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Purpose The purpose of this paper is to place the idea of the learning organization in a historical, multidisciplinary context with the aim of identifying obstacles and opportunities for its greater realization in practice. Design/methodology/approach Marking the 30th anniversary of publication of Peter Senge's “The Fifth Discipline”, the paper reflects on approaches to the study and analysis of organizations over the past century from German sociology, human relations, organization development, the learning organization to responses to the Covid-19 pandemic. Findings It is suggested that distributed leadership is critical to the realization of organizational learning and its absence is a major inhibitor of such learning. Following Argyris, it is argued that high levels of skill (personal mastery) may, in some circumstances, provide a barrier to organizational learning in the face of contextual uncertainty and change. Research limitations/implications While no specific areas of research are proposed, questions are raised which may only be answered in the wake of appropriate (interdisciplinary) research. Practical implications The reflective nature of the paper suggests that significant reform is required in the legislation that encourages short-term thinking on the part of institutional investors to the detriment of strategic thinking and long-term planning. Social implications The Covid-19 pandemic seems to have provided an opportunity to redress a perceived imbalance between traditional organizational thinking and opportunities demonstrated by effective community action, for reappraisal of organizations as communities of people as well as being formalized structures, systems and processes. Originality/value This paper seeks to synthesize diverse theories of organization with the aim of stimulating further innovation in approaches to organizational learning.

Purpose This paper aims to locate its appreciation of the life and work of Arie de Geus within the context of developments in approaches to management practice, education and learning since the Second World War. It emphasizes the important influence of top management-led applications of social science (Beckhard) and the impact of crises upon planning and the generation of memories of the future for effective organizational learning. The paper also describes the roles of learning from experience and of reflective practice in shaping de Geus’ contribution. Design/methodology/approach The approach traces the development of de Geus' career and thinking from Shell cost accountant, to top line manager in three continents, to Head of Shell Group Planning, to prize winning author, to global adviser to the World bank, etc., and as an inspirational speaker as champion of the learning organization. Findings The paper acknowledges Arie de Geus as coining the phrase “The Learning Organization” together with his role in the foundation and development of the Society for Organizational Learning (SOL) and as an international champion of young people's learning through the processes of the Finnish Team Academy model. Social implications Arie de Geus was an exemplar of reflective practice and applied learning. As such, his contribution might be considered as that of a sage rather than as a guru. Originality/value The paper endeavours to emphasize the importance of the role of both the internal and external contexts for effective organizational learning, suggesting that the contribution of Arie de Geus to the field exemplifies this importance.

Introduction and objectivesThe ongoing respiratory sequelae of COVID-19 pneumonia remain unclear, and the ideal follow-up of these patients is still a work in progress. We describe our experience of using a pre-follow-up multidisciplinary team (MDT) to decide the follow-up stream in patients hospitalised for COVID-19 pneumonia.We reviewed all patients with a clinico-radiological diagnosis of COVID-19 admitted to hospital during a 3-month period and assigned a follow-up stream based on British Thoracic Society guidance.We changed the follow-up pathway in 71% (277/392) and refined the pathway in 67% (261/392) of indeterminate cases. We also created an automated process for the general practitioner to book follow-up imaging and will use this process going forward.These findings highlight the importance of the MDT review of cases with suspected COVID-19 pneumonia prior to clinic attendance to ensure appropriate patients are followed up and to optimise utilisation of outpatient imaging and clinics.

This article explores the link between CEOs’ language and hubristic leadership. It is based on the precepts that leaders’ linguistic utterances provide insights into their personality and behaviours; hubris is associated with unethical and potentially destructive leadership behaviours; if it is possible to identify linguistic markers of CEO hubris then these could serve as early warnings sign and help to mitigate the associated risks. Using computational linguistics, we analysed spoken utterances from a sample of hubristic CEOs and compared them with non-hubristic CEOs. We found that hubristic CEOs’ linguistic utterances show systematic and consistent differences from the linguistic utterances of non-hubristic CEOs. Demonstrating how hubristic leadership manifests in CEO language contributes to wider research regarding the diagnosis and prevention of the unethical and potentially destructive effects of hubristic leadership. This research contributes to the wider study of hubris and unethical leadership by applying a novel method for identifying linguistic markers and offers a way of militating against the risk of unethical and destructive CEO behaviours induced or aggravated by hubristic leadership.

