Journal articles on the topic 'Air travel – Italy'

Three case studies about tourism impacts caused by air travel were presented in the first workshop of the 44th AIEST‐conference. The three presenters were discussing the impacts of airtravel in European regions: France (Claude Origet du Cluzeau), Pisa (Harald Pechlaner) and Southern Italy (Andrea Macchiavelli).

Legionnaires’ disease (LD) incidence has been increasing in several European countries since 2011. Currently, Italy is experiencing high notification rates for LD, whose cause still remains scarcely understood. We sought to summarize the available evidence on the epidemiology of LD in Italy (2004–2019), characterizing the risk of LD by region, sex, age group, and settings of the case (i.e., community, healthcare, or travel-associated cases). Environmental factors (e.g., average air temperatures and relative humidity) were also included in a Poisson regression model in order to assess their potential role on the annual incidence of new LD cases. National surveillance data included a total of 23,554 LD cases occurring between 2004 and 2019 (70.4% of them were of male gender, 94.1% were aged 40 years and older), with age-adjusted incidence rates increasing from 1.053 cases per 100,000 in 2004 to 4.559 per 100,000 in 2019. The majority of incident cases came from northern Italy (43.2% from northwestern Italy, 25.6% from northeastern Italy). Of these, 5.9% were healthcare-related, and 21.1% were travel-associated. A case-fatality ratio of 5.2% was calculated for the whole of the assessed timeframe, with a pooled estimate for mortality of 0.122 events per 100,000 population per year. Poisson regression analysis was associated with conflicting results, as any increase in average air temperature resulted in reduced risk for LD cases (Incidence Rate Ratio [IRR] 0.807, 95% Confidence Interval [95% CI] 0.744–0.874), while higher annual income in older individuals was associated with an increased IRR (1.238, 95% CI 1.134–1.351). The relative differences in incidence between Italian regions could not be explained by demographic factors (i.e., age and sex distribution of the population), and also a critical reappraisal of environmental factors failed to substantiate both the varying incidence across the country and the decennial trend we were able to identify.

The world is becoming more connected, with the internet bringing us closer together, 24- hour news allowing us to see what is happening around the world, and more efficient planes allowing us to travel from place to place. Over the next decade, China will overtake the US as the highest source of passengers, flying to, from, and within the country, potentially rising to over 1 billion. Even if there is a downturn in productivity and restrictions in trade agreements, globally there should still be more than 6 billion passengers every year by the end of the next decade, significantly higher than today. Passengers numbering in the billions will continue to use planes, and many millions of new fliers will experience it for the first time, eventually becoming loyal customers. Job Growth: Job growth is also increasing Aviation industry growth. An increase in passengers will have a knock-on effect of stimulating more jobs in the Aviation industry. There are already 65 million jobs supported by the industry, but even more, will be needed to handle the volume of new flights. The IATA surveyed growth in the Aviation sector and found that the majority of respondents predict growth in ground operations, cabin crew, and customer service personnel jobs over the next two years, which will allow the industry to maintain its high standards. The 10 million jobs directly in the Aviation sector are around 4.4 times more productive than the average job around the world, and there will be millions more Aviation jobs created over the next decade. Supersonic Flight: New Aviation technology is emerging all the time, making flights faster, more efficient, and a more enjoyable experience for customers.

Reactions, measures as well as discourses dealing with the current pandemic vary significantly across the world. While some countries were completely locked down, as was the case in Italy, some had claimed to have very few or no cases, as was the case in Turkey and Indonesia by March 10th, 2020. Nevertheless, the spread of COVID-19 from China has been clearly linked to those travelling from Wuhan in Hubei province in Central China. Therefore, it is important to understand the travel density/volume of passengers carried as well as routes from Wuhan through connected main regional air travel hubs across China. In this study, we developed a model on migration and travel intensity that can explain outbreak and spread COVID-19 since it appeared at the end of 2019. We show that the presence of migrant stock populations of Chinese origin and the immigrant stock in China are useful indicators in the prediction of the spread of the outbreak worldwide in the event of interaction with several other macro factors. We argue that monitoring immigrant stock data and travel volume data based on human mobility corridors (i.e. origins and destinations), countries could have been better prepared and taken early measures to contain the spread of COVID-19.

Background: Roundabouts eliminate some of the most complex and dangerous aspects of traditional at-grade road intersections. In recent times, novel two-level roundabout layouts have been proposed (i.e. target-roundabout and four-flyover roundabout). Nevertheless, no research on underground roundabouts is available. This paper analyzed the underground roundabout planned in the city of Trento (Italy). Objective: The paper examines an underground roundabout in an urban context, planned with the purpose of alleviating traffic congestion in the city of Trento (Italy). Four different layouts have been studied. Methods and Results: This study was conducted with the help of traffic microsimulation in the AIMSUN environment. The traffic model was calibrated using GEH index. The simulated queues are significantly close to the real queues measured in the year 2020. Conclusion: Underground roundabout can reduce queues, travel times, fuel consumption, air pollutant emissions etc. This particular type of roundabout could be used in urban contexts with a traffic demand and congestion problems comparable to those of the present study.

The article is aimed at analyzing the proposals from leading operators in the tourist market of Ukraine, in particular in the city of Kharkiv. The article analyzes the charter offers of travel operators for the summer season 2020. After the analysis, it can be stated that travel operators plan to significantly increase volumes for Turkey (for example, two flights a week to the Turkish Dalaman are planned (in the season 2019, one flight per week was operated)). It is worth noting that travel operators also plan to significantly increase volumes for European areas, in particular Italy. In addition to the proposed flights to the swimming and beach resorts, the summer navigation will also feature direct flights of the airline Ernest, which will allow to develop interesting excursion routes, focusing on the arrival airports in Rome and Milan. At the same time, the expediency of increasing the volume of flights to Calabria can be questioned, because two flights a week is too much for a place that has not yet become a mass resort, which means that it experiences problems with infrastructure development and sufficient availability of accommodation facilities. The article analyzes the proposals of leading operators in the tourist market of Ukraine, according to the findings it can be noted that almost all travel operators - leaders in the number of tourists served consider the Kharkiv region as an attractive market for expanding travel content. The leaders in the number of tourists served were two travel operators who have their own airlines, namely: Sky Up (Join Up) and Azur Air Ukraine (Anex Tour). The undisputed leader in the number of exclusive destinations represented with a guaranteed flight is Join Up, and there is also a tendency to increase volumes with the travel operator TUI. On the basis of a survey, the best travel operators were identified by the ratings of agent-friendly and tourist-friendly, they were: Tez Tour, Join Up, Pegas Touristik, Coral Travel, and TUI.

The novel COVID-19 pandemic has placed medical triage decision-making in the spotlight. As life-saving ventilators become scarce, clinicians are being forced to allocate scarce resources in even the wealthiest countries. The pervasiveness of air travel and high rate of transmission has caused this pandemic to spread swiftly throughout the world. Ethical triage decisions are commonly based on the utilitarian approach of maximising total benefits and life expectancy. We present triage guidelines from Italy, USA and the UK as well as the Jewish ethical prospective on medical triage. The Jewish tradition also recognises the utilitarian approach but there is disagreement between the rabbis whether human discretion has any role in the allocation of scarce resources and triage decision-making.

Abstract. We describe a 0.5 Mm3 rock avalanche that occurred in 2008 in the western Alps and discuss possible roles of controlling factors in the context of current climate change. The source is located between 2410 m and 2653 m a.s.l. on Mont Crammont and is controlled by a densely fractured rock structure. The main part of the collapsed rock mass deposited at the foot of the rock wall. A smaller part travelled much farther, reaching horizontal and vertical travel distances of 3050 m and 1560 m, respectively. The mobility of the rock mass was enhanced by channelization and snow. The rock-avalanche volume was calculated by comparison of pre- and post-event DTMs, and geomechanical characterization of the detachment zone was extracted from LiDAR point cloud processing. Back analysis of the rock-avalanche runout suggests a two stage event. There was no previous rock avalanche activity from the Mont Crammont ridge during the Holocene. The 2008 rock avalanche may have resulted from permafrost degradation in the steep rock wall, as suggested by seepage water in the scar after the collapse in spite of negative air temperatures, and modelling of rock temperatures that indicate warm permafrost (T > −2 °C).

Rail and metro systems are characterized by high-performing and environmentally friendly features that make them a crucial factor for driving modal split towards public transport modes, thus reducing private car use and related externalities (such as air and noise pollution, traffic congestion and accidents). Within this framework, the implementation of suitable energy-saving policies, allowing to reduce energy consumption, but, at the same time, preserving timetable stability and passengers’ satisfaction, may turn out to be imperative. In particular, this study aims to develop an analytical framework for properly supporting the implementation of eco-driving strategies in a passenger-oriented perspective. An application to a rail line in southern Italy is performed so as to demonstrate the usefulness of the proposed approach in determining the optimal compromise between energy reductions and travel time increases.

This article describes the great distance that separates Sardinia from mainland Italy has made the island – the second largest island of the Mediterranean – a marginal and remote region. Its system of ferry links for people travelling to and from Sardinia has such long journey times (8-12 hours) that it is clearly in no way a valid alternative to air transport. It was mainly on the basis of these reasons and with a view to protecting and ensuring the mobility of Sardinian residents that Public Service Obligations (PSO) were imposed on some of the main air routes starting from 2002. Our study is set against this background. It aims to resolve one of the main critical factors that distinguish the PSO network: the shortage of flights on certain routes and the concomitant over-scheduling of others. More specifically, the insufficient scheduling of weekly flights to certain airports, such as Verona and Turin, forces a number of passengers to decide not to travel at all and another part to use connecting flights to Rome/Milan airports or to travel using more than one route, via air or ground transport, with inevitably higher transport costs. The problem was addressed by using a linear scheduling model applied to a network of nodes and arcs representing, respectively, the airports and their connecting routes, and the airport of Cagliari. The decision variables identified were the number of passengers travelling on all of the arcs and the impedance measures associated with the distance travelled by the arcs, represented by the generalized cost of transport. The objective is to determine a network structure which corresponds to the distribution of passengers on the various branches capable of minimizing the total cost. This cost was considered as a useful parameter for comparing the various network scenarios which were obtained by changing the passenger load coefficient and the number of flights. Our study demonstrates that a simple intervention, aimed at the internal reallocation of the flights on the various routes, is able to guarantee categories of users (here divided into business and non-business users) greater access to air transport services. The scenario that more than others is able to improve service efficiency, granting undeniable benefits for all users without having an impact on the costs of air carriers, particularly stands out because it: • Allows access to all network airports through direct flights; • Decongests the Rome and Milan routes

The development and the diffusion of the electromobility is crucial for reducing air pollution and increase sustainable transport. In particular, electrification of private mobility has a significantly role in the energy transition within urban areas, since the progressive substitution of conventional passenger cars by electric vehicles (EVs) leads to the decarbonisation of transport sector without direct emissions. However, increasing EV penetration in the market forces an expansion of the existing charging infrastructure with potential negative impacts on the distribution grid. In this context, a simplified approach is proposed to estimate the energy and power demand owing to the recharge of electric passenger cars within the city of Turin in Italy. This novel approach is based on the usage of floating car data (FCD) to identify the travel behaviour and parking habits of a non-EV passenger car in the city. Mobility data were then used to evaluate EVs energy consumption and charging needs considering different charging options (public or domestic) and range anxiety in different scenarios of EV diffusion. Aggregated load profiles and demand were finally evaluated both for the whole and for each zone of the city as possible resource for city planner or distribution system operators (DSO).

Korona virüs salgınıyla ilgili tepkiler, önlemler ve söylemler dünya çapında önemli farklılıklar göstermektedir. İtalya'da olduğu gibi bazı ülkeler vaka ve ölüm sayılarının çok dramatik olduğu bir durumdayken, 10 Mart 2020 tarihi itibariyle Türkiye ve Endonezya gibi ülkelerde çok az sayıda vaka olduğu veya hiç vaka bulunmadığı açıklanmıştı. KOVİD-19 salgınının Çin'de başladığı ve yayıldığı konusunda bir uzlaşma olmasa da ilk vakalar Wuhan kentinde görüldüğü açıklandı. Bu bağlamda Wuhanla ilişkili seyahat yoğunluğu / hacminin yanı sıra Çinle bağlantılı uluslararası göç stoklarını ve/veya insan hareketliliğini anlamak önemli gözükmektedir. Bu çalışmada, 2019 yılı nın sonunda ortaya çıkışından beri Wuhan merkezli uluslararası seyahat hacminden hareketle KOVİD-19 salgınının yayılmasını insan hareketliliği / göç yoğunluğu modeliyle açıklamayı amaçladık. Araştırmamızda, ülkelerdeki Çin kökenli göçmen stoku nüfus ile Çin'deki uluslararası göçmen stokunun varlığının, diğer makro faktörlerle etkileşerek salgının dünya çapında yayılmasının tahmininde önemli göstergeler olduğunu ortaya koymaktayız. Bu noktadan hareketle çalışmamızda, göçmen stoku verilerinin ile seyahat hacmi verilerinin insan hareketliliği koridorlarına (köken ve hedef bölgelere) göre izlenmesinin, ülkelerin KOVİD-19 ve benzeri salgınların yayılmasını kontrol altına almak için daha erken önlemler alabilmede önemli bir faktör olabileceğini savunmaktayız. ABSTRACT IN ENGLISH Analysing the Spread of COVİD-19 Using Human Mobility Data Reactions, measures as well as discourses dealing with the current pandemic vary significantly across the world. While some countries were completely locked down, as was the case in Italy, some had claimed to have very few or no cases, as was the case in Turkey and Indonesia by March 10th, 2020. The COVID-19 outbreak is allegedly started in China and the spread has been linked to those travelling from Wuhan in Hubei province in Central China. Therefore, it is important to understand the travel density/volume of passengers carried as well as routes from Wuhan through connected main regional air travel hubs across China. In this study, we developed a model on migration and travel intensity that can explain outbreak and spread of COVID-19 since it appeared at the end of 2019. We show that the presence of migrant stock populations of Chinese origin and the immigrant stock in China are useful indicators in the prediction of the spread of the outbreak worldwide in the event of interaction with several other macro factors. We argue that monitoring immigrant stock data and travel volume data based on human mobility corridors (i.e. origins and destinations), countries could have been better prepared and taken early measures to contain the spread of COVID-19.

As the competition between airlines grows, their customer-centered strategies are becoming increasingly popular. In this context, the marketing strategies are the result of investigations carried out directly on users, usually through the Customer Satisfaction Surveys. Investigating on airline passengers’ preferences represents a useful action to pursue the most convenient strategy for increasing their satisfaction and improving the provided service. With this aim, we propose the design of a Stated Preference survey and the preliminary outcomes obtained from the analysis and modelling of the collected data. A deep study of the literature review drove us to consider the land services separately from the air ones. Even if the travel experience of an airline passenger starts at the airport, only the services provided by the airlines are the object of this study. The Stated Preference survey was designed with the aim to capture the passengers’ desires on airlines’ services by proposing hypothetical scenarios to them. The survey was addressed to the whole population of the University of Calabria (Italy). A sample of 1907 survey responses was obtained. For analyzing the collected data, discrete choice models have been calibrated to obtain the weights assigned by users to each service quality aspect included in the experiment.

The object of research is the methods for monitoring and forecasting strong space weather disturbances affecting the radiation environment and radio communication during air travels. The monitoring techniques used by the existing space weather centers are analyzed: the U.S. Center, the PECASUS consortium (Great Britain, Finland, Germany, Poland, Austria, Italy, the Netherlands, Belgium, Cyprus, and South Africa), the AJCF consortium (Australia, Japan, Canada, France), and the Russian-Chinese space weather consortium.

Due to the motivations of climate change, the health impacts of poor air quality, and the importance of cities for economic growth, transport policy at all levels of governance places emphasis on reducing and managing urban traffic and congestion. Whilst the majority of urban traffic is created by personal travel, freight vehicles make a relatively large contribution per vehicle to congestion, pollution and severe accidents. The European Commission (EC 2011) estimates that 6% of all EU transport carbon emissions are from urban freight. For these reasons, a well-structured portfolio of measures and policies oriented towards more sustainable and efficient management of supply chain activities carried out in urban areas is needed, in order to reduce negative externalities related to urban mobility and improve economic performance. In recent years, there has been enthusiasm amongst commentators that shared-resource economic models can both create new commercial opportunities and address policy problems, including in the transport sector. Within the city logistics subsector, this new model is exemplified by the emergence of Urban freight Consolidation Centres (UCCs). UCCs replace multiple ‘last-mile’ delivery movements, many of which involving small consignments, by a common receiving point (the consolidation centre), normally on the periphery of a city, with the final part of the delivery being shared by the consignments in a small freight vehicle. Such arrangements can represent a good compromise between the needs of city centre businesses and their customers on the one hand (i.e. high availability of a range of goods) and local and global sustainability objectives on the other. At the same time, by sharing logistics facilities and delivery vehicles, UCCs offer added-value services to both urban economic actors, such as retailers, and network logistics providers. However, UCCs add to the complexity of logistics chains, requiring additional contracts, communications and movement stages. These arrangements also introduce additional actors within the supply of delivery services, notably local authorities present as promoters and funders, rather than simply as regulators, companies specialised in the UCC operation, and companies, which provide specialist technologies, such as electric delivery vehicles. UCCs therefore also represent an example of multi-stakeholder collaboration. Drawing on the results of a 2013 survey in Bristol (United Kingdom) and a further survey carried out in 2015 in Cagliari (Italy), the present paper will provide an in-depth comparison of the differences in the perceptions of urban freight users and stakeholders towards UCCs. Retailers involved in the survey carried out in Bristol showed high satisfaction with the delivery service provided by the UCC. Different topic areas (e.g. timeliness, reliability, safety) are examined through analyses of both qualitative and quantitative data. The survey carried out in Cagliari investigated the inclination of potential users to join a UCC scheme. The comparison between the two cities considers factors such as the nature of business holding (e.g. SME versus multiple retailers), operational practices (e.g. pattern of deliveries) and operating subsector (e.g. food versus no food). An analysis on the barriers to the implementation of UCCs in Bristol and in Cagliari is provided at the end of the paper.

Arresting the emission of road transport is one of the significant issues to develop the low-carbon transportation in urban area. This paper mainly discusses the substantial approaches both from technological and behavioral aspects to reduce even arrest the environmental impact from vehicle emissions. The technological approaches from supply side include constructing the transport facilities, transport system management and technological upgrading of fleet and fuel; while behavior modifications from travel demand side take account of the traffic restraint measures such as road pricing, the promotion of public transport and land use modification. This paper focuses on evaluating the potential and limitations of these approaches through the examples in the countries of the UK, America, Japan, Netherlands, Italy and China.

Efficient urban infrastructure interventions make it possible to pursue goals of sustainable mobility, that nowadays are extremely important in light of the need to reduce the negative impact produced by human activities on the environment. In addition and to a no lesser extent, the implementation of the investment requires the monetary resources to realise the works. In relation to this aspect, the scarcity of public funds in the current economic contingency makes the involvement of private capital and entrepreneurial skills indispensable in the execution and performance of these works.This work shows how the use of a suitable economic evaluation model is indispensable in order to encourage public-private partnerships aimed at the execution and correct management of an intervention in the field of sustainable mobility. The proposed evaluation model implements the instrument of inter-sectorial matrices, which allow to determine the impacts (output) generated by a change in aggregate demand (input, such as the investment costs in an industry) on the economy of the territory where the matrix is associated.The analysis and calculations are carried out in relation to the project for the construction of a mechanical vector in the town of Vietri sul Mare in the province of Salerno (Italy), which is useful in ensuring the decongestion of road traffic and the consequent reduction in travel times along the Amalfi Coast.

