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This retrospective analysis aimed to establish the overall cardiac safety profile of bortezomib using patient-level data from one phase 2 and seven phase 3 studies in previously untreated and relapsed/refractory multiple myeloma (MM). Seven clinically relevant primary [congestive heart failure (CHF), arrhythmias, ischaemic heart disease (IHD), cardiac death] and secondary (hypertension, dyspnoea, oedema) cardiac endpoints were defined based on MedDRA v16.0 preferred terms. 2509 bortezomib-treated patients and 1445 patients in non-bortezomib-based control arms were included. The incidence of grade ≥3 CHF was 1·3-4·0% in studies in relapsed/refractory MM and 1·2-4·7% in previously untreated MM (2·0-7·6% all grades), with no significant differences between bortezomib- and non-bortezomib-based arms in comparative studies. Incidences of arrhythmias (1·3-5·9% grade ≥2; 0·6-4·1% grade ≥3), IHD (1·2-2·9% all grades; 0·4-2·7% grade ≥3) and cardiac death (0-1·4%) were low, with no differences between bortezomib-based and non-bortezomib-based arms. Higher rates of oedema (mostly grade 1/2) were seen in bortezomib-based versus non-bortezomib-based arms in one study and a pooled transplant study analysis. Logistic regression analyses of comparative studies showed no impact on cardiac risk with bortezomib-based versus non-bortezomib-based treatment. Bortezomib-based treatment was associated with low incidences of cardiac events.

This is the first broad survey using major, minor and trace element analyses of 8th–15th AD plant ash glass from the Middle East across a 2000 mile area stretching from Egypt to northern Iran. This was part of the ancient Silk Road that extended from the Middle East, through central Asia to China. Up to now, some compositional distinctions have been identified for such glasses mainly using major and minor element oxides and radiogenic isotopes. Our new trace element characterisation is for such glasses, mainly found in selected cosmopolitan hubs, including one where there is archaeological evidence for primary glass making. It provides not only far clearer provenance definitions for regional centres of production, in the Levant, northern Syria and in Iraq and Iran, but also for sub-regional zones of production. This fingerprinting is provided by trace elements associated with the primary glass making raw materials used: ashed halophytic plants and sands. Even more surprising is a correlation between some of the sub-regional production hubs and the types of glass vessels with diagnostic decoration apparently manufactured in or near the cosmopolitan hubs where the glass was found such as colourless cut and engraved vessels (in Iraq and Iran) and trail-decorated vessels (in the Levant). This therefore provides evidence for centres of specialisation. Our trace element characterisation provides a new way of defining the Silk Road by characterising the glass that was traded or exchanged along it. Taken together this data provides a new decentralised model for ancient glass production.

This is the first broad survey using major, minor and trace element analyses of 8th–15th AD plant ash glass from the Middle East across a 2000 mile area stretching from Egypt to northern Iran. This was part of the ancient Silk Road that extended from the Middle East, through central Asia to China. Up to now, some compositional distinctions have been identified for such glasses mainly using major and minor element oxides and radiogenic isotopes. Our new trace element characterisation is for such glasses, mainly found in selected cosmopolitan hubs, including one where there is archaeological evidence for primary glass making. It provides not only far clearer provenance definitions for regional centres of production, in the Levant, northern Syria and in Iraq and Iran, but also for sub-regional zones of production. This fingerprinting is provided by trace elements associated with the primary glass making raw materials used: ashed halophytic plants and sands. Even more surprising is a correlation between some of the sub-regional production hubs and the types of glass vessels with diagnostic decoration apparently manufactured in or near the cosmopolitan hubs where the glass was found such as colourless cut and engraved vessels (in Iraq and Iran) and trail-decorated vessels (in the Levant). This therefore provides evidence for centres of specialisation. Our trace element characterisation provides a new way of defining the Silk Road by characterising the glass that was traded or exchanged along it. Taken together this data provides a new decentralised model for ancient glass production.

