Magnus Klofsten
email: magnus.klofsten@liu.se

Peter Heydebreck#

Dylan Jones-Evans+

Peter Heydebreck
email: p.heydebreck@inno-group.com

Dylan Jones-Evans

Critical surveys paper! TRANSFERRING GOOD PRACTICE BEYOND ORGANISATIONAL BORDERS: LESSONS FROM TRANSFERRING AN ENTREPRENEURSHIP PROGRAMME

Keywords: Entrepreneurship, Best practice, Transfer, Training

This paper examines the transfer of a 'good practice' entrepreneurship initiative from Linköping in Sweden to nine other regions. It shows that the success of transferring 'good practice' is dependent on various pre-conditions in respect to the sender and recipient systems, as well as the interaction between these two systems. These include openness to continue the learning process and adapting the knowledge to be transferred to local conditions. A long-term commitment by both parties is also required which derives not only from the role of institutions, but also from enthusiastic individuals who drive the transfer process and sustainably link the systems after the initial transfer.

Cet article cherche à examiner le transfert des 'meilleures pratiques', sous forme d'une initiative favorisant l'esprit d'entreprise, de Linköping en Suède à neuf autres régions. On montre que réussir à transférer les 'meilleures pratiques' dépend des conditions préalables différentes pour ce qui est du système de la zone d'origine et celui de la zone d'accueil, aussi bien que de l'interaction entre ces deux systèmes. Celles-là comprennent être prêt à développer l'apprentissage et à adapter la connaissance à transférer aux conditions locales. Il faut aussi un engagement à long terme des deux parties qui remonte non seulement du rôle des institutions, mais aussi des individus enthousiastes qui pilotent le processus de transfert et relient durablement les systèmes suite au transfert initial. Transferir buenas prácticas tras las fronteras organizativas: lecciones de traspasar un programa empresarial Magnus Klofsten, Peter Heydebreck And Dylan Jones-Evans En este artículo analizamos la transferencia de una iniciativa empresarial de 'buenas prácticas' de Linköping en Suecia a otras nueve regiones. Se demuestra que el éxito de transferir 'buenas prácticas' depende de diferentes precondiciones con respecto a los sistemas del emisor y el receptor, así como de la interacción entre estos dos sistemas. Estas precondiciones incluirían la disposición a continuar el proceso de aprendizaje y adaptar el conocimiento que se transferirá a las condiciones locales. También es necesario un compromiso a largo plazo por ambas partes que surja no sólo del rol de las instituciones sino también de individuos entusiastas que estimulen el proceso de transferencia y enlacen de modo sostenible los sistemas después de la transferencia inicial.

INTRODUCTION

Greater commercialisation of R&D from the university sector is seen as one of the key drivers of the future economic growth of many nations, although there is an increasing consensus that Europe continues to lag behind the U.S. and Japan in this respect. Whilst European researchers produce scientific results which are comparable to those in the United States, these results are not commercialised as frequently and quickly as in competing nations (OECD, 2002).

At a sub-national level, policymakers have also recognised the important role of the university in developing the innovation potential of a region [START_REF] Jones-Evans | Comparing academic entrepreneurship within peripheral regions -the case of Sweden and Ireland[END_REF]HOMMEN et al, 2006;[START_REF] Benneworth | Seven Samurai Opening Up the Ivory Tower? The Construction of Newcastle as an Entrepreneurial University[END_REF] with an increasing number of academic institutions becoming involved in certain commercialisation activities such as the protection of intellectual property through patenting and licensing activities and the encouragement of spin-offs that originate from university research [START_REF] Etzkowitz | Triple Helix[END_REF]. There is also external pressure on universities to achieve an increase in the effectiveness and efficiency of their contribution to regional economic development and competitiveness [START_REF]Creating entrepreneurial universities: Organizational pathways of transformation[END_REF][START_REF] Etzkowitz | The innovative region: Toward a theory of knowledge-based regional development[END_REF], especially in developing initiatives aimed at boosting entrepreneurship and innovation within local firms.

As a result, there has been an increase in the number of initiatives at a European, national and regional level to encourage greater linkages between universities and industry [START_REF] Jones-Evans | The role of the university in the technology transfer process -a European view[END_REF]COOKE and LEYDESDORFF, 2005;[START_REF] Bergek | Incubator best practices: A framework[END_REF] Not surprisingly, there have been criticisms of the practice of encouraging the transfer of policy initiatives from one region to another. For example, [START_REF] Todtling | One size fits all?: Towards a differentiated regional innovation policy approach[END_REF] have argued that whilst many regional innovation policies have been shaped by good practice derived from well performing regions, there is no ideal model for innovation policy as innovation activities will differ between different types of areas with respect to their preconditions for innovation, networking and innovation barriers. [START_REF] Hospers | Silicon Somewhere?[END_REF] has also evaluated the usefulness of the diffusion of 'best practice' in regional policy in order to identify the lessons that should really be drawn from regional success stories. He suggests that adopting 'best practice' in regional policy is, at best, limited, as the very conditions that explain the success of a particular region will be the most difficult elements to learn from i.e. the success of a region is determined by its culture, its history, and its institutional set up, and even the most powerful 'best practice' policy will only have a limited effect [START_REF] Hospers | Silicon Somewhere?[END_REF][START_REF] Wink R | Transnationales lernen: Leerformel oder regionalpolitische zukunftsstrategie? Gesellschaft für Regionalforschung[END_REF].

Whilst these criticisms are valid, they may not have taken into account the potential role of the actors within the knowledge transfer system and, it can be argued, one of the key limitations to the transfer of 'best' or 'good' practice between regions is the pre-dominance of third party actors, such as consultants, who will only have access to 'public knowledge' produced by the good practice actor [START_REF] Klofsten | Stimulation of technology-based small firms -a case study of university-industry co-operation[END_REF]) rather than any confidential information from the good practice system itself. As a result, any learning from third party experience can only be effective if the 'champions' who initiated and managed the good practice case in one region are substantially involved in the implementation of lessons learned by a partner in another region. Consequently, this paper investigates ways of establishing partnerships between a good practice case of stimulating and fostering a supportive entrepreneurial environment in one region and partner systems in other regions, a process which is characterized by mutual trust, motivation and competence. When the relationship is established, knowledge and experience can be effectively communicated and jointly adapted to the recipients' systems. Once in place, the 'good practice' needs to be continuously improved and further developed in respect to knowledge content and its transferability.

AIM AND SCOPE

This paper examines the key factors in successfully transferring good practice in regional policy beyond organisational borders between the 'sender' (the originator of the good practice) and recipient organisations. Of course, analysis of good practice in regional policy can result in collections of anecdotal evidence that will have little benefit to the actors involved. As a result, most attempts to learn from others will fail before the knowledge transfer process is initiated properly. In this paper, the interorganisational transfer of good practice is perceived as the initiation, implementation, and mainstreaming of one system's superior routine use of knowledge (including tacit components) into the recipient's system [START_REF] Nelson | An evolutionary theory of economic change[END_REF][START_REF] Kogut | Knowledge of the firm, combinative capabilities and the replication of technology[END_REF]. Whereas there is a substantial pent-up demand in respect to empirical studies on the key determinants of inter-organisational transfer of good practice, there is some evidence in respect to how to make use of good practice within an organisation. Although this particular study has a strong exploratory character, the theoretical framework is based on the experiences of intra-organisational transfers of good In this paper, success is partly determined by the quality and complexity of what is to be transferred and the quality of the transfer process itself. It draws partly on the work of [START_REF] Szulanski | Exploring internal stickiness: Impediments to the transfer of best practice within the firm[END_REF], who identified the complexity and uncertainty with respect to the causal mechanisms in ensuring success as one of the three most important determinants of transferring good practice within an organisation. Due to the exploratory nature of the work, no specific hypotheses have been formulated, although particular attention has been paid to a set of three variables:

• Absorptive capacity of the recipient. This would include the ability of a firm to recognise the value of new externally generated information, its assimilation and application to commercial ends [START_REF] Cohen | Absorptive capacity: A new perspective to learning and innovation[END_REF]. This capacity is primarily determined by the attitudes of the recipient (such as the not-invented here syndrome or a motivation to engage in transfer process) and the assets of the recipient (dedication to both the learning process and the implementation of the good practice).

• Characteristics of the sender. The important factors here are the attitudes of the sender (including openness to allow re-branding of the good practice and the motivation to engage in transfer process) and the assets of the sender (reputation and transfer champions). The decisive importance of the sender for the efficiency and effectiveness of communication within a transfer process has been empirically validated in wide range of different disciplines. For instance, human resource management theory defines different roles in the communication process both within the firm as well as between the firm and its business environment, highlighting the importance of a clear communication strategy (FRINK and • The transfer of knowledge from one system to another. This is no 'spot market' interaction but, as discussed in [START_REF] Håkansson | Business network learning: Basic considerations[END_REF], is a longterm process which requires a sustainable and learning environment and a trustbased relationship. Within the framework of this study, we have focused on examining a relationship's degree of mutual trust, its power balance, and geographic/cultural proximity between partners as well as some key determinants of these variables such as the duration of the relationship and its impact on trust between partners.

Obviously, the three variables above do not constitute an exhaustive list of relevant success determinants of the knowledge transfer process. However, we believe that it makes sense to focus on these three as most other variables will either be identical for all analysed transfer processes or be determinants of the three variables we analyse.

For instance, it will have a major impact on the transfer process if the sender system competes with other sender systems or with some parts of the recipient system and its close affiliates. Such competition will then be mirrored in the recipient system's motivation, the sender system's reputation (is the sender seen as the only provider, the best provider, or simply a possible provider amongst others?), and trust and openness amongst partners (is the sender system invited to actively participate in the definition of the transfer process or has the recipient system defined the process and asked or competitive tenders?). Figure 1 illustrates the authors' theoretical frame of reference.

