Apart from the numerous social, economic, and environmental impacts of car dependence, the time people spend sitting in motorised vehicles has been identified as a sedentary behaviour that can negatively impact people's physical and psychological health. The climate breakdown and the COVID-19 pandemic have continued to expose the fragility and vulnerability of the urban environment and the imminent need for response, management, and radical re-thinking through innovation, especially within the transport sector. The incidence of the COVID-19 pandemic has also reiterated the need for urban centres to re-establish a sense of community, extend the benefits reaped from reduced motorised transport usage and boost small/medium-size businesses through the provision of active travel spaces. This paper investigates the role of pedestrian-focused intervention to encourage walking rather than car use for short-distance trips, within the context of the car-dependent small island state of Malta. The research includes the use of semi-structured interviews with a broad range of stakeholders to develop a virtual platform for citizen participation. The platform is an interactive space for participants to identify barriers that discourage walking and explore and evaluate options that encourage walking as a mode of transport. A discussion of preliminary findings sheds light on the impact of pedestrian interventions that encourage active travel and contribute policy-relevant outcomes based on the perceptions and direct feedback from citizens and stakeholders alike. © 2023 The Authors. Published by ELSEVIER B.V.

Machine learning model to predict vehicle electrification impacts on urban air quality and related human health effects.

Air pollution is a prevailing environmental problem in cities worldwide. The future vehicle electrification (VE), which in Europe will be importantly fostered by the ban of thermal engines from 2035, is expected to have an important effect on urban air quality. Machine learning models represent an optimal tool for predicting changes in air pollutants concentrations in the context of future VE. For the city of Valencia (Spain), a XGBoost (eXtreme Gradient Boosting package) model was used in combination with SHAP (SHapley Additive exPlanations) analysis, both to investigate the importance of different factors explaining air pollution concentrations and predicting the effect of different levels of VE. The model was trained with 5 years of data including the COVID-19 lockdown period in 2020, in which mobility was strongly reduced resulting in unprecedent changes in air pollution concentrations. The interannual meteorological variability of 10 years was also considered in the analyses. For a 70% VE, the model predicted: 1) improvements in nitrogen dioxide pollution (-34% to -55% change in annual mean concentrations, for the different air quality stations), 2) a very limited effect on particulate matter concentrations (-1 to -4% change in annual means of PM2.5 and PM10), 3) heterogeneous responses in ground-level ozone concentrations (-2% to +12% change in the annual means of the daily maximum 8-h average concentrations). Even at a high VE increase of 70%, the 2021 World Health Organization Air Quality Guidelines will be exceeded for all pollutants in some stations. VE has a potentially important impact in terms of reducing NO2-associated premature mortality, but complementary strategies for reducing traffic and controlling all different air pollution sources should also be implemented to protect human health.

Investigation of Employee Related Airport Ground Access Strategies from a Post-COVID Perspective

Until recently, addressing the environmental externalities associated with the use of the private car and single occupancy vehicles has been the focus of the airport ground access policies worldwide. However, with the emerging unprecedented challenges of the COVID-19 pandemic, which have already changed the way we live, work, and travel, encouraging a change in commuter behavior has become even more important. This has necessitated that existing strategies be reconsidered in favor of adapting to a highly uncertain ‘‘COVID-19 world.'' Historically, there has been a dearth of literature relating to airport employees' ground access even though as a group employees represent an important segment of airport users with complex access requirements. This paper therefore focuses on airport employee related airport ground access strategies considering an emerging understanding of the future impacts of COVID-19 on global air travel. Pre-COVID strategies are investigated by conducting a documentary analysis of the most recent ground access strategies of 27 UK airports. The findings reveal that airport ground access strategies were mainly focused on setting targets and producing policy measures in favor of reducing car use and increasing the use of more sustainable transport modes including public transport, car sharing, and active travel (walking, cycling). However, measures encouraging public transport and car sharing will be more difficult to implement because of social distancing and fear of proximity to others. Instead, initiatives encouraging remote working, active travel, and improved staff awareness will be at the forefront of the future ground access strategy development. © National Academy of Sciences: Transportation Research Board 2021.

Research on Affective Interaction in Mini Public Transport Based on IPA-FMEA

In the promotion of sustainable modes of transport, especially public transport, reasonable failure risk assessment at the critical moment in the process of service provider touch with users can improve the service quality to a certain extent. This study presents a product service touch point evaluation approach based on the importance–performance analysis (IPA) of user and failure mode and effect analysis (FMEA). Firstly, the authors capture service product service touch points in the process of user interaction with the product by observing the user behavior in a speculative design experiment, and perform the correlation analysis of the service product service touch point. Second, the authors use the IPA analysis method to evaluate and classify the product service touch points and identify the key product service touch points. Thirdly, the authors propose to analyze the failure of key product service touch points based on user-perceived affective interaction and clarify the priority of each key touch point. Finally, reluctant interpersonal communication, as the key failure caused by high risk, is derived according to the evaluation report, which leads to establishing new product service touch points and improving the overall user experience to promote sustainable transports with similar forms and characteristics.