In this research, the radioactive noble gas radon was used as a tracer for Non-Aqueous Phase Liquids (NAPLs) contamination, since it is much more soluble in these substances than in air or water. Soil radon remains trapped within the NAPLs, resulting in a local reduction in the radon concentration within close proximity to the contaminated area. This technique was applied to a contaminated site in Roma (Italy). The main residual NAPLs are total hydrocarbons and methyl-tertiary-butyl ether (MTBE), a water-soluble additive. The monitoring activities included two sampling campaigns of groundwater from 18 wells in February and May 2020. Concentration maps were produced using radon data. The results show that the radon deficit traces the location of NAPLs in the fuelling station very well, with a residual source zone extending in a NNW-SSE direction. A good correspondence between a low amount of radon and a higher concentration of NAPLs was found. A reduction in the average amount of radon in the May 2020 survey indicated a stronger remobilization of NAPLs compared to that of the February 2020 monitoring campaign. The peaks of Volatile Organic Compounds (VOCs) detected between 8–9 and 11–12 m depths indicate the presence of residual blobs of NAPLs in the vadose zone of the aquifer.

Abstract. Black carbon (BC) mass, size distribution and mixing state in sub-micron aerosols were characterized from late February to March 2007 using a single particle incandescence method at the high alpine research station Jungfraujoch (JFJ), Switzerland (46.33° N, 7.59° E, 3580 m a.s.l.). JFJ is a ground based location, which is at times exposed to continental free tropospheric air. A median mass absorption coefficient (MAC) of 10.2±3.2 m2 g−1 at λ = 630 nm was derived by comparing single particle incandescence measurements of black carbon mass with continuous measurements of absorption coefficient. This value is comparable with other estimates at this location. The aerosols measured at the site were mostly well mixed and aged during transportation via the free troposphere. Pollutant sources were traced by air mass back trajectories, trace gases concentrations and the mass loading of BC. In southeasterly wind directions, mixed or convective weather types provided the potential to vent polluted boundary layer air from the southern Alpine area and industrial northern Italy, delivering enhanced BC mass loading and CN concentrations to the JFJ. The aerosol loadings at this site were also significantly influenced by precipitation, which led to the removal of BC from the atmosphere. Precipitation events were shown to remove about 65% of the BC mass from the free tropospheric background reducing the mean loading from 10±5 ngm−3 to 4±2 ngm−3. Overall, 40±15% of the observed BC particles within the detectable size range were mixed with large amounts of non-refractory materials present as a thick coating around the BC core. The growth of particle size into the accumulation mode was positively linked with the degree of BC mixing, suggesting the important role of condensable materials in increasing particle size as well as enhancing BC mixing state. It is the first time that BC mass, size distribution and mixing state are reported in the free troposphere over Europe. These ground based measurements also provide the first temporal study of BC in the European free troposphere quantitatively measured by single particle methods. At the present time there is only limited information of BC and its mixing state in the free troposphere, especially above Europe. The results reported in this paper provide an important constraint on modelled representation of BC.

Abstract. The refractory black carbon (rBC) mass, size distribution (190–720 nm) and mixing state in sub-micron aerosols were characterized from late February to March 2007 using a single particle incandescence method at the high alpine research station Jungfraujoch (JFJ), Switzerland (46.33° N, 7.59° E, 3580 m a.s.l.). JFJ is a ground based location, which is at times exposed to continental free tropospheric air. A median mass absorption coefficient (MAC) of 10.2±3.2 m2 g−1 at λ=630 nm was derived by comparing single particle incandescence measurements of black carbon mass with continuous measurements of absorption coefficient. This value is comparable with other estimates at this location. The aerosols measured at the site were mostly well mixed and aged during transportation via the free troposphere. Pollutant sources were traced by air mass back trajectories, trace gases concentrations and the mass loading of rBC. In southeasterly wind directions, mixed or convective weather types provided the potential to vent polluted boundary layer air from the southern Alpine area and industrial northern Italy, delivering enhanced rBC mass loading and CN concentrations to the JFJ. The aerosol loadings at this site were also significantly influenced by precipitation, which led to the removal of rBC from the atmosphere. Precipitation events were shown to remove about 65% of the rBC mass from the free tropospheric background reducing the mean loading from 13±5 ng m−3 to 6±2 ng m−3(corrected to standard temperature and pressure). Overall, 40±15% of the observed rBC particles within the detectable size range were mixed with large amounts of non-refractory materials present as a thick coating. The growth of particle size into the accumulation mode was positively linked with the degree of rBC mixing, suggesting the important role of condensable materials in increasing particle size and leading to enhanced internal mixing of these materials with rBC. It is the first time that BC mass, size distribution and mixing state are reported in the free troposphere over Europe. These ground based measurements also provide the first temporal study of rBC in the European free troposphere quantitatively measured by single particle methods. At the present time there is only limited information of BC and its mixing state in the free troposphere, especially above Europe. The results reported in this paper provide an important constraint on modelled representation of BC.

Abstract. The source contributions to carbonaceous PM2.5 aerosol were investigated at a European background site at the edge of the Po Valley, in Northern Italy, during the period January–December 2007. Carbonaceous aerosol was described as the sum of eight source components: primary (1) and secondary (2) biomass burning organic carbon, biomass burning elemental carbon (3), primary (4) and secondary (5) fossil fuel burning organic carbon, fossil fuel burning elemental carbon (6), primary (7) and secondary (8) biogenic organic carbon. The concentration of each component was quantified using a set of macro tracers (organic carbon OC, elemental carbon EC, and levoglucosan), micro tracers (arabitol and mannitol), and 14C measurements. This was the first time that 14C measurements were performed on a long time series of data able to represent the entire annual cycle. This set of 6 tracers, together with assumed uncertainty ranges of the ratios of OC-to-EC, and the fraction of modern carbon in the 8 source categories, provides strong constraints to the source contributions to carbonaceous aerosol. The uncertainty of contributions was assessed with a Quasi-Monte Carlo (QMC) method accounting for the variability of OC and EC emission factors, and the uncertainty of reference fractions of modern carbon. During winter biomass burning composed 50% of the total carbon (TC) concentration, while in summer secondary biogenic OC accounted for 45% of TC. The contribution of primary biogenic aerosol particles was negligible during the entire year. Moreover, aerosol associated with fossil fuel burning represented 26% and 43% of TC in winter and summer, respectively. The comparison of source apportionment results in different urban and rural areas showed that the sampling site was mainly affected by local aerosol sources during winter and regional air masses from the nearby Po Valley in summer. This observation was further confirmed by back-trajectory analysis applying the Potential Source Contribution Function method to identify potential source regions. The contribution of secondary organic aerosol (SOA) to the organic mass (OM) was significant during the entire year. SOA accounted for 23% and 83% of OM during winter and summer, respectively. While the summer SOA was dominated by biogenic sources, winter SOA was mainly due to biomass and fossil fuel burning. This indicates that the oxidation of intermediate volatility organic compounds co-emitted with primary organics is a significant source of SOA, as suggested by recent model results and Aerosol Mass Spectrometer measurements in urban regions. Comparison with previous global model simulations, indicates a strong underestimate of wintertime primary aerosol emissions in this region.

Abstract. The source contributions to carbonaceous PM2.5 aerosol were investigated at a European background site at the edge of the Po Valley, in Northern Italy, during the period January–December 2007. Carbonaceous aerosol was described as the sum of 8 source components: primary (1) and secondary (2) biomass burning organic carbon, biomass burning elemental carbon (3), primary (4) and secondary (5) fossil organic carbon, fossil fuel burning elemental carbon (6), primary (7) and secondary (8) biogenic organic carbon. The mass concentration of each component was quantified using a set of macro tracers (organic carbon OC, elemental carbon EC, and levoglucosan), micro tracers (arabitol and mannitol), and 14C measurements. This was the first time that 14C measurements covered a full annual cycle with daily resolution. This set of 6 tracers, together with assumed uncertainty ranges of the ratios of OC-to-EC, and the reference fraction of modern carbon in the 8 source categories, provides strong constraints to the source contributions to carbonaceous aerosol. The uncertainty of contributions was assessed with a Quasi-Monte Carlo (QMC) method accounting for the variability of OC and EC emission factors, the uncertainty of reference fractions of modern carbon, and the measurement uncertainty. During winter, biomass burning composed 64 % (±15 %) of the total carbon (TC) concentration, while in summer secondary biogenic OC accounted for 50 % (±16 %) of TC. The contribution of primary biogenic aerosol particles was negligible during the entire year. Moreover, aerosol associated with fossil sources represented 27 % (±16 %) and 41 % (±26 %) of TC in winter and summer, respectively. The contribution of secondary organic aerosol (SOA) to the organic mass (OM) was significant during the entire year. SOA accounted for 30 % (±16 %) and 85 % (±12 %) of OM during winter and summer, respectively. While the summer SOA was dominated by biogenic sources, winter SOA was mainly due to biomass burning and fossil sources. This indicates that the oxidation of semi-volatile and intermediate volatility organic compounds co-emitted with primary organics is a significant source of SOA, as suggested by recent model results and Aerosol Mass Spectrometer measurements. Comparison with previous global model simulations, indicates a strong underestimate of wintertime primary aerosol emissions in this region. The comparison of source apportionment results in different urban and rural areas showed that the sampling site was mainly affected by local aerosol sources during winter and regional air masses from the nearby Po Valley in summer. This observation was further confirmed by back-trajectory analysis applying the Potential Source Contribution Function method to identify potential source regions.

Covid 19 – living the experience As I sit at my desk at home in suburban Brisbane, following the dictates on self-isolation shared with so many around the world, I am forced to contemplate the limits of human prediction. I look out on a world which few could have predicted six months ago. My thoughts at that time were all about 2020 as a metaphor for perfect vision and a plea for it to herald a new period of clarity which would arm us in resolving the whole host of false divisions that surrounded us. False, because so many appear to be generated by the use of polarised labelling strategies which sought to categorise humans by a whole range of identities, while losing the essential humanity and individuality which we all share. This was a troublesome trend and one which seemed reminiscent of the biblical tale concerning the tower of Babel, when a single unified language was what we needed to create harmony in a globalising world. However, yesterday’s concerns have, at least for the moment, been overshadowed by a more urgent and unifying concern with humanity’s health and wellbeing. For now, this concern has created a world which we would not have recognised in 2019. We rely more than ever on our various forms of electronic media to beam instant shots of the streets of London, New York, Berlin, Paris, Hong Kong etc. These centres of our worldly activity normally characterised by hustle and bustle, are now serenely peaceful and ordered. Their magnificent buildings have become foregrounded, assuming a dignity and presence that is more commonly overshadowed by the mad ceaseless scramble of humanity all around them. From there however the cameras can jump to some of the less fortunate areas of the globe. These streets are still teeming with people in close confined areas. There is little hope here of following frequent extended hand washing practices, let alone achieving the social distance prescribed to those of us in the global North. From this desk top perspective, it has been interesting to chart the mood as the crisis has unfolded. It has moved from a slightly distant sense of superiority as the news slowly unfolded about events in remote Wuhan. The explanation that the origins were from a live market, where customs unfamiliar to our hygienic pre-packaged approach to food consumption were practised, added to this sense of separateness and exoticism surrounding the source and initial development of the virus. However, this changed to a growing sense of concern as its growth and transmission slowly began to reveal the vulnerability of all cultures to its spread. At this early stage, countries who took steps to limit travel from infected areas seemed to gain some advantage. Australia, as just one example banned flights from China and required all Chinese students coming to study in Australia to self-isolate for two weeks in a third intermediate port. It was a step that had considerable economic costs associated with it. One that was vociferously resisted at the time by the university sector increasingly dependent on the revenue generated by servicing Chinese students. But it was when the epicentre moved to northern Italy, that the entire messaging around the event began to change internationally. At this time the tone became increasingly fearful, anxious and urgent as reports of overwhelmed hospitals and mass burials began to dominate the news. Consequently, governments attracted little criticism but were rather widely supported in the action of radically closing down their countries in order to limit human interaction. The debate had become one around the choice between health and economic wellbeing. The fact that the decision has been overwhelmingly for health, has been encouraging. It has not however stopped the pressure from those who believe that economic well-being is a determinant of human well-being, questioning the decisions of politicians and the advice of public health scientists that have dominated the responses to date. At this stage, the lives versus livelihoods debate has a long way still to run. Of some particular interest has been the musings of the opinion writers who have predicted that the events of these last months will change our world forever. Some of these predictions have included the idea that rather than piling into common office spaces working remotely from home and other advantageous locations will be here to stay. Schools and universities will become centres of learning more conveniently accessed on-line rather than face to face. Many shopping centres will become redundant and goods will increasingly be delivered via collection centres or couriers direct to the home. Social distancing will impact our consumption of entertainment at common venues and lifestyle events such as dining out. At the macro level, it has been predicted that globalisation in its present form will be reversed. The pandemic has led to actions being taken at national levels and movement being controlled by the strengthening and increased control of physical borders. Tourism has ground to a halt and may not resume on its current scale or in its present form as unnecessary travel, at least across borders, will become permanently reduced. Advocates of change have pointed to some of the unpredicted benefits that have been occurring. These include a drop in air pollution: increased interaction within families; more reading undertaken by younger adults; more systematic incorporation of exercise into daily life, and; a rediscovered sense of community with many initiatives paying tribute to the health and essential services workers who have been placed at the forefront of this latest struggle with nature. Of course, for all those who point to benefits in the forced lifestyle changes we have been experiencing, there are those who would tell a contrary tale. Demonstrations in the US have led the push by those who just want things to get back to normal as quickly as possible. For this group, confinement at home creates more problems. These may be a function of the proximity of modern cramped living quarters, today’s crowded city life, dysfunctional relationships, the boredom of self-entertainment or simply the anxiety that comes with an insecure livelihood and an unclear future. Personally however, I am left with two significant questions about our future stimulated by the events that have been ushered in by 2020. The first is how is it that the world has been caught so unprepared by this pandemic? The second is to what extent do we have the ability to recalibrate our current practices and view an alternative future? In considering the first, it has been enlightening to observe the extent to which politicians have turned to scientific expertise in order to determine their actions. Terms like ‘flattening the curve’, ‘community transmission rates’, have become part of our daily lexicon as the statistical modellers advance their predictions as to how the disease will spread and impact on our health systems. The fact that scientists are presented as the acceptable and credible authority and the basis for our actions reflects a growing dependency on data and modelling that has infused our society generally. This acceptance has been used to strengthen the actions on behalf of the human lives first and foremost position. For those who pursue the livelihoods argument even bigger figures are available to be thrown about. These relate to concepts such as numbers of jobless, increase in national debt, growth in domestic violence, rise in mental illness etc. However, given that they are more clearly estimates and based on less certain assumptions and variables, they do not at this stage seem to carry the impact of the data produced by public health experts. This is not surprising but perhaps not justifiable when we consider the failure of the public health lobby to adequately prepare or forewarn us of the current crisis in the first place. Statistical predictive models are built around historical data, yet their accuracy depends upon the quality of those data. Their robustness for extrapolation to new settings for example will differ as these differ in a multitude of subtle ways from the contexts in which they were initially gathered. Our often uncritical dependence upon ‘scientific’ processes has become worrying, given that as humans, even when guided by such useful tools, we still tend to repeat mistakes or ignore warnings. At such a time it is an opportunity for us to return to the reservoir of human wisdom to be found in places such as our great literature. Works such as The Plague by Albert Camus make fascinating and educative reading for us at this time. As the writer observes Everybody knows that pestilences have a way of recurring in the world, yet somehow, we find it hard to believe in ones that crash down on our heads from a blue sky. There have been as many plagues as wars in history, yet always plagues and wars take people equally by surprise. So it is that we constantly fail to study let alone learn the lessons of history. Yet 2020 mirrors 1919, as at that time the world was reeling with the impact of the Spanish ‘Flu, which infected 500 million people and killed an estimated 50 million. This was more than the 40 million casualties of the four years of the preceding Great War. There have of course been other pestilences since then and much more recently. Is our stubborn failure to learn because we fail to value history and the knowledge of our forebears? Yet we can accept with so little question the accuracy of predictions based on numbers, even with varying and unquestioned levels of validity and reliability. As to the second question, many writers have been observing some beneficial changes in our behaviour and our environment, which have emerged in association with this sudden break in our normal patterns of activity. It has given us the excuse to reevaluate some of our practices and identify some clear benefits that have been occurring. As Australian newspaper columnist Bernard Salt observes in an article titled “the end of narcissism?” I think we’ve been re-evaluating the entire contribution/reward equation since the summer bushfires and now, with the added experience of the pandemic, we can see the shallowness of the so-called glamour professions – the celebrities, the influencers. We appreciate the selflessness of volunteer firefighters, of healthcare workers and supermarket staff. From the pandemic’s earliest days, glib forays into social media by celebrities seeking attention and yet further adulation have been met with stony disapproval. Perhaps it is best that they stay offline while our real heroes do the heavy lifting. To this sad unquestioning adherence to both scientism and narcissism, we can add and stir the framing of the climate rebellion and a myriad of familiar ‘first world’ problems which have caused dissension and disharmony in our communities. Now with an external threat on which to focus our attention, there has been a short lull in the endless bickering and petty point scoring that has characterised our western liberal democracies in the last decade. As Camus observed: The one way of making people hang together is to give ‘em a spell of the plague. So, the ceaseless din of the topics that have driven us apart has miraculously paused for at least a moment. Does this then provide a unique opportunity for us together to review our habitual postures and adopt a more conciliatory and harmonious communication style, take stock, critically evaluate and retune our approach to life – as individuals, as nations, as a species? It is not too difficult to hypothesise futures driven by the major issues that have driven us apart. Now, in our attempts to resist the virus, we have given ourselves a glimpse of some of the very things the climate change activists have wished to happen. With few planes in the air and the majority of cars off the roads, we have already witnessed clearer and cleaner air. Working at home has freed up the commuter driven traffic and left many people with more time to spend with their family. Freed from the continuing throng of tourists, cities like Venice are regenerating and cleansing themselves. This small preview of what a less travelled world might start to look like surely has some attraction. But of course, it does not come without cost. With the lack of tourism and the need to work at home, jobs and livelihoods have started to change. As with any revolution there are both winners and losers. The lockdown has distinguished starkly between essential and non-essential workers. That represents a useful starting point from which to assess what is truly of value in our way of life and what is peripheral as Salt made clear. This is a question that I would encourage readers to explore and to take forward with them through the resolution of the current situation. However, on the basis that educators are seen as providing essential services, now is the time to turn to the content of our current volume. Once again, I direct you to the truly international range of our contributors. They come from five different continents yet share a common focus on one of the most popular of shared cultural experiences – sport. Unsurprisingly three of our reviewed papers bring different insights to the world’s most widely shared sport of all – football, or as it would be more easily recognised in some parts of the globe - soccer. Leading these offerings is a comparison of fandom in Australia and China. The story presented by Knijnk highlights the rise of the fanatical supporters known as the ultras. The origin of the movement is traced to Italy, but it is one that claims allegiances now around the world. Kniijnk identifies the movement’s progression into Australia and China and, in pointing to its stance against the commercialisation of their sport by the scions of big business, argues for its deeper political significance and its commitment to the democratic ownership of sport. Reflecting the increasing availability and use of data in our modern societies, Karadog, Parim and Cene apply some of the immense data collected on and around the FIFA World Cup to the task of selecting the best team from the 2018 tournament held in Russia, a task more usually undertaken by panels of experts. Mindful of the value of using data in ways that can assist future decision making, rather than just in terms of summarising past events, they also use the statistics available to undertake a second task. The second task was the selection of the team with the greatest future potential by limiting eligibility to those at an early stage in their careers, namely younger than 28 and who arguably had still to attain their prime as well as having a longer career still ahead of them. The results for both selections confirm how membership of the wealthy European based teams holds the path to success and recognition at the global level no matter what the national origins of players might be. Thirdly, taking links between the sport and the world of finance a step further, Gomez-Martinez, Marques-Bogliani and Paule-Vianez report on an interesting study designed to test the hypothesis that sporting success within a community is reflected in positive economic outcomes for members of that community. They make a bold attempt to test their hypothesis by examining the relationship of the performance of three world leading clubs in Europe - Bayern Munich, Juventus and Paris Saint Germain and the performance of their local stock markets. Their findings make for some interesting thoughts about the significance of sport in the global economy and beyond into the political landscape of our interconnected world. Our final paper comes from Africa but for its subject matter looks to a different sport, one that rules the subcontinent of India - cricket. Norrbhai questions the traditional coaching of batting in cricket by examining the backlift techniques of the top players in the Indian Premier league. His findings suggest that even in this most traditional of sports, technique will develop and change in response to the changing context provided by the game itself. In this case the context is the short form of the game, introduced to provide faster paced entertainment in an easily consumable time span. It provides a useful reminder how in sport, techniques will not be static but will continue to evolve as the game that provides the context for the skilled performance also evolves. To conclude our pages, I must apologise that our usual book review has fallen prey to the current world disruption. In its place I would like to draw your attention to the announcement of a new publication which would make a worthy addition to the bookshelf of any international sports scholar. “Softpower, Soccer, Supremacy – The Chinese Dream” represents a unique and timely analysis of the movement of the most popular and influential game in the world – Association Football, commonly abbreviated to soccer - into the mainstream of Chinese national policy. The editorial team led by one of sports histories most recognised scholars, Professor J A Mangan, has assembled a who’s who of current scholars in sport in Asia. Together they provide a perspective that takes in, not just the Chinese view of these important current developments but also, the view of others in the geographical region. From Japan, Korea and Australia, they bring with them significant experience to not just the beautiful game, but sport in general in that dynamic and fast-growing part of the world. Particularly in the light of the European dominance identified in the Karog, Parim and Cene paper this work raises the question as to whether we can expect to see a change in the world order sooner rather than later. It remains for me to make one important acknowledgement. In my last editorial I alerted you to the sorts of decisions we as an editorial and publication team were facing with regard to ensuring the future of the journal. Debates as to how best to proceed while staying true to our vision and goals are still proceeding. However, I am pleased to acknowledge the sponsorship provided by The University of Macao for volume 42 and recognise the invaluable contribution made by ISCPES former president Walter Ho to this process. Sponsorship can provide an important input to the ongoing existence and strength of this journal and we would be interested in talking to other institutions or groups who might also be interested in supporting our work, particularly where their goals align closely with ours. May I therefore commend to you the works of our international scholars and encourage your future involvement in sharing your interest in and expertise with others in the world of comparative and international sport studies, John Saunders, Brisbane, May 2020