Insert figure 1 [START_REF] Szulanski | Exploring internal stickiness: Impediments to the transfer of best practice within the firm[END_REF] found statistically significant evidence that the partners' motivation is of limited importance for the success of knowledge transfer, this aspect is still included as a key construct in this paper's frame of reference. This is because Szulanski's finding only holds true for intra-organisational processes (i.e. within an organisation) where the lack of motivation of sender and recipient can be partly compensated with hierarchical power. Inter-organisational relationships, as found in the type of knowledge transfer examined in this paper, are dependent on the dedication of all involved parties. Another purpose of the paper is to increase awareness of the crucial importance of process-related 'how-questions' which tend to be overshadowed by the more appealing 'what questions'. Furthermore, the authors wish to provide an insight into the communication of 'how-knowledge' between actors i.e. how partners can increase their success rate in accessing, adapting and implanting other systems' knowledge.

Ultimately, this would lead to an increased number of knowledge transfer processes supporting both universities and companies and engaging in valorising academic know-how.

METHOD

The sample

This paper has selected the transfer of a university entrepreneurship programme to other milieus as the object of analysis. In total, nine transfer processes have been analysed and the sample was selected by drawing upon the following criteria.

The first selection criterion is the success of the object of transfer, namely the Linköping Entrepreneurship programme (ENP). This was launched in 1994 to sup- The second selection criterion is that the object of transfer has been transferred a substantial number of times beyond organisational borders, with a track record of a minimum of five years of transfer in order to capture strategic effects. Initially, CIE did not intend to transfer the programme to other parts of Sweden but due to the programme's initial success in the home region, the former CEO of the Technology Park in Västerås contacted CIE in 1999 to request a proposal for an entrepreneurship programme for his region. CIE (the sender) provided fee-based delivery of ENP's conceptual content and human resources under the following conditions:

• CIE provides a programme leader, coach, and conducts workshops

•

The receiving partner provides on-site coordination, recruitment of participants and mentors and organization of training premises, audio visual and technical equipment, and other infrastructural tasks.

•

The on-site assistant programme leader should become programme leader once the sender has transferred the ENP programme to the recipient.

•

The recipient markets the programme.

• Sender and recipient agree to exchange information informally over a prolonged time period.

•

The recipient gradually takes over and carries on the programme independently. (SIDJE and TILBURG, 2000). It was initially transferred to Moldavia and was followed by the Kaluga region in Russia in 2004. As of mid-2006, about 50 programmes had been conducted (less than half in the Linköping area) and 500 new businesses created. Programme statistics show that 75 per cent of all project ideas developed within the programme become businesses, with a survival rate of 70 per cent, and one in five of the businesses from the programme now have more than five employees.

The third and final selection criterion is full access to sensitive data from the good practice system and the recipients' systems. Interview probes have been used to clarify statements and their meaning and to elaborate on the participant's experiences and judgements on the transfer process and its impact. Aspects of the 'critical incidence' technique [START_REF] Flanagan | Critical incidence technique[END_REF]POLIT and HUNGLER, 1999) were also used in asking respondents about episodes of helpful and unhelpful elements in the preparation and implementation of the transfer process.

Data has been collected through face-to-face interviews with key stakeholders in the original Linköping environment as well as in the recipients' environments, i.e. the model developer, financial bodies, programme participants/clients, transfer agents and operative staff. Twelve in-depth face-to-face interviews were performed, taking a minimum of two hours and typically followed-up by a series of shorter conversations.

More specifically, the key representatives of nine recipient milieus have been interviewed and three key people from the sender system have been interviewed. An additional forty interviews addressing specific aspects identified in the core interviews and in the follow-up interviews were also conducted. Therefore, a total of 21 interviews have been conducted with participants in the courses (three interviews in Linköping and two interviews in each recipient milieu, with 14 interviews performed with programme directors and trainers in the recipient milieus). In addition, five Linköping trainers acting as programme leaders were interviewed in order to analyse and validate the underlying reasons for challenges in the knowledge transfer process.

The interview findings have been systemised and complemented by previous evaluations of the entrepreneurship programme scheme with different foci [START_REF] Klofsten | Training entrepreneurship at universities: A Swedish case[END_REF][START_REF] Klofsten | Supporting academic enterprise: A case study of an entrepreneurship programme[END_REF]. The results and conclusions have been validated with the interview partners who have proofread the documentation of the interviews and the final version of the paper. First of all, the critical incidence method has been employed to identify decisive moments for overall transfer success and to judge the adequacy of measures employed to master key challenges. Although implementation of the entrepreneurship programme has been relatively smooth, problems have occurred with workshop content and its presentation. However, the principal problem has not been how to transfer programme content, but how to transfer the personal experience and professional expertise of the CIE staff.

Secondly, the overall success was measured after implementation of the transfer and was measured as the satisfaction of the recipient, the recipient's clients and the sender.

The main subjective indicators used comprised of a number of elements such as the partners' statements on whether they had engaged in the transfer process if they had known what they know today upfront (the key representatives of all nine recipient systems answered positively although this question was not asked to course participants); the partners' satisfaction with the total cost of the transfer process (both in terms of financial resources and human resources); and the time to transfer the best practice and impact of the transfer in the respective milieu (in the case of participants' impact on the participant). Satisfaction was measured on a six point rating scale where the respondent was asked to rate his judgement on the actual transfer process relative to his expectations before the transfer process started (table 1).

Insert table 1 here

The expectations of the recipients in respect to costs were very realistic, as initial discussions between sender and recipient emphasised the necessity for substantial contribution of human resources from the recipient. Overall, the expectations in respect to time (measured in months) were also realistic and well met. However, both the sender and recipient considered further potential for speeding up the process. Two recipient representatives believed upfront that they would be capable to conduct the transfer process substantially faster than it could be done in previous cases. These expectations were not satisfied.

The positive feedback on the impact was high and there appears to be a direct relationship between the perception of the success and the length of participation in the programme. It is also remarkable that all sender representatives expected a positive impact of the transfer process on their home system and even more remarkable that these expectations were over achieved. Apart from obvious gains in terms of reputation and funding, sender representatives stressed the aspects of mutual learning, both in terms of running a programme and in terms of transferring the knowledge from the programme. Furthermore, the sender emphasised the benefits of interlinking the different communities. This illustrates that the transfer of a good practice is a dyadic process where both sender and recipient benefit. Actually, one might ask whether transfer of good practice is an adequate label for such a partnership at all and it may be more relevant to describe this as a good practice based mutual learning process.

Eight of the recipient systems have continued with their new programmes whereas one has stopped all related activities due to serious budget cuts. Four recipient systems currently serve as reference clients to the sender. Meanwhile, the sender has The analysis in this paper is based on subjective data mainly due to the following three reasons:

• The good practice policy has been transferred to a set of quite heterogeneous recipient milieus, although it is important to compare the quality of the process to these different milieus. Consequently, we opted for subjective data allowing the respondents to take into account specific local circumstances (e.g. language barriers in the Russian case, non-existence of a university in the Lidköping case).

• The importance of the different dimensions of the quality of the transfer process varies from case to case. An adequate aggregation of objective data (such as the total costs of the transfer process, number of start-ups in the recipient's milieu due to the transfer process) is hardly possible. Consequently, the individual recipients were asked to integrate their satisfaction with specific aspects and the importance of these aspects in summarising judgements of satisfaction.

• Partners' satisfaction is the key determinant of the partners' future action. This determines whether the recipient will serve as a reference client and whether the sender, before transferring to other environments, will undertake substantial changes to the transfer process before doing so.

SUCCESS DETERMINANTS IN THE TRANSFER OF GOOD PRACTICE

Based upon our theoretical frame of reference, we have attempted to specify the theo- 18 retical constructs which determine the success of a transfer of a practice. Apart from the quality of the practice itself (which is more or less constant for all cases analysed as it is always the ENP programme which is transferred), the main determinant is the quality of the transfer process. The findings show that even the quality of the process is overall judged as good, which implies that no systematic comparisons can be made between successful and unsuccessful transfer processes due to limited variance. Consequently, the authors have thoroughly investigated what the partners involved in the transfer process actually judged as the decisive explanations of success. This exploratory qualitative research results in the following specification of the theoretical constructs:

Delivery capacity of sender: Motivation (success-based transfer fee).

The programme must satisfy a mutual need for both recipient and sender. A strong regional growth initiative that includes plans for marketing communications, trademarking, branding and promotion is conducive to the ENP transfer. The recipient should be assured that the model is well known and has been successful elsewhere.

The sender should also receive a "royalty" from revenues for ongoing improvement and recognition of its high quality. This reciprocity allows both parties to enjoy success while supporting each other, although the recipient's needs must remain central both during and following the completion of the transfer. The transfer of knowledge is pedagogic in nature (sender) and fulfils a need to learn (recipient). A constant transfer of knowledge between sender and recipient allows continual development of the ENP and generates knowledge for the sender. A programme representative from the sender put it as follows "We continuously improve the programme based upon the feedback we receive. Thus, we always deliver a bit more then the client expects. This is more or less a guarantee for repeated business". All experience gleaned from testing the programme in other environments with different types of participants by programme managers, coaches, and workshop leaders is beneficial to the home programme in Linköping and to future programme transfers to other communities.

Delivery capacity of sender: Competence (holder of a transferable model).

The recipient will only be interested in well-tested, successful models and the sender will not want to undertake a transfer process unless the participating partner has every chance to succeed. However, the model must be transferable and the basic elements in any entrepreneurship programme (workshops, mentoring, coaching) are well known.

