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Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
This chapter considers the growth performance of western European countries since 1870, and relates this to the degree of openness. A theoretical explanation of why convergence is predicted by economic theory is presented and some statistics are presented on GDP per capita and the contributions of various factors to growth performance. Three periods are considered: 1870 until World War I; the interwar period; and after World War II. The first and the last are associated with globalization and convergence, whereas the interwar period witnessed increasing levels of economic isolation and lack of convergence. All western European countries are much richer today than they were in 1870, but some countries have performed much more strongly than others. Over- and underperforming countries, whose growth performances were markedly different from what might be expected from their initial levels of income, are highlighted, and possible interpretations suggested.
Premature mortality affects the economy directly due to the loss of productivity of individuals who die, thus ceasing to contribute economically to the country. The one-third reduction in premature mortality (30–69 years) from chronic noncommunicable diseases is goal 3.4 of the United Nations Sustainable Development Goals (UN SDG). Although cancer is a chronic disease, it comprises more than 100 different conditions, with different risk factors and prognosis. This study aimed to calculate current and predicted premature mortality by 2030 for Brazil and regions, compared with the SDG 3.4 target and identify regional progress and future needs.
Mortality data were extracted from the National Mortality Information System of Brazil (SIM) and subsequently corrected for ill-defined causes. Crude and age-standardized mortality rates per 100,000 inhabitants were calculated. NordPred package by software R was used to calculate predictions up to 2030 and compared with the goal of one-third reduction of premature deaths.
Comparison of observed (2011–2015) and predicted (2026–2030) mortality rates show a 12.0% reduction in the likelihood of death among men and 4.6 percent among women nationally. Although predicted rates for 2026–2030 are lower than those observed in 2011–2015, the predicted number of deaths increases by 75,341 for men and 90,513 for women. Lung cancer mortality rates are predicted to decrease more among men than women, while colorectal cancer mortality will increase for both sexes.
The profile of cancer premature mortality is diverse in Brazil. Nationally, only male lung cancer will be close to reaching the SDG 3.4 target, endorsing the government's long-term efforts to reduce tobacco consumption. Colorectal cancer mortality increases in most regions, reflecting the epidemiological transition. Despite progress in cervical cancer control, it will continue to be a major challenge, especially in the North and Northeast. Our results provide a baseline for public policies for both prevention and access to treatment to reduce premature mortality in Brazil. Differences in cancer patterns show the need to plan and to adapt regionally for each reality.
Early death from cancer is potentially preventable. In developing countries, it is not only a human tragedy but also an economic tragedy. In Latin America and the Caribbean, the estimated number of deaths for people 15–64 years in 2018 was 262,141, with Brazil being the country with the largest number of cases in the region (38.2%). The mortality rate for cancer in Brazil was 68.7/100,000. The analysis of causes impacting premature mortality is an essential function of public health surveillance. This study aims to estimate Potential Productive Life Years of Lost (YPPLL) due to cancer from 2000 to 2016, according to the region, sex and cancer site.
Official data from the Brazilian government were used for the period 2000–2016 for the 15–64 age group (economically active population). For each cancer death in working-age people, potential years of productive life lost (YPPLL) were calculated as the difference between pensionable age and age at death from cancer (based on the age group mid-point). The limit considered as pensionable age was 65 years for men and 60 years for women.
The total of cancer deaths among working-age people was 61,547 in 2000 and increased to 93,551 in 2016. The correspondent YPPLL was 717,883 and 944,565, respectively (increase of 31.6%), mostly coming from males (56.8%). Highest individual YPPLL were observed in the North and Northeast and Midwest, for both sexes. The most substantial changes observed from 2000 to 2016 in total YPPLL were for colorectal cancer, which moved from sixth to the second position nationally.
The YPPLL due to cancer is increasing in Brazil and present different patterns by sex and geographic regions. While in the South and Southeast lung cancer has the highest impact among males, in the North and Northeast most YPPLL come from stomach cancer. Among females, a clear pattern is observed with breast cancer being responsible for most YPPLL excepting in the North, where cervical cancer still having a major impact compared to other tumors.
The traditional agenda: States, war and law
Geoffrey Wiseman, Professor and the Director of the Asia Pacific College of Diplomacy at the Australian National University,
Paul Sharp, Professor in the Department of Political Science at the University of Minnesota Duluth.
This chapter makes three main arguments. First, ideas and practices of diplomacy have a multi-millennial history – much longer than is generally thought. Second, this long history has been characterised by both continuity and change. As a result, diplomacy has been as much adaptive as resistant to change. Third, diplomacy is not diminishing in importance and both it and the diplomats who carry it out should be regarded as evolving and as important to the theory and practice of international relations. To assess these claims, the chapter first addresses the issue of defining diplomacy, before examining the evolution of diplomacy in terms that may be characterised broadly as pre-modern, modern and postmodern. The relationship between diplomacy and the study of international relations (IR) is then evaluated.