In this chapter we will make the transition towards the design of business models and the related critical issues. We develop a model that helps us understand the causalities that play a role in understanding the viability and feasibility of the business models, i.e. long-term profitability and market adoption. We argue that designing viable business models requires balancing the requirements and interests of the actors involved, within and between the various business model domains. Requirements in the service domain guide the design choices in the technology domain, which in turn affect network formation and the financial arrangements. It is important to understand the Critical Design Issues (CDIs) involved in business models and their interdependencies. In this chapter, we present the Critical Design Issues involved in designing mobile service business models, and demonstrate how they are linked to the Critical Success Factors (CSFs) with regard to business model viability. This results in a causal model for understanding business model viability, as well as providing grounding for the business model design approach outlined in Chapter 5.

Intermediaries have introduced electronic services with varying success. One of the problems an intermediary faces is deciding what kind of exchange service it should offer to its customers and suppliers. For example, should it only provide a catalogue or should it also enable customers to order products? Developing the right exchange design is a complex undertaking because of the many design options on the one hand and the interests of multiple actors to be considered on the other. This is far more difficult than simple prescriptions like ‘creating a win-win situation’ suggest. We address this problem by developing design patterns for the exchanges between customers, intermediary, and suppliers related to role, linkage, transparency, and ovelty choices. For developing these design patterns, we studied four distinct electronic intermediaries and dentified exchange design choices that require trade-offs relating to the interests of customers, intermediary, and suppliers. The exchange design patterns contribute to the development of design theory for electronic intermediaries by filling a gap between basic business models and detailed business process designs.

This is the first broad survey using major, minor and trace element analysis of 8th-15th AD plant ash glass from the Middle East across a 2000 mile area stretching from Egypt to northern Iran. This was part of the ancient Silk Road that extended from the Middle East, through central Asia to China. Up to now, some compositional distinctions have been identified for such glasses mainly using major and minor element oxides and radiogenic isotopes. Our new trace element characterisation is for glass found in selected cosmopolitan hubs, including one where there is archaeological evidence for primary glass making. It provides not only far clearer provenance definitions for regional centres of production, in the Levant, northern Syria and in Iraq and Iran, but also for sub-regional zones of production. This fingerprinting is provided by trace elements associated with the primary glass making raw materials used: ashed halophytic plants and sands. Even more surprising is a correlation between some of the sub-regional production hubs and the types of glass vessels with diagnostic decoration apparently manufactured in or near the cosmopolitan hubs where the glass was found such as colourless cut and engraved vessels (in Iraq and Iran) and trail-decorated vessels (in the Levant). This therefore provides evidence for centres of specialisation. Our trace element characterisation provides a new way of defining the Silk Road by characterising the glass that was traded or exchanged along it. Taken together this data provides a new decentralised model for ancient glass production.

This is the first broad survey using major, minor and trace element analysis of 8th-15th AD plant ash glass from the Middle East across a 2000 mile area stretching from Egypt to northern Iran. This was part of the ancient Silk Road that extended from the Middle East, through central Asia to China. Up to now, some compositional distinctions have been identified for such glasses mainly using major and minor element oxides and radiogenic isotopes. Our new trace element characterisation is for glass found in selected cosmopolitan hubs, including one where there is archaeological evidence for primary glass making. It provides not only far clearer provenance definitions for regional centres of production, in the Levant, northern Syria and in Iraq and Iran, but also for sub-regional zones of production. This fingerprinting is provided by trace elements associated with the primary glass making raw materials used: ashed halophytic plants and sands. Even more surprising is a correlation between some of the sub-regional production hubs and the types of glass vessels with diagnostic decoration apparently manufactured in or near the cosmopolitan hubs where the glass was found such as colourless cut and engraved vessels (in Iraq and Iran) and trail-decorated vessels (in the Levant). This therefore provides evidence for centres of specialisation. Our trace element characterisation provides a new way of defining the Silk Road by characterising the glass that was traded or exchanged along it. Taken together this data provides a new decentralised model for ancient glass production.

This is the first broad survey using major, minor and trace element analysis of 8th-15th AD plant ash glass from the Middle East across a 2000 mile area stretching from Egypt to northern Iran. This was part of the ancient Silk Road that extended from the Middle East, through central Asia to China. Up to now, some compositional distinctions have been identified for such glasses mainly using major and minor element oxides and radiogenic isotopes. Our new trace element characterisation is for glass found in selected cosmopolitan hubs, including one where there is archaeological evidence for primary glass making. It provides not only far clearer provenance definitions for regional centres of production, in the Levant, northern Syria and in Iraq and Iran, but also for sub-regional zones of production. This fingerprinting is provided by trace elements associated with the primary glass making raw materials used: ashed halophytic plants and sands. Even more surprising is a correlation between some of the sub-regional production hubs and the types of glass vessels with diagnostic decoration apparently manufactured in or near the cosmopolitan hubs where the glass was found such as colourless cut and engraved vessels (in Iraq and Iran) and trail-decorated vessels (in the Levant). This therefore provides evidence for centres of specialisation. Our trace element characterisation provides a new way of defining the Silk Road by characterising the glass that was traded or exchanged along it. Taken together this data provides a new decentralised model for ancient glass production.