Quality and programme transferability will vary depending on controls established for recruitment of participants and relationships between management and participants. A key characteristic of management -responsible for transfer of the programme's soft values -is the ability to inspire participants in their work.

Key characteristic of the relationship between sender and recipient: Openness.

In principle, the information exchange between sender and recipient should be unlimited and open during all stages of programme transfer and implementation. This builds a firm foundation for future development. Recipients' tasks include progress reports on the budget, recruitment of participants and mentors, programme evaluations and suggestions for future co-operation. Senders should propose new ideas and methods for developing and improving the programme. People with strong driving forces who are prepared to invest whole-heartedly in the process are the key to the successful transfer of the ENP programme. As one said, "Without Evert (the programme leader of the sender), we would never have succeeded." In return, the community in which these people will work must support them strongly. One question that should be addressed in advance is how much external competence the recipient needs in order to establish its own programme as total resource needs and the overall timing of the transfer of the programme can then be determined. Enthusiasts must have the courage to bridge barriers and create opportunities for the adoption of external ideas, and both senders and recipients need such enthusiasts on their teams.

Key characteristic of the relationship between sender and recipient: partners sharing common view on success.

The measurement of the success of an entrepreneurship programme is not obvious and concrete results -such as the development of a cluster of growing companies -can take years to achieve. Typical criteria for success include the number of programme applicants, the number of applicants qualified to participate, the quality of final company presentations, the programme evaluations, and the number of participants who actually start a company. One way or another, a programme should prove that it actually fosters new companies. Long-term access to resources such as infrastructure (premises, administration and equipment), finance, and local mentors are essential to the success of a transfer. A critical voice from a recipient system put it as follows, "You cannot expect us to start working on the basis of a promise. We need financial resources dedicated to the programme. Once the financial situation was clear, things went very well, although we could have avoided the initial delay". Therefore, recipients must plan how to sustain the programme under its own management during the initial stages of programme development. Although the recipient should prove its ability in managing the ENP, it is also entitled to make demands concerning programme content and quality.

Key characteristic of the relationship between sender and recipient: champions.

In practice, successful transfer of the ENP model depends on recruiting human resources who have an experienced understanding of the entrepreneurial processes involved in the early stages of a new firm's development. As a sender representative put it "It would be almost impossible to fail with the entrepreneur of the year onboard".

All ENP staff should have this trait, and programme leaders will have actually run a company previously. As a result, they make the best role models for younger entrepreneurs and are a vital component of the programme. The programme leader is central to the programme's execution and must always be present. This person is an important link between the sender and the recipient and must anticipate programme changes, communicate information, and share participant's achievements. Since the

CONCLUDING REMARKS

The demand for good practice studies and benchmarking exercises have received considerable attention from policymakers, although there remains a worrying lack of knowledge on how to make use of all these studies, especially if third party actors alone are involved in transferring programmes between regions. This paper shows the critical role of the original developer of the programme in ensuring that the "sender system" and the "recipient system" engage in a long-term trust-based relationship.

Since most studies of the transfer of good practice focus on intra-organisational applications [START_REF] Szulanski | Exploring internal stickiness: Impediments to the transfer of best practice within the firm[END_REF], the vital aspect of partner selection has not been given adequate attention. As this paper indicates, in transferring good practice between different regions, it is vital that the complementarities between the sending and receiving systems is encouraged through the careful selection of partners and further investment into the on-going relationship. In particular, such partner systems should:

• Have consciously implemented a relevant process of outstanding effectiveness and efficiency in order that it makes sense to learn what it takes to succeed from them.

• Have succeeded under similar circumstances (in respect to the determinants of a superior process design) in order to make the lessons learned relevant for the transfer.

• Be motivated to fully share their insights and support the transfer of know-how in order to make use of even sensitive but crucial information (e.g. what was done • Be known as a successful system in order to overcome scepticism from recipients.

• Be "close" to the recipient system both in terms of geographical distance and, if possible, language in order to limit transaction costs.

Critically, the relationship between sender and recipient has to be honoured and communicated as important by both partners as policy makers can hardly be expected to enforce such bilateral or small network exercises. However, they can establish arenas and platforms of mutual learning where members learn with each other instead of just from each other and where members build up the necessary trust to invest into bilateral relationships.

The authors hope that this paper contributes to the discussion on how to ensure that much more of the existing knowledge within good practice initiatives can be successfully applied to other regions. Whereas there is a growing consensus that there needs to be better valorisation of the research results emerging from universities and an increased awareness of good valorisation practices, there still is a huge demand for additional research to fully understand the success determinants of integrating third party good practice in a given system. There is also a need to provide support for developing policies supporting such knowledge transfer processes and to further develop the process by which valorisation takes place professionally.

F

  优秀实践 学术企业家Le transfert des meilleures pratiques au-delà des frontières organisationnelles: des leçons à tirer du transfert d'un programme favorisant l'esprit d'entreprise.

  Esprit d'entreprise / Transfert de la connaissance / Systèmes d'apprentisage / Meilleures pratiques / Esprit d'entreprise académique Übertragung guter Praxis über organisationelle Grenzen hinweg: Lektionen aus der Übertragung eines Programms für Unternehmertum MAGNUS KLOFSTEN, PETER HEYDEBRECK and DYLAN JONES-EVANS In diesem Beitrag überprüfen wir die Übertragung einer Unternehmensinitiative für 'gute Praxis' von Linköping in Schweden nach neun anderen Regionen. Wie sich zeigt, hängt der Erfolg einer Übertragung 'guter Praxis' von verschiedenen Vorbedingungen hinsichtlich der Systeme des Senders und Empfängers sowie von den Wechselwirkungen zwischen diesen beiden Systemen ab. Zu diesen Vorbedingungen gehört eine Bereitschaft zur Fortsetzung des Lernprozesses und zur Anpassung des übertragenen Wissens an die Bedingungen vor Ort. Ebenso ist ein langfristiges Engagement beider Seiten erforderlich, das sich nicht nur aus der Rolle der Institutionen ableitet, sondern auch von enthusiastischen Einzelpersonen gefördert wird, die den Übertragungsprozess vorantreiben und die Systeme nach der ersten Übertragung dauerhaft miteinander verknüpfen.

  with a concomitant focus by policymakers on identifying 'best practice' in commercialisation activities and transferring these to other regions to generate knowledge-based sustainable economic growth(POLT et al

  for knowledge-intensive firms with roots in the university milieu. Since its commencement, participants from the programme have established about 130 firms, with 30 firms growing to employ over 10 employees. The Centre for Innovation and Entrepreneurship (CIE) at Linköping University developed the ENP as an outgrowth of the experience at the university in supporting established firms and their ability in encouraging spin-offs from these firms. At that time, support programmes were not geared towards younger entrepreneurs and this new initiative was aimed at improving the frequency and quality of new start-ups emerging directly from the university. The two main targets of the tuition-free programme were university staff and students, in addition to staff within knowledge-intensive local organisations.On average, twenty participants took part in each programme with the aim of initiating 15 new firms. Each programme lasted between four and six months, allowing participants to work or study concurrently.Since starting a new business requires various kinds of knowledge, the ENP covers a wide range of topics, including business development, funding, leadership, legal matters and presentation techniques, through the following methods:• Business development plan -Participants develop simple business plans to structure and clarify their ideas.• Workshops -Primary components in the business development process are addressed. Presentation of the business idea is emphasized.• Mentoring -Each participant is assigned a mentor who has been or still is a senior entrepreneur.• Supervision -Each group is assigned a supervisor for progress checks and coaching.Participants are expected to possess driving force and commitment prior to joining must be open about their ideas for their business plans. In addition, the trainers involved in teaching the programmes cannot take equity stakes or be operatively involved in the participating ventures. Access to a network of experienced entrepreneurs and to financiers and supporting organisations are other vital components of training.

  of the ENP proved enormously successful and other cities in Sweden inquired about starting similar programmes. As a result, the importance of the external programmes grew, both financially and for competence and network development, for the CIE at the University of Linkoping. Indeed, the added value of ENP's transfer to other regions strengthened the home programme in Linköping and the virtual network of handpicked, experienced entrepreneurs made it possible to conduct various ENPs simultaneously in different locations. These persons, some 20 in all, have been regularly engaged in programme execution and have become a close-knit group adding enormous value to the process of knowledge transfer. Transnational transfer of the programme began in 2003 as part of the European Union-funded Unispin project

  of the study, the authors have measured the importance of different determinants for transfer success pursuing two complementary approaches.

  the good practice programme to other regions to developing and implementing programmes for specific client groups without a narrow geographical focus (e.g. industry associations).

  the relationship between sender and recipient: enthusiasts with community support.

  the recipient: critical mass of resources.

  an important purveyor of the programme's philosophy, the leader must be chosen with care.

  speed up the transfer into the recipient system and serve as partner for continued mutual learning.

Table 1 .

 1 The quality of the transfer process Figure 1: Key variables in the transfer of good practice

	o r
	P
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	R
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http://mc.manuscriptcentral.com/cres Email: regional.studies@newcastle.ac.uk

Regional Studies

DATA COLLECTION

The nature of the subject demands a qualitative-based approach and broad open-ended questions were employed in order to encourage the respondents to narrate more freely.


