Sickle cell anaemia (SCA) is the consequence of abnormal haemoglobin production due to an inherited point mutation in the beta-globin gene. The resulting haemoglobin tetramer is poorly soluble when deoxygenated, and when this is prolonged, intracellular gelation of sickle haemoglobin occurs, followed by haemoglobin polymerisation. If many cycles of sickling and unsickling occur, the red cell membrane will be disrupted leading to haemolysis and vaso-occlusive events. Recent studies have also shown that leucocyte adhesion molecules and nitric oxide (NO) depletion are involved in endothelial damage. New insights in SCA pathophysiology and vascular biology have shown that cell-derived microparticle (MP) generation is also involved in the vaso-occlusion. Endothelial damage is perpetuated by impaired production or increased consumption of protective modulators such as protein C, protein S and NO. New therapeutic interventions should address these aspects of SCA pathogenesis. To date, the only US-FDA-approved therapy to prevent painful vaso-occulsive episodes is hydroxyurea that reduces haemoglobin polymerisation in sickle cells by increasing the production of foetal haemoglobin and L-glutamine. However, several new drugs have been tested in the last years in randomised clinical trials. We here report an update on the current status of knowledge on SCA.

Sickle cell anaemia ( SCA ) is the consequence of abnormal haemoglobin production due to an inherited point mutation in the β‐globin gene. The resulting haemoglobin tetramer is poorly soluble when deoxygenated, and when this is prolonged, intracellular gelation of sickle haemoglobin occurs, followed by haemoglobin polymerisation. If many cycles of sickling and unsickling occur, the red cell membrane will be disrupted leading to haemolysis and vaso‐occlusive events. Recent studies have also shown that leucocyte adhesion molecules and nitric oxide ( NO ) depletion are involved in endothelial damage. New insights in SCA pathophysiology and vascular biology have shown that cell‐derived microparticle ( MP ) generation is also involved in the vaso‐occlusion. Endothelial damage is perpetuated by impaired production or increased consumption of protective modulators such as protein C, protein S and NO . New therapeutic interventions should address these aspects of SCA pathogenesis. To date, the only US ‐ FDA ‐approved therapy to prevent painful vaso‐occulsive episodes is hydroxyurea that reduces haemoglobin polymerisation in sickle cells by increasing the production of foetal haemoglobin and L‐glutamine. However, several new drugs have been tested in the last years in randomised clinical trials. We here report an update on the current status of knowledge on SCA .

Student retention is important to all Higher Education Institutions. The typical focus has seen institutions identifying 'at risk' students by monitoring a set of factors such as student attendance, engagement, performance, socioeconomic background, etc. Institutions want to identify 'at risk' students and intervene before the 'at risk' student becomes a retention statistic. Institutions provide relevant data to leaders creating an opportunity to craft an intervention to change student behaviour. In a data driven culture, leaders make decisions based on data and information rather than intuition and bias. What is interesting however, is that there are a number of methodological and theoretical gaps in the area of student retention research. The vast majority of the research has used positivist approaches to collect and analyse data and focused, understandably, on the perspective of the student. Exploiting these gaps, this exploratory study is building theory by analyzing data gathered through interviews, surveys and participant observation in a Higher Education Institution. A single case study design is chosen with an Irish Higher Education Institution as the case. Another crucial difference is that this research focuses on the perspective of the leader rather than the student. After moving towards a data driven culture, the paper will ask a number of key questions:Does this move impact on leadership styles?Do leaders then gravitate towards or away from particular leadership styles?