Hubristic leaders are powerful and successful individuals who become excessively confident and ambitious in their strategic decision choices. In doing so they show contempt for the advice and criticism of others. As a result, they often end-up over-reaching themselves and inflicting damage, both financial and reputational, on themselves and their organizations. Perhaps the highest profile recent example of hubristic leadership in management is Richard J. Fuld who helped build Lehman Brothers into one of the most formidable Wall Street trading businesses. His hubris contributed not only to his own and the company's demise but also to the 2007/2008 financial crisis, the effects of which are still being felt a decade on. Business is replete with examples of organizational failures which were linked to hubristic leadership. These include Long-Term Capital Management (which went into liquidation following its crash in 1998) and BP's Deepwater Horizon blow-out in the Gulf of Mexico (the costs of which are estimated at the time of writing to be $65billion). Hubristic leadership's damaging effects are not limited to business. In politics, George W Bush exhibited hubris in his decision to invade Iraq in 2003. President Trump shows many of the hallmarks of hubris. Given the scale of its destructive effects, it is surprising that compared to leadership topics such as narcissism and charisma, hubris has received comparatively little attention in management research. In this article we bring hubristic leadership to the attention of management scholars, practitioners and students by explaining its characteristics and causes and suggesting how its potentially destructive consequences might be combatted.

Summary Background Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding UK Medical Research Council and Health Technology Assessment Programme.

Whilst traditional chemically amplified resists (CAR) support the initial insertion of EUV lithography, a wide range of other resist materials are being examined for future nodes, aiming to identify a photoresist that simultaneously meets RLS and defectivity requirements. It is becoming increasingly clear that this should involve a novel mechanism—a new chemistry that can be tuned to allow for improvement of the RLS requirements. One potential approach is the multi-trigger concept wherein a reaction will only occur when multiple elements of the resist are initiated concurrently and in close spatial proximity. At the centre of exposed features, where the exposure dose is sufficient the resist reaction is thus catalytic as in a CAR, but at the edge of the features the reaction is secondorder in nature, and thus the chemical gradient is increased. In effect the resist features an intrinsic, inversely dose dependent, quenching of the catalysis, enhancing chemical contrast and thus resolution, and reducing roughness, whilst eliminating the materials stochastics impact of a separate quencher. The multi-trigger material previously presented consists of a base molecule and a crosslinker, which represent the resist matrix, together with a photoacid generator (PAG). Research has been undertaken to improve this resist, in particular focusing on improving resist opacity and crosslinking density. Our work on high-Z cross-linker molecules mark I and mark II has previously been reported and LER figures below 3 nm for lines and spaces patterned at 14 nm half pitch using the high opacity MTR resist on the EUV-IL exposure tool at PSI were shown. Here we present results from further work focused on the enhancement of the high-opacity MTR resist. A new high- Z crosslinker molecule, mark III, has been synthesized and introduced in the MTR resist to make the high opacity MTR compatible with the ethyl lactate and PGMEA casting solvents. We report results obtained using the new MTR system containing the high-Z cross-linker mark III, with a variation of process conditions and formulation variations. The lithographic performance, of a formulation containing this crosslinker, at pitch 32nm patterned on an NXE3350 is presented A biased LWR of 4.2 nm for a line width of 15.1 nm is shown. Introducing a PEB induces performance changes for the MTR4L3Y(2) resist. The sensitivity improves by over 20% with 80 °C PEB. However, the PEB does lead to a 12% increase of the LWR. Overall, the lowest Z factor (using biased LWR) occurs with a 60 °C PEB temperature. The Z factor is also significantly lower with a film thickness of 22.5 nm compared to 20 nm. The thickest film thickness tested using the NXE3350 is 22.5 nm. However, at PSI, 12 nm lines on a 28 nm pitch were patterned with an LWR of 2.07 nm using a film thickness of 25 nm. In addition to varying the opacity of the resist, we have also investigated increasing the activation energy of the selfquenching aspect of the MTR system. In this case, MTR8 has a higher activation energy than MTR4. Having a higher activation energy should allow introduction of PEB to increase crosslinking and reduce pattern collapse, whilst simultaneously preserving the self-quenching behaviour. We present results which show a decrease in dose and Zfactor using MTR8 at this formulation ratio compared to MTR4, when tested at PSI. The results also show a Z factor improvement when using a 60 °C PEB. A standard opacity multi trigger resist was patterned on the MET5 at the Lawrence Berkeley National Laboratory, and the effect of different development processes was studied using 1:1 dense line features at pitch 32nm. Reducing the development time in nBA had an adverse effect on pattern collapse and LWR. However, changing to on track development process using 2-heptanone gives a 10% LWR improvement at the 25 nm film thickness studied. Additionally, a pillar pattern was studied when using a film thickness of 28 nm. Here we present pillars with a LCDU of 1.85 nm with a CD of 21.4 nm patterned at a 40 nm pitch.