E R Pomp

K J Stralen

S Cessie

J P Vandenbroucke

F R Rosendaal
email: f.r.rosendaal@lumc.nl

C J M Doggen

K J Van Stralen
email: k.j.vanstralen@amc.uva.nl

S Le Cessie

Á K J Van Stralen

Á F R Rosendaal

Experience with multiple control groups in a large

Keywords: Control group, Case-control study, Gene-environment interaction, Matched and unmatched analyses

published or not. The documents may come

Introduction

When designing a case-control study an important decision is the choice of the appropriate control group. The general requirement is that the control group should reflect the exposure frequency in the source population of the cases [START_REF] Rothman | Modern Epidemiology[END_REF][START_REF] Miettinen | The ''case-control'' study: valid selection of subjects[END_REF]. Still, various practical solutions exist. Control subjects can be selected randomly from the general population, or can be partners, friends or neighbours of the patient. Another source of control subjects is the hospital in which cases are hospitalized. There are advantages and disadvantages for each choice. For example, random population control subjects may be more difficult to locate and less motivated to take part in the study than patient-related control subjects such as partners, friends, neighbours or (unaffected) family members. Asking patient-related control subjects as control subjects has the risk of overmatching on the study exposure because of joint exposures [START_REF] Wacholder | Selection of control subjects in case-control studies II. Types of control subjects[END_REF]. Population control subjects potentially have the drawback of recall bias and selective participation; their motivation to recall past events is likely to be different from that of cases [START_REF] Wacholder | Selection of control subjects in case-control studies II. Types of control subjects[END_REF]. Hospital control subjects are readily accessible, usually cooperative and more likely to have the same recall ability as the cases, but always pose the problem whether exposure is unrelated to the disease leading to the hospitalization of the control [START_REF] Wacholder | Selection of control subjects in case-control studies II. Types of control subjects[END_REF].

Situations arise in which the investigator may consider to include two or more control groups. On one hand, the use of multiple control groups could lead to inconsistent results with the different control groups, and proper analysis may become complex [START_REF] Rothman | Modern Epidemiology[END_REF]. On the other hand, when different types of research questions are addressed and adjustment for different variables is required, multiple control groups might be useful.

In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study), a very large population-based case-control study, we initially included partners of patients as control subjects because the main focus of the study was on genetic risk factors for venous thrombosis and their interaction with environmental and lifestyle factors. It seemed unlikely that partners would select each other based on similarities in genetic risk factors for venous thrombosis.

We also expected that asking partners would make it easier to recruit control subjects with malignancies, pregnancy, or chronic diseases, which was necessary if we wanted to study these diseases in relation to the risk of venous thrombosis. However, as a result of selecting partners of patients, who usually are of the opposite sex, the age-sex distribution of the partner controls showed some peculiarities. In particular, there was only a small group of young men with venous thrombosis, while there was a relatively large group of young women with venous thrombosis (due to pregnancy and oral contraceptive use). The small group of young men yielded an even smaller control group of young female partners, which made women-specific risk factors difficult to analyze, due to a relative lack of control subjects. Moreover, not all patients had a partner, so there were less available partners than patients, and in addition individuals with a partner may be different than those without a partner [START_REF] Rothman | Modern Epidemiology[END_REF]. To remedy the case-control imbalance and to boost statistical power, we included an additional population control group that would be useful for certain analyses (such as pregnancy in young women), and increased the overall numbers for the genetic analyses (in particular for interactions)-as no differences in genetic make-up between partner control subjects and population control subjects were expected.

Although the odds ratios for all studied risk factors were in the same direction, and of similar order of magnitude with the two control groups, the point estimates differed somewhat, in particular for life-style variables. This represented a challenge of coming to the optimal combination of the information from the two control groups. In this paper, we describe how we proceeded.

MEGA study

Patients and partners

Between March 1999 and September 2004, we included consecutive patients with a first diagnosis of venous thrombosis. Patients were selected from the files of six large anticoagulation clinics in the Netherlands, which monitor anticoagulation treatment in all patients in a geographically well-defined area. Patients between the age of 18 and 70 with deep venous thrombosis of the leg, pulmonary embolism or a combination of these diagnoses were included. Patients with severe psychiatric problems or those unable to speak Dutch were considered as ineligible for practical reasons.

During the inclusion period, partners of patients were asked to participate as control subjects. Only partner control subjects between the age of 18 and 70 without a history of deep venous thrombosis were included and the same exclusion criteria were applied as for patients.

Random digit dialling control subjects

From January 2002 until September 2004, a second control group was recruited by using the random digit dialling (RDD) method according to Waksberg [START_REF] Waksberg | Sampling methods for Random Digit Dialing[END_REF]. RDD control subjects between the age of 18 and 70 with no recent history of deep venous thrombosis were included and the same exclusion criteria were applied as for patients. The RDD method has proved to be a suitable method that yields a control group that can be regarded as approximating a random sample of all individuals in the population [START_REF] Hartge | Random digit dialing in selecting a population-based control group[END_REF].

For efficiency reasons, we frequency matched the RDD control subjects to the patients who provided a blood sample according to age and sex. With each telephone call we asked a specific person within a household to participate depending on our needs to fill age and sex specific strata (e.g. we asked for youngest woman between 20 and 50, or oldest man over age 50); this procedure also avoided that the first person who picked up the phone was always included as control subject. This procedure of control sampling was expensive and time-consuming; on average only three control subjects per hour were included. The response rate is known to be dependent on demographic characteristics of the target population and telephone skills of the interviewers [START_REF] Hartge | Random digit dialing in selecting a population-based control group[END_REF]. In addition the RDD method is only useful if the vast majority of individuals live in households with a fixed (land-line) telephone. In December 2005 fixed (land-line) telephone coverage in the Netherlands was very high (96%) [6], indicating that telephone coverage was sufficient for our RDD method.

Data collection

Within a few weeks after diagnosis and registration at the anticoagulation clinics patients with venous thrombosis received a letter with information about the study and were subsequently contacted by phone. Partners of patients were also invited to participate. If patients or partners refused to participate the reason for refusal was asked for. Patients, partners and RDD control subjects received a standardized questionnaire shortly after inclusion by phone. The questionnaires included items on potential risk factors for venous thrombosis such as body weight, body height and injuries. Most questions referred to a period of 12 months prior to the index date, which was the date of venous thrombosis for patients and the date of completing the questionnaire for partners and RDD control subjects.

From March 1999 till June 2002, patients and their partners were asked to visit the anticoagulation clinic at least 3 months after withdrawal of anticoagulation, where, after an overnight fast, a blood sample was drawn. Only in case of continuous use for more than 1 year a blood sample was taken during anticoagulation therapy. From December 1999 onwards, self-administered buccal swabs were obtained by mail when participants were unable or unwilling to provide a blood sample. From June 2002 onwards, blood draws were no longer performed in patients and their partners, and the study was restricted to DNA collection by buccal swabs sent by mail. RDD control subjects were invited for a blood draw within a few weeks after they returned the questionnaire. Within this group buccal swabs were sent when the blood draw was refused. In the blood samples and buccal swabs prothrombotic mutations including the Factor V Leiden (G1691A) mutation were determined. A detailed description of blood collection and DNA analysis for factor V Leiden in the MEGA study has been published [START_REF] Blom | Malignancies, prothrombotic mutations, and the risk of venous thrombosis[END_REF].

Different research questions, different use of control subjects

To discuss the analytic considerations that arose from having two different control groups we will describe the association of a general lifestyle risk factor (body mass index), an external risk factor (injuries), an example of a genetic risk factor (factor V Leiden mutation), and an analysis for the interaction between body mass index and the factor V Leiden mutation-all with the risk of venous thrombosis.

Results

Response rates and general characteristics

During the inclusion period, 5,961 eligible patients, 3,586 eligible partners and 4,346 eligible RDD control subjects were approached to participate. In the patient group, 4,957 patients (83%) were willing to participate, partners had a similar response rate (n = 2,917, 81%), and 3,000 (69%) RDD control subjects participated (Fig. 1). Furthermore DNA was available for 86.5% of the patients, 87.2% of the partner control subjects and 67.4% of the RDD control subjects. A possible explanation for this difference may be that partners motivated each other to participate and were able to join each other at the location of the blood draw. General characteristics and reasons for non-response are presented in Table 1.

Body mass index

When we investigated the BMI distribution in patients, partners and the RDD control subjects, frequencies of overweight (BMI: 25-29 kg/m 2 ) and obesity (BMI: C30 kg/m 2 ) differed less between patients and their partners than between patients and the RDD control subjects [START_REF] Pomp | Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations[END_REF]. This is most likely due to 'assortative mating' as well as shared lifestyle over many years in couples, resulting in lower risk estimates with the partner control group than with the RDD control group. As these partners are matched with patients (who are likely to be more obese, as obesity is a risk factor for venous thrombosis), this matching has to be considered in the statistical analysis [START_REF] Rothman | Modern Epidemiology[END_REF]. In Table 2 the result of the matched analysis (conditional logistic regression analysis) with patient-partner pairs is presented. Risk estimates appeared to be still somewhat lower than in the analysis with the RDD control subjects (overweight partners OR 1.45, CI95 Netherlands the prevalence of overweight and obesity was respectively 36 and 11% during the study period [START_REF]The Netherlands[END_REF], while we found 33 and 11% in the RDD group.

To obtain an overall effect estimate with a greater precision, we combined the matched and unmatched analyses using an approach in which the estimates of the odds ratios of the two analyses were pooled, taking into account that most patients were in the analysis twice [START_REF] Cessie | Combining matched and unmatched control groups in case-control studies[END_REF]. In this combined analysis we accounted for the correlation between the estimated odds ratios since most patients were included both in the matched and the unmatched analysis. Table 2 presents the odds ratios of the combined analysis (OR overweight 1.71, CI95 1.54-1.89, OR obesity 2.45, CI95 2.14-2.80), which were in-between the odds ratios for the partner and RDD odds ratios.