Abstract Background: Bromodomain and extra-terminal domain (BET) family proteins represent a novel target class for patients (pts) with myeloid malignancies. Pharmacologic inhibition of BET proteins transcriptionally downregulates critical pro-survival and anti-apoptotic genes. We hypothesized that combination of BET inhibitor (BETi) with hypomethylating agent (HMA) azacitidine (AZA) could lead to clinical benefit for high-risk (HR) pts with R/R MDS and AML. Methods: We conducted an investigator-initiated, single-center, phase I, 3+3 dose-escalation and cohort expansion study of PLX51107 (BETi) + AZA in pts with R/R HR MDS (intermediate-2 score or >10% blasts) or R/R AML. PLX51107 was administered PO on days 1-21 and AZA 75 mg/m2 IV on days 8-14 of a 28-day cycle. Dose-escalation phase of PLX51107 doses included: 40mg (n=4), 80mg (n=3), and 120mg; ultimately, no formal MTD was reached, therefore the 120mg dose was administered to the remaining 30 pts treated on study. Results: 37 pts were treated [R/R AML (n=33); R/R HR MDS (n= 4)]. Baseline characteristics included in Table. Median age was 64 years [18-85 years]. 51% female. Baseline cytogenetics: Notably, 18 pts (49%) had chromosome (chr) 3 abnormalities (abnl) [(either alone or with complex cytogenetics) with 15/18, or 89%, + for EVI1/MECOM gene rearrangement by FISH. 81-gene panel Next Generation Sequencing (NGS) showed: NRAS (n=11); TP53 (n=9); ASXL1, PTPN11, RUNX1, SF3B1, & WT1 (n=6 each). Median prior # therapies = 3 [1-9]; 97% had prior HMA therapy; 84% had prior venetoclax (VEN).17 (46%) pts had prior stem cell transplant (SCT); 7 of whom were on concurrent active immunosuppressive therapy for GVHD prophylaxis at time of enrollment and continued on study (n=6 tacrolimus; n=1 sirolimus). 9 had prior myeloproliferative neoplasm (MPN) or MDS preceding AML. 16 (43%) had prior malignancy (including lymphoma n=3). Toxicities: Median # cycles on therapy = 2 [1-19+]. Most common grade 1/2 non-hematologic toxicities: fatigue 3%; cholecystitis 3% and vomiting 3%. Notable grade 3/4 non-hematologic toxicities: 9 (24%) pts had elevated bilirubin/liver function tests (n=2 Grade 4 and n=7 Grade 3) and n=24 had infections. Hematologic toxicities were n=7 (4 Grade 3, 3 Grade 4) anemia; n=6 (all Grade 4) thrombocytopenia, n=3 (2 Grade 3, 1 Grade 4) neutropenia. Outcomes: Overall Response Rate (ORR) = 8/37 (22%): complete remission with incomplete platelet counts (CRp) (n=1); morphological leukemia-free state (MLFS) (n=2) (both MLFS responders had chr 3 abnl); hematologic improvement (HI) (n=5). Additionally, 5 other pts had >50% bone marrow blast reduction. 4 pts were able to stay on study ≥6 months, with one patient staying on active therapy with ongoing clinical benefit for ≥1 year (16.7 months+). Notably, 10/13 (77%) of all of these responding pts occurred in prior VEN-treated pts. 6/13 (46%) of all responses occurred in RUNX1 or NRAS/KRAS family-mutated pts. Median time on study was 4.8 months [0.4-16.7]. Median overall survival was 3.6 [0.4 - 16.7] months (Figure). One remarkable responder, a 70 year-old woman with R/R AML and extensive leukemia cutis, (prior VEN-based therapy), achieved CRp and almost complete resolution of all skin lesions with no major toxicities after 3 cycles of therapy. Laboratory correlative analysis: RNA-Seq analysis of mononuclear cells harvested on- treatment (day 3) vs pre-treatment demonstrated markedly greater fold changes in mRNA expressions in the complete responders, with downregulation of MYC, BCL2, IL7R and CDK6 genes and upregulation of HEXIM, CD93, DCXR and CDKN1A genes. Immunoblot analyses confirmed reduction in the protein levels of c-Myc, CDK6, BCL2 and BCL-xL and induction of BRD4 and HEXIM1 protein levels in the responding pts. Conclusions: In a heavily pre-treated, high-risk group of pts with R/R HR MDS and AML, with 49% chr 3 abnl, 46% prior SCT, and 25% TP53-mutated, we demonstrate that the combination of BETi and HMA is safe, well-tolerated, and results in modest clinical benefit predominantly in prior VEN-treated pts. Future directions may include investigation of novel BETi combinations in VEN-naïve pts, further investigation into high-risk subsets of pts with chr 3 abnl/EVI1/MECOM rearrangements, RUNX1, and RAS-family mutated pts, and further clinical/translational investigation of BETi activity in leukemia cutis/skin lesions in myeloid malignancies. ClinicalTrials.gov Identifier: NCT04022785. Figure 1 Figure 1. Disclosures Pemmaraju: Sager Strong Foundation: Other; Samus: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Cellectis S.A. ADR: Other, Research Funding; CareDx, Inc.: Consultancy; Aptitude Health: Consultancy; Springer Science + Business Media: Other; DAVA Oncology: Consultancy; Roche Diagnostics: Consultancy; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Daver: Abbvie: Consultancy, Research Funding; Novartis: Consultancy; Hanmi: Research Funding; Genentech: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Trovagene: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Amgen: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Glycomimetics: Research Funding; Novimmune: Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Ravandi: Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Prelude: Research Funding. Kadia: AstraZeneca: Other; Genfleet: Other; Astellas: Other; Cellonkos: Other; Ascentage: Other; Sanofi-Aventis: Consultancy; Pulmotech: Other; Pfizer: Consultancy, Other; Novartis: Consultancy; Liberum: Consultancy; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. DiNardo: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Forma: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Burger: Beigene: Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Short: Novartis: Honoraria; NGMBio: Consultancy; Jazz Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; Astellas: Research Funding; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Alvarado: Astex Pharmaceuticals: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Sun Pharma: Consultancy, Research Funding. Jain: TG Therapeutics: Honoraria; Beigene: Honoraria; Precision Biosciences: Honoraria, Research Funding; Incyte: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pfizer: Research Funding; AstraZeneca: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Pharmacyclics: Research Funding; Janssen: Honoraria; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Servier: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Verstovsek: Promedior: Research Funding; PharmaEssentia: Research Funding; NS Pharma: Research Funding; Ital Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding; Celgene: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Issa: Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding. Khoury: Kiromic: Research Funding; Angle: Research Funding; Stemline Therapeutics: Research Funding. Konopleva: Ablynx: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Cellectis: Other: grant support; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Rafael Pharmaceuticals: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Sanofi: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; KisoJi: Research Funding. Kantarjian: Astra Zeneca: Honoraria; Aptitude Health: Honoraria; Jazz: Research Funding; Daiichi-Sankyo: Research Funding; Astellas Health: Honoraria; Ipsen Pharmaceuticals: Honoraria; AbbVie: Honoraria, Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; BMS: Research Funding; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Borthakur: Takeda: Membership on an entity's Board of Directors or advisory committees; ArgenX: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy.

Abstract Background: DEC10-VEN is an effective regimen and offers better outcomes compared to intensive chemotherapy in older pts with newly diagnosed (ND) or relapsed/refractory (R/R) AML (Maiti. Am J Hematol 2021; Maiti. Cancer 2021). We report long term outcomes in major genomic subgroups. Methods: Pts received decitabine 20 mg/m 2 on D1-10 until CR/CRi, followed by 5-day cycles. VEN dose was 400 mg daily but held on C1D21 if D21 bone marrow (BM) had ≤5% blasts. VEN could be reduced to <14 days in cases of myelosuppression (DiNardo. Lancet Haematol 2020). Treatment-naïve group included pts with ND and secondary AML (sAML) without therapy for antecedent hematological disorder (AHD). Previously treated AML included sAML with prior therapy for AHD and R/R AML. Concomitant TKIs included gilteritinib (18), sorafenib (13), midostaurin (5), enasidenib (3) and ponatinib (1). Eligible pts could proceed to stem cell transplantation (SCT) after response. Endpoints were defined per ELN2017. NGS targeting entire coding regions of 81 myeloid genes was performed on screening BM sample with an analytical sensitivity of 5%. Measurable residual disease (MRD) was tested by multiparametric flow cytometry (sensitivity 0.1%). Results: Between January 2018 and April 2021 we enrolled 199 pts with ND AML (n=83), untreated sAML (n=20), treated sAML (n=25), and R/R AML (n=71). Median age of treatment-naïve pts was 72 yrs (range 61-72) and of previously treated pts was 67 yrs (range 18-85, Table 1). No pts had favorable risk cytogenetics. Median no. of prior therapies in previously treated pts was 2 (range 1-8) and 24% pts (23/96) had prior SCT. 21 treatment-naïve and 20 previously treated pts underwent SCT after response. Median follow-up for all pts was 25.4 mo. Among treatment-naïve pts, CR/CRi rates were high in all mutations subgroups ranging from 70-88% in pts with NPM1mut, FLT3mut, IDH1/2mut, TP53mut, RUNX1mut, K/NRASmut. Pts with ASXL1mut had modest CR/CRi rate of 56% (Table 2). FLT3 TKI was used in 71% FLT3mut pts (n=15/21). MRD negative rate among responding pts were high across all mutational subgroups ranging from 62-91%, except 55% in pts with ASXL1mut and 50% in pts with TP53mut. Median overall survival (OS) for treatment-naïve pts with NPM1mut was not reached (NR), IDH1/2mut was 29.6 mo, FLT3mut was 24.5 mo, RUNX1mut was 16.2 mo, ASXL1mut was 15.2 mo, K/NRASmut was 12.1 mo and TP53mut was 5.4 mo (Fig 1a-b). The median relapse-free survival (RFS) among treatment-naïve pts with NPM1mut was NR, IDH1/2mut was NR, FLT3mut was 20.0 mo, RUNX1mut was 9.7 mo, ASXL1mut was 8.5 mo, K/NRASmut was 6.5 mo and TP53mut was 3.1 mo (Fig 1c-d). Among NPM1+FLT3 co-mutated pts, outcomes in treatment-naïve pts (n=26) included ORR of 96%, CR/CRi in 88%, MRD negative in 92% (22/24), median OS NR and median RFS NR. Among previously treated NPM1+FLT3 pts (n=9), ORR was 78%, CR/CRi in 56%, MRD negative in 86% (6/7), median OS 12.4 mo and median RFS 6.6 mo. Among NPM1+DNMT3A co-mutated pts, outcomes in treatment-naïve pts (n=28) included ORR of 93%, CR/CRi in 89%, MRD negative in 79% (19/24), median OS 15.2 mo and median RFS 9.0 mo. Among previously treated NPM1+DNMT3A pts (n=6), ORR was 75%, CR/CRi in 50%, MRD negative in 75% (3/4), median OS was 4.7 mo and median RFS was 5.2 mo. Among previously treated pts CR/CRi rates in pts with NPM1mut was 68%, IDH1/2mut 50%, FLT3mut 42%, RUNX1mut 45%, ASXL1mut 38%, TP53mut 30%, and K/NRASmut was 26% (Table 2). FLT3 TKI used in 95% of FLT3mut pts (n=18/19). MRD negative rate among responding pts were high for pts with NPM1mut, FLT3mut, IDH1/2mut, RUNX1mut and ASXL1mut ranging from 60-87%, but were low for pts with K/NRASmut at 56% and TP53mut at 37%. The median OS among previously treated pts with IDH1/2mut was 16.9 mo, RUNX1mut was 13.7 mo, NPM1mut was 12.4 mo, ASXL1mut was 9.0 mo, FLT3mut was 6.4 mo, K/NRASmut was 6.0 mo, and for TP53mut was 4.5 mo (Fig 1e-f). The median RFS among treatment-naïve pts with K/NRASmut was 18.9 mo, NPM1mut was 15.6 mo, IDH1/2mut was 15.3, RUNX1mut was 12.9 mo, ASXL1mut was 10.7 mo, TP53mut was 9.4 mo, and for FLT3mut was 6.6 mo (Fig 1g-h). Conclusions: DEC10-VEN offered high rates of CR/CRi, negative MRD, favorable OS and RFS across several genomic subgroups of treatment-naïve AML including NPM1, FLT3, IDH1/2 and modest outcomes in pts with these mutations in salvage setting. Outcomes in pts with TP53, RUNX1, ASXL1 and K/NRAS were suboptimal. Outcomes with FLT3 VEN HMA triplet was encouraging, particularly for frontline FLT3mut pts. Figure 1 Figure 1. Disclosures DiNardo: Novartis: Honoraria; Takeda: Honoraria; ImmuneOnc: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Agios/Servier: Consultancy, Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Forma: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Pemmaraju: Affymetrix: Consultancy, Research Funding; Cellectis S.A. ADR: Other, Research Funding; Samus: Other, Research Funding; Blueprint Medicines: Consultancy; Celgene Corporation: Consultancy; Clearview Healthcare Partners: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Protagonist Therapeutics, Inc.: Consultancy; Aptitude Health: Consultancy; Incyte: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; LFB Biotechnologies: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Plexxicon: Other, Research Funding; CareDx, Inc.: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Springer Science + Business Media: Other; DAVA Oncology: Consultancy; Roche Diagnostics: Consultancy; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Daver: Amgen: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Sevier: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Hanmi: Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Borthakur: Astex: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; Ryvu: Research Funding; Protagonist: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; ArgenX: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy. Ravandi: Taiho: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Prelude: Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria; Novartis: Honoraria; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Alvarado: BerGenBio: Research Funding; Jazz Pharmaceuticals: Research Funding; Sun Pharma: Consultancy, Research Funding; MEI Pharma: Research Funding; FibroGen: Research Funding; CytomX Therapeutics: Consultancy; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding. Kadia: BMS: Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; Jazz: Consultancy; Liberum: Consultancy; Aglos: Consultancy; Amgen: Other: Grant/research support; Novartis: Consultancy; AbbVie: Consultancy, Other: Grant/research support; Genentech: Consultancy, Other: Grant/research support; Pfizer: Consultancy, Other; Pulmotech: Other; Sanofi-Aventis: Consultancy; Cellonkos: Other; Ascentage: Other; Genfleet: Other; Astellas: Other; AstraZeneca: Other. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Short: Novartis: Honoraria; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Astellas: Research Funding; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Jain: Adaptive Biotechnologies: Honoraria, Research Funding; Janssen: Honoraria; Aprea Therapeutics: Research Funding; Genentech: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Servier: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; TG Therapeutics: Honoraria; Beigene: Honoraria; Incyte: Research Funding; Cellectis: Honoraria, Research Funding; Pfizer: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Research Funding; AbbVie: Honoraria, Research Funding. Wierda: Juno Therapeutics: Research Funding; KITE Pharma: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Cyclacel: Research Funding; Loxo Oncology, Inc.: Research Funding; Acerta Pharma Inc.: Research Funding; Genzyme Corporation: Consultancy; Miragen: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Sunesis: Research Funding; GSK/Novartis: Research Funding; Genentech: Research Funding; Gilead Sciences: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; AbbVie: Research Funding; AstraZeneca: Research Funding. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Takahashi: GSK: Consultancy; Celgene/BMS: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Burger: Beigene: Research Funding, Speakers Bureau; Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Verstovsek: Incyte Corporation: Consultancy, Research Funding; PharmaEssentia: Research Funding; Promedior: Research Funding; AstraZeneca: Research Funding; NS Pharma: Research Funding; Ital Pharma: Research Funding; Celgene: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; Sierra Oncology: Consultancy, Research Funding; Gilead: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Andreeff: Karyopharm: Research Funding; Syndax: Consultancy; Medicxi: Consultancy; Oxford Biomedica UK: Research Funding; Amgen: Research Funding; ONO Pharmaceuticals: Research Funding; Glycomimetics: Consultancy; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Research Funding; Breast Cancer Research Foundation: Research Funding; Aptose: Consultancy; Senti-Bio: Consultancy; AstraZeneca: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company. Bose: CTI BioPharma: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Sierra Oncology: Honoraria; NS Pharma: Research Funding; Celgene Corporation: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Novartis: Honoraria; Constellation Pharmaceuticals: Research Funding; Pfizer: Research Funding; Promedior: Research Funding. Ferrajoli: BeiGene: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board ; AstraZeneca: Other: Advisory Board, Research Funding. Thompson: Gilead: Other: Institution: Advisory/Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding. Welch: Janssen: Research Funding; Notable Labs: Research Funding. Kantarjian: Ipsen Pharmaceuticals: Honoraria; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; Aptitude Health: Honoraria; Jazz: Research Funding; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria; Astellas Health: Honoraria; Daiichi-Sankyo: Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Astra Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Ascentage: Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Konopleva: Ablynx: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Ascentage: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Cellectis: Other: grant support; KisoJi: Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Sanofi: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding. OffLabel Disclosure: Off-label use - venetoclax in relapsed/refractory AML