Introduction: Circulating microparticles (MP) have been described in sickle cell anaemia (SCA); however, their interaction with endothelial markers remains unclear. We investigated the relationship between MP, protein C (PC), free protein S (PS), nitric oxide (NO), endothelin-1 (ET-1) and adrenomedullin (ADM) in a large cohort of paediatric patients. Method: A total of 111 children of African ethnicity with SCA: 51 in steady state; 15 in crises; 30 on hydroxyurea (HU) therapy; 15 on transfusion; 17 controls (HbAA) of similar age/ethnicity. MP were analysed by flow cytometry using: Annexin V (AV), CD61, CD42a, CD62P, CD235a, CD14, CD142 (tissue factor), CD201 (endothelial PC receptor), CD62E, CD36 (TSP-1), CD47 (TSP-1 receptor), CD31 (PECAM), CD144 (VE-cadherin). Protein C, free PS, NO, pro-ADM and C-terminal ET-1 were also measured. Results: Total MP AV was lower in crisis (1.26×106 ml−1; 0.56–2.44×106) and steady state (1.35×106 ml−1; 0.71–3.0×106) compared to transfusion (4.33×106 ml−1; 1.6–9.2×106, p<0.01). Protein C levels were significantly lower in crisis (median 0.52 IU ml−1; interquartile range 0.43–0.62) compared with all other groups: HbAA (0.72 IU ml−1; 0.66–0.82, p<0.001); HU (0.67 IU ml−1; 0.58–0.77, p<0.001); steady state (0.63 IU ml−1; 0.54–0.70, p<0.05) and transfusion (0.60 IU ml−1; 0.54–0.70, p<0.05). In addition, levels were significantly reduced in steady state (0.63 IU ml−1; 0.54–0.70) compared with HbAA (0.72 IU ml−1; 0.66–0.80, p<0.01). PS levels were significantly higher in HbAA (0.85 IU ml−1; 0.72–0.97) compared with crisis (0.49 IU ml−1; 0.42–0.64, p<0.001), HU (0.65 IU ml−1; 0.56–0.74, p<0.01) and transfusion (0.59 IU ml−1; 0.47–0.71, p<0.01). There was also a significant difference in crisis patients compared with steady state (0.49 IU ml−1; 0.42–0.64 vs. 0.68 IU ml−1; 0.58–0.79, p<0.05). There was high correlation (R>0.9, p<0.05) between total numbers of AV-positive MP (MP AV) and platelet MP expressing non-activation platelet markers. There was a lower correlation between MP AV and MP CD62P (R=0.73, p<0.05) (platelet activation marker), and also a lower correlation between percentage of MP expressing CD201 (%MP CD201) and %MP CD14 (R=0.627, p<0.001). %MP CD201 was higher in crisis (11.6%) compared with HbAA (3.2%, p<0.05); %MP CD144 was higher in crisis (7.6%) compared with transfusion (2.1%, p<0.05); %CD14 (0.77%) was higher in crisis compared with transfusion (0.0%, p<0.05) and steady state (0.0%, p<0.01); MP CD14 was detectable in a higher number of samples (92%) in crisis compared with the rest (40%); %MP CD235a was higher in crisis (17.9%) compared with transfusion (8.9%), HU (8.7%) and steady state (9.9%, p<0.05); %CD62E did not differ significantly across the groups and CD142 was undetectable. Pro-ADM levels were raised in chest crisis: 0.38 nmol L−1 (0.31–0.49) versus steady state: 0.27 nmol L−1 (0.25–0.32; p<0.01) and control: 0.28 nmol L−1 (0.27–0.31; p<0.01). CT-proET-1 levels were reduced in patients on HU therapy: 43.6 pmol L−1 (12.6–49.6) versus control: 55.1 pmol L−1 (45.2–63.9; p<0.05). NO levels were significantly lower in chest crisis (19.3 mmol L−1 plasma; 10.7–19.9) compared with HU (22.2 mmol L−1 plasma; 18.3–28.4; p<0.05), and HbSC (30.6 mmol L−1 plasma; 20.8–39.5; p<0.05) and approach significance when compared with steady state (22.5mmol L−1 plasma; 16.9–28.2; p=0.07). Conclusion: Protein C and free PS are reduced in crisis with lower numbers of platelet MP and higher percentage of markers of endothelial damage and of red cell origin. During chest crisis, ADM and ET-1 were elevated suggesting a role for therapy inhibiting ET-1 in chest crisis.

Low circulating protein C (PC) levels have been observed in sepsis, especially in patients with Neisseriae Meningitides infections. Poor clinical outcome and high limb amputation rates have been associated in infected patients with low circulating PC levels. Published studies using activated PC replacement therapy patients with sepsis have shown reduced mortality rates, however, its use has been associated with severe bleeding events. Paediatric sepsis studies using non-activated plasma-derived PC (Ceprotin®) are lacking. We present a retrospective study in children with sepsis who were treated with Ceprotin® focusing on amputation rate post treatment. Thirty subjects were identified. Median age at diagnosis was 2 years. Twenty-one (70%) were treated for Nesseria Meningitides and one (3%) for Streptococcus-A β-haemolyticus, another 8 (26%) patients with malignancies were treated for neutopenic sepsis. Following Ceprotin® administration, a significant increase in leukocyte count (p = 0.004), neutrophil count (p = 0.001) and PC (pretreatment = 13%, posttreatment = 88.5%; p = 0.0001) was seen. Prothrombin time (pretreatment =30.3 seconds, posttreatment =16.5; p = 0.000) and activated partial thromboplastin time (pretreatment =61.8 sec, postreatment =42.6 sec; p = 0.000) were significantly reduced, while fibrinogen levels were significantly elevated (pretreatment =1.9 g/dL, posttreatment =4.4 g/dL; p = 0.000). The median time between admission to intensive care and Ceprotin® administration was 10 hrs. Limb amputation rate was reduced (16-23% versus 30-50% from previous studies) and there were no haemorrhagic events observed. This study demonstrates the safe administration of non-activated plasma-derived PC concentrate in patients with sepsis who are coagulopathic and it associated with a reduction in amputation rates.