The most likely explanation for the difference in risk estimates between partners and RDD control subjects is that the matched analysis will include adjustment for measured as well as unmeasured confounders but also for causal intermediary variables if those are related to couple formation or shared lifestyles. Because of these additional (over)adjustments the odds ratios in the partner analyses could be closer to 1 than with the RDD control subjects. However, the analysis of injuries as risk factor for venous thrombosis proved that this is not always the case.

Injuries

We also studied the effect of minor injuries, such as contusions and ankle sprains, on the risk of venous thrombosis [START_REF] Van Stralen | Minor injuries of the leg increase the risk of venous thrombosis five fold[END_REF]. Minor injuries can be caused by occasional events such as traffic accidents, but are also partly related to lifestyle as for instance sports injuries will occur more often in individuals with active lifestyles. Percentages of injuries in the weeks before the index date are presented in Fig. 2. Overall, patients had suffered from a minor injury in 11.7 percent in the 3 months prior to the venous thrombosis. Partners of patients had suffered from a minor injury in 3.6 percent, while in RRD control subjects 4.8 percent had had a minor injury. The odds ratios were 4.2 (CI95 2.9-6.0) with partner control subjects and 2.8 (CI95 2.3-3.6) with RDD control subjects after adjustment for various confounders, even after including sports activities, resulting in a combined estimate of 3.5 (CI95 2.8-4.3). These risk estimates indicate that adjustment for confounders and intermediates could also result in a higher risk estimate in the matched analysis than in the unmatched analysis. It is possible that RDD control subjects are spending more time outdoors than partner control subjects, resulting in more injuries than partners, because patients might have been more sedentary (for example, patients with DVT are generally more obese), and therefore their partners might also have been more sedentary-either by assortative mating or a shared development of habits. Another possibility is influence of the partners by the patients during the answering of the questionnaire. As the patient has a serious medical problem, namely thrombosis, the partner might not want to complain about his or her relative minor injury, resulting in a lower rate of (reported) minor injuries, and therefore a higher risk estimate. Finally, active individuals may be more likely to participate as controls than others.

Factor V Leiden

For genetic risk factors it seemed a priori unlikely that their frequency is different in partners than in RDD control subjects. However, the prevalence of factor V Leiden is related to ethnicity [START_REF] Dowling | The epidemiology of venous thromboembolism in Caucasians and African-Americans: the GATE Study[END_REF] so one might speculate that if partners chose their partner according to ethnicity the factor V Leiden distribution in partners might become different from RDD control subjects. In the MEGA study most participants were of Dutch origin, so differences between RDD control subjects and partner controls in the distribution of factor V Leiden due to intra-racial partnerships were unlikely. For the RDD control subjects one might hypothesize that RDD control subjects with a positive family history of venous thrombosis may be more willing to give blood than RDD control subjects without a positive family history, leading to an overestimation of the prevalence of factor V Leiden in this group. This was found not to be true as rates of positive family history were similar in the two control groups and we found the same percentage of individuals with factor V Leiden in the partner and the RDD group. Obviously, both percentages could be an overestimation of the true prevalence, but the percentages were equal to the previously recorded prevalence of factor V Leiden in Caucasians [START_REF] Rosendaal | Venous thrombosis: a multicausal disease[END_REF].

Since both control groups had the same percentage of factor V Leiden carriers and this percentage was supported by literature, both control groups were combined as if they were a single group in an unconditional logistic regression analysis (Table 3).

BMI and factor V Leiden

The joint effect of overweight or obesity and the factor V Leiden mutation [START_REF] Pomp | Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations[END_REF] is presented as an example of the analysis of gene-environment interaction. Since the analyses of BMI required a combination of the matched analyses when using partner control subjects and unconditional logistic regression when using the RDD control subjects [START_REF] Cessie | Combining matched and unmatched control groups in case-control studies[END_REF], this approach was also used when analyzing the combined effect of BMI and the factor V Leiden mutation (Table 4). A disadvantage of using matched analyses when studying interaction is that only discordant patient-partner pairs can be included in the analyses resulting in small numbers for those groups in which both exposures are present (e.g. obese and factor V Leiden), as can be seen in Table 4. When there are only a limited number of control subjects, it is also possible to check for interaction using a case-only analysis [START_REF] Rosenbaum | The case-only odds ratio as a causal parameter[END_REF], which results in a multiplicative synergy index [START_REF] Rothman | Modern Epidemiology[END_REF]. This calculation of a multiplicative synergy index [(1,077*124)/(217*643) = 0.96)] suggested interaction at the multiplicative level and a tenfold [(0.96*2.48*4.18 = 10.0)] increased risk for those being obese and having the factor V Leiden mutation compared with those being lean without factor V Leiden. This estimation of the risk corresponds well with the 7.9 fold increased risk that was found when combining the conditional and unconditional regression analyses.

Discussion

In the MEGA study, a large population-based case-control study, we collected two different control groups, a partner control group and an RDD control group. Although for each risk factor, the odds ratios were always in the same direction and of the same order of magnitude with both control groups, they were nevertheless different. Moreover, when comparing several risk factors, it was not always the same control group that produced the lower or higher estimates, and a matched analysis did not completely annul the differences.

We presented examples of analyses of different types of research questions where we had to take decisions during the analyses about how the results of the two control groups could be combined. For the evaluation of body mass index and the risk of minor injuries we used a method for statistically combining the control groups in the analysis, because for the partner control group a matched analysis was required, which was neither necessary nor feasible in the RDD group. For body mass index the RDD control group produced somewhat higher risk estimates than partner control subjects. However, this was not the case for all analyses: for the analysis for the risk of minor injuries the inverse was found, as RDD control subjects suffered more injuries than partner control subjects. Finally, frequencies of the factor V Leiden mutation, a genetic risk factor, were identical in both control groups and independent of lifestyles, indicating that for the analyses of this genetic risk factor we could simply combine both control groups. When studying the interaction between body mass index and the factor V Leiden mutation the same statistical approach was used as in the body mass index analyses. An important aim of the MEGA study was to assess the risk of venous thrombosis associated with the combination of risk factors. When studying the interaction between a risk factor specific to women and a lifestyle risk factor (e.g. the joint effect of oral contraceptive use and BMI) it is not straightforward to use a matched design with partner controls. In this case, intuitively one might believe that it is not possible to use the matched case-control design, because only women are users of oral contraceptives and most control subjects have the opposite sex as their matched patients. However, after a publication from the MEGA study it was suggested that one could think of being male as just a reason for a person to be unexposed [START_REF] Rothman | Thrombosis after travel[END_REF]. This should not lead to exclusion of men from analyses of oral contraceptive use (in the same way as it should not lead to exclusion of women who are opposed to oral contraceptives for religious or health reasons). When this idea was tried out on the MEGA data, an analysis of oral contraceptive use and travel with opposite sex controls proved not only possible but gave more reliable results [START_REF] Cannegieter | Thrombosis after travel: reply to a Perspective[END_REF].

There are only a small number of studies reporting their experience with multiple control groups. In 1983, Stavraky and Clarke wrote a paper that summarized their experience in using hospital and neighbourhood control subjects [START_REF] Stavraky | Hospital or population control subjects? An unanswered question[END_REF]. When testing the hypothesis whether oxidative hair dyes were carcinogenic, they found lower rates of hair dye use among 314 hospital (40.5%) than among 470 neighbourhood control subjects (52.8%). Several other differences were observed. Compared with hospital control subjects, neighbourhood control subjects were older, ethnically more heterogeneous, less likely to be oral contraceptive users and more likely to be smokers. The investigators believed that most of these differences arose from different lifestyles in the relatively rural region from which the hospital control subjects were derived and in the urban region that provided the neighbourhood group. A study investigating the association between machining fluid and laryngeal cancer risk included control subjects with oral cancer as well as a stratified random sample of all deaths in a distinct geographical area as control subjects [START_REF] Russi | Occupational exposure to machining fluids and laryngeal cancer risk: contrasting results using two separate control groups[END_REF]. When cases (n = 888) were compared to oral cancer control subjects (n = 752) high exposure to machining fluids resulted in a 1.5-fold increased risk of laryngeal cancer. However, when cases were compared with population control subjects (n = 3,594) no increased risk of exposure was found. An explanation, besides a chance finding, may be that data quality on exposure for the cases and oral cancer control subjects may have differed from that of the population control subjects. These studies illustrate, paradoxically, that if only one control group would have been included, unrecognized bias might have influenced the results.

Besides differences in risk estimates also response rates may vary between control groups. In the MEGA study Only discordant couples provided information in this analyses and were included partner control subjects were more willing to participate than RDD control subjects. An explanation for this difference may be that patients motivated their partners to participate. Also the fact that partners of non-participating patients were not included in the non-response may be an explanation; if a patient refused to participate, we did not ask the patients' partner to participate. Thus a selection was made of persons who were more willing to participate. Selection bias could have occurred if RDD control subjects would be more willing to participate if they had a family member with thrombosis. However, there was no difference between the control groups with respect to a positive family history, nor between the prevalences of the factor V Leiden mutation, suggesting a limited selection bias in this respect. In contrast, at the start of the study we assumed that pregnant partners or partners with a severe disease such as cancer would be easier to recruit because of a higher motivation than RDD control subjects with similar characteristics. However, this was found not to be true as RDD control subjects with a partner had even slightly higher pregnancy rates than partners controls [START_REF] Pomp | Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study[END_REF], and both control groups had equal rates of cancer.