Abstract Background: Older patients (pt) with acute myeloid leukemia (AML) and patients with high-risk myelodysplastic syndrome / chronic myelomonocytic leukemia (HR MDS/CMML) have poor outcomes. We showed that 10-day decitabine with venetoclax (DEC10-VEN) is a safe and effective strategy and offers potentially better outcomes compared to intensive chemotherapy in older pts with newly diagnosed (ND) AML, as well as relapsed or refractory (R/R) AML (DiNardo et al. Lancet Haematol 2020; Maiti et al. Am J Hematol 2021; Maiti et al. Cancer 2021). We here in present updated results of this prospective phase II trial (NCT03404193). Methods: Eligibility criteria included ECOG PS ≤3, WBC ≤10 x10 9/L, and adequate organ function. Decitabine dose was 20 mg/m 2 IV daily on D1-10 until CR/CRi, followed by 5-day cycles. Venetoclax was given on D1-28 in cycle 1 but was interrupted on C1D21 until count recovery if the D21 bone marrow (BM) had ≤5% blasts. Venetoclax dose was 400 mg PO daily or equivalent with concomitant azole antifungals as previously described (DiNardo et al. Lancet Haematol. 2020). Venetoclax duration could be reduced to 14 to 7 days in subsequent cycles in cases of prolonged myelosuppression. All pts received cytoreduction prior to start, tumor lysis syndrome (TLS) prophylaxis and antimicrobial prophylaxis. Concomitant FLT3 tyrosine kinase inhibitors were allowed in FLT3-mutated AML. Pts could proceed to allogeneic stem-cell transplantation (SCT) after response, if eligible. Primary objective was overall response rate and secondary objectives included safety and overall survival. Outcomes and endpoints were defined per ELN2017 criteria. Measurable residual disease (MRD) was assessed using multiparametric flow cytometry (sensitivity 0.1%) and reported for all responding pts with evaluable MRD sample. Results: Between January 2018 and April 2021 we enrolled 219 pts with ND AML (n=83), untreated sAML (n=20), treated sAML (n=25), R/R AML (n=71) and HR MDS/CMML (n=20). This high-risk cohort included 54% of pts ≥70 yrs (n=119), 57% pts were men, 29% pts had ECOG PS ≥2, and 57% pts had adverse-risk AML (Table 1). The 30 mortality was 1% for ND pts and 3.6% for all pts. There were 346 treatment-related adverse events in 181 patients including infections with grade 3/4 neutropenia (40%), febrile neutropenia (29%), and infection with unknown ANC (17%, Table 2). There were 11 grade 5 events including infections with grade 3/4 neutropenia (n=6), infections with unknown ANC (n=4), and renal failure (n=1). The CR/CRi rate in ND AML was 83%, in untreated sAML was 65%, in treated sAML was 40%, in R/R AML was 42% and in HR-MDS/CMML was 20% (Table 3). Rates of negative measurable residual disease (MRD) by flow cytometry (0.1%) in ND AML was 73%, in untreated sAML was 53%, in treated sAML was 65%, and in R/R AM was 58%. After a median follow-up of 24.7 months (mo), the median OS in ND AML was 16.2 mo, in untreated sAML was 10.7 mo, in treated sAML was 5.8 mo, in R/R AML was 7.8 mo, and in HR-MDS/CMML was 10.1 mo (Fig. 1a). The 1-yr OS in ND AML was 54%, in untreated sAML was 41%, in treated sAML was 36%, in R/R AML was 41%, and in HR MDS/CMML was 35%. Median RFS for pts with ND AML was 10.9 mo, in the untreated sAML was 6.7 mo, in treated sAML was 11.4 mo, and in R/R AML was 8.4 mo (Fig. 1b). 44 pts underwent SCT after achieving response including ND AML (n=17), untreated sAML (n=4), treated sAML (n=3), R/R AML (n=16), and HR-MDS/CMML (n=4). The 100-day post-SCT mortality was 9% (n=4). Median OS after SCT in pts with previously untreated AML was 31.1 mo and in previously treated AML was 15.0 mo (Fig. 1c) 199 pts (91%) have discontinued treatment and 69 pts (32%) are alive. The most common reasons for treatment discontinuation included refractory disease in 49 pts (22%), relapse in 45 pts (21%), SCT in 44 pts (20%). Conclusions: DEC10-VEN is an effective therapy for older pts with ND and R/R AML. Transition to SCT after response with DEC10-VEN may offer long-term survival advantage in this older/unfit population with both ND and R/R AML. The trial continues to accrue. Based on these findings we have initiated a phase II trial of 10-day oral decitabine (ASTX727) with venetoclax in R/R AML (NCT04975919). Figure 1 Figure 1. Disclosures DiNardo: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Pemmaraju: DAVA Oncology: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Cellectis S.A. ADR: Other, Research Funding; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; MustangBio: Consultancy, Other; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Affymetrix: Consultancy, Research Funding; Roche Diagnostics: Consultancy; Samus: Other, Research Funding; Blueprint Medicines: Consultancy; Clearview Healthcare Partners: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Celgene Corporation: Consultancy; Incyte: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Plexxicon: Other, Research Funding; Aptitude Health: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Daver: Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Trovagene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Hanmi: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novimmune: Research Funding; Astellas: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Glycomimetics: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Issa: Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Astex: Research Funding; Protagonist: Consultancy. Ravandi: Astex: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AstraZeneca: Honoraria; Prelude: Research Funding; Novartis: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Alvarado: MEI Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; Sun Pharma: Consultancy, Research Funding. Kadia: AbbVie: Consultancy, Other: Grant/research support; Cure: Speakers Bureau; Genfleet: Other; Cellonkos: Other; Sanofi-Aventis: Consultancy; Liberum: Consultancy; Astellas: Other; AstraZeneca: Other; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; BMS: Other: Grant/research support; Dalichi Sankyo: Consultancy; Ascentage: Other; Pulmotech: Other; Novartis: Consultancy; Pfizer: Consultancy, Other; Aglos: Consultancy; Amgen: Other: Grant/research support. Short: Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; Astellas: Research Funding; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Novartis: Honoraria. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Jain: Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pfizer: Research Funding; Servier: Honoraria, Research Funding; Janssen: Honoraria; Incyte: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Beigene: Honoraria; Cellectis: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; TG Therapeutics: Honoraria; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Wierda: Janssen: Research Funding; Karyopharm: Research Funding; Genentech: Research Funding; Xencor: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta Pharma Inc.: Research Funding; AstraZeneca: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Cyclacel: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Miragen: Research Funding; Sunesis: Research Funding; GSK/Novartis: Research Funding; KITE Pharma: Research Funding; Loxo Oncology, Inc.: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. Sasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Takahashi: Novartis: Consultancy; Celgene/BMS: Consultancy; GSK: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Burger: AstraZeneca: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Verstovsek: CTI BioPharma: Research Funding; Ital Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; Genentech: Research Funding; PharmaEssentia: Research Funding; Promedior: Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Andreeff: Glycomimetics: Consultancy; Aptose: Consultancy; AstraZeneca: Research Funding; Oxford Biomedica UK: Research Funding; Amgen: Research Funding; Syndax: Consultancy; Medicxi: Consultancy; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Breast Cancer Research Foundation: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; ONO Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Senti-Bio: Consultancy. Bose: Pfizer: Research Funding; Constellation Pharmaceuticals: Research Funding; Novartis: Honoraria; Sierra Oncology: Honoraria; Kartos Therapeutics: Honoraria, Research Funding; Blueprint Medicines: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding. Ferrajoli: AstraZeneca: Other: Advisory Board, Research Funding; BeiGene: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board . Thompson: Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding. Kantarjian: AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; BMS: Research Funding; Jazz: Research Funding; Ascentage: Research Funding; Daiichi-Sankyo: Research Funding; Ipsen Pharmaceuticals: Honoraria; Astra Zeneca: Honoraria; KAHR Medical Ltd: Honoraria; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; Astellas Health: Honoraria; Novartis: Honoraria, Research Funding; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Konopleva: Agios: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; KisoJi: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Cellectis: Other: grant support; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Stemline Therapeutics: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support.

Abstract Background Anemia is common in patients (pts) with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF). Furthermore, anemia is an on-target effect of therapeutic Janus kinase 2 (JAK2) inhibition, and is a frequent cause of ruxolitinib (rux) discontinuation (d/c) in clinical practice (Kuykendall, Ann Hematol 2018). Current therapies for anemia of MF (erythropoietin and analogs, danazol, IMiDs®) are unsatisfactory. Sotatercept (ACE-011) is a first-in-class, activin receptor type IIA ligand trap that may improve anemia by sequestering stromal transforming growth factor beta superfamily ligands that suppress terminal erythropoiesis (Iancu-Rubin, Exp Hematol 2013). Methods This is a phase 2, investigator-initiated, open-label, single institution study of sotatercept, administered subcutaneously every 3 weeks, in 2 cohorts of anemic pts (Hgb <10 g/dl on every determination for 12 w or transfusion-dependent (TD) per IWG-MRT criteria (Tefferi, Blood 2013)) with MF: as a single agent, and in combination with a stable dose of rux. Pts on rux must have been on it for ≥6 months with a stable dose for the preceding ≥8 weeks, and receive sotatercept at a dose of 0.75 mg/kg. Monotherapy pts receive either 0.75 or 1 mg/kg of sotatercept. In both cohorts, anemia response is defined as achievement of transfusion independence (TI) in TD pts, or an increase in Hgb level from baseline of ≥1.5 g/dl sustained for ≥12 wks in non-TD pts (Gale, Leuk Res 2011). Pts must be on-study for ≥12 w (84 d) to be response-evaluable. Results A total of 56 pts have been treated; one pt received only 0.3 mg/kg of sotatercept and is not considered further. Thirty four pts received sotatercept alone and 21 in combination with rux. Baseline characteristics appear in Table 1, panel A. Seventeen TD and 17 non-TD pts received sotatercept alone for a median of 11 (3-73) cycles. Sixteen pts received 0.75 mg/kg and 18, 1 mg/kg. Eight of 27 (30%) evaluable pts responded. Of these, 5 were anemia responses; 3 TD pts achieved TI. Six responses occurred at the 0.75 mg/kg dose, and 2 at the 1 mg/kg dose. Median time to response (TTR) was 19 (1-22) days and median duration of response (DOR), 23.3 (3.9-68.4) months. Seven pts (21%) were on-study for <84 d and hence not response-evaluable: 2 because of stem cell transplant (SCT), 2 due to logistical (travel) issues, and 1 each d/ced sotatercept because of hypertension (HTN), unrelated medical problems and pt decision. Two pts continue on study. Reasons for d/c include lack or loss of response (14), progressive MF (6), SCT (4), travel logistics (3), patient decision (2), hypertension (1), unrelated medical complications (1) and transformation to AML (1). The combination cohort comprised 15 non-TD pts and 6 TD pts. Median rux dose at study entry was 10 (5-25) mg bid. Median number of cycles was 25 (2-49). Six of 19 (32%) evaluable pts in the combination cohort responded, all non-TD pts. Median TTR was 14 (6-147) days and median DOR, 18.2 (3.7-56.8) months. Two pts (10%) were on-study for <84 d and hence not response-evaluable, 1 due to SCT and 1 due to loss of insurance. Two pts remain on study. Reasons for d/c include lack or loss of response (8), SCT (4), progressive MF (3), travel logistics (2), loss of insurance (1) and pt decision (1). Several non-response-evaluable pts in both cohorts achieved ≥1.5 g/dl increments in Hgb from baseline that were not sustained for ≥12 w because of early d/c from the study. An additional pt in the combination cohort required a rux dose increase, leading to failure to sustain a ≥1.5 g/dl Hgb improvement for ≥12 w. Across both cohorts, several responding pts required multiple protocol-specified drug holidays because of Hgb levels ≥11.5 g/dl, with resumption of sotatercept once Hgb was <11 g/dl. Sotatercept was well-tolerated (Table 1, panel B). Grade 3 adverse events possibly related to sotatercept were HTN (n=7) and limb (bone/muscle/joint) or back pain (n=2). Conclusions Sotatercept is safe and effective against anemia of MPN-associated MF, both in non-TD and TD pts, with a response rate of 30% when used alone and 32% when used in conjunction with a stable dose of rux. All responses in the rux cohort occurred in non-TD pts. The trial (NCT01712308) has been closed to new pt enrollment. Figure 1 Figure 1. Disclosures Bose: Sierra Oncology: Honoraria; NS Pharma: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Novartis: Honoraria; BMS: Honoraria, Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Promedior: Research Funding. Pemmaraju: Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Cellectis S.A. ADR: Other, Research Funding; Sager Strong Foundation: Other; CareDx, Inc.: Consultancy; Plexxicon: Other, Research Funding; Aptitude Health: Consultancy; DAVA Oncology: Consultancy; Celgene Corporation: Consultancy; MustangBio: Consultancy, Other; Roche Diagnostics: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; LFB Biotechnologies: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Samus: Other, Research Funding; Incyte: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Springer Science + Business Media: Other; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Daver: Trovagene: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Glycomimetics: Research Funding; Novimmune: Research Funding; FATE Therapeutics: Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Hanmi: Research Funding; ImmunoGen: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Genentech: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Kadia: BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support; Novartis: Consultancy; AstraZeneca: Other; Astellas: Other; Genfleet: Other; Ascentage: Other; Jazz: Consultancy; Liberum: Consultancy; Dalichi Sankyo: Consultancy; Genentech: Consultancy, Other: Grant/research support; Cure: Speakers Bureau; Pfizer: Consultancy, Other; Pulmotech: Other; Sanofi-Aventis: Consultancy; Cellonkos: Other. Andreeff: Karyopharm: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy; Syndax: Consultancy; ONO Pharmaceuticals: Research Funding; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Medicxi: Consultancy; AstraZeneca: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; Aptose: Consultancy; Breast Cancer Research Foundation: Research Funding; Oxford Biomedica UK: Research Funding; Amgen: Research Funding; Senti-Bio: Consultancy. Cortes: Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Jain: ADC Therapeutics: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; Janssen: Honoraria; Fate Therapeutics: Research Funding; Beigene: Honoraria; Cellectis: Honoraria, Research Funding; TG Therapeutics: Honoraria; AstraZeneca: Honoraria, Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Servier: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Borthakur: Ryvu: Research Funding; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees. Alvarado: MEI Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; Sun Pharma: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; Jazz Pharmaceuticals: Research Funding. Huynh-Lu: Incyte Corporation: Speakers Bureau. Nguyen-Cao: Incyte Corporation: Speakers Bureau. Kantarjian: AbbVie: Honoraria, Research Funding; Jazz: Research Funding; Astellas Health: Honoraria; Precision Biosciences: Honoraria; NOVA Research: Honoraria; Taiho Pharmaceutical Canada: Honoraria; Immunogen: Research Funding; Ipsen Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Ascentage: Research Funding; Daiichi-Sankyo: Research Funding; Aptitude Health: Honoraria; Astra Zeneca: Honoraria; Pfizer: Honoraria, Research Funding; BMS: Research Funding; KAHR Medical Ltd: Honoraria; Amgen: Honoraria, Research Funding. Verstovsek: NS Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Promedior: Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; Ital Pharma: Research Funding; Gilead: Research Funding; Roche: Research Funding; Protagonist Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. OffLabel Disclosure: Sotatercept is an activin receptor ligand trap. This trial evaluates sotatercept for the treatment of anemia in patients with MPN-associated myelofibrosis.

Introduction: Emicizumab-a subcutaneously administered, bispecific, humanized, monoclonal antibody-promotes effective hemostasis in people with hemophilia A (PwHA). The primary efficacy and safety of emicizumab were reported previously, but long-term data are limited. Here, data from a wide age-range of PwHA with/without factor (F)VIII inhibitors enrolled in the Phase III HAVEN 1 (NCT02622321), HAVEN 2 (NCT02795767), HAVEN 3 (NCT02847637), and HAVEN 4 (NCT03020160) studies are pooled to establish the durable efficacy and safety of emicizumab. Methods: The studies enrolled pediatric and adult PwHA with/without FVIII inhibitors. Participants received emicizumab prophylaxis 1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. All participants assigned to receive emicizumab (including those assigned to control arms who later switched) are included in this analysis. Participants and/or caregivers recorded outcomes of bleeding events via the Bleed and Medication Questionnaire (BMQ). Data from HAVEN 1-4 were pooled for an aggregate analysis of emicizumab efficacy and safety. Efficacy endpoints include calculated mean annualized bleed rates (ABRs; discrete, consecutive 24-week treatment intervals), model-based ABRs (calculated via negative binomial regression for full study period), percentage of participants with zero and 1-3 treated bleeds, and annualized cumulative dose of coagulation factor (ACD). Safety endpoints include incidence of adverse events (AEs) and AEs of special interest. Results: Overall, 400 PwHA in HAVEN 1, 2, 3 and 4 (n=113, 88, 151, and 48, respectively) are included in the efficacy analysis for a total of 970.3 patient years (cutoff: 15 May 2020). The safety population comprises 399 PwHA who received ≥1 dose of emicizumab (1 PwHA was randomized to receive emicizumab but did not start treatment). The median age at baseline was 28.5 (range 1-77) years. The majority of participants were White (66.8%) or Asian (18.8%); 52.3% had FVIII inhibitors. In the 24 weeks prior to study entry, 60.9% of participants had target joints. The median duration of efficacy period was 120.4 (interquartile range 89.0-164.4) weeks; 85.0% of participants had an efficacy period of ≥74 weeks; 11 participants (2.8%) discontinued study treatment. Across all 4 studies, 90.9-94.8% of the observation period was covered by completed BMQs. Across all studies, the model-based treated bleed ABR was 1.4 (95% confidence interval 1.1-1.7); treated bleed ABRs remained low throughout, and were seen to decrease with successive 24-week treatment intervals (Table 1). During Weeks 121-144 (n=170), 82.4% of participants had zero treated bleeds, and 15.3% of participants had 1-3 treated bleeds. During the same period, 91.8% and 90.0% had zero treated spontaneous/joint bleeds respectively (Figure 1). The proportion of participants with target joints reduced from 60.9% prior to study entry to 4.6% at Weeks 1-24, then <1.5% in all subsequent treatment intervals. ACD of FVIII (Table 2), activated prothrombin complex concentrate (aPCC) and activated recombinant FVII (rFVIIa, Table 3) generally decreased across each 24-week treatment interval. Emicizumab was well tolerated (Table 4), and no participants discontinued due to AEs beyond the five previously described (Oldenburg et al. N Engl J Med 2017; Young et al. Blood 2019; Mahlangu et al. N Engl J Med 2018; Pipe et al. Lancet Haem 2019). At data cut, 1 fatality, 3 thrombotic microangiopathies (TMAs), and 4 thromboembolic events (TEs) have been reported; all but 1 occurred in HAVEN 1. All TMAs and 2 of 4 TEs were associated with concomitant aPCC use. The percentage of participants with ≥1 drug-related AE in Weeks 1-24, 25-48 and 49-72 were 28.8%, 6.8%, and 3.0% respectively; over the same intervals, injection site reactions were observed in 23.3%, 4.8%, and 2.5% of participants. Conclusions: With nearly 3 years of follow-up, emicizumab maintained low bleed rates in PwHA of all ages, with/without FVIII inhibitors. ABRs continued to decrease and the proportion of participants with zero treated bleeds increased with each consecutive 24-week period; the trend was the same for the proportion of participants with zero joint bleeds and almost all target joints resolved. The ACDs of FVIII, aPCC, and rFVIIa decreased with successive treatment intervals. Emicizumab remains well tolerated over long-term follow-up, and no new safety concerns have been identified to date. Disclosures Callaghan: Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biomarin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Research Funding; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Hema Biologics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alnylum: Current equity holder in publicly-traded company; Spark: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; Roche/Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; NovoNordisk: Other, Speakers Bureau; Sancillio: Other. Négrier:CSL Behring, Octapharma, Shire/Takeda, Sobi: Research Funding; CSL, F. Hoffmann-La Roche Ltd, Sobi: Other: Travel support; Bayer, Biomarin, CSL Behring, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche Ltd, Sanofi, Shire/Takeda, Sobi, Spark: Consultancy. Paz-Priel:Genentech, Inc: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Other: All authors received editorial support for this abstract, provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche.. Chang:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Chebon:F. Hoffmann-La Roche Ltd: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Lehle:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in private company. Mahlangu:CSL Behring, Catalyst Biosciences, Freeline Therapeutics, Novo Nordisk, F. Hoffmann-La Roche Ltd, Sanofi, Spark and Takeda: Consultancy; South Africa Medical Research Council, Wits Health Consortium, Colleges of Medicine of South Africa: Membership on an entity's Board of Directors or advisory committees; CSL Behring, Catalyst Biosciences, Novo Nordisk, F. Hoffmann-La Roche Ltd, Sanofi, Spark and Takeda: Speakers Bureau; BioMarin, CSL Behring, Freeline Therapeutics, Novo Nordisk, Novartis, Pfizer, Sanofi, F. Hoffmann-La Roche Ltd, uniQure: Research Funding. Young:Bayer, CSL Behring, Freeline, UniQure: Consultancy; Genentech/Roche, Grifols, and Takeda: Research Funding; BioMarin, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Sanofi Genzyme, Spark, Takeda, and UniQure: Honoraria. Kruse-Jarres:Biomarin, Chugai Pharmaceutical Co., CSL Behring, CRISPR Therapeutics, Genentech, Inc.: Consultancy; CSL Behring, Genentech, Inc., Spark: Research Funding; Biomarin, Chugai Pharmaceutical Co., CSL Behring, CRISPR Therapeutics, Genentech, Inc.: Honoraria; F. Hoffmann-La Roche Ltd: Speakers Bureau. Mancuso:Bayer, CSL Behring, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd, Octapharma, Kedrion, Grifols, Sobi, PedNet Foundation: Consultancy; Bayer, CSL Behring, Novo Nordisk, F. Hoffmann-La Roche Ltd, Octapharma, Grifols, Sobi: Speakers Bureau; Bayer, CSL Behring, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd, Octapharma, Kedrion, Grifols, Catalyst, Kedrion, Sobi: Membership on an entity's Board of Directors or advisory committees; Center for Thrombosis and Hemorrhagic Diseases, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy: Current Employment. Niggli:F Hoffmann-La Roche Ltd: Current Employment. Kuebler:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Selak Bienz:F. Hoffmann-La Roche Ltd: Current Employment. Shima:Chugai Pharmaceutical Co., F. Hoffmann-La Roche Ltd, BioMarin, Bayer, Sanofi: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co. , Sanofi, Bayer, Sysmex: Speakers Bureau; Patents related to anti-FIXa/FX bispecific antibodies: Patents & Royalties; Chugai Pharmaceutical Co.: Honoraria; Chugai Pharmaceutical Co. , F. Hoffmann-La Roche Ltd, Sanofi, CSL Behring, KM Biologics, Novo Nordisk, Shire/Takeda: Research Funding; Chugai Pharmaceutical Co.: Consultancy. Jimenez-Yuste:F. Hoffman-La Roche Ltd, Novo Nordisk, Takeda, Sobi, Pfizer, Grifols, Octapharma, CSL Behring, Bayer: Honoraria; F. Hoffman-La Roche Ltd, Novo Nordisk, Takeda, Sobi, Pfizer: Consultancy; Grifols, Novo Nordisk, Takeda, Sobi, Pfizer: Research Funding. Schmitt:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Asikanius:Fimea: Current Employment; F Hoffman-La Roche Ltd: Ended employment in the past 24 months; F Hoffmann-La Roche Ltd: Divested equity in a private or publicly-traded company in the past 24 months. Levy:F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Ended employment in the past 24 months; Spark Therapeutics: Current Employment; Baxalta US: Patents & Royalties: Royalties from ADAMTS13 patent . Pipe:Medical and Scientific Advisory Council to the National Hemophilia Foundation; Medical Advisory Board to World Federation of Hemophilia: Membership on an entity's Board of Directors or advisory committees; Apcintex, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure: Consultancy; Siemens: Research Funding. Oldenburg:Bayer, BioMarin, Biotest, Chugai Pharmaceuticals Co., CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche, Ltd, Spark, Swedish Orphan Biovitrum and Takeda: Speakers Bureau; Bayer, BioMarin, Biotest, Chugai Pharmaceuticals Co., CSL Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche. Ltd, Spark, Swedish Orphan Biovitrum and Takeda: Other; Bayer, BioMarin, Biotest, Chugai Pharmaceuticals Co., CSL Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche, Ltd, Spark, Swedish Orphan Biovitrum and Takeda: Membership on an entity's Board of Directors or advisory committees; University Clinic Bonn: Current Employment; Bayer, Biotest, CSL Behring, Novo Nordisk, Octapharma, Pfizer and Takeda: Research Funding; Bayer, BioMarin, Biotest, Chugai Pharmaceuticals Co., CSL Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche, Ltd, Spark, Swedish Orphan Biovitrum and Takeda: Honoraria.