BOX 20.1: TERMINOLOGY
Some definitions of diplomacy
Diplomacy is the application of intelligence and tact to the conduct of official relations between the governments of independent states, extending sometimes also to their relations with vassal states; or, more briefly still, the conduct of business between states by peaceful means. (Satow 1979 : 1)
Diplomacy is the management of international relations by negotiation; the method by which these relations are adjusted and managed by ambassadors and envoys; the business or art of the diplomatist. (Harold Nicolson 1969 : 4–5)
[Diplomacy is] the conduct of relations between states and other entities with standing in world politics by official agents and by peaceful means. (Bull 1977: 162)
Diplomacy is concerned with the management of relations between states and other actors. From a state perspective diplomacy is concerned with advising, shaping and implementing foreign policy. (Barston 1988: 1)
Diplomacy is the conduct of international relations by negotiation rather than by force, propaganda, or recourse to law, and by other peaceful means (such as gathering information or engendering goodwill) which are either directly or indirectly designed to promote negotiation. (Berridge 2015: 1)
Diplomacy is the peaceful conduct of relations amongst political entities, their principals and accredited agents. (Hamilton and Langhorne 2011: 1)
Diplomacy is conventionally said to refer to the processes and institutions by which states [and others with standing] represent themselves and their interests in the conduct of their relations with one another. (Sharp 2019: 1)
β-Hydroxy-β-methylbutyrate (HMB), a leucine metabolite, has long been supplemented as a Ca salt (Ca-HMB) to increase strength and performance gains with exercise and to reduce recovery time. Recently, the free acid form of HMB (HMB-FA) has become commercially available in capsule form (gelcap). The current study was conducted to compare the bioavailability of HMB using the two commercially available capsule forms of HMB-FA and Ca-HMB. We also compared the pharmacokinetics of each form when administered mixed in water. Ten human subjects (five male and five female) were studied in a randomised crossover design. There was no significant sex by treatment interaction for any of the pharmacokinetic parameters measured. HMB-FA administered in capsules was more efficient than Ca-HMB capsule at HMB delivery with a 37 % increase in plasma clearance rate (74·8 (sem 4·0) v. 54·5 (sem 3·2) ml/min, P<0·0001) and a 76 % increase in peak plasma HMB concentration (270·2 (sem 17·8) v. 153·9 (sem 17·9) μmol/l, P<0·006), which was reached in one-third the time (P<0·009). When HMB-FA and Ca-HMB were administered in water, the differences still favoured HMB-FA, albeit to a lesser degree. Plasma HMB with HMB-FA administered in water was greater during the early phase of absorption (up to 45 min postadministration, P<0·05); this resulted in increased AUC during the first 60 min after administration, when compared with Ca-HMB mixed in water (P<0·03). In conclusion, HMB-FA in capsule form improves clearance rate and availability of HMB compared with Ca-HMB in capsule form.
The hype around globalization in early-twenty-first-century political and economic debates may convey an impression that we now are in an entirely new phase of economic development. This chapter will show that the presumption is wrong. A dose of elementary economic history is often helpful when the popular media forget about the past.
Globalization is market integration on a world scale. Market integration means that domestic markets are increasingly dependent on international markets. Prices and hence factor rewards will reflect global rather than local demand and supply conditions. Globalization is the product of intensified trade, capital mobility and migration. In that process prices, interest rates and – with a time lag – wages tend to converge and react faster to international shocks. The first wave of globalization started in the middle of the nineteenth century when barriers to trade, migration and capital mobility were abolished or weakened at the same time as the speed of information transmission increased. In most respects markets were as globalized around 1900 as they were at the beginning of the present century. In fact labour mobility across borders was less restricted before 1914 than it is now. However, there was an anti-globalization backlash early in the twentieth century with two World Wars and the Great Depression. That policy reversal affected commodity, labour and capital markets to the extent that the late-nineteenth-century globalization level was not regained until the 1970s or 1980s, when the second globalization period gained momentum.
Market integration operates through trade and arbitrage and the ultimate manifestation of a fully integrated market is the law of one price. The law of one price proposes that the price of identical goods that are traded is the same in all geographical locations. This is strictly true, of course, only if transport and transaction costs are zero, which they are not.
This edition has been thoroughly revised and a large amount of new material has been added reflecting new research results and the recent development of the European economy. Paul Sharp, my former PhD student and now Professor at the University of Southern Denmark in Odense, has assisted me in this work and he has the principal responsibility for Chapters 8 and 9.
We thank Marc Klemp for revising the Glossary and for his comments and suggestions on Chapter 3.
Claudia Riani has contributed to the development of the companion website and we thank Martin Lundrup Ingerslev for research assistance.