This paper lays a theoretical foundation from which it builds a typology of innovation search activities that can be used to characterize the openness of organisations. The typology is subsequently used as the conceptual lens when reviewing the extant literature in order to draw out recommendations for future research. This paper proposes that there are major issues with the extant literature and provides some recommendations for addressing these issues. This paper is of value to innovation scholars and those interested in building typologies as theoretical artefacts. More must be done to discover and to probe into why and how organisational elements interrelate and complement each other to impact the performance of organisations. Therefore, we suggest that scholars looking at innovation performance should consider combinations of search activities rather than the activities in isolation. Unfortunately existing studies tend to concentrate on either single activities or on the dichotomised choice between internal and external sources.

A complex relationship exists between venous hemoglobin level and thrombosis risk. The hemoglobin content of capillary blood varies in healthy individuals in relation to that of venous blood with sex, age, season of the year, and venous hemoglobin level. (Murphy WG, et al. Blood 2010;116:2861-2). To study further the dynamics of this relationship, venous and capillary (finger pulp blood) hemoglobin levels were compared in 462 frequent blood donors with hereditary hemochromatosis. A linear mixed effects model was fitted to compare capillary hemoglobin with the difference between the venous and capillary hemoglobin. Random slopes and intercepts for each donor were modelled to account for inter-individual variability. A linear mixed effects model was fitted to hemoglobin levels over cumulative time since first donation for each person in separate analyses for capillary and venous hemoglobin levels. Random intercepts and random slopes were modelled within individuals. For each change of 1g/dL in capillary hemoglobin, the difference between venous and capillary hemoglobin changed by -0.694 g/dL, significantly different from zero (p<0.001), indicating a dynamic relationship between the two compartments. After venesection capillary hemoglobin rose by a mean of 0.496 mg/dL/day, (p<0.001) and venous hemoglobin by 0.113 mg/dL/day (p=0.019). The recovery rate for capillary hemoglobin between venesections was 4.39 times faster than for venous hemoglobin [t(4798)=2.743; p=0.006]. These data indicate that healthy individuals preserve venous hemoglobin at the expense of capillary hemoglobin as the red cell mass rises and falls, and that the capillary space buffers the venous hemoglobin level from changes in red cell mass. Since this space occupies > 10% of the intravascular volume (Chaplin H, et al. JCI 1953:32;1309-16) we estimate that 27% or more of a decrease or increase in red cell mass is accommodated by changes in hemoglobin level of capillary blood relative to the venous hemoglobin level. The mechanisms underlying these dynamics, such as NO-induced vasodilation by deoxyhemoglobin and modulation of the Fåhraeus effect, remain to be elucidated; however their implications for the relationship between hemoglobin level and thrombosis may be considerable.

Measurement of innovation is critical to management but unfortunately it is an extremely tall order, which results in it being referred to as a 'black art'. It is particularly troublesome for firms, which operate in highly complex and turbulent environments. Extant literature is characterized by a diversity of approaches, prescriptions, and practices that are more often than not confusing and contradictory. We require good theory both to suggest which metrics are needed and to interpret the resulting data. In this paper we return to the literature in order to build a conceptual framework to guide the measurement of innovation. In addition we perform an initial validation of the framework against an online repository of content on innovation measurement and in so doing we arrive at a taxonomy of innovation metrics. While useful in its own right, the taxonomy also highlights both the strengths and weaknesses in the current approach to innovation measurement. Finally we use the framework to draw out four key questions that should be addressed by management before choosing appropriate metrics. We foresee management using both the taxonomy and the guiding questions to evaluate their own measurement activities.