To assess the feasibility and reliability of the use of artificial intelligence post-processing to calculate the RV:LV diameter ratio on computed tomography pulmonary angiography (CTPA) and to investigate its prognostic value in patients with acute PE.Single-centre, retrospective study of 101 consecutive patients with CTPA-proven acute PE. RV and LV volumes were segmented on 1-mm contrast-enhanced axial slices and maximal ventricular diameters were derived for RV:LV ratio using automated post-processing software (IMBIO LLC, USA) and compared to manual analysis in two observers, via intraclass coefficient correlation analysis. Each CTPA report was analysed for mention of the RV:LV ratio and compared to the automated RV:LV ratio. Thirty-day all-cause mortality post-CTPA was recorded.Automated RV:LV analysis was feasible in 87% (n = 88). RV:LV ratios ranged from 0.67 to 2.43, with 64% (n = 65)1.0. There was very strong agreement between manual and automated RV:LV ratios (ICC = 0.83, 0.77-0.88). The use of automated analysis led to a change in risk stratification in 45% of patients (n = 40). The AUC of the automated measurement for the prediction of all-cause 30-day mortality was 0.77 (95% CI: 0.62-0.99).The RV:LV ratio on CTPA can be reliably measured automatically in the majority of real-world cases of acute PE, with perfect reproducibility. The routine use of this automated analysis in clinical practice would add important prognostic information in patients with acute PE.• Automated calculation of the right ventricle to left ventricle ratio was feasible in the majority of patients and demonstrated perfect intraobserver variability. • Automated analysis would have added important prognostic information and altered risk stratification in the majority of patients. • The optimal cut-off value for the automated right ventricle to left ventricle ratio was 1.18, with a sensitivity of 100% and specificity of 54% for the prediction of 30-day mortality.

The aim of this study was to analyse the use of the chest radiograph (CXR) as the first-line investigation in primary care patients with suspected lung cancer.Of 16,945 primary care referral CXRs (June 2018 to May 2019), 1,488 were referred for suspected lung cancer. CXRs were coded as follows: CX1, normal but a CT scan is recommended to exclude malignancy; CX2, alternative diagnosis; or CX3, suspicious for cancer. Kaplan-Meier survival analysis was undertaken by stratifying patients according to their CX code.In the study period, there were 101 lung cancer diagnoses via a primary care CXR pathway. Only 10% of patients with a normal CXR (CX1) underwent subsequent CT and there was a significant delay in lung cancer diagnosis in these patients (p0.001). Lung cancer was diagnosed at an advanced stage in 50% of CX1 patients, 38% of CX2 patients and 57% of CX3 patients (p = 0.26). There was no survival difference between CX codes (p = 0.42).Chest radiography in the investigation of patients with suspected lung cancer may be harmful. This strategy may falsely reassure in the case of a normal CXR and prioritises resources to advanced disease.• Half of all lung cancer diagnoses in a 1-year period are first investigated with a chest X-ray. • A normal chest X-ray report leads to a significant delay in the diagnosis of lung cancer. • The majority of patients with a normal or abnormal chest X-ray have advanced disease at diagnosis and there is no difference in survival outcomes based on the chest X-ray findings.