Industrial Revolution, Industrious Revolution and Industrial Enlightenment
The pre-industrial era witnessed a number of ground-breaking innovations and improvements, but they were typically generated by learning by doing. Producers learned that things worked, but had limited understanding of why things worked. From the seventeenth century, decisive efforts were directed towards gaining more and better knowledge of the ‘laws of nature’. However, it is wrong to believe that the British Industrial Revolution, the period 1770–1830, was based on scientific discoveries. Decisive steps were taken in that period towards a more profound understanding of nature, but these accomplishments had little immediate impact on production technologies. The iconic invention of the eighteenth century, the steam engine, is the exception that confirms this rule. The steam engine developed by Thomas Newcomen (1663–1729) relied on the results of scientific inquiry from the preceding century by the Italians Galileo Galilei (1564–1642) and Evangelista Torricelli (1608–97), the Dutchman Christiaan Huygens (1629–95), and Otto von Guericke (1602–86), a German, regarding atmospheric pressure, the weight of air and the nature of a vacuum. Contemporaries of Newcomen made significant contributions, in particular the French inventor Denis Papin (1647–1712?), who invented the piston. In the first generation of steam engines, the steam was condensed in a cylinder, which created a vacuum, and then the piston was pushed into the cylinder by atmospheric pressure.
The massive breakthrough of technologies, which sprang out of abstract theoretical inquiry coupled with empirical testing, did not arrive until the second half of the nineteenth century and mostly in the closing decades of that century. There is no denying, however, that systematic experiments, often combined with limited or flawed theoretical knowledge, became more common before and during the Industrial Revolution.
These misconceptions regarding the role of science contributed to very optimistic assessments of economic growth in the traditional historical narrative of what made Britain ‘the first industrial nation’.
We have learned that one major cause of productivity increase in pre-industrial economies is the gains from division of labour resulting from occupational diversification in an economy where regions and nations exploit their comparative advantages. But these gains cannot be reaped without exchange between increasingly specialized producers. Money, as a means of exchange, developed alongside the occupational and regional division of labour. The first money, some five or six thousand years ago, did not consist of stamped coins, but rather of standardized ingots of metal which were generally accepted as a means of payment. The Chinese and Greek civilizations introduced coins which were stamped like a modern coin. To understand the advantages of money it is worth looking at its historical antecedent and alternative. Direct bilateral exchange of one commodity for another, so-called barter, requires coincidence of wants between trading partners. It means that if you want to exchange a pair of shoes for wheat you have to find someone who has wheat and wants a pair of shoes. The matching process necessary to detect coincidence of wants will be very time-consuming, and time matters because it is scarce and has alternative uses. Barter will not only be associated with high search costs, but will also reduce the volume of trade to below its potential level because trade must be balanced. However, the volumes participants want to trade need not balance and in those cases the ‘minimum’ trader will determine the volume of trade. For example, a weaver might find a baker willing to exchange bread for cloth at an agreed price, but the weaver might not be willing to buy as much bread as the baker wants to sell. After all, bread is more perishable than cloth and is typically bought daily in small quantities. The volume traded when relying on bilateral balanced trade will thus, in this particular example, be constrained by the cloth maker, the ‘minimum’ trader.
This revised and extended edition of the leading textbook on European economic history has been updated to take account of contemporary economic developments and the latest research and debates. A concise and accessible introduction that covers the full sweep of the European history, the book focuses on the interplay between the development of institutions and the generation and diffusion of knowledge-based technologies. With simple explanations of key economic principles, the book is an ideal introduction for students in history and economics. Revised textboxes and figures, an extensive glossary, suggestions for further reading and a suite of online resources lead students to a comprehensive understanding of the subject. New material covers contemporary economic developments such as the financial crises of 2007/2008, the Eurozone crisis, new trends in inequality and the austerity debates. This remains the only textbook students need to understand Europe's unique economic development and its global context.
This book evolved over the years from the lectures I have given and give to my students at the Department of Economics in Copenhagen. I have, however, attempted to write a book for a wider audience who are searching for a very concise introduction to European economic history which is in tune with recent research. I make use of a few basic and simple economic tools which turn out to be very effective in the interpretation of history. The book offers a panoramic view rather than close-ups. However, the analytical framework will be useful in further studies of the specialized literature. For readers with little background knowledge in economics I provide a glossary defining key concepts, which are marked in bold, for example barter. Economic ideas demanding more attention are explained in the text or in appendices.
This is a work of synthesis, but it attempts to give challenging and new insights. I am indebted to generations of economic historians as well as to a great many of my contemporaries. That normally shows itself in endless footnotes, which not only interrupt the narrative flow but also drown the general historical trends amidst all the details. Instead, I have chosen to end each chapter with a selective list of references which is also a suggestion for further reading. Authors I am particularly influenced by are referred to in the main text.
A large number of colleagues have guided me. Cormac Ó Gráda has as usual been a very stimulating critic and Paul Sharp has not only saved me from embarrassing grammatical errors but is also the co-author of two chapters. I would also like to thank Carl-Johan Dalgaard, Bodil Ejrnæs, Giovanni Federico, Christian Groth, Tim Guinnane, Ingrid Henriksen, Derek Keene, Markus Lampe, Barbro Nedstam and Jacob Weisdorf for helpful comments and suggestions.
Mette Bjarnholt was my research assistant during the initial phase of the project and Marc Klemp and Mekdim D. Regassa in the final stage and they have all been enthusiastic and good to have around.