Abstract Abstract 5193 Essenthial thrombocythemia (ET) patients are at risk of developing an arterious or venous thrombotic event. Recent studies have shown that there is no clear association between platelet (PLT) count and thrombotic events, but that white cell count plays a role. Qualitative PLT abnormalities, activation of endothelial cells (EC) and PLT may be involved in these processes. Following activation of blood cells, plasma membrane vescicles are released, these are known as microparticles (MP) (<1. 5μm of size). They may originate from PLT (PMP), EC (EMP) or red cells (RMP). MP may affect endothelial modulators such as vasorelaxant nitric oxide (NO), adrenomedullin (ADM) and endothelin-1 (ET-1), a potent vasocostrictor agent. Previous studies [Trappenburg MC et al 2009] demonstrated that MP are present in elevated numbers in ET. However, the relationship between MP with treatment and MP with endothelial modulators is unknown. We investigated the relationship between MP, NO, ADM and ET-1 in ET patients on treatment with hydroxyurea (HU), anagrelide (AN) and aspirin(ASA) only. 52 patients with ET diagnosis were studied: 18 on HU, 15 on AN, and 19 on ASA. Platelet-poor-plasma aliquotes were stored at −80°C and subsequently processed. Samples were analysed for MP numbers (absolute total values) and functional markers (percentage values) by flow cytometry, as previously described [Jy W et al JTH 2004]. PMP was identified using CD62P, CD36, and CD63, EMP using CD105 and RMP using CD235a. Endothelial modulator markers NO, ADM and ET-1 were measured by ELISA. Statistical analysis included Kruskal-Wallis test, Bonferroni test, correlation matrix, principal component (PCA) and partial least square regression analysis (PLSR). Total-MP were increased in all patients groups compared to controls (p<0. 01). Strong correlations were seen for tot-MP and %MP CD62P (R=0. 89, p<0. 05), tot-MP and %MPCD36 (R=0. 97, p<0. 05), tot-MP CD62P+ and CD36+ (R=0. 85, p<0. 05) and for tot -MP TF+ and %MP CD105+ (R=0. 66, p<0. 05). Bonferroni test, showed higher MP total number in the AN group compared to the HU and the ASA group (p <0. 05). The percentage of CD63 MP was higher than control both in the HU and in the AN group (p <0. 05), while CD36 MP% was higher in the AN group compared to the HU group (p <0. 05). NO and ADM values were higher in the HU group, while ET-1 values were lower in the AN group (p <0. 05). The principle components (PC) responsible for value variations were PC1 [positive loading for WCC, PMP and EMP] reflecteing PLT and EC activation, and PC4 [positive loadings for PLT, PMP; negative loadings for RMP, NO]. Both PC1 and PC4 were statistically significant for treatment. This study confirms previous findings that MP are present in ET. We also showed that MP are affected by treatment and that MP are mainly PMP and express CD62P and CD36, a marker of immature PLT, which suggests that reticulated PLT partecipate in these processes. We also showed that HU increase NO and ADM levels, while AN reduces ET-1. As NO and ET-1 have antagonistic actions on endothelial cells, we suggest that HU and AN may have overlapping effects on endothelium, although using different biochemichal pathways. The finding that treatment influences PC1 (PMP and EMP) supports the idea that in ET, treatment impacts directly on MP. The finding that NO and RMP have a negative loading within PC4, suggests that they have an antagonist-action to PMP and EMP in ET. Disclosures: Pizzolo: Hoffmann-La Roche: Consultancy, Honoraria.

Wicked problems demand what Simon refers to as non- programmable decisions, which are novel, unstructured and unusually consequential (Simon, 1977, p. 46). Despite recognising the importance of decision design in tackling such problems, Simon described himself as someone who "devoted his scientific career to understanding human choice" and he focused far less attention on decision design (Simon, 1991, p. xvii). This paper takes a critical look at innovation studies and provides a much needed review of the oft- cited generations of innovation models (cf. Rothwell, 1994). In addressing our concerns, we present a new typology of models and from it we recast the concept of the innovation model as a design tool for practitioners. This approach supports the emerging trend of viewing management as a design activity rather than solely a decision making activity. This redirection serves to reinvigorate the academic discourse.