Introduction This Hospital’s Alcohol Team provides a 7-day service, cited in the 10 Year NHS England Plan as having improved the quality of alcohol-related care. The Alcohol Team receive over 1700 referrals per year – predominantly from assessment wards where screening for potential alcohol issues of new admissions is mandatory and routine. Alcohol screening had not traditionally been routine for A&E patients. There were concerns that the introduction of mandatory screening might risk complicating patient assessment, treatment and timely discharge. Initiatives were introduced to increase the incidence of screening in A&E. An analysis was undertaken on the impact of these initiatives on referrals and patients. Methods Initiatives introduced in 2018 1) Partnership working between AE Development of an Alcohol Assessment sticker, for optional incorporation into patient AE Training targeted to AE A&E Link Nurse developed promotional displays and acted as a champion in A&E to raise awareness. Referral data was audited to assess the impact of the initiatives on referrals. A 10% randomised sample of referrals was further analysed to assess the impact of the increase in referrals. Case Studies were captured to illustrate the benefits of earlier identification of alcohol issues. Results There was a 16% increase (240 patients) in total referrals received: 1523 (2017) to 1763 (2018). AE the average length of stay of those discharged patients was 5.6 hours (compared to 6.0 hours in 2017), and 48% of these patients were discharged in under four hours (compared to 42% the previous year). Specific cases were captured in case studies to illustrate the mechanisms through which early identification of potential alcohol issues can lead to better management of alcohol-related issues, facilitate safe discharge and reduce length of stay. Conclusions The screening, education, and partnership initiatives led to an increase in referrals from A&E to the hospital alcohol team. An audit of referrals suggests the earlier identification of alcohol-related issues in A&E has not had negative impacts on discharges and length of stay from A&E. In practice the Alcohol Team has found that earlier identification of potential issues has enabled them to intervene earlier to improve the management and timely discharge of patients.

An 84-year-old gentleman was referred to the chest clinic with low oxygen saturations on pulse oximetry. He reported breathlessness and wheeze since his retirement as a surveyor 16 years previously. His exercise tolerance was 350 m. He had pre-existing diagnoses of chronic obstructive pulmonary disease and hypertension. He had no avian or occupational exposures, a minimal smoking history while in his teens and had not smoked since, and no history of transient ischaemic attack or cerebrovascular accident. On examination, he was comfortable with no respiratory distress but had slight peripheral cyanosis and oxygen saturations of 89% on room air. Auscultation of his chest revealed increased vocal fremitus and crackles over the right lower lobe with occasional wheeze. The patient was investigated using lung function testing, capillary blood gas sampling, a chest radiograph and thoracic computed tomography (CT). His haemoglobin at presentation was 16.1 g·dL−1. ### Lung function The results of the lung function investigations performed as shown in table 1. Supine and erect spirometry demonstrated oxygen saturations of 93% when lying down and 86% on sitting. There was no significant reversibility to 2.5 mg nebulised salbutamol. View this table: Table 1 Lung function A capillary blood gas taken on air at rest showed an oxygen tension ( P O2) of 8.0 kPa (normal 12.0–15.0 kPa), a carbon dioxide tension ( P CO2) of 4.4 kPa (normal 4.5–6.1 kPa) and pH of 7.44 (normal 7.36–7.42). ### CT CT images are shown in figure 1. Figure 1 a) Axial and b) coronal CT slice. ### Task 1 1. What is seen on the initial CT scan (fig. 1). 2. What conditions can be associated with this? 3. Can you interpret the lung function results (table 1)? ### Answer 1 1. There is a 2-cm vascular abnormality in the right lower lobe consistent with a pulmonary arteriovenous malformation (PAVM). 2. PAVMs are most commonly seen with hereditary haemorrhagic telangiectasia (>90%) and post-cardiac …

Hubristic leaders over-estimate significantly their own abilities and believe their performance to be superior to that of others; as a consequence, they make over-confident and over-ambitious judgements and decisions. The fact that hubristic leaders tend to be resistant to criticism, and invulnerable to and contemptuous of the advice of others further compounds the problem. In this article, we review conceptual, theoretical and methodological aspects of hubristic leadership research. We examine hubristic leadership from two standpoints: first, from a psychological and behavioural perspective, we review hubris in terms of over-confidence and its relationship to core self-evaluation and narcissism; second, from a psychiatric perspective, we review hubris as an acquired disorder with a distinctive set of symptoms (Hubris Syndrome), the onset of which is associated with the acquisition of significant power. In doing so, we draw distinctions between hubris and several related constructs, such as over-confidence, narcissism, core self-evaluation and pride. Methodologically, we review how hubris and Hubris Syndrome can be recognised, diagnosed and researched, and we explore some of the unique challenges and opportunities hubris research presents. We conclude by offering some directions for future inquiry and recapitulate the practical and pedagogical significance of this vitally important but under-researched leadership phenomenon.