Abstract Background The COVID-19 pandemic has elicited imposition of some form of travel restrictions by almost all countries in the world. Most restrictions currently persist, although some have been gradually eased. It remains unclear if the trade-off from the unprecedented disruption to air travel was well worth for pandemic containment. Method A comparative analysis was conducted on Singapore, Taiwan, Hong Kong and South Korea’s COVID-19 response. Data on COVID-19 cases, travel-related and community interventions, socio-economic profile were consolidated. Trends on imported and local cases were analyzed using computations of moving averages, rate of change, particularly in response to distinct waves of travel-related interventions due to the outbreak in China, South Korea, Iran & Italy, and Europe. Results South Korea’s travel restrictions were observed to be consistently more lagged in terms of timeliness and magnitude, with their first wave of travel restrictions on flights departing from China implemented 34 days after the outbreak in Wuhan, compared to 22–26 days taken by Singapore, Taiwan and Hong Kong. South Korea’s restrictions against all countries came after 91 days, compared to 78–80 days for the other three countries. The rate of change of imported cases fell by 1.08–1.43 across all four countries following the first wave of travel restrictions on departures from China, and by 0.22–0.52 in all countries except South Korea in the fifth wave against all international travellers. Delayed rate of change of local cases resulting from travel restrictions imposed by the four countries with intrinsic importation risk, were not observed. Conclusions Travel restriction was effective in preventing COVID-19 case importation in early outbreak phase, but may still be limited in preventing general local transmission. The impact of travel restrictions, regardless of promptness, in containing epidemics likely also depends on the effectiveness of local surveillance and non-pharmaceutical interventions concurrently implemented.

The coronavirus disease 2019 (COVID-19) pandemic has affected almost all countries and territories. As of December 6, 2020, the United States of America and India have the highest prevalence. Each country has implemented different strategies to control and reduce the spread of disease. Here, the association between prevalence number and health policies is evaluated by comparing 2 groups of countries: (1) Italy, the United States of America, Germany, Spain, and India with a higher prevalence than a linear trend line; and (2) Singapore and China with a lower or equal prevalence than linear forecasts. A rapid overview revealed that many countries have similar strategies for controlling COVID-19, including the suspension of air travel, the lockdown on the cities with the most cases detected, active case findings, monitoring of close contacts, and raising public awareness. Also, they used a gradual and phased plan to reopen activities. So, the difference between countries in the burden of COVID-19 can be attributable to the strict mode and nonstrict mode of implementation of strategies. Limitations at the national levels call for systemic rather than regional strategies.

Since the beginning of 2020, with the eclosion of the Covid-19 pandemic, airports have been included among the main hotspots for the diffusion of the disease. Several limitations affected the possibility for people to travel, with diverse approaches between the countries, and with differences among who was authorized to travel and who was not. This caused a contraction on the number of passengers transiting in the airports in all the countries. However the commercial international aviation has never stopped, and despite the reduction of passengers the airports managed to implement health security protocols for the Covid-19 diffusion control. Before the pandemic, other challenges already affected airports’ security protocols, such as the “terrorist threat”, making of these places “nervous systems” (as defined by Maguire and Pétercsak). After one year and half from the beginning of the pandemic, with the vaccination campaigns accelerating in various countries (with the clear differences due to governments’ political choices and countries’ access to vaccines) the air travels have returned to a condition similar to previous one. An increasing number of planes flying and an increasing number of passengers can be registered everywhere. Meanwhile, the sanitary attention to the Covid-19 diffusion contention continues to be a concern in the space organization of airports.This ethnographic photoessay aims at describing the visual presence of the Covid in the airports. The work focuses on four airports in three countries the author passed through in June 2021. They are the airports of Salvador da Bahia (Brazil), Lisbon (Portugal), Rome and Venice (Italy). Despite the differences between the countries in the approached adopted to contain the diffusion of the pandemic, airports are subjected to standardized international protocols. These are intended to (re)produce similar safety measures in the diverse airports. Meanwhile, airports are designed not to be identitarian, historical and relational, but yes to be experienced as “non places” (as Augé defined these places). However, each airport introduces several dimensions of its specific location, of its specific local health politics, of its specific passengers’ flow, and so on, making of them a peculiar place to observe the space design for Covid diffusion control. Despite the definition of the Covid as an “invisible enemy”, used in general media in diverse countries, the thesis is that the presence of the virus is highly visible to everyone passing in some airport, independently from the specific country. Meanwhile, the diverse airports introduce their own local and specific visual modalities to achieve passengers. Pictures included in this ethnographic photoessay focus on some of these modalities, such as the hand gel dispensers, instructions and prohibitions for preventing Covid dissemination, among other. Covid’s aesthetics in airports highlights how the pandemic affected people visual and sensorial experiences of these places and of their designs.

Abstract Novel Coronavirus (2019-nCoV [SARS-COV-2]) was detected in humans during the last week of December 2019 at Wuhan city in China, and caused 24 554 cases in 27 countries and territories as of 5 February 2020. The objective of this study was to estimate the risk of transmission of 2019-nCoV through human passenger air flight from four major cities of China (Wuhan, Beijing, Shanghai and Guangzhou) to the passengers' destination countries. We extracted the weekly simulated passengers' end destination data for the period of 1–31 January 2020 from FLIRT, an online air travel dataset that uses information from 800 airlines to show the direct flight and passengers' end destination. We estimated a risk index of 2019-nCoV transmission based on the number of travellers to destination countries, weighted by the number of confirmed cases of the departed city reported by the World Health Organization (WHO). We ranked each country based on the risk index in four quantiles (4th quantile being the highest risk and 1st quantile being the lowest risk). During the period, 388 287 passengers were destined for 1297 airports in 168 countries or territories across the world. The risk index of 2019-nCoV among the countries had a very high correlation with the WHO-reported confirmed cases (0.97). According to our risk score classification, of the countries that reported at least one Coronavirus-infected pneumonia (COVID-19) case as of 5 February 2020, 24 countries were in the 4th quantile of the risk index, two in the 3rd quantile, one in the 2nd quantile and none in the 1st quantile. Outside China, countries with a higher risk of 2019-nCoV transmission are Thailand, Cambodia, Malaysia, Canada and the USA, all of which reported at least one case. In pan-Europe, UK, France, Russia, Germany and Italy; in North America, USA and Canada; in Oceania, Australia had high risk, all of them reported at least one case. In Africa and South America, the risk of transmission is very low with Ethiopia, South Africa, Egypt, Mauritius and Brazil showing a similar risk of transmission compared to the risk of any of the countries where at least one case is detected. The risk of transmission on 31 January 2020 was very high in neighbouring Asian countries, followed by Europe (UK, France, Russia and Germany), Oceania (Australia) and North America (USA and Canada). Increased public health response including early case recognition, isolation of identified case, contract tracing and targeted airport screening, public awareness and vigilance of health workers will help mitigate the force of further spread to naïve countries.

AbstractThis project is funded by the US National Science Foundation (NSF) through their NSF RAPID program under the title “Modeling Corona Spread Using Big Data Analytics.” The project is a joint effort between the Department of Computer & Electrical Engineering and Computer Science at FAU and a research group from LexisNexis Risk Solutions.The novel coronavirus Covid-19 originated in China in early December 2019 and has rapidly spread to many countries around the globe, with the number of confirmed cases increasing every day. Covid-19 is officially a pandemic. It is a novel infection with serious clinical manifestations, including death, and it has reached at least 124 countries and territories. Although the ultimate course and impact of Covid-19 are uncertain, it is not merely possible but likely that the disease will produce enough severe illness to overwhelm the worldwide health care infrastructure. Emerging viral pandemics can place extraordinary and sustained demands on public health and health systems and on providers of essential community services.Modeling the Covid-19 pandemic spread is challenging. But there are data that can be used to project resource demands. Estimates of the reproductive number (R) of SARS-CoV-2 show that at the beginning of the epidemic, each infected person spreads the virus to at least two others, on average (Emanuel et al. in N Engl J Med. 2020, Livingston and Bucher in JAMA 323(14):1335, 2020). A conservatively low estimate is that 5 % of the population could become infected within 3 months. Preliminary data from China and Italy regarding the distribution of case severity and fatality vary widely (Wu and McGoogan in JAMA 323(13):1239–42, 2020). A recent large-scale analysis from China suggests that 80 % of those infected either are asymptomatic or have mild symptoms; a finding that implies that demand for advanced medical services might apply to only 20 % of the total infected. Of patients infected with Covid-19, about 15 % have severe illness and 5 % have critical illness (Emanuel et al. in N Engl J Med. 2020). Overall, mortality ranges from 0.25 % to as high as 3.0 % (Emanuel et al. in N Engl J Med. 2020, Wilson et al. in Emerg Infect Dis 26(6):1339, 2020). Case fatality rates are much higher for vulnerable populations, such as persons over the age of 80 years (> 14 %) and those with coexisting conditions (10 % for those with cardiovascular disease and 7 % for those with diabetes) (Emanuel et al. in N Engl J Med. 2020). Overall, Covid-19 is substantially deadlier than seasonal influenza, which has a mortality of roughly 0.1 %.Public health efforts depend heavily on predicting how diseases such as those caused by Covid-19 spread across the globe. During the early days of a new outbreak, when reliable data are still scarce, researchers turn to mathematical models that can predict where people who could be infected are going and how likely they are to bring the disease with them. These computational methods use known statistical equations that calculate the probability of individuals transmitting the illness. Modern computational power allows these models to quickly incorporate multiple inputs, such as a given disease’s ability to pass from person to person and the movement patterns of potentially infected people traveling by air and land. This process sometimes involves making assumptions about unknown factors, such as an individual’s exact travel pattern. By plugging in different possible versions of each input, however, researchers can update the models as new information becomes available and compare their results to observed patterns for the illness.In this paper we describe the development a model of Corona spread by using innovative big data analytics techniques and tools. We leveraged our experience from research in modeling Ebola spread (Shaw et al. Modeling Ebola Spread and Using HPCC/KEL System. In: Big Data Technologies and Applications 2016 (pp. 347-385). Springer, Cham) to successfully model Corona spread, we will obtain new results, and help in reducing the number of Corona patients. We closely collaborated with LexisNexis, which is a leading US data analytics company and a member of our NSF I/UCRC for Advanced Knowledge Enablement.The lack of a comprehensive view and informative analysis of the status of the pandemic can also cause panic and instability within society. Our work proposes the HPCC Systems Covid-19 tracker, which provides a multi-level view of the pandemic with the informative virus spreading indicators in a timely manner. The system embeds a classical epidemiological model known as SIR and spreading indicators based on causal model. The data solution of the tracker is built on top of the Big Data processing platform HPCC Systems, from ingesting and tracking of various data sources to fast delivery of the data to the public. The HPCC Systems Covid-19 tracker presents the Covid-19 data on a daily, weekly, and cumulative basis up to global-level and down to the county-level. It also provides statistical analysis for each level such as new cases per 100,000 population. The primary analysis such as Contagion Risk and Infection State is based on causal model with a seven-day sliding window. Our work has been released as a publicly available website to the world and attracted a great volume of traffic. The project is open-sourced and available on GitHub. The system was developed on the LexisNexis HPCC Systems, which is briefly described in the paper.

Problem setting. One of the most important tasks of modern science of public management and administration is the further improvement of management technologies, management decisions in banking in particular and the increase of their efficiency and effectiveness. Accordingly, the scientific interest is not only in the study and the analysis of banking legislation of certain countries, but in the adaptation of national legislation to the directives of the European Union. The urgency of improving the mechanism of state regulation of the market for the provision of services for the collection of funds and transportation of currency valuables in the banking system of Ukraine is undeniable, the implementation of which should include the mandatory establishment of real requirements and measures of responsibility of managers of both individual financial institutions and regulatory bodies. Recent research and publications analysis. The organization of central banks of the world, their legal status, main functions, comparative aspects, regulatory activities in the field of the organization of cash circulation and cash collection were studied in the works of L. Voronova, D. Hetmantsev, V. Krotyuk, S. Yehorychev, M. Starynsky, P. Melnyk, S. Laptev, I. Zaverukha. Legal problems of legalization of firearms circulation in Ukraine were studied by А. Kolosok, P. Mitrukhov, P. Fries, S. Shumilenko and others. The works of V. Baranyak, V. Меzhyvy, М. Pinchuk, T. Pryhodko, V. Rybachuk, В. Tychyi, etc. are devoted to the study of legal problems of illegal handling of weapons. However, these works do not reflect the peculiarities of the use of firearms in subdivisions of collection of funds. Native and foreign scholars generally have not paid due attention to the study and the analysis of the existing model of cash circulation in Ukraine, its advantages, risks and disadvantages as well as the effective functioning of the market of collection of funds and transportation of currency valuables in the banking system of Ukraine. Highlighting previously unsettled parts of the general problem. The purpose of this article is to analyze the innovative foreign experience of state regulation of the market of collection of funds and transportation of currency valuables in the banking system of Ukraine (hereinafter – collection of funds) and to justify the need for its implementation in Ukraine. Another important problem in collection activities is the lack of legislative regulation of firearms trafficking as there is no law on weapons in Ukraine, there are only regulations of the Ministry of Internal Affairs of Ukraine, which greatly complicates its regulation by the state according to P. Fries. Paper main body. The market of collection of funds and transportation of currency valuables (hereinafter – the market of collection) is one of the most closed segments of the banking system of any country as a whole. The most popular way to pay for services and goods during the last few years, according to annual surveys conducted by the Swiss central bank, is cash. The important factor is that even with the spread of the COVID-19 coronavirus pandemic, the demand for cash and cash flow has increased significantly. The National Bank of Ukraine carries out regulatory activities in accordance with the requirements of the Law of Ukraine “On Principles of State Regulatory Policy in the Field of Economic Activity”. Collection of funds has never been a particularly profitable activity, for the subdivisions of collection of any country along with the staff and transportation costs, that is why to ensure the proper security of cash transportation is a very costly item of the estimate. In this regard, there is an urgent need for the adoption of the Law of Ukraine “On collection of funds and transportation of currency valuables” and “On firearms”, which would define the basic foundations, principles, forms of activities in the field of collection services, rights, duties and responsibilities of all participants in the collection market, in order to increase their reliability, safety and efficiency. In the countries of the European Union (EU), services for the collection and transportation of currency valuables are provided by public and private enterprises. In many EU countries there is no legal definition of the concept ‘collection’. In most cases, collection falls under the general legislation on the basics of security, except for Austria and Germany, which regulate such activities through professional organizations, insurance and collective agreements. Today, five foreign global CIT companies account for almost 60% of the global CIT market for cash collection and cash handling services. They are: – Brinks (USA) – 23%; – G4S (England) – 15%; – Loomis (Sweden) – 12%; – Prosegur (Spain) – 7%; – Garda (Canada) – 4%; – GSLS – 0.01%; – Other regional independent companies – 39%. In six EU countries (Denmark, Ireland, Greece, Sweden, Great Britain and the Netherlands) the presence of firearms during collection of funds is prohibited. In Belgium, Germany, France, Italy, Luxembourg and Spain, the presence of a weapon in the performance of professional collection duties is mandatory. Safe collection of funds largely depends on the fast, without delays, safe travel by road. Ukraine needs to reform its transport system to gain access to the European Union’s rail, road, river and air transport markets and to financial resources for building safe infrastructure of high quality. Conclusions of the research and prospects for further studies. Unfortunately, there are no well-known world CIT collection companies in the Ukrainian market of collection services and therefore Ukrainian banks and legal entities have to deal with local CIT companies, the authorized capital of which in some cases may be significantly less than the amount of the collected cash. In accordance with the mentioned above, for the effective functioning of the Ukrainian market of collection of funds and a balanced regulatory policy of the state, we suggest making appropriate changes and additions to the Laws of Ukraine on “Banks and Banking”, “National Bank of Ukraine”. To initiate the development and adoption of the Laws of Ukraine “On Collection and Transportation of Currency Valuables” and “On Firearms” which will ensure equal competitive conditions in the collection market for all its participants, reliable labor protection, social guarantees and rights of employees of collection divisions.