We are aware that most teaching in epidemiology emphasises the choice of one control group. We deviated from this, because we thought to have good reasons to do so. Rosenbaum has suggested that it might be wise to include two control groups which differ with respect to a covariate that, though unmeasured, is know to differ substantially between the two groups [START_REF] Rosenbaum | Design of observational studies[END_REF]. Similar outcomes in two such control groups then provide evidence that imbalances in the unmeasured covariate are not responsible for treatment-vscontrol differences in outcomes [START_REF] Rosenbaum | Design of observational studies[END_REF]. This was the case in our study, as all odds ratios when using the partner or the RDD control group were in the same direction. Still, some differences in the behaviour of several variables between the control groups were surprising. This gave us the opportunity to study the effects of the choice for particular control subjects: different choices for different control groups may have consequences that may not always be anticipated beforehand. Both control groups had very similar prevalences of the FVL mutation, and were therefore equally suitable. When studying environmental or lifestyle risk factors, however, no control group gave results that differed in a predictable and systematic way from the other, and a matched analyses did not solve the problem. In the end both control groups had their own contribution.

Fig. 2

 2 Fig.2Percentage of injuries per week before the index date, which was the diagnosis of venous thrombosis (in patients) or completion of the questionnaire (in control subjects). Adapted from[START_REF] Van Stralen | Minor injuries of the leg increase the risk of venous thrombosis five fold[END_REF]

  Response rates of patients, partners and RDD control subjects

	PATIENTS
	PARTNERS
	Fig. 1 Table 1 Demographic characteristics and reasons for non-response in patients,	Patients	Partners	RDD control subjects
	partners and RDD control subjects -Not an option provided to the patients responders, * of participating	Responders (N) Median age (5th-95th perc.) Female sex (N, %) Non-responders (N) No willingness (N, %) Not mobile (N, %) Untraceable (N, %) Filled in question-naire about recurrent 1.63-2.05; obesity partners OR 1.81, CI95 1.49-2.20; obes-4,957 2,917 3,000 48.6 (25.7-67.9) 48.3 (28.0-66.1) 45.3 (29.0-66.1) 1.26-1.67; overweight RDD OR 1.83, CI95 2,682 (54.1) 1,464 (50.2) 1,719 (57.3) 922 651* 1,331 ity RDD OR 2.87, CI95 2.45-3.35). 607 (65.8) 628 (96.5) 1,243 (93.4) The use of the RDD control subjects in the analyses of 17 (1.8) 1 (0.2) -BMI as risk factor for venous thrombosis may result in a 271 (29.3) 14 (2.2) 88 (6.6) slight overestimation of the true relative risk because of 5 (0.5) --selective inclusion: there were fewer RDD control subjects VT (N, %) with overweight than in the general Dutch population. According to data of the Central Bureau of Statistics in the Reason unknown (N, %) 22 (2.4) 8 (1.2) -

Table 2

 2 BMI as risk factor for venous thrombosis-Analyses with patients, partners and RDD control subjects

	Multiple control groups in a case-control study
	BMI (kg/m 2 )	Patients N (%)	Partners N (%)	RDD N (%)	OR partner * (CI95)	OR RDD * (CI95)	OR combined * (CI95)
	Lean (\25)	1,369 (36.4%)	925 (44.0%)	1,409 (55.7%)	1	1	1
	Overweight (25-29)	1,593 (42.4%)	860 (40.9%)	848 (33.5%)	1.45 (1.26-1.67)	1.83 (1.63-2.05)	1.71 (1.54-1.89)
	Obese (C30)	794 (21.1%)	318 (15.1%)	274 (10.8%)	1.81 (1.49-2.20)	2.87 (2.45-3.35)	2.45 (2.14-2.80)
	Total	3,756	2,103	2,531
	Note BMI analyses were performed in non-pregnant individuals without malignancies
	Adapted from [8]
	OR partner calculated with a matched analysis
	OR RDD calculated with unconditional logistic regression
	OR combined calculated by the method of Le Cessie e.a. (2008)
	*Adjusted for age and sex

Table 3

 3 Factor V Leiden mutation (FVL) as risk factor for venous thrombosis-Analysis with patients, partners and RDD control subjects

	FVL	Patients N (%)	Partners N (%)	RDD N (%)	OR partner * (CI95)	OR RDD * (CI95)	OR total * (CI95)
	-	3,612 (84.3%)	2,403 (94.7%)	1,914 (94.6%)	1	1	1
	?	675 (15.7%)	134 (5.3%)	109 (5.4%)	3.38 (2.78-4.09)	3.36 (2.72-4.15)	3.36 (2.88-3.92)
	Total	4,287	2,537	2,023
	All ORs calculated with unconditional logistic regression
	OR total calculated by pooling the two control groups

* Adjusted for age and sex

Table 4

 4 Combined effect of body mass index and the factor V Leiden (FVL) mutation on the risk of venous thrombosis

	BMI (kg/m 2 )	FVL	Patients N (%)	Partners N (%)	RDD N (%)	OR partner *	O R RDD *	O R combined *
	Lean	-	1,077 (29.9%)	675 (41.7%)	956 (52.4%)	1	1	1
	Overweight	-	1,289 (35.8%)	664 (41.1%)	580 (31.8%)	1.40 (1.18-1.65)	1.92 (1.68-2.20)	1.72 (1.54-1.93)
	Obese	-	643 (17.9%)	229 (14.2%)	194 (10.6%)	1.78 (1.49-2.35)	2.88 (2.40-3.46)	2.48 (2.13-2.88)
	Lean	?	217 (6.0%)	24 (1.5%)	45 (2.5%)	3.56 (2.32-6.41)	4.31 (3.09-6.02)	4.18 (3.12-5.61)
	Overweight	?	250 (6.9%)	20 (1.2%)	38 (2.1%)	5.97 (3.24-11.00)	5.67 (3.98-8.08)	5.77 (4.20-7.93)
	Obese	?	124 (3.4%)	5 (0.3%)	13 (0.7%)	6.15 (2.26-16.75)	8.48 (4.75-15.12)	7.86 (4.70-13.15)
	Total		3,600	1,617	1,826
	Adapted from [8]
	OR partner calculated with a matched analysis
	OR RDD calculated with unconditional logistic regression
	OR combined calculated by the method of Le Cessie e.a. (2008)
	* Adjusted for age and sex

Acknowledgments The MEGA study was supported by the Netherlands Heart Foundation (NHS 98.113), the Dutch Cancer Foundation (RUL 99/1992) and the Netherlands Organisation for Scientific Research (912-03-033| 2003). The funding organizations did not play a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript.

Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.


Per- Märit Lundblad
email: marit.lundblad@karolinska.se

Arne Lönnqvist

Staffan Eksborg

Peter Marhofer

Keywords: caudal, anesthesia, ultrasound, children

Segmental distribution of high volume caudal anesthesia

in neonates, infants and toddlers as assessed by ultrasonography.

Reviewer No 3:

1. The reviewer adequately points out the intraspinal component of spread (posterior compartment/ anterior compartment). To clarify this point we have added text on page 13 that we hope is sufficient to address this point raised by the reviewer. 2. Abstract; Background. A change according to the suggestion made by the reviewer has been performed. 3. Ropivacaine 0.2 % is now used at the appropriate places in the abstract as suggested. 4. All the other language alterations suggested by reviewer No 3 have now been changed.

Comment regarding Reviewers own comment No 8. A smaller volume could

obviously have been used in these patients but due to the standardization of the study it was chosen from the outset of the study to use the same volume in all patients, even though this would represent a somewhat excessive volume for more distal surgery.

Material and methods

Following Ethics Committee approval and written parental informed consent, children 0-4 years of age (ASA physical status I -III) were enrolled in the study. Patients scheduled for elective subumbilical surgical procedures (e.g. urogenital, anal, foot and inguinal surgery),

were eligible for study inclusion. Known contraindications to regional anesthesia (e.g. coagulation disorders, allergy to amide local anesthetics or local infection at the planned injection site) or anatomical abnormalities of the lumbosacral spine were defined as exclusion criteria.

The study patients were stratified according to age and divided into three different age groups;

Group I: preterm and neonatal babies younger than 1 month (≤ 45 gestational weeks), Group II: infants 1-12 months, and Group III: toddlers 1-4 years of age (maximum weight 25 kg). A total of 45 patients were planned to be included (n = 15 per study group).

Biometric data

According to established clinical routine the children were weighed on admission. Patient height was measured with the patient lying supine on the operating table after induction of anesthesia, using a regular measuring tape. Body mass index (BMI) was subsequently calculated according to standard practice [weight (kg)/ height 2 (m 2 )].

Anesthetic protocol

A peripheral venous cannula was inserted already on the general pediatric ward after prior EMLA cream application. General anesthesia was induced by IV atropine (10 mcg/kg) and propofol (2-3 mg/kg), subsequently followed by insertion of a laryngeal mask airway to secure the airway. Anesthesia was thereafter maintained by sevoflurane-oxygen-air (Fi0 2 0.

Haemodynamic data

Heart rate and NIBP was recorded immediately before turning the patient to the left lateral decubitus position for insertion of the caudal block (baseline) and also immediately after surgical skin incision (to determine block success/failure).

Ultrasound investigation and caudal block procedure

After induction of anesthesia the child was positioned in the left lateral decubitus position.

By manual palpation the lumbo-sacral junction was determined and the spinous process of L5 was thereby identified. The lumbar spinal processes were thereafter palpated and counted in a rostral fashion to identify the 12 th thoracic spinous process. The 12 th rib was subsequently identified by ultrasound visualization and followed medially to further verify that the spinous process of Th 12 had been correctly identified. The skin overlying the spinous process of Th 12 was then marked using a skin marking pen.

The ultrasound equipment used for the study was a portable Sonosite M-Turbo software 3.4.1 (Sonosite Inc.Bothell, WA, USA) with a 38 mm wide 7-13 MHz linear array probe.

