Have the Olympics outgrown cities? A longitudinal comparative analysis of the growth and planning of the Olympics and former host cities

This paper examines the growth of the Olympic Games against that of former host cities to understand whether this mega-event may have ‘outgrown’ its hosts. The increasing hosting requirements and governments’ expansive use of mega-events as tools for urban development would suggest that the ‘Olympic city’ – a term we use for describing the size of the Olympics as hosted in different cities over the decades – has grown at a faster rate than former host cities. The analysis contrasts historical indicators that capture the evolving size of planning for the event based on four dimensions – sport, spectators, marketing and costs – as well as the urban dimension of hosting experiences (venues and infrastructure) with city trajectories based on demographic and economic indicators. This is done through a longitudinal analysis of former Olympic host cities from the 1960s and 1970s and from which continuous longitudinal data are available: Tokyo, Munich, and Montreal. The findings indicate that the Olympic city has grown more strongly than these former host cities, although not uniformly across trajectories. This gives evidence for the need to review the size of mega-event impacts if they ought to continue to generate interest in hosting them in the future

The mega-events database: systematising the evidence on mega-event outcomes

Although events such as the Olympic Games and World’s Fairs are among the largest of mega-projects, there is little systematic data to evaluate their outcomes over a longer period of time and across multiple sites. This research note describes the first longitudinal database on mega-event outcomes. It lays out the rationale and major goals of the database, its methodological approach and content, and its challenges and limitations. The database allows analysing larger patterns of mega-event contexts and outcomes, and helps evaluating mega-events as public policies. © 2021 Informa UK Limited, trading as Taylor & Francis Group.Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, SNF: PP00P1_172891The Swiss National Science Foundation (SNSF) funded the research of this paper under the grant ‘Mega-events: growth and impacts’, grant number PP00P1_172891

Patient-reported outcomes (PROs) with first-line (1L) cemiplimab in patients with locally advanced non-small cell lung cancer (laNSCLC): EMPOWER-Lung 1 subpopulation

In this post hoc analysis of patients with laNSCLC and PD-L1 ≥50%, cemiplimab resulted in significant favourable overall change from BL in GHS/QoL and important cancer-related and lung cancerespecific symptoms versus chemo. PRO results further support the favourable benefit-risk profile of 1L cemiplimab versus chemo in laNSCLC with PD-L1 ≥50%. Clinical trial identification: NCT03088540

Characterization of a New Mouse Model for Peripheral T Cell Lymphoma in Humans

Peripheral T cell lymphomas (PTCLs) are associated with a poor prognosis due to often advanced disease at the time of diagnosis and due to a lack of efficient therapeutic options. Therefore, appropriate animal models of PTCL are vital to improve clinical management of this disease. Here, we describe a monoclonal CD8+ CD4− αβ T cell receptor Vβ2+ CD28+ T cell lymphoma line, termed T8-28. T8-28 cells were isolated from an un-manipulated adult BALB/c mouse housed under standard pathogen-free conditions. T8-28 cells induced terminal malignancy upon adoptive transfer into syngeneic BALB/c mice. Despite intracellular expression of the cytotoxic T cell differentiation marker granzyme B, T8-28 cells appeared to be defective with respect to cytotoxic activity as read-out in vitro. Among the protocols tested, only addition of interleukin 2 in vitro could partially compensate for the in vivo micro-milieu in promoting growth of the T8-28 lymphoma cells

Discovery of novel CSF biomarkers to predict progression in dementia using machine learning

Providing an accurate prognosis for individual dementia patients remains a challenge since they greatly differ in rates of cognitive decline. In this study, we used machine learning techniques with the aim to identify cerebrospinal fluid (CSF) biomarkers that predict the rate of cognitive decline within dementia patients. First, longitudinal mini-mental state examination scores (MMSE) of 210 dementia patients were used to create fast and slow progression groups. Second, we trained random forest classifiers on CSF proteomic profiles and obtained a well-performing prediction model for the progression group (ROC–AUC = 0.82). As a third step, Shapley values and Gini feature importance measures were used to interpret the model performance and identify top biomarker candidates for predicting the rate of cognitive decline. Finally, we explored the potential for each of the 20 top candidates in internal sensitivity analyses. TNFRSF4 and TGF β -1 emerged as the top markers, being lower in fast-progressing patients compared to slow-progressing patients. Proteins of which a low concentration was associated with fast progression were enriched for cell signalling and immune response pathways. None of our top markers stood out as strong individual predictors of subsequent cognitive decline. This could be explained by small effect sizes per protein and biological heterogeneity among dementia patients. Taken together, this study presents a novel progression biomarker identification framework and protein leads for personalised prediction of cognitive decline in dementia

Rapid Regulatory T-Cell Response Prevents Cytokine Storm in CD28 Superagonist Treated Mice