IntroductionThree broad stages of Australia’s arts and culture sectors may be discerned with reference to the Northern Hemisphere. The first is in Australia’s early years where artists travelled to the metropoles of Europe to learn from acknowledged masters, to view the great works and to become part of a broader cultural scene. The second is where Australian art was promoted internationally, which to some extent began in the 1960s with exhibitions such as the 1961 ‘Survey of recent Australian painting’ at the Whitechapel gallery. The third relates to the strong promotion and push to display and sell Indigenous art, which has been a key area of focus since the 1970s.The Allure of the NorthFor a long time Australasian artists have mostly travelled to Britain (Britain) or Europe (Cooper; Frost; Inkson and Carr), be they writers, painters or musicians for example. Hecq (36) provides a useful overview of the various periods of expatriation from Australia, referring to the first significant phase at the end of the twentieth century when many painters left “to complete their atelier instruction in Paris and London”. Many writers also left for the north during this time, with a number of women travelling overseas on account of “intellectual pressures as well as intellectual isolation”(Hecq 36). Among these, Miles Franklin left Australia in “an open act of rebellion against the repressive environment of her family and colonial culture” (37). There also existed “a belief that ‘there’ is better than ‘here’” (de Groen vii) as well as a “search for the ideal” (viii). World War I led to stronger Anglo-Australian relations hence an increase in expatriation to Europe and Britain as well as longer-term sojourns. These increased further in the wake of World War II. Hecq describes how for many artists, there was significant discontent with Australian provincialism and narrow-mindedness, as well as a desire for wider audiences and international recognition. Further, Hecq describes how Europe became something of a “dreamland”, with numerous artists influenced by their childhood readings about this part of the world and a sense of the imaginary or the “other”. This sense of a dream is described beautifully by McAuliffe (56), who refers to the 1898 painting by A.J. Daplyn as a “melancholic diagram of the nineteenth-century Australian artist’s world, tempering the shimmering allure of those northern lights with the shadowy, somnolent isolation of the south”.Figure 1: The Australian Artist’s Dream of Europe; A.J. Daplyn, 1898 (oil on canvas; courtesy artnet.com)In ‘Some Other Dream’, de Groen presents a series of interviews with expatriate Australian artists and writers as an insight into what drove each to look north and to leave Australia, either temporarily or permanently. Here are a few examples:Janet Alderson: “I desperately wanted to see what was going on” (2)Robert Jacks: “the dream of something else. New York is a dream for lots of people” (21)Bruce Latimer: “I’d always been interested in America, New York in particular” (34)Jeffrey Smart: “Australia seemed to be very dull and isolated, and Italy seemed to be thrilling and modern” (50)Clement Meadmore: “I never had much to do with what was happening in Melbourne: I was never accepted there” (66)Stelarc: “I was interested in traditional Japanese art and the philosophy of Zen” (80)Robert Hughes: “I’d written everything that I’d wanted to write about Australian art and this really dread prospect was looming up of staying in Australia for the rest of one’s life” (128)Max Hutchison: “I quickly realised that Melbourne was a non-art consuming city” (158)John Stringer: “I was not getting the latitude that I wanted at the National Gallery [in Australia] … the prospects of doing other good shows seemed rather slim” (178)As the testimony here suggests, the allure of the north ranges from dissatisfaction with the south to the attraction of various parts of the world in the north.More recently, McAuliffe describes a shift in the impact of the overseas experience for many artists. Describing them as business travellers, he refers to the fact that artists today travel to meet international art dealers and to participate in exhibitions, art fairs and the like. Further, he argues that the risk today lies in “disorientation and distraction rather than provincial timidity” (McAuliffe 56). That is, given the ease and relatively cheap costs of international travel, McAuliffe argues that the challenge is in adapting to constantly changing circumstances, rather than what are now arguably dated concepts of cultural cringe or tyranny of distance. Further, given the combination of “cultural nationalism, social cosmopolitanism and information technology”, McAuliffe (58) argues that the need to expatriate is no longer a requirement for success.Australian Art Struggles InternationallyThe struggles for Australian art as a sector to succeed internationally, particularly in Britain, Europe and the US, are well documented (Frost; Robertson). This is largely due to Australia’s limited history of white settlement and established canon of great art works, the fact that power and position remain strong hence the dominance of Europe and North America in the creative arts field (Bourdieu), as well as Australia’s geographical isolation from the major art centres of the world, with Heartney (63) describing the “persistent sense of isolation of the Australian art world”. While Australia has had considerable success internationally in terms of its popular music (e.g. INXS, Kylie Minogue, The Seekers) and high-profile Hollywood actors (e.g. Geoffrey Rush, Hugh Jackman, Nicole Kidman), the visual arts in particular have struggled (O’Sullivan), including the Indigenous visual arts subsector (Stone). One of the constant criticisms in the visual art world is that Australian art is too focussed on place (e.g. the Australian outback) and not global art movements and trends (Robertson). While on the one hand he argues that Australian visual artists have made some inroads and successes in the international market, McAuliffe (63) tempers this with the following observation:Australian artists don’t operate at the white-hot heart of the international art market: there are no astronomical prices and hotly contested bidding wars. International museums acquire Australian art only rarely, and many an international survey exhibition goes by with no Australian representation.The Push to Sell Australian Cultural Product in the NorthWriting in the mid-nineties at the time of the release of the national cultural policy Creative Nation, the then prime minister Paul Keating identified a need for Australia as a nation to become more competitive internationally in terms of cultural exports. This is a theme that continues today. Recent decades have seen several attempts to promote Australian visual art overseas and in particular Indigenous art; this has come with mixed success. However, there have been misconceptions in the past and hence numerous challenges associated with promoting and selling Aboriginal art in international markets (Wright). One of the problems is that a lot of Europeans “have often seen bad examples of Aboriginal Art” (Anonymous 69) and it is typically the art work which travels north, less so the Indigenous artists who create them and who can talk to them and engage with audiences. At the same time, the Indigenous art sector remains a major contributor to the Australian art economy (Australia Council). While there are some examples of successful Australian art managers operating galleries overseas in such places as London and in the US (Anonymous-b), these are limited and many have had to struggle to gain recognition for their artists’ works.Throsby refers to the well-established fact that the international art market predominantly resides in the US and in Europe (including Britain). Further, Throsby (64) argues that breaking into this market “is a daunting task requiring resources, perseverance, a quality product, and a good deal of luck”. Referring specifically to Indigenous Australian art, Throsby (65) reveals how leading European fairs such as those at Basel and Cologne, displaying breath-taking ignorance if not outright stupidity, have vetoed Aboriginal works on the grounds that they are folk art. This saga continues to the present day, and it still remains to be seen whether these fairs will eventually wake up to themselves.It is also presented in an issue of Artlink that the “challenge is to convince European buyers of the value of Australian art, even though the work is comparatively inexpensive” (Anonymous 69). Is the Rite of Passage Relevant in the 21st Century?Some authors challenge the notion that the rite of passage to the northern hemisphere is a requirement for success for an Australian artist (Frost). This challenge is worthy of unpacking in the second decade of the twenty-first century, and particularly so in what is being termed the Asian century (Bice and Sullivan; Wesley). Firstly, Australia is far closer to Asia than it is to Europe and North America. Secondly, the Asian population is expected to continue to experience rapid economic and population growth, for example the rise of the middle class in China, potentially representing new markets for the consumption of creative product. Lee and Lim refer to the rapid economic modernisation and growth in East Asia (Japan to Singapore). Hence, given the struggles that are often experienced by Australian artists and dealers in attempting to break into the art markets of Europe and North America, it may be more constructive to look towards Asia as an alternative north and place for Australian creative product. Fourthly, many Asian countries are investing heavily in their creative industries and creative economy (Kim and Kim; Kong), hence representing an opportune time for Australian creative practitioners to explore new connections and partnerships.In the first half of the twentieth century, Australians felt compelled to travel north to Europe, especially, if they wanted to engage with the great art teachers, galleries and art works. Today, with the impact of technology, engaging with the art world can be achieved much more readily and quickly, through “increasingly transnational forms of cultural production, distribution and consumption” (Rowe et al. 8). This recent wave of technological development has been significant (Guerra and Kagan), in relation to online communication (e.g. skype, email), social media (e.g. Facebook, Twitter) as well as content available on the Web for both informal and formal learning purposes. Artists anywhere in the world can now connect online while also engaging with what is an increasing field of virtual museums and galleries. For example, the Tate Gallery in London has over 70,000 artworks in its online art database which includes significant commentary on each work. While online engagement does not necessarily enable an individual to have the lived experience of a gallery walk-through or to be an audience member at a live performance in an outstanding international venue, online technologies have made it much easier for developing artists to engage from anywhere in the world. This certainly makes the ‘tyranny of distance’ factor relevant to Australia somewhat more manageable.There is also a developing field of research citing the importance of emerging artists displaying enterprising and/or entrepreneurial skills (Bridgstock), in the context of a rapidly changing global arts sector. This broadly refers to the need for artists to have business skills, to be able to seek out and identify opportunities, as well as manage multiple projects and/or various streams of income in what is a very different career type and pathway (Beckman; Bridgstock and Cunningham; Hennekam and Bennett). These opportunity seeking skills and agentic qualities have also been cited as critical in relation to the fact that there is not only a major oversupply of artistic labour globally (Menger), but there is a growing stream of entrants to the global higher education tertiary arts sector that shows no signs of subsiding (Daniel). Concluding RemarksAustralia’s history features a strong relationship with and influences from the north, and in particular from Britain, Europe and North America. This remains the case today, with much of Australian society based on inherited models from Britain, be this in the art world or in such areas as the law and education. As well as a range of cultural and sentimental links with this north, Australia is sometimes considered to be a satellite of European civilisation in the Asia-Pacific region. It is therefore explicable why artists might continue this longstanding relationship with this particular north.In our interesting and complex present of the early twenty-first century, Australia is hampered by the lack of any national cultural policy as well as recent significant cuts to arts funding at the national and state levels (Caust). Nevertheless, there are opportunities to be further explored in relation to the changing patterns of production and consumption of creative content, the impact of new and next technologies, as well as the rise of Asia in the Asian Century. The broad field of the arts and artists is a rich area for ongoing research and inquiry and ultimately, Australia’s links to the north including the concept of the rite of passage deserves ongoing consideration.ReferencesAnonymous a. "Outposts: The Case of the Unofficial Attache." Artlink 18.4 (1998): 69–71.Anonymous b. "Who’s Selling What to Whom: Australian Dealers Taking Australian Art Overseas." Artlink 18. 4 (1998): 66–68.Australia Council for the Arts. Arts Nation: An Overview of Australian Arts. 2015. <http://www.australiacouncil.gov.au/workspace/uploads/files/arts-nation-final-27-feb-54f5f492882da.pdf>.Beckman, Gary D. "'Adventuring' Arts Entrepreneurship Curricula in Higher Education: An Examination of Present Efforts, Obstacles, and Best Practices." The Journal of Arts Management, Law, and Society 37.2 (2007): 87–112.Bice, Sara, and Helen Sullivan. "Abbott Government May Have New Rhetoric, But It’s Still the ‘Asian Century’." The Conversation 2013. <https://theconversation.com/abbott-government-may-have-new-rhetoric-but-its-still-the-asian-century-19769>.Bourdieu, Pierre. Distinction: A Social Critique of the Judgement of Taste. Routledge & Kegan Paul, 1984.Bridgstock, Ruth. "Not a Dirty Word: Arts Entrepreneurship and Higher Education." Arts and Humanities in Higher Education 12.2–3 (2013,): 122–137. doi:10.1177/1474022212465725.———, and Stuart Cunningham. "Creative Labour and Graduate Outcomes: Implications for Higher Education and Cultural Policy." International Journal of Cultural Policy 22.1 (2015): 10–26. doi:10.1080/10286632.2015.1101086.Britain, Ian. Once an Australian: Journeys with Barry Humphries, Clive James, Germaine Greer and Robert Hughes. Oxford: Oxford UP, 1997.Caust, Josephine. "Cultural Wars in an Australian Context: Challenges in Developing a National Cultural Policy." International Journal of Cultural Policy 21.2 (2015): 168–182. doi:10.1080/10286632.2014.890607.Cooper, Roslyn Pesman. "Some Australian Italies." Westerly 39.4 (1994): 95–104.Daniel, Ryan, and Robert Johnstone. "Becoming an Artist: Exploring the Motivations of Undergraduate Students at a Regional Australian University". Studies in Higher Education 42.6 (2017): 1015-1032.De Groen, Geoffrey. Some Other Dream: The Artist the Artworld & the Expatriate. Hale & Iremonger, 1984.Frost, Andrew. "Do Young Australian Artists Really Need to Go Overseas to Mature?" The Guardian, 9 Oct. 2013. <https://www.theguardian.com/culture/australia-culture-blog/2013/oct/09/1https://www.theguardian.com/culture/australia-culture-blog/2013/oct/09/1, July 20, 2016>.Guerra, Paula, and Sacha Kagan, eds. Arts and Creativity: Working on Identity and Difference. Porto: University of Porto, 2016.Heartney, Eleanor. "Identity and Locale: Four Australian Artists." Art in America 97.5 (2009): 63–68.Hecq, Dominique. "'Flying Up for Air: Australian Artists in Exile'." Commonwealth (Dijon) 22.2 (2000): 35–45.Hennekam, Sophie, and Dawn Bennett. "Involuntary Career Transition and Identity within the Artist Population." Personnel Review 45.6 (2016): 1114–1131.Inkson, Kerr, and Stuart C. Carr. "International Talent Flow and Careers: An Australasian Perspective." Australian Journal of Career Development 13.3 (2004): 23–28.Keating, P.J. "Exports from a Creative Nation." Media International Australia 76.1 (1995): 4–6.Kim, Jeong-Gon, and Eunji Kim. "Creative Industries Internationalization Strategies of Selected Countries and Their Policy Implications." KIEP Research Paper. World Economic Update-14–26 (2014). <https://ssrn.com/abstract=2488416>.Kong, Lily. "From Cultural Industries to Creative Industries and Back? Towards Clarifying Theory and Rethinking Policy." Inter-Asia Cultural Studies 15.4 (2014): 593–607.Lee, H., and Lorraine Lim. Cultural Policies in East Asia: Dynamics between the State, Arts and Creative Industries. Springer, 2014.McAuliffe, Chris. "Living the Dream: The Contemporary Australian Artist Abroad." Meanjin 71.3 (2012): 56–61.Menger, Pierre-Michel. "Artistic Labor Markets and Careers." Annual Review of Sociology 25.1 (1999): 541–574.O’Sullivan, Jane. "Why Australian Artists Find It So Hard to Get International Recognition." AFR Magazine, 2016.Robertson, Kate. "Yes, Capon, Australian Artists Have Always Thought about Place." The Conversation, 2014. <https://theconversation.com/yes-capon-australian-artists-have-always-thought-about-place-31690>.Rowe, David, et al. "Transforming Cultures? From Creative Nation to Creative Australia." Media International Australia 158.1 (2016): 6–16. doi:10.1177/1329878X16629544.Stone, Deborah. "Presenters Reject Indigenous Arts." ArtsHub, 2016. <http://www.artshub.com.au/news-article/news/audience-development/deborah-stone/presenters-reject-indigenous-arts-252075?utm_source=ArtsHub+Australia&utm_campaign=7349a419f3-UA-828966-1&utm_medium=email&utm_term=0_2a8ea75e81-7349a419f3-302288158>.Throsby, David. "Get Out There and Sell: The Visual Arts Export Strategy, Past, Present and Future." Artlink 18.4 (1998): 64–65.Wesley, Michael. "In Australia's Third Century after European Settlement, We Must Rethink Our Responses to a New World." The Conversation, 2015. <https://theconversation.com/in-australias-third-century-after-european-settlement-we-must-rethink-our-responses-to-a-new-world-46671>.Wright, Felicity. "Passion, Rich Collectors and the Export Dollar: The Selling of Aboriginal Art Overseas." Artlink 18.4 (1998): 16.