An initial longitudinal paramedian ultrasonographic investigation was performed to identify the epidural space, the conus medullaris, cauda equina and the termination of the dural sac. During the injection the ultrasound probe was maintained in the previously determined optimum paramedian position (see above) in order to visualize the cranial spread of the local anesthetic within the caudal/epidural space. The probe was moved cranially as needed in order to follow the advancement of the front of the local anesthetic bulk flow within the epidural space, as evidenced by an anterior displacement of the dura mater, resulting in a reduction of the antero-posterior diameter of the intrathecal space (Figure 1).

For a caudal block to be effective in patients undergoing inguinal hernia repair, the most frequent surgical procedure performed in this age group, a level of at least Th12 needs to be reached by the LA. Thus Th12 was used as an end point target level. When the local anesthetic reached the Th 12 level (the front of the local anesthetic having been identified as reaching the Th 12 skin mark), the volume so far injected was noted and the injection continued until the full total volume of 1.5 ml/kg had been injected.

After the injection of 1. The caudal block was performed by the attending anesthetist. Ultrasound scans were performed by two of the authors (ML, PAL).

Following the ultrasound examination the child was again placed in the supine position and prepared for surgery. Skin incision was not performed earlier than 15 minutes after the performance of the caudal block.

The caudal block was considered a failure if one or more of the following was noted: 1) movement of the limbs in association with skin incision, 2) an increase in heart rate and/or NIBP of >15% compared to baseline in association with skin incision, 3) intraoperative need for supplemental administration of fentanyl (1 mcg/kg), as judged by the attending anesthetist or anesthetic nurse.

Statistics

The two main study parameters were maximal cranial segmental spread and the number of patients in each age group where the local anesthetic was identified to have reached the target level of Th 12.

Associations between two variables were established by the Spearman rank correlation test.

Kruskal-Wallis Test (non-parametric ANOVA) and the Mann-Whitney U-test was used for comparison of percentage of blocks reaching the target level Th12 in the three age groups. Demographic data are presented in Table 1. All 47 blocks were judged to be clinically successful.

An inverse relationship was observed between the different age groups and maximal ultrasonography assessed cranial spread (Figure 2).

An inverse relationship was also observed with regards to individual age (r s = -0.5325; p=0.0001), weight (r s = -0.5104; p = 0.0002) and height (r s = -0.5326; p =0.0001) (Figure 3A,B,C).

The percentage of patients where the volume of 1.5 ml/kg of local anesthetic did reach the target level of Th12 was significantly different in the three age groups (Table 2, Figure 4). In

Study design issues

Before commenting on the study results we would like to draw the readers' attention to two design features of the study. The first relates to the accuracy of the ultrasonography assessed segmental distribution. Due to the limited ossification of the sacrum and the vertebrae the ultrasonographic visualization of the intraspinal space is relatively easy in neonates and young infants but as ossification progress the visualization will gradually become more difficult.

(7,9,10) Thus, the determination of the actual cranial extension of the injected volume was slightly more difficult to assess in the older age group in our study.

Secondly, a segmental determination based on cutaneous stimulation should ideally have been included in the study protocol to allow for comparison versus the ultrasound assessed levels. However, currently there does not exist any validated method or consensus view on how to perform such a cutaneous stimulation-based assessment of segmental spread in anaesthetized children. Furthermore, to be adequate such cutaneous testing must be performed approximately 20 minutes after the injection of the local anesthetic to allow for a reasonable onset time, something that for logistical reasons is not possible in many institutions due to case load and through-put demands. Deleted text.

Correlation between cranial spread and patient characteristics

An inverse relationship between age (as well as weight and height) and the maximal cranial segmental spread could be identified in this study (Figures 2 and3). A reflection of this fact was that almost all blocks in the neonatal age group did at least reach the level of Th 12 whereas only a minority of blocks in the oldest age group managed to reach this level (Table 2, Figure 4). The absence of the normal spinal curvatures in non-walking children, a difference in the amount of and the characteristics of epidural fat and various other factors may explain why a standardized injected volume reached more cephalad in neonates and infants as compared to toddlers. However, we believe that an important factor that may explain the inverse relationship found in this study is the pressure generated within the spinal canal during the injection of the local anesthetic. Usubiaga have previously described that spread within the epidural space in adults is directly correlated to the pressure generated by the injection. [START_REF] Usubiaga | Epidural pressure and its relation to spread of anesthetic solutions in epidural space[END_REF] In our study we chose to use a fixed injection rate regardless of the age/size of the patient. This fact may result in a higher end-injection pressure within the caudalepidural space in neonates as compared to toddlers and may, thus, explain the more cranial levels reached in younger children. If the injection rates had been normalized to patient age/size (equating to the use of progressively higher injection rates with increasing age/size) the results of the study may well have been different. This points to the need for further studies addressing the relative influence of pressure on the cranial extension of caudal blocks in children.

Cranial extension assessed by ultrasound vs. previously published predictive equations

Contrary to our expectations, the agreement between the cranial level of the injectate determined by ultrasonography and the calculated levels based on previously published predictive equations (1-3) was very poor (Figure 5A,B). The use of the equations consistently This situation obviously ends up in an "apple and pear" comparison that can explain the discrepancy between ultrasound assessment and the predictive equations. Second, there is also an important difference in the timing of the assessments of segmental spread. When using different objective visualization techniques, e.g. ultrasound assessment or radio-opaque dye injection, the determination of cranial block extension will be assessed almost immediately after the completion of the injection. This situation substantially differs compared to assessment by means of cutaneous stimulation that regularly is performed about 20 minutes after the injection of the local anesthetic. (1-4) Thus, the result generated by actual cutaneous testing will allow for a certain degree of redistribution of the local anesthetic within the spinal canal (e.g. later spread to the anterior compartment), which is quite different compared to the immediate snapshot produced by ultrasound visualization. Koo have recently provided support for this line of reasoning by showing that also immediate radiographic visualization of local anesthetics mixed with radio-opaque dye (volumes ranging 0.5-1.25 ml/kg) usually fails to reach higher than the thoraco-lumbar junction (Th10-L2) [START_REF] Koo | Spread of ropivacaine by a weight-based formula in a pediatric caudal block: a fluoroscopic examination[END_REF], corroborating previously published results from the same group [START_REF] Hong | A comparison of high volume/low concentration and low volume/high concentration ropivacaine in caudal analgesia for pediatric orchiopexy[END_REF]. Similar observations following the injection of radio opaque dye has also been found by Thomas & Howard (personal communication, to be ). Thus, both immediate ultrasound assessment and early radiographic determination using radio-opaque dye will generate comparable results that both differ considerably from results generated by use of the predictive equations based on cutaneous testing.

The above raises the question whether ultrasound visualization of caudal blockade is clinically useful and should be incorporated as standard procedure in daily practice. As pointed out by previous authors, [START_REF] Roberts | Caudal injectate can be reliably imaged using portable ultrasound -a preliminary study[END_REF][START_REF] Marhofer | Pilot study of neuraxial imaging by ultrasound in infants and children[END_REF][START_REF] Rapp | Ultrasound-guided epidural catheter insertion in children[END_REF] ultrasound visualization of the spread of local anesthetics within the caudal/epidural space provides objective evidence that the injection is made in the proper anatomical space, thereby providing an almost complete guarantee that an appropriate block will develop if an adequate volume is used and a proper onset time is allowed. In this regard there is no alternative that currently can compete with ultrasound visualization and it is the authors' opinion that the use of ultrasound for this purpose should be encouraged.

However, due to the poor agreement with previously published predictive equations, that in fact are based on actual segmental cutaneous testing after a period of adequate onset time, it can be questioned whether an immediate snapshot ultrasound assessment of the cranial extension is of any major clinical value when trying to predict the final analgesic spread of a caudal block.

Conclusion

In conclusion, the current study found an inverse relationship between age and the number of segments covered by a caudal injection of 1. • Group I ○ Group II ▲ Group III. The numbers adjacent to some of the points in the graph refer to the number of patients represented in each point.

B.

Maximal cranial level in relation to weight with regression line (r s = -0.5104; p = 0.0002)

• Group I ○ Group II ▲ Group III.

C. Maximal cranial level in relation to height with regression line (r s = -0.5326; p = 0.0001).

• Group I ○ Group II ▲ Group III.

Introduction

  There were no objections to this part of the study design by the Ethics Committee. No action taken.Caudal block is the most widely used regional anesthesia method in neonates and small children. Despite being the most common pediatric regional anesthetic block there are still certain issues that remain unclear. One such issue is the relationship between the injected volume of local anesthetics and the resultant spread of the local anesthetic solution within the spinal canal.Various patient related factors have been used to determine predictive equations regarding the cranial extension of a caudal block (e.g. Schulte-Steinberg, Takasaki, Busoni). (1-3) The methodology to determine the cranial extension of the block has also varied considerably between publications; reaction to surgical stimulation, pin-prick or pinching, injection of radio-opaque dye with subsequent X-ray visualization or cadaver studies. (1-5) However, none of these methods allow real-time visualization of the spread within the spinal canal.Due to the incomplete ossification of the sacrum and the vertebrae in young children it has been shown that the spread of local anesthetics inside the spinal canal can be visualized by the use of real-time high frequency ultrasound. (6-7) However, no published data so far describe the relationship between injected volume and cranial segmental spread as assessed by this new methodology. Thus, the aim of this prospective, age-stratified, observational study was to determine the cranial spread of a large volume (1.5 ml/kg) of local anesthetic as determined by real-time ultrasonography.

  of the injection site, the sacral cornuae and sacro-coccygeal membrane were palpated. The caudal space was subsequently cannulated using a pediatric 30 mm 25G caudal needle (Epican®, B Braun, Melsungen, Germany) attached to an extension tubing (BD Connecta TM , Becton, Dickinson & Co, NJ, USA) An aspiration test was performed to exclude inadvertent intravascular placement, where after the local anesthetic solution was manually injected at a rate of approximately 0.5 ml/s. A total volume of 1.5 ml/kg of 0.2 % ropivacaine (Narop®, AstraZeneca, Södertälje, Sweden) was used, representing the upper limit of safe dosage (3 mg/kg) as described by Bosenberg.[START_REF] Bosenberg | Plasma concentrations of ropivacaine following a singleshot caudal block of 1, 2 or 3 mg/kg in children[END_REF]

  5 ml/kg of local anesthetic the front of the epidural local anesthetic was identified and was positioned in the middle of the ultrasound picture. A skin mark was made corresponding to the middle of the ultrasound probe and the level reached was determined by counting the spinous processes from the previously indicated Th 12 spinous the ultrasonographic front of the local anesthetic was "hidden" behind the bone shadow of the vertebral lamina the front was approximated to the middle of the corresponding bone shadow.

  and the resulting number of segments covered by the caudally injected LA a predictive equation was derived. 50 children were enrolled in the study. Three of these patients had to be excluded due to study protocol violations (n = 2) or inadvertent vascular puncture (n = 1), leaving 47 subjects to be included in the final analysis (Group I, n = 15; Group II, n = 16; Group III, n = 16).