Children with sickle cell anemia may undergo acute splenic sequestration. Splenectomy is performed in an attempt to reduce further events. Histologic studies of spleens have revealed the presence of granuloma-like nodules, known as Gamna-Gandy bodies with amorphous inclusions; however, their significance is unknown. The medical case records and histologic samples of consecutive children with sickle cell anemia treated with splenectomy between 2001 and 2007 at Our Lady's Children's Hospital, Dublin, were reviewed. Seventeen patients were identified. Gamna-Gandy bodies were studied by scanning electron microscopy and x-ray fluorescence spectroscopy. Gamna-Gandy bodies were identified in 7 (41%) patients, and amorphous inclusions were always seen. Patient age correlated significantly with Gamna-Gandy bodies (P = .002). Scanning electron microscopic analysis demonstrated the crystalline nature of Gamna-Gandy bodies and the chemical composition (C 47.1%; O2 29.7%; P 9.0%; K+ 0.4%; Ca2+ 6.4%; Fe2+ 7.4%), whereas x-ray diffraction studied the structure (CaPO4 ∙ FeOH). A crystal-formation gradient was observed, increasing from the red pulp to the white pulp. Our study shows that Gamna-Gandy bodies contain crystals and that their formation is age dependent. We also demonstrated the crystal structure and chemical composition and the relationship between Gamna-Gandy bodies and chest crises presplenectomy or postsplenectomy.

Management literature is renowned for producing concepts and models but few of these are ever translated into software-based tools even though they could offer value to managers. Innovation models are theoretical constructions that attempt to abstract from reality a set of interesting features that are useful in describing, explaining, and predicting the reality of the innovation processes in organisations. But it is troubling to find that even the latest models emanating from the academic discourse fall well short of organisational reality. The objective of this paper is to recast the concept of the innovation model but this time from a strong theoretical base. We, therefore, start by presenting a conceptual framework for the innovation processes in organizations. From this we set out to develop an ontology that defines the words and sentences that can be used to represent innovation models. So we do not seek to present yet another model of innovation but instead we work towards a conceptually derived ontology of innovation models that can provide a foundation for future software-based tools. We suggest that computer-aided innovation modelling is an interesting area of research deserving of future attention.

It is widely believed that knowledge work is a relatively new phenomenon and that it constitutes the main form of activity in post-industrial organizations. While the term remains undefined, knowledge work is taken to refer to the knowledge that individuals apply in performing role-related business activities in “knowledge-intensive” organizations. In this scheme of things, the conventional wisdom holds that the subjective knowledge of individual social actors is applied to “objectified” organizational knowledge (i.e., data held in various paper and electronic repositories) as the raw material of the production process. Thus, knowledge is considered to be both an input to, and an output of, business processes: It also is argued to underpin the process by which knowledge inputs are transformed to outputs.

Management literature is renowned for producing concepts and frameworks but few of these are translated into software-based tools, even when they could be valuable to management. The area of innovation modelling is unfortunately a case in point. Management has heretofore been unable to effectively capture, communicate, and share its innovation models. Owing to the limited cognitive abilities of the human mind and the complexity and ambiguity surrounding innovation in organisations, the role of software-based tools in the future of innovation modelling should not be overlooked. But no standard approach to representing innovation models exists. The objective of this paper is to describe a prototype of an innovation modelling tool that resulted from our 24-month research initiative. We also include descriptions of an ontology upon which the prototype is built and the design science approach through which it emerged.

As academic scholars in an applied field our central mission is to develop theory that both contributes knowledge to the academic discipline and applies that knowledge to practice. However, our efforts in this regard are being impacted by communication deficits that in turn limit the effectiveness of our theories. The goal of this paper is twofold: a diagnostic one, which reviews the causes of the communication deficits but primarily a therapeutic one whereby we propose a course of treatment for content and presentation issues. While the 'ultimate criterion' for determining the effectiveness of theory is market acceptance this does not prevent us in this paper from putting forward principles, a model, and a method to assist the IS scholar in building effective theory. These tools are derived after considered reflection on the ancient craft and science of map-making. We finish by asking ourselves and our readers whether we need a design science of theory-building.

As academic scholars in an applied field our central mission is to develop theory that both contributes knowledge to the academic discipline and applies that knowledge to practice. However, our efforts in this regard are impacted by communication deficits, which limit the effectiveness of our theories. The effectiveness of theory is attributable to the quality of both its presentation and its content. We put forward a model and principles to assist in building effective theory. The conceptual basis for this paper is the ancient craft and science of map-making. Perhaps controversially, we posit that theory-building efforts should focus primarily on ‘effective theory’ rather than ‘good theory’. We conclude by proposing that in future our theories should be viewed as cognitive devices and that we need to understand which of their features contribute to making them successes or failures in different environments as well as why and how they work.