The curtain rose. The howling of desert wind filled the performance hall in the Shanghai Grand Theatre. Into the center stage, where a scenic construction of a mountain cliff and a desert landscape was dimly lit, entered the character of the Daoist priest Wang Yuanlu (1849–1931), performed by Chen Yizong. Dressed in a worn and dusty outfit of dark blue cotton, characteristic of Daoist priests, Wang began to sweep the floor. After a few moments, he discovered a hidden chambre sealed inside one of the rock sanctuaries carved into the cliff.Signaled by the quick, crystalline, stirring wave of sound from the chimes, a melodious Chinese ocarina solo joined in slowly from the background. Astonished by thousands of Buddhist sūtra scrolls, wall paintings, and sculptures he had just accidentally discovered in the caves, Priest Wang set his broom aside and began to examine these treasures. Dawn had not yet arrived, and the desert sky was pitch-black. Priest Wang held his oil lamp high, strode rhythmically in excitement, sat crossed-legged in a meditative pose, and unfolded a scroll. The sound of the ocarina became fuller and richer and the texture of the music more complex, as several other instruments joined in.Below is the opening scene of the award-winning, theatrical dance-drama Dunhuang, My Dreamland, created by China’s state-sponsored Lanzhou Song and Dance Theatre in 2000. Figure 1a: Poster Side A of Dunhuang, My Dreamland Figure 1b: Poster Side B of Dunhuang, My DreamlandThe scene locates the dance-drama in the rock sanctuaries that today are known as the Dunhuang Mogao Caves, housing Buddhist art accumulated over a period of a thousand years, one of the best well-known UNESCO heritages on the Silk Road. Historically a frontier metropolis, Dunhuang was a strategic site along the Silk Road in northwestern China, a crossroads of trade, and a locus for religious, cultural, and intellectual influences since the Han dynasty (206 B.C.E.–220 C.E.). Travellers, especially Buddhist monks from India and central Asia, passing through Dunhuang on their way to Chang’an (present day Xi’an), China’s ancient capital, would stop to meditate in the Mogao Caves and consult manuscripts in the monastery's library. At the same time, Chinese pilgrims would travel by foot from China through central Asia to Pakistan, India, Nepal, Bangladesh, and Sri Lanka, playing a key role in the exchanges between ancient China and the outside world. Travellers from China would stop to acquire provisions at Dunhuang before crossing the Gobi Desert to continue on their long journey abroad. Figure 2: Dunhuang Mogao CavesThis article approaches the idea of “abroad” by examining the present-day imagination of journeys along the Silk Road—specifically, staged performances of the various Silk Road journey-themed dance-dramas sponsored by the Chinese state for enhancing its cultural and foreign policies since the 1970s (Kuang).As ethnomusicologists have demonstrated, musicians, choreographers, and playwrights often utilise historical materials in their performances to construct connections between the past and the present (Bohlman; Herzfeld; Lam; Rees; Shelemay; Tuohy; Wade; Yung: Rawski; Watson). The ancient Silk Road, which linked the Mediterranean coast with central China and beyond, via oasis towns such as Samarkand, has long been associated with the concept of “journeying abroad.” Journeys to distant, foreign lands and encounters of unknown, mysterious cultures along the Silk Road have been documented in historical records, such as A Record of Buddhist Kingdoms (Faxian) and The Great Tang Records on the Western Regions (Xuanzang), and illustrated in classical literature, such as The Travels of Marco Polo (Polo) and the 16th century Chinese novel Journey to the West (Wu). These journeys—coming and going from multiple directions and to different destinations—have inspired contemporary staged performance for audiences around the globe.Home and Abroad: Dunhuang and the Silk RoadDunhuang, My Dreamland (2000), the contemporary dance-drama, staged the journey of a young pilgrim painter travelling from Chang’an to a land of the unfamiliar and beyond borders, in search for the arts that have inspired him. Figure 3: A scene from Dunhuang, My Dreamland showing the young pilgrim painter in the Gobi Desert on the ancient Silk RoadFar from his home, he ended his journey in Dunhuang, historically considered the northwestern periphery of China, well beyond Yangguan and Yumenguan, the bordering passes that separate China and foreign lands. Later scenes in Dunhuang, My Dreamland, portrayed through multiethnic music and dances, the dynamic interactions among merchants, cultural and religious envoys, warriors, and politicians that were making their own journey from abroad to China. The theatrical dance-drama presents a historically inspired, re-imagined vision of both “home” and “abroad” to its audiences as they watch the young painter travel along the Silk Road, across the Gobi Desert, arriving at his own ideal, artistic “homeland”, the Dunhuang Mogao Caves. Since his journey is ultimately a spiritual one, the conceptualisation of travelling “abroad” could also be perceived as “a journey home.”Staged more than four hundred times since it premiered in Beijing in April 2000, Dunhuang, My Dreamland is one of the top ten titles in China’s National Stage Project and one of the most successful theatrical dance-dramas ever produced in China. With revenue of more than thirty million renminbi (RMB), it ranks as the most profitable theatrical dance-drama ever produced in China, with a preproduction cost of six million RMB. The production team receives financial support from China’s Ministry of Culture for its “distinctive ethnic features,” and its “aim to promote traditional Chinese culture,” according to Xu Rong, an official in the Cultural Industry Department of the Ministry. Labeled an outstanding dance-drama of the Chinese nation, it aims to present domestic and international audiences with a vision of China as a historically multifaceted and cosmopolitan nation that has been in close contact with the outside world through the ancient Silk Road. Its production company has been on tour in selected cities throughout China and in countries abroad, including Austria, Spain, and France, literarily making the young pilgrim painter’s “journey along the Silk Road” a new journey abroad, off stage and in reality.Dunhuang, My Dreamland was not the first, nor is it the last, staged performances that portrays the Chinese re-imagination of “journeying abroad” along the ancient Silk Road. It was created as one of many versions of Dunhuang bihua yuewu, a genre of music, dance, and dramatic performances created in the early twentieth century and based primarily on artifacts excavated from the Mogao Caves (Kuang). “The Mogao Caves are the greatest repository of early Chinese art,” states Mimi Gates, who works to increase public awareness of the UNESCO site and raise funds toward its conservation. “Located on the Chinese end of the Silk Road, it also is the place where many cultures of the world intersected with one another, so you have Greek and Roman, Persian and Middle Eastern, Indian and Chinese cultures, all interacting. Given the nature of our world today, it is all very relevant” (Pollack). As an expressive art form, this genre has been thriving since the late 1970s contributing to the global imagination of China’s “Silk Road journeys abroad” long before Dunhuang, My Dreamland achieved its domestic and international fame. For instance, in 2004, The Thousand-Handed and Thousand-Eyed Avalokiteśvara—one of the most representative (and well-known) Dunhuang bihua yuewu programs—was staged as a part of the cultural program during the Paralympic Games in Athens, Greece. This performance, as well as other Dunhuang bihua yuewu dance programs was the perfect embodiment of a foreign religion that arrived in China from abroad and became Sinicized (Kuang). Figure 4: Mural from Dunhuang Mogao Cave No. 45A Brief History of Staging the Silk Road JourneysThe staging of the Silk Road journeys abroad began in the late 1970s. Historically, the Silk Road signifies a multiethnic, cosmopolitan frontier, which underwent incessant conflicts between Chinese sovereigns and nomadic peoples (as well as between other groups), but was strongly imbued with the customs and institutions of central China (Duan, Mair, Shi, Sima). In the twentieth century, when China was no longer an empire, but had become what the early 20th-century reformer Liang Qichao (1873–1929) called “a nation among nations,” the long history of the Silk Road and the colourful, legendary journeys abroad became instrumental in the formation of a modern Chinese nation of unified diversity rooted in an ancient cosmopolitan past. The staged Silk Road theme dance-dramas thus participate in this formation of the Chinese imagination of “nation” and “abroad,” as they aestheticise Chinese history and geography. History and geography—aspects commonly considered constituents of a nation as well as our conceptualisations of “abroad”—are “invariably aestheticized to a certain degree” (Bakhtin 208). Diverse historical and cultural elements from along the Silk Road come together in this performance genre, which can be considered the most representative of various possible stagings of the history and culture of the Silk Road journeys.In 1979, the Chinese state officials in Gansu Province commissioned the benchmark dance-drama Rain of Flowers along the Silk Road, a spectacular theatrical dance-drama praising the pure and noble friendship which existed between the peoples of China and other countries in the Tang dynasty (618-907 C.E.). While its plot also revolves around the Dunhuang Caves and the life of a painter, staged at one of the most critical turning points in modern Chinese history, the work as a whole aims to present the state’s intention of re-establishing diplomatic ties with the outside world after the Cultural Revolution. Unlike Dunhuang, My Dreamland, it presents a nation’s journey abroad and home. To accomplish this goal, Rain of Flowers along the Silk Road introduces the fictional character Yunus, a wealthy Persian merchant who provides the audiences a vision of the historical figure of Peroz III, the last Sassanian prince, who after the Arab conquest of Iran in 651 C.E., found refuge in China. By incorporating scenes of ethnic and folk dances, the drama then stages the journey of painter Zhang’s daughter Yingniang to Persia (present-day Iran) and later, Yunus’s journey abroad to the Tang dynasty imperial court as the Persian Empire’s envoy.Rain of Flowers along the Silk Road, since its debut at Beijing’s Great Hall of the People on the first of October 1979 and shortly after at the Theatre La Scala in Milan, has been staged in more than twenty countries and districts, including France, Italy, Japan, Thailand, Russia, Latvia, Hong Kong, Macao, Taiwan, and recently, in 2013, at the Lincoln Center for the Performing Arts in New York.“The Road”: Staging the Journey TodayWithin the contemporary context of global interdependencies, performing arts have been used as strategic devices for social mobilisation and as a means to represent and perform modern national histories and foreign policies (Davis, Rees, Tian, Tuohy, Wong, David Y. H. Wu). The Silk Road has been chosen as the basis for these state-sponsored, extravagantly produced, and internationally staged contemporary dance programs. In 2008, the welcoming ceremony and artistic presentation at the Olympic Games in Beijing featured twenty apsara dancers and a Dunhuang bihua yuewu dancer with long ribbons, whose body was suspended in mid-air on a rectangular LED extension held by hundreds of performers; on the giant LED screen was a depiction of the ancient Silk Road.In March 2013, Chinese president Xi Jinping introduced the initiatives “Silk Road Economic Belt” and “21st Century Maritime Silk Road” during his journeys abroad in Kazakhstan and Indonesia. These initiatives are now referred to as “One Belt, One Road.” The State Council lists in details the policies and implementation plans for this initiative on its official web page, www.gov.cn. In April 2013, the China Institute in New York launched a yearlong celebration, starting with "Dunhuang: Buddhist Art and the Gateway of the Silk Road" with a re-creation of one of the caves and a selection of artifacts from the site. In March 2015, the National Development and Reform Commission (NDRC), China’s top economic planning agency, released a new action plan outlining key details of the “One Belt, One Road” initiative. Xi Jinping has made the program a centrepiece of both his foreign and domestic economic policies. One of the central economic strategies is to promote cultural industry that could enhance trades along the Silk Road.Encouraged by the “One Belt, One Road” policies, in March 2016, The Silk Princess premiered in Xi’an and was staged at the National Centre for the Performing Arts in Beijing the following July. While Dunhuang, My Dreamland and Rain of Flowers along the Silk Road were inspired by the Buddhist art found in Dunhuang, The Silk Princess, based on a story about a princess bringing silk and silkworm-breeding skills to the western regions of China in the Tang Dynasty (618-907) has a different historical origin. The princess's story was portrayed in a woodblock from the Tang Dynasty discovered by Sir Marc Aurel Stein, a British archaeologist during his expedition to Xinjiang (now Xinjiang Uygur autonomous region) in the early 19th century, and in a temple mural discovered during a 2002 Chinese-Japanese expedition in the Dandanwulike region. Figure 5: Poster of The Silk PrincessIn January 2016, the Shannxi Provincial Song and Dance Troupe staged The Silk Road, a new theatrical dance-drama. Unlike Dunhuang, My Dreamland, the newly staged dance-drama “centers around the ‘road’ and the deepening relationship merchants and travellers developed with it as they traveled along its course,” said Director Yang Wei during an interview with the author. According to her, the show uses seven archetypes—a traveler, a guard, a messenger, and so on—to present the stories that took place along this historic route. Unbounded by specific space or time, each of these archetypes embodies the foreign-travel experience of a different group of individuals, in a manner that may well be related to the social actors of globalised culture and of transnationalism today. Figure 6: Poster of The Silk RoadConclusionAs seen in Rain of Flowers along the Silk Road and Dunhuang, My Dreamland, staging the processes of Silk Road journeys has become a way of connecting the Chinese imagination of “home” with the Chinese imagination of “abroad.” Staging a nation’s heritage abroad on contemporary stages invites a new imagination of homeland, borders, and transnationalism. Once aestheticised through staged performances, such as that of the Dunhuang bihua yuewu, the historical and topological landscape of Dunhuang becomes a performed narrative, embodying the national heritage.The staging of Silk Road journeys continues, and is being developed into various forms, from theatrical dance-drama to digital exhibitions such as the Smithsonian’s Pure Land: Inside the Mogao Grottes at Dunhuang (Stromberg) and the Getty’s Cave Temples of Dunhuang: Buddhist Art on China's Silk Road (Sivak and Hood). They are sociocultural phenomena that emerge through interactions and negotiations among multiple actors and institutions to envision and enact a Chinese imagination of “journeying abroad” from and to the country.ReferencesBakhtin, M.M. The Dialogic Imagination: Four Essays. Austin, Texas: University of Texas Press, 1982.Bohlman, Philip V. “World Music at the ‘End of History’.” Ethnomusicology 46 (2002): 1–32.Davis, Sara L.M. Song and Silence: Ethnic Revival on China’s Southwest Borders. New York: Columbia University Press, 2005.Duan, Wenjie. “The History of Conservation of Mogao Grottoes.” International Symposium on the Conservation and Restoration of Cultural Property: The Conservation of Dunhuang Mogao Grottoes and the Related Studies. Eds. Kuchitsu and Nobuaki. Tokyo: Tokyo National Research Institute of Cultural Properties, 1997. 1–8.Faxian. A Record of Buddhistic Kingdoms. Translated by James Legge. New York: Dover Publications, 1991.Herzfeld, Michael. Ours Once More: Folklore, Ideology, and the Making of Modern Greece. Austin: University of Texas Press, 1985.Kuang, Lanlan. Dunhuang bi hua yue wu: "Zhongguo jing guan" zai guo ji yu jing zhong de jian gou, chuan bo yu yi yi (Dunhuang Performing Arts: The Construction and Transmission of “China-scape” in the Global Context). Beijing: She hui ke xue wen xian chu ban she, 2016.Lam, Joseph S.C. State Sacrifice and Music in Ming China: Orthodoxy, Creativity and Expressiveness. New York: State University of New York Press, 1998.Mair, Victor. T’ang Transformation Texts: A Study of the Buddhist Contribution to the Rise of Vernacular Fiction and Drama in China. Cambridge, Mass.: Council on East Asian Studies, 1989.Pollack, Barbara. “China’s Desert Treasure.” ARTnews, December 2013. Sep. 2016 <http://www.artnews.com/2013/12/24/chinas-desert-treasure/>.Polo, Marco. The Travels of Marco Polo. Translated by Ronald Latham. Penguin Classics, 1958.Rees, Helen. Echoes of History: Naxi Music in Modern China. Oxford: Oxford University Press, 2000.Shelemay, Kay Kaufman. “‘Historical Ethnomusicology’: Reconstructing Falasha Liturgical History.” Ethnomusicology 24 (1980): 233–258.Shi, Weixiang. Dunhuang lishi yu mogaoku yishu yanjiu (Dunhuang History and Research on Mogao Grotto Art). Lanzhou: Gansu jiaoyu chubanshe, 2002.Sima, Guang 司马光 (1019–1086) et al., comps. Zizhi tongjian 资治通鉴 (Comprehensive Mirror for the Aid of Government). Beijing: Guji chubanshe, 1957.Sima, Qian 司马迁 (145-86? B.C.E.) et al., comps. Shiji: Dayuan liezhuan 史记: 大宛列传 (Record of the Grand Historian: The Collective Biographies of Dayuan). Beijing: Zhonghua shuju, 1959.Sivak, Alexandria and Amy Hood. “The Getty to Present: Cave Temples of Dunhuang: Buddhist Art on China’s Silk Road Organised in Collaboration with the Dunhuang Academy and the Dunhuang Foundation.” Getty Press Release. Sep. 2016 <http://news.getty.edu/press-materials/press-releases/cave-temples-dunhuang-buddhist-art-chinas-silk-road>.Stromberg, Joseph. “Video: Take a Virtual 3D Journey to Visit China's Caves of the Thousand Buddhas.” Smithsonian, December 2012. Sep. 2016 <http://www.smithsonianmag.com/smithsonian-institution/video-take-a-virtual-3d-journey-to-visit-chinas-caves-of-the-thousand-buddhas-150897910/?no-ist>.Tian, Qing. “Recent Trends in Buddhist Music Research in China.” British Journal of Ethnomusicology 3 (1994): 63–72.Tuohy, Sue M.C. “Imagining the Chinese Tradition: The Case of Hua’er Songs, Festivals, and Scholarship.” Ph.D. Dissertation. Indiana University, Bloomington, 1988.Wade, Bonnie C. Imaging Sound: An Ethnomusicological Study of Music, Art, and Culture in Mughal India. Chicago: University of Chicago Press, 1998.Wong, Isabel K.F. “From Reaction to Synthesis: Chinese Musicology in the Twentieth Century.” Comparative Musicology and Anthropology of Music: Essays on the History of Ethnomusicology. Eds. Bruno Nettl and Philip V. Bohlman. Chicago: University of Chicago Press, 1991. 37–55.Wu, Chengen. Journey to the West. Tranlsated by W.J.F. Jenner. Beijing: Foreign Languages Press, 2003.Wu, David Y.H. “Chinese National Dance and the Discourse of Nationalization in Chinese Anthropology.” The Making of Anthropology in East and Southeast Asia. Eds. Shinji Yamashita, Joseph Bosco, and J.S. Eades. New York: Berghahn, 2004. 198–207.Xuanzang. The Great Tang Dynasty Record of the Western Regions. Hamburg: Numata Center for Buddhist Translation & Research, 1997.Yung, Bell, Evelyn S. Rawski, and Rubie S. Watson, eds. Harmony and Counterpoint: Ritual Music in Chinese Context. Stanford: Stanford University Press, 1996.