Superagonistic CD28-specific monoclonal antibodies (CD28SA) are highly effective activators of regulatory T-cells (Treg cells) in rats, but a first-in-man trial of the human CD28SA TGN1412 resulted in an unexpected cytokine release syndrome. Using a novel mouse anti-mouse CD28SA, we re-investigate the relationship between Treg activation and systemic cytokine release. Treg activation by CD28SA was highly efficient but depended on paracrine IL-2 from CD28SA-stimulated conventional T-cells. Systemic cytokine levels were innocuous, but depletion of Treg cells prior to CD28SA stimulation led to systemic release of proinflammatory cytokines, indicating that in rodents, Treg cells effectively suppress the inflammatory response. Since the human volunteers of the TGN1412 study were not protected by this mechanism, we also tested whether corticosteroid prophylaxis would be compatible with CD28SA induced Treg activation. We show that neither the expansion nor the functional activation of Treg cells is affected by high-dose dexamethasone sufficient to control systemic cytokine release. Our findings warn that preclinical testing of activating biologicals in rodents may miss cytokine release syndromes due to the rapid and efficacious response of the rodent Treg compartment, and suggest that polyclonal Treg activation is feasible in the presence of antiphlogistic corticosteroid prophylaxis

Discovery of novel CSF biomarkers to predict progression in dementia using machine learning

Providing an accurate prognosis for individual dementia patients remains a challenge since they greatly differ in rates of cognitive decline. In this study, we used machine learning techniques with the aim to identify cerebrospinal fluid (CSF) biomarkers that predict the rate of cognitive decline within dementia patients. First, longitudinal mini-mental state examination scores (MMSE) of 210 dementia patients were used to create fast and slow progression groups. Second, we trained random forest classifiers on CSF proteomic profiles and obtained a well-performing prediction model for the progression group (ROC-AUC = 0.82). As a third step, Shapley values and Gini feature importance measures were used to interpret the model performance and identify top biomarker candidates for predicting the rate of cognitive decline. Finally, we explored the potential for each of the 20 top candidates in internal sensitivity analyses. TNFRSF4 and TGF [Formula: see text]-1 emerged as the top markers, being lower in fast-progressing patients compared to slow-progressing patients. Proteins of which a low concentration was associated with fast progression were enriched for cell signalling and immune response pathways. None of our top markers stood out as strong individual predictors of subsequent cognitive decline. This could be explained by small effect sizes per protein and biological heterogeneity among dementia patients. Taken together, this study presents a novel progression biomarker identification framework and protein leads for personalised prediction of cognitive decline in dementia

Inducible deletion of CD28 prior to secondary nippostrongylus brasiliensis infection impairs worm expulsion and recall of protective memory CD4 (+) T cell responses

IL-13 driven Th2 immunity is indispensable for host protection against infection with the gastrointestinal nematode Nippostronglus brasiliensis. Disruption of CD28 mediated costimulation impairs development of adequate Th2 immunity, showing an importance for CD28 during the initiation of an immune response against this pathogen. In this study, we used global CD28−/− mice and a recently established mouse model that allows for inducible deletion of the cd28 gene by oral administration of tamoxifen (CD28−/loxCre+/−+TM) to resolve the controversy surrounding the requirement of CD28 costimulation for recall of protective memory responses against pathogenic infections. Following primary infection with N. brasiliensis, CD28−/− mice had delayed expulsion of adult worms in the small intestine compared to wild-type C57BL/6 mice that cleared the infection by day 9 post-infection. Delayed expulsion was associated with reduced production of IL-13 and reduced serum levels of antigen specific IgG1 and total IgE. Interestingly, abrogation of CD28 costimulation in CD28−/loxCre+/− mice by oral administration of tamoxifen prior to secondary infection with N. brasiliensis resulted in impaired worm expulsion, similarly to infected CD28−/− mice. This was associated with reduced production of the Th2 cytokines IL-13 and IL-4, diminished serum titres of antigen specific IgG1 and total IgE and a reduced CXCR5+ TFH cell population. Furthermore, total number of CD4+ T cells and B220+ B cells secreting Th1 and Th2 cytokines were significantly reduced in CD28−/− mice and tamoxifen treated CD28−/loxCre+/− mice compared to C57BL/6 mice. Importantly, interfering with CD28 costimulatory signalling before re-infection impaired the recruitment and/or expansion of central and effector memory CD4+ T cells and follicular B cells to the draining lymph node of tamoxifen treated CD28−/loxCre+/− mice. Therefore, it can be concluded that CD28 costimulation is essential for conferring host protection during secondary N. brasiliensis infection

Cellular Therapy with Engineered T Cells, Efficacy and Side Effects

The cellular basis of cancer immune surveillance, already hypothesized in ancient times, was only demonstrated with the advent of HSCT. Indeed, the discovery of the nature of GVHD and its antileukemic effects (Weiden et al