The PROSPER (Proof and Specification Assisted Design Environments) project advocates the use of toolkits which allow existing verification tools to be adapted to a more flexible format so that they may be treated as components. A system incorporating such tools becomes another component that can be embedded in an application. This paper describes the PROSPER Toolkit which enables this. The nature of communication between components is specified in a language-independent way. It is implemented in several common programming languages to allow a wide variety of tools to have access to the toolkit.

The development of a commercial manufacturing process for fulvestrant (the active ingredient in ‘Faslodex’) is described. Key steps in the synthesis are stereoselective 1,6-addition of an organocuprate to a steroidal dienone followed by copper-mediated aromatisation of the A-ring. The strategy for dealing with noncrystalline intermediates is outlined. The production of drug substance of acceptable quality is critically dependent on limiting the formation of key impurities. The origin of these impurities is discussed, and measures to prevent or control their formation are described.

Virtual reality (VR) has the potential to substantially alter the manner in which products of the future are engineered. Currently there are many applications of VR during the product engineering process from design and analysis through to process planning, assembly, machining and shop floor layout. VR takes a multitude of forms, including immersive, desktop, augmented, and is rapidly developing as a tool that can be used in the engineering of products. This paper looks at the use of immersive VR as a tool for analysing both design and manufacturing product engineering activities in a series of research projects involving assembly planning and cable harness design. It focuses particularly on the use of the non-intrusive logging of users in such environments as a means to obtaining a rich data source for activity analysis and its potential within computer integrated manufacturing environments as a means of providing downstream engineering data.

Purpose – The purpose of this paper is to provide an overview of the potential use of virtual reality systems in facilities management design solutions.Design/methodology/approach – The approach focuses on the human designer and acknowledges the importance of human input to the design process. The development of a metaphor‐based VR system is reported along with initial field trials, which compare VR with conventional CAD systems.Findings – In the context of facilities management solutions advantages of using VR over CAD are shown and discussed along with strengths, weaknesses and future work.Research limitations/implications – The literature reviewed is not exhaustive. Many concepts are mentioned and referenced but not explained fully due to space constraints. The research suggests the future use of VR systems in FM solutions.Practical implications – This paper discusses immersive virtual reality (VR) in support of building design tasks as an innovative tool, enabling more effective facilities management ...

The term “transformation” is much used in the practice and literature of management and organizations. We are curious as to why there has been little challenge to or questioning of usage of the term. In this paper we identify a number of dimensions on which usage of ‘transformation’ appears to vary. This results in a tentative classification into a matrix of four types. While these clusters overlap they imply a variety of agendas, expectations and modes of working, with widely differing implications for those involved in associated change processes. The aim of the article is to stimulate debate about the idea of transformation, not to attempt to define what transformation “is”. Thus we treat this variety of usage as interesting and potentially significant, not as a problem or as an inadequacy of terminology that has to be resolved.

The asymmetric sulfoxidation of an aryl ethyl sulfide in high enantioselectivity was required as part of a manufacturing route to a candidate drug (ZD3638) within AstraZeneca Pharmaceuticals. The initial discovery process provided small quantities of the required material to satisfy early toxicological work. The optimisation of this sulfoxidation process was required to improve enantioselectivity and therefore yield, and also to improve robustness for manufacturing routinely. Previous studies had indicated that asymmetric sulfoxidation of an aryl ethyl sulfide proceeded with moderate enantioselectivity. Initially, Sharpless conditions which are used for the oxidation of allylic alcohols were employed to effect sulfoxidation in 60% ee; this system was then studied extensively to provide new conditions in 80% ee. Finally, the use of factorial experimental design to explore key parameters in the catalyst formation for these conditions was then studied. This showed the equivalents of the titanium (IV) isoprop...

Purpose: To assess the effect of prescription parameters on the dose received by the spine during palliative radiotherapy. Methods and Materials: In a survey, members of the Canadian Association of Radiation Oncologists were asked to define their prescription parameters for vertebral metastases. The depth of the spinal canal and vertebral body at 8 spinal levels was measured in 20 magnetic resonance imaging studies (MRIs). Survey results were applied to the measurements to assess the dose received at depth. The depth of spinal structures assessed