Introduction In November 2020, upon learning that the company’s Covid-19 vaccine trial had been successful, the head of Pfizer’s Vaccine Research and Development, Kathrin Jansen, celebrated with champagne – “some really good stuff” (Cohen). Bubbles seem to go naturally with celebration, and champagne is fundamentally associated with bubbles. Yet, until the late-seventeenth century, champagne was a still wine, and it only reached the familiar levels of bubbliness in the late-nineteenth century (Harding). During this period and on into the early twentieth century, “champagne” was in many ways created, defined, and defended. A “champagne bubble” was created, within which the “nature” of champagne was contested and constructed. Champagne today is the result of hundreds of years of labour by many sorts of bubble-makers: those who make the bubbly drink, and those who construct, maintain, and defend the champagne bubble. In this article, I explore some elements of the champagne bubble, in order to understand both its fragility and rigidity over the years and today. Creating the Champagne Bubble – the Labour of Centuries It is difficult to separate the physical from the mythical as regards champagne. Therefore the categorisations below are always overlapping, and embedded in legal, political, economic, and socio-cultural factors. Just as assemblage – the mixing of wine from different grapes – is an essential element of champagne wine, the champagne bubble may be called heterogeneous assemblage. Indeed, the champagne bubble, as we will see below, is a myriad of different sorts of bubbles, such as terroir, appellation, myth and brand. And just as any assemblage, its heterogeneous elements exist and operate in relation to each other. Therefore the “champagne bubble” discussed here is both one and many, all of its elements fundamentally interconnected, constituting that “one” known as “champagne”. It is not my intention to be comprehensive of all the elements, historical and contemporary. Indeed, that would not be possible within such a short article. Instead, I seek to demonstrate some of the complexity of the champagne bubble, noting the elaborate labour that has gone into its creation. The Physical Champagne and Champagne – from Soil to Bubbles Champagne means both a legally protected geographical area (Champagne), and the wine (here: champagne) produced in this area from grapes defined as acceptable: most importantly pinot noir, pinot meunier (“black” grapes), and chardonnay (“white” grape). The method of production, too, is regulated and legally protected: méthode champenoise. Although the same method is used in numerous locations, these must be called something different: metodo classico (Italy), método tradicional (Spain), Methode Cap Classique (South Africa). The geographical area of Champagne was first legally defined in 1908, when it only included the areas of Marne and Aisne, leaving out, most importantly, the area of Aube. This decision led to severe unrest and riots, as the Aube vignerons revolted in 1911, forcing the inclusion of “zone 2”: Aube, Haute-Marne, and Seine-et-Marne (Guy). Behind these regulations was a surge in fraudulent production in the early twentieth century, as well as falling wine prices resulting from increasing supply of cheap wines (Colman 18). These first appellations d’origine had many consequences – they proved financially beneficial for the “zone 1”, but less so for the “zone 2”. When both these areas were brought under the same appellation in 1927, the financial benefits were more limited – but this may have been due to the Great Depression triggered in 1929 (Haeck et al.). It is a long-standing belief that the soil and climate of Champagne are key contributors to the quality of champagne wines, said to be due to “conditions … most suitable for making this type of wine” (Simon 11). Already in the end of the nineteenth century, the editor of Vigneron champenois attributed champagne’s quality to “a fortunate combination of … chalky soil … [and] unrivalled exposure [to the sun]” (Guy 119) among other things. Factors such as soil and climate, commonly included in and expressed through the idea of terroir, undoubtedly influence grapes and wines made thereof, but the extent remains unproven. Indeed, terroir itself is a very contested concept (Teil; Inglis and Almila). It is also the case that climate change has had, and will continue to have, devastating effects on wine production in many areas, while benefiting others. The highly successful English sparkling wine production, drawing upon know-how from the Champagne area, has been enabled by the warming climate (Inglis), while Champagne itself is at risk of becoming too hot (Robinson). Champagne is made through a process more complicated than most wines. I present here the bare bones of it, to illustrate the many challenges that had to be overcome to enable its production in the scale we see today. Freshly picked grapes are first pressed and the juice is fermented. Grape juice contains natural yeasts and therefore will ferment spontaneously, but fermentation can also be started with artificial yeasts. In fermentation, alcohol and carbon dioxide (CO2) are formed, but the latter usually escapes the liquid. The secret of champagne is its second fermentation, which happens in bottles, after wines from different grapes and/or vineyards have been blended for desired characteristics (assemblage). For the second fermentation, yeast and sugar are added. As the fermentation happens inside a bottle, the CO2 that is created does not escape, but dissolves into the wine. The average pressure inside a champagne bottle in serving temperature is around 5 bar – 5 times the pressure outside the bottle (Liger-Belair et al.). The obvious challenge this method poses has to do with managing the pressure. Exploding bottles used to be a common problem, and the manner of sealing bottles was not very developed, either. Seventeenth-century developments in bottle-making, and using corks to seal bottles, enabled sparkling wines to be produced in the first place (Leszczyńska; Phillips 137). Still today, champagne comes in heavy-bottomed bottles, sealed with characteristically shaped cork, which is secured with a wire cage known as muselet. Scientific innovations, such as calculating the ideal amount of sugar for the second fermentation in 1836, also helped to control the amount of gas formed during the second fermentation, thus making the behaviour of the wine more predictable (Leszczyńska 265). Champagne is characteristically a “manufactured” wine, as it involves several steps of interference, from assemblage to dosage – sugar added for flavour to most champagnes after the second fermentation (although there are also zero dosage champagnes). This lends champagne particularly suitable for branding, as it is possible to make the wine taste the same year after year, harvest after harvest, and thus create a distinctive and recognisable house style. It is also possible to make champagnes for different tastes. During the nineteenth century, champagnes of different dosage were made for different markets – the driest for the British, the sweetest for the Russians (Harding). Bubbles are probably the most striking characteristic of champagne, and they are enabled by the complicated factors described above. But they are also formed when the champagne is poured in a glass. Natural impurities on the surface of the glass provide channels through which the gas pockets trapped in the wine can release themselves, forming strains of rising bubbles (Liger-Belair et al.). Champagne glasses have for centuries differed from other wine glasses, often for aesthetic reasons (Harding). The bubbles seem to do more than give people aesthetic pleasure and sensory experiences. It is often claimed that champagne makes you drunk faster than other drinks would, and there is, indeed, some (limited) research showing that this may well be the case (Roberts and Robinson; Ridout et al.). The Mythical Champagne – from Dom Pérignon to Modern Wonders Just as the bubbles in a champagne glass are influenced by numerous forces, so the metaphorical champagne bubble is subject to complex influences. Myth-creation is one of the most significant of these. The origin of champagne as sparkling wine is embedded in the myth of Dom Pérignon of Hautvillers monastery (1638–1715), who according to the legend would have accidentally developed the bubbles, and then enthusiastically exclaimed “I am drinking the stars!” (Phillips 138). In reality, bubbles are a natural phenomenon provoked by winter temperatures deactivating the fermenting yeasts, and spring again reactivating them. The myth of Dom Pérignon was first established in the nineteenth century and quickly embraced by the champagne industry. In 1937, Moët et Chandon launched a premium champagne called Dom Pérignon, which enjoys high reputation until this day (Phillips). The champagne industry has been active in managing associations connected with champagne since the nineteenth century. Sparkling champagnes had already enjoyed fashionability in the later seventeenth and early eighteenth century, both in the French Court, and amongst the British higher classes. In the second half of the nineteenth century, champagne found ever increasing markets abroad, and the clientele was not aristocratic anymore. Before the 1860s, champagne’s association was with high status celebration, as well as sexual activity and seduction (Harding; Rokka). As the century went on, and champagne sales radically increased, associations with “modernity” were added: “hot-air balloons, towering steamships, transcontinental trains, cars, sports, and other ‘modern’ wonders were often featured in quickly proliferating champagne advertising” (Rokka 280). During this time, champagne grew both drier and more sparkling, following consumer tastes (Harding). Champagne’s most important markets in later nineteenth century included the UK, where the growing middle classes consumed champagne for both celebration and hospitality (Harding), the US, where (upper) middle-class women were served champagne in new kinds of consumer environments (Smith; Remus), and Russia, where the upper classes enjoyed sweeter champagne – until the Revolution (Phillips 296). The champagne industry quickly embraced the new middle classes in possession of increasing wealth, as well as new methods of advertising and marketing. What is remarkable is that they managed to integrate enormously varied cultural thematics and still retain associations with aristocracy and luxury, while producing and selling wine in industrial scale (Harding; Rokka). This is still true today: champagne retains a reputation of prestige, despite large-scale branding, production, and marketing. Maintaining and Defending the Bubble: Formulas, Rappers, and the Absolutely Fabulous Tipplers The falling wine prices and increasing counterfeit wines coincided with Europe’s phylloxera crisis – the pest accidentally brought over from North America that almost wiped out all Europe’s vineyards. The pest moved through Champagne in the 1890s, killing vines and devastating vignerons (Campbell). The Syndicat du Commerce des vins de Champagne had already been formed in 1882 (Rokka 280). Now unions were formed to fight phylloxera, such as the Association Viticole Champenoise in 1898. The 1904 Fédération Syndicale des Vignerons was formed to lobby the government to protect the name of Champagne (Leszczyńska 266) – successfully, as we have seen above. The financial benefits from appellations were certainly welcome, but short-lived. World War I treated Champagne harshly, with battle lines stuck through the area for years (Guy 187). The battle went on also in the lobbying front. In 1935, a new appellation regime was brought into law, which came to be the basis for all European systems, and the Comité National des appellations d'origine (CNAO) was founded (Colman 1922). Champagne’s protection became increasingly international, and continues to be so today under EU law and trade deals (European Commission). The post-war recovery of champagne relied on strategies used already in the “golden years” – marketing and lobbying. Advertising continued to embrace “luxury, celebration, transport (extending from air travel to the increasingly popular automobile), modernity, sports” (Guy 188). Such advertisement must have responded accurately to the mood of post-war, pre-depression Europe. Even in the prohibition US it was known that the “frivolous” French women might go as far as bathe in champagne, like the popular actress Mistinguett (Young 63). Curiously, in the 1930s Soviet Russia, “champagne” (not produced in Champagne) was declared a sign of good living, symbolising the standard of living that any Soviet worker had access to (at least in theory) (Gronow). Today, the reputation of champagne is fiercely defended in legal terms. This is not only in terms of protection against other sparkling wine making areas, but also in terms of exploitation of champagne’s reputation by actors in other commercial fields, and even against mass market products containing genuine champagne (Mahy and d’Ath; Schneider and Nam). At the same time, champagne has been widely “democratised” by mass production, enabled partly by increasing mechanisation and scientification of champagne production from the 1950s onwards (Leszczyńska 266). Yet champagne retains its association with prestige, luxury, and even royalty. This has required some serious adaptation and flexibility. In what follows, I look into three cultural phenomena that illuminate processes of such adaptation: Formula One (F1) champagne spraying, the 1990s sitcom Absolutely Fabulous, and the Cristal racism scandal in 2006. The first champagne bottle is said to have been presented to F1 grand prix winner in Champagne in 1950 (Wheels24). Such a gesture would have been fully in line with champagne’s association with cars, sport, and modernity. But what about the spraying? Surely that is not in line with the prestige of the wine? The first spraying is attributed to Jo Siffert in 1966 and Dan Gurney in 1967, the former described as accidental, the latter as a spontaneous gesture of celebration (Wheels24; Dobie). Moët had become the official supplier of F1 champagnes in 1966, and there are no signs that the new custom would have been problematic for them, as their sponsorship continued until 1999, after which Mumm sponsored the sport for 15 years. Today, the champagne to be popped and sprayed is Chanson, in special bottles “coated in the same carbon fibre that F1 cars are made of” (Wheels24). Such an iconic status has the spraying gained that it features in practically all TV broadcasts concerning F1, although non-alcoholic substitute is used in countries where sale of alcohol is banned (Barker et al., “Quantifying”; Barker et al., “Alcohol”). As disturbing as the champagne spraying might look for a wine snob, it is perfectly in line with champagne’s marketing history and entrepreneurial spirit shown since the nineteenth century. Nor is it unheard of to let champagne spray. The “art” of sabrage, opening champagne bottle with a sable, associated with glamour, spectacle, and myth – its origin is attributed to Napoleon and his officers – is perfectly acceptable even for the snob. Sparkling champagne was always bound up with joy and celebration, not a solemn drink, and the champagne bubble was able to accommodate middle classes as well as aristocrats. This brings us to our second example, the British sitcom Absolutely Fabulous. The show, first released in 1992, featured two women, “Eddy” (Jennifer Saunders) and “Patsy” (Joanna Lumley), who spent their time happily smoking, taking drugs, and drinking large quantities of “Bolly” (among other things). Bollinger champagne may have initially experienced “a bit of a shock” for being thus addressed, but soon came to see the benefits of fame (French). In 2005, they hired PR support to make better use of the brand’s “Ab Fab” recognisability, and to improve its prestige reputation in order to justify their higher price range (Cann). Saunders and Lumley were warmly welcomed by the Bollinger house when filming for their champagne tour Absolutely Champers (2017). It is befitting indeed that such controversial fame came from the UK, the first country to discover sparkling champagne outside France (Simon 48), and where the aspirational middle classes were keen to consume it already in the nineteenth century (Harding). More controversial still is the case of Cristal (made by Louis Roederer) and the US rap world. Enthusiastically embraced by the “bling-bling” world of (black) rappers, champagne seems to fit their ethos well. Cristal was long favoured as both a drink and a word in rap lyrics. But in 2006, the newly appointed managing director at the family owned Roederer, Frédéric Rouzaud, made comments considered racist by many (Woodland). Rouzard told in an interview with The Economist that the house observed the Cristal-rap association “with curiosity and serenity”. He reportedly continued: “but what can we do? We can’t forbid people from buying it. I’m sure Dom Pérignon or Krug would be delighted to have their business”. It was indeed those two brands that the rapper Jay-Z replaced Cristal with, when calling for a boycott on Cristal. It would be easy to dismiss Rouzard’s comments as snobbery, or indeed as racism, but they merit some more reflection. Cristal is the premium wine of a house that otherwise does not enjoy high recognisability. While champagne’s history involves embracing new sorts of clientele, and marketing flexibly to as many consumer groups as possible (Rokka), this was the first spectacular crossing of racial boundaries. It was always the case that different houses and their different champagnes were targeted at different clienteles, and it is apparent that Cristal was not targeted at black rap artists. Whereas Bollinger was able to turn into a victory the questionable fame brought by the white middle-class association of Absolutely Fabulous, the more prestigious Cristal considered the attention of the black rapper world more threatening and acted accordingly. They sought to defend their own brand bubble, not the larger champagne bubble. Cristal’s reputation seems to have suffered little – its 2008 vintage, launched in 2018, was the most traded wine of that year (Schultz). Jay-Z’s purchase of his own champagne brand (Armand de Brignac, nicknamed Ace of Spades) has been less successful reputation-wise (Greenburg). It is difficult to break the champagne bubble, and it may be equally difficult to break into it. Conclusion In this article, I have looked into the various dilemmas the “bubble-makers” of Champagne encountered when fabricating what is today known as “champagne”. There have been moments of threat to the bubble they formed, such as in the turn of nineteenth and twentieth centuries, and eras of incomparable success, such as from the 1860s to 1880s. The discussion has demonstrated the remarkable flexibility with which the makers and defenders of champagne have responded to challenges, and dealt with material, socio-cultural, economic, and other problems. It feels appropriate to end with a note on the current challenge the champagne industry faces: Covid-19. The pandemic hit champagne sales exceptionally hard, leaving around 100 million bottles unsold (Micallef). This was not very surprising, given the closure of champagne-selling venues, banning of public and private celebrations, and a general mood not particularly prone to (or even likely to frown upon) such light-hearted matters as glamour and champagne. Champagne has survived many dramatic drops in sales during the twentieth century, such as the Great Depression of the 1930s, and the post-financial crisis collapse in 2009. Yet they seem to be able to make astonishing recoveries. Already, there are indicators that many people consumed more champagne during the festive end-of-year season than in previous years (Smithers). For the moment, it looks like the champagne bubble, despite its seeming fragility, is practically indestructible, no matter how much its elements may suffer under various pressures and challenges. References Barker, Alexander, Magdalena Opazo-Breton, Emily Thomson, John Britton, Bruce Granti-Braham, and Rachael L. Murray. “Quantifying Alcohol Audio-Visual Content in UK Broadcasts of the 2018 Formula 1 Championship: A Content Analysis and Population Exposure.” BMJ Open 10 (2020): e037035. <https://bmjopen.bmj.com/content/10/8/e037035>. Barker, Alexander B., John Britton, Bruce Grant-Braham, and Rachael L. Murray. “Alcohol Audio-Visual Content in Formula 1 Television Broadcasting.” BMC Public Health 18 (2018): 1155. <https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-018-6068-3>. Campbell, Christy. Phylloxera: How Wine Was Saved for the World. London: Harper, 2004. Cann, Richard. “Bolllinger Signs Agency to Reclaim Ab Fab Status.” PR Week 4 Mar. 2005. 4 Mar. 2021 <https://www.prweek.com/article/472221/bollinger-signs-agency-reclaim-ab-fab-status>. Cohen, Jon. “Champagne and Questions Greet First Data Showing That a COVID-19 Vaccine Works.” Science 9 Nov. 2020. 4 Mar. 2021 <https://www.sciencemag.org/news/2020/11/champagne-and-questions-greet-first-data-showing-covid-19-vaccine-works>. Colman, Tyler. Wine Politics: How Governments, Environmentalists, Mobsters, and Critics Influence the Wines We Drink. Berkeley: University of California Press, 2008. Dobie, Stephen. “The Story of Motorsport’s First Ever Champagne Spray.” TopGear 15 Jan. 2018. 4 Mar. 2021 <https://www.topgear.com/car-news/motorsport/story-motorsports-first-ever-champagne-spray>. European Commission. “Wine.” 4 Mar. 2021 <https://ec.europa.eu/info/food-farming-fisheries/plants-and-plant-products/plant-products/wine_en#:~:text=Related%20links-,Overview,consumption%20and%2070%25%20of%20exports>. French, Phoebe. “Joanna Lumley and Jennifer Saunders to Star in Absolutely Champers.” The Drinks Business 20 Dec. 2017. 4 Mar. 2021 <https://www.thedrinksbusiness.com/2017/12/joanna-lumley-and-jennifer-saunders-to-star-in-absolutely-champers/>. Greenburg, Zack O. “The Real Story behind Jay Z's Champagne Deal.” Forbes 6 Nov. 2014. 4 Mar. 2021 <https://www.forbes.com/sites/zackomalleygreenburg/2014/11/06/why-jay-zs-champagne-news-isnt-so-new/?sh=6e4eb8f07528>. Gronow, Jukka. “Caviar with Champagne Good Life and Common Luxury in Stalin's Soviet Union.” Suomen Antropologi 4 (1998). Guy, Colleen M. When Champagne Became French: Wine and the Making of a National Identity. London: Johns Hopkins University Press, 2003. Haeck, Catherine, Giulia Meloni, and Johan Swinnen. “The Value of Terroir: A Historical Analysis of the Bordeaux and Champagne Geographical Indications.” Applied Economic Perspectives and Policy 41.4 (2019): 598–619. <https://onlinelibrary.wiley.com/doi/abs/10.1093/aepp/ppz026>. Harding, Graham. “The Making of Modern Champagne: How and Why the Taste for and the Taste of Champagne Changed in Nineteenth Century Britain.” Consumption Markets & Culture 42.1 (2021): 6-29. <https://www.tandfonline.com/doi/abs/10.1080/10253866.2020.1713765?journalCode=gcmc20>. Inglis, David. “Wine Globalization: Longer-Term Dynamics and Contemporary Patterns.” The Globalization of Wine. Eds. David Inglis and Anna-Mari Almila. London: Bloomsbury, 2019. 21-46. Inglis, David, and Anna-Mari Almila. “Introduction: The Travels and Tendencies of Wine.” The Globalization of Wine. Eds. David Inglis and Anna-Mari Almila. London: Bloomsbury, 2019. 1-20. Leszczyńska, D. “A Cluster and Its Trajectory: Evidence from the History of the French Champagne Production Cluster.” Labor History 57.2 (2016): 258-276. <https://www.tandfonline.com/doi/abs/10.1080/0023656X.2016.1161140>. Liger-Belair, Gérard, Guillaume Polidori, and Philippe Jeandet. “Recent Advances in the Science of Champagne Bubbles.” Chemical Society Reviews 37 (2008): 2490–2511. <https://pubs.rsc.org/en/content/articlelanding/2008/cs/b717798b#!divAbstract>. Mahy, Aude, and Florence d’Ath. “The Case of the ‘Champagner Sorbet’ – Unlawful Exploitation or Legitimate Use of the Protected Name ‘Champagne’?” EFFL 1 (2017): 43-48. <https://www.jstor.org/stable/26451418?seq=1>. Micallef, Joseph V. “How Champagne Is Bouncing Back after the COVID-19 Pandemic.” Forbes 15 Nov. 2020. 4 Mar. 2021 <https://www.forbes.com/sites/joemicallef/2020/11/15/how-champagne-is-bouncing-back-after-the-covid-19-pandemic/?sh=3300e4125784>. Phillips, Rod. A Short History of Wine. London: Penguin, 2000. Remus, Emily A. “Tippling Ladies and the Making of Consumer Culture: Gender and Public Space in ‘Fin-de- Siècle’ Chicago.” The Journal of American History 101.3 (2014): 751-77. <https://academic.oup.com/jah/article/101/3/751/796447?login=true>. Ridout, Fran, Stuart Gould, Carlo Nunes, and Ian Hindmarch. “The Effects of Carbon Dioxide in Champagne on Psychometric Performance and Blood-Alcohol Concentration.” Alcohol and Alcoholism 38.4 (2003): 381-85. <https://academic.oup.com/alcalc/article/38/4/381/232628>. Roberts, C., and S.P. Robinson. “Alcohol Concentration and Carbonation of Drinks: The Effect on Blood Alcohol Levels.” Journal of Forensic and Legal Medicine 14.7 (2007): 398-405. <https://pubmed.ncbi.nlm.nih.gov/17720590/>. Robinson, Frances. “Champagne Will Be Too Hot for Champagne Research Warns.” Decanter. 12 Jan. 2004. 4 Mar. 2021 <https://www.decanter.com/wine-news/champagne-will-be-too-hot-for-champagne-research-warns-103258/>. Rokka, Joonas. “Champagne: Marketplace Icon.” Consumption Markets & Culture 20.3 (2017): 275-283. <https://www.tandfonline.com/doi/abs/10.1080/10253866.2016.1177990?journalCode=gcmc20>. Schneider, Marius, and Nora Ho Tu Nam. “Champagne Makes the Dough Sour: EUIPO Board of Appeal Allows Opposition against Registration of Champagnola Trade Mark Based on Evocation of Champagne PDO.” Journal of Intellectual Property Law & Practice 15.9 (2020): 675-676. <https://academic.oup.com/jiplp/article/15/9/675/5905791>. Schultz, Abby. “20 Minutes With: Frédéric Rouzaud on Cristal, Biodynamics, and Zero Dosage.” Penta. 31 Dec. 2018. 4 Mar. 2021 <https://www.barrons.com/articles/20-minutes-with-frederic-rouzaud-on-cristal-biodynamics-and-zero-dosage-01546280265>. Simon, André L. The History of Champagne. London: Octobus, 1972. Smith, Andrew F. Drinking History: Fifteen Turning Points in the Making of American Beverages. New York: Columbia University Press, 2013. Smithers, Rebecca. “Britons Turn to Luxury Food and Drink to See Out Dismal 2020 in Style.” The Guardian 28 Dec. 2020. 4 Mar. 2021 <https://www.theguardian.com/business/2020/dec/28/britons-turn-luxury-food-drink-see-out-dismal-2020-style?CMP=Share_AndroidApp_Gmail>. Teil, Geneviève. “No Such Thing as Terroir? Objectivities and the Regimes of Existence of Objects.” Science, Technology & Human Values 37.5 (2012): 478-505. <https://journals.sagepub.com/doi/abs/10.1177/0162243911423843>. Wheels24. “Champagne Returns to F1 podium.” 2 Aug. 2017. 4 Mar. 2021 <https://www.news24.com/wheels/FormulaOne/champagne-returns-to-f1-podium-20170802>. Woodland, Richard. “Rapper Jay-Z Boycotts ‘Racist’ Cristal.” Decanter 16 June 2006. 4 Mar. 2021 <https://www.decanter.com/wine-news/rapper-jay-z-boycotts-racist-cristal-94054/>. Young, Robert K. “Out of the Ashes: The American Press and France's Postwar Recovery in the 1920s.” Historical Reflections / Réflexions Historiques 28.1 (2002): 51-72. <https://www.jstor.org/stable/41299224?seq=1>.