Group I the targetDiscussion

  of Th 12 was reached in 93 % of patients, whereas the corresponding values were 73 % and 25 % of patients in Groups II and III, respectively. The relationship between volume of local anesthetic per covered segment vs. biometric patient data (age, weight and height) is shown in Figure 5ABC. Compared to the predictive ultrasound assessment overestimated the volume per segmentrelationship by a factor of approximately 2.5 (median 2.4; range 1.9-3.0) (Figure5B).If compared to the Schulte-Steinberg equation, which is age-based, ultrasound assessment overestimated the volume per segment relationship by a factor of more than three (Figure5A).A predictive equation based on our observed data is given below: Dose (ml/spinal segment) = 0.1539 . (BW in kg) -0.0937The main finding of the current study was an inverse relationship between age and the number of segments covered by a caudal injection of 1.5 ml/kg of local anesthetic in children 0-4 years of age. A significantly higher proportion of blocks did reach the Th 12 level in newborns (93 %) as compared to infants (73 %) and toddlers (25 %).

  the number of blocked segments per volume of local anesthetic as compared to what could be observed by ultrasound. The poor correlation between ultrasound assessment and the predictive equations cannot be explained by the study data but we would like to put forward two different potential explanations for this lack of agreement.First, the end point of the studies that has generated the predictive equations differs considerably from the end point used in this study. Thus, in the previous studies the extension of the caudal block was determined by cutaneous stimulation (e.g. pin-prick or pinching) in children under light halothane anesthesia, whereas the end-point of the current study was the visualized front of the local anesthetic within the posterior compartment of the spinal canal.

Figure 1 :

 1 Figure 1: Ultrasound image of intraspinal local anesthetic spread in a 4 kg neonate. The

Figure 2 :

 2 Figure 2: Maximal cranial level in neonates (group I), infants (group II) and toddlers (group

Figure 3 :A.

 3 Figure 3:

Figure 4 :

 4 Figure 4: Percentage of blocks reaching the target level Th12.

Figure 5 :A.

 5 Figure 5:

Figure 1 :Figure 2 :Figure 3A :Figure 3 BFigure 3 C:Figure 4 :Figure 5 A:Figure 5 B.Figure 5 C

 123A334555 Figure 1: Ultrasound image of intraspinal local anesthetic spread in a 4 kg neonate. The large-size arrow indicates the front of the local anesthetic bulk flow, the smaller arrows point at the dura mater. 216x164mm (600 x 600 DPI)

Table 1 :

 1 Patient data; median (range).

		Group I	Group II	Group III
		< 1 month	1 mo-1 year	1-4 years
	Number of patients	15	16	16
	Age (gestational weeks)	41.6 (35-45)
	Age (months)	≤ 1	4.75 (2-10)	18.0 (13-40)
	Weight (kg)	3.2 (2.23-4.9)	7.8 (4.5-10.9)	11.9 (8.5-14.5)
	Height (cm)	52 (47-58)	66 (55-77)	83.5 (73-100)
	BMI kg/m 2	12.7 (11.8-16.2)	17.0 (14.3-21.0)	16.1 (13.7-20.0)

Table 2 :

 2 Segmental spread

		Group I	Group II	Group III
		< 1 month	1 mo-1 year	1-4 years
	Maximal cranial	Th 12 (L 1-Th 9)	Th12 (L 2-Th 10)	L1 (L 2 -Th 11)
	level; median (range)
	Maximal level
	>Th12, No of	14 (93 %)	11 (73 %)	4 (25 %)
	patients (%)
	Volume of LA
	needed to reach Th12	1.38 (0.67-1.5)	1.41 (0.85-1.5)	1.38 ( 1.2-1.5)
	level (ml/kg);
	median (range)


Instabilities and transition in three-dimensional flows with rotation EXPERIMENTAL INVESTIGATION ON TORQUE SCALING IN TURBULENT TAYLOR-COUETTE FLOW

1 Angular momentum flux and torque in Taylor-Couette

The concentric rotating Taylor-Couette flow (TC) is a well known system of instabilities in fluid dynamics (see Fig. 1a). In this work the transitions between different three dimensional flows of counter-and corotating Taylor-Couette flow and its dependence on different parameters is investigated. Depending on the rotation rate of the cylinders, one is able to create a linear stable (like pipe) or unstable flow (like Rayleigh-Bénard convection). From this background one can see TC flow as a link between Rayleigh-Bénard and pipe flow. [START_REF] Eckhardt | Fluxes and energy dissipation in thermal convection and shear flows[END_REF][START_REF] Eckhardt | Torque scaling in turbulent Taylor-Couette flow between independently rotating cylinders[END_REF] also compare these three systems by an analytical derivation. It is possible to calculate the heat flux J θ for Rayleigh-Bénard [START_REF] Grossmann | Scaling in thermal convection: a unifying theory[END_REF] , a transverse u z flux J uz for pipe flow, and angular momentum flux J ω for Taylor-Couette flow, which have a similar analytical form [START_REF] Eckhardt | Fluxes and energy dissipation in thermal convection and shear flows[END_REF]. The Analogy of these three systems is obvious. For the example of Taylor-Couette-flow this flux is given as

J ω = r 3 (< u r ω > A,t -ν∂ r < ω > A,t ), (1)
where < ... > A,t denotes a spacial temporal average over a cylindrical surface of height L at radius r. Analytically, J ω has to be independent of all radii (∂ r J ω = 0). So it is of great interest to quantify the angular momentum flux J ω as a parameter for the flow. At the wall the magnitude of J ω corresponds to the torque the fluid works on the cylinders: Thus the dimensionless torque G = T /(2πLρν 2 ) = ν -2 J ω can be used to quantify the angular momentum flux J ω . So the scaling of the torque with the rotation rate of the system gives the scaling of the angular momentum flux [START_REF] Eckhardt | Torque scaling in turbulent Taylor-Couette flow between independently rotating cylinders[END_REF]. How the Torque scales for different Rotation numbers of the inner and outer cylinders needs to be investigated.

Experiments in Taylor-Couette flow

Figure 1a shows a sketch of the experimental apparatus used in the present investigations. Both cylinders can rotate independently and relative to each other with Reynolds numbers of inner (1) and outer rotation (2)

Re 1,2 = R 1,2 ω 1,2 (R 2 -R 1 )
/ν of order of 10 3 up to 10 5 for a radius ratio η = R 1 /R 2 = 0.5. This includes single rotations of both cylinders as well as co-and counterrotation. The end plates of the concentric cylinder gap are also able to rotate separately at an aspect ratio up to Γ = (R 2 -R 1 )/L <= 20. As working fluid its used a silicone oil with a kinematic viscosity of ν = 0.65 • 10 -6 m 2 /s. The outer cylinder is made out of glass to enable optical measurements and is located inside a water box to keep the experiment isothermal. The inner cylinder is devided in three sections (Fig. 1b) where the middle section is constructed to measure the torque T the fluid interacts on the rotating cylinder wall. The two end sections are used to reduce the influence of the top and bottom end plates. We use Particle Image Velocimetry (PIV) to measure the axial-radial and radial-azimuthal velocity fields (see Fig. 2) and to characterize different instabilities and flow patterns inside the cylinder gap. Laser Doppler Anemometry (LDA) is used to measure time series of the turbulent flow at different positions. The radialazimuthal time dependent velocity field is measured in a second Taylor-Couette apparatus by LDA and PIV. This one has the identical geometry as the one used for torque measurements and is equipped with a transparent end plate attached to the outer cylinder. The azimuthal boundary layer profiles of inner and outer cylinder are also measured for different inner and outer Reynolds numbers. The measured velocity fields (i.e. angular velocity profiles see Fig. 3) and the torque at inner cylinder are compared to verify equation [START_REF] Eckhardt | Fluxes and energy dissipation in thermal convection and shear flows[END_REF]. The radial conservation of the angular momentum flux (∂ r J ω = 0) can be checked for turbulent Taylor-Couette flows.

Financial support by Deutsche Forschungsgemeinschaft (DFG FOR1182 EG100/15-1) is gratefully acknowledged.

R 1 R 2 Ω 1 Ω 2 R 1 R 2 Ω 1

Figure 1 :Figure 2 :Figure 3 :

 123 Figure 1: (a) Shematic drawing of the Taylor-Couette-system, R 1 = 35mm, R 2 = 70mm, η = 0.5, Gamma = 20 (b) Drawing of the inner cylinder with torque measuring unit