This is the first broad survey using major, minor and trace element analysis of 8th-15th AD plant ash glass from the Middle East across a 2000 mile area stretching from Egypt to northern Iran. This was part of the ancient Silk Road that extended from the Middle East, through central Asia to China. Up to now, some compositional distinctions have been identified for such glasses mainly using major and minor element oxides and radiogenic isotopes. Our new trace element characterisation is for glass found in selected cosmopolitan hubs, including one where there is archaeological evidence for primary glass making. It provides not only far clearer provenance definitions for regional centres of production, in the Levant, northern Syria and in Iraq and Iran, but also for sub-regional zones of production. This fingerprinting is provided by trace elements associated with the primary glass making raw materials used: ashed halophytic plants and sands. Even more surprising is a correlation between some of the sub-regional production hubs and the types of glass vessels with diagnostic decoration apparently manufactured in or near the cosmopolitan hubs where the glass was found such as colourless cut and engraved vessels (in Iraq and Iran) and trail-decorated vessels (in the Levant). This therefore provides evidence for centres of specialisation. Our trace element characterisation provides a new way of defining the Silk Road by characterising the glass that was traded or exchanged along it. Taken together this data provides a new decentralised model for ancient glass production.

This is the first broad survey using major, minor and trace element analysis of 8th-15th AD plant ash glass from the Middle East across a 2000 mile area stretching from Egypt to northern Iran. This was part of the ancient Silk Road that extended from the Middle East, through central Asia to China. Up to now, some compositional distinctions have been identified for such glasses mainly using major and minor element oxides and radiogenic isotopes. Our new trace element characterisation is for glass found in selected cosmopolitan hubs, including one where there is archaeological evidence for primary glass making. It provides not only far clearer provenance definitions for regional centres of production, in the Levant, northern Syria and in Iraq and Iran, but also for sub-regional zones of production. This fingerprinting is provided by trace elements associated with the primary glass making raw materials used: ashed halophytic plants and sands. Even more surprising is a correlation between some of the sub-regional production hubs and the types of glass vessels with diagnostic decoration apparently manufactured in or near the cosmopolitan hubs where the glass was found such as colourless cut and engraved vessels (in Iraq and Iran) and trail-decorated vessels (in the Levant). This therefore provides evidence for centres of specialisation. Our trace element characterisation provides a new way of defining the Silk Road by characterising the glass that was traded or exchanged along it. Taken together this data provides a new decentralised model for ancient glass production.

This is the first broad survey using major, minor and trace element analysis of 8th-15th AD plant ash glass from the Middle East across a 2000 mile area stretching from Egypt to northern Iran. This was part of the ancient Silk Road that extended from the Middle East, through central Asia to China. Up to now, some compositional distinctions have been identified for such glasses mainly using major and minor element oxides and radiogenic isotopes. Our new trace element characterisation is for glass found in selected cosmopolitan hubs, including one where there is archaeological evidence for primary glass making. It provides not only far clearer provenance definitions for regional centres of production, in the Levant, northern Syria and in Iraq and Iran, but also for sub-regional zones of production. This fingerprinting is provided by trace elements associated with the primary glass making raw materials used: ashed halophytic plants and sands. Even more surprising is a correlation between some of the sub-regional production hubs and the types of glass vessels with diagnostic decoration apparently manufactured in or near the cosmopolitan hubs where the glass was found such as colourless cut and engraved vessels (in Iraq and Iran) and trail-decorated vessels (in the Levant). This therefore provides evidence for centres of specialisation. Our trace element characterisation provides a new way of defining the Silk Road by characterising the glass that was traded or exchanged along it. Taken together this data provides a new decentralised model for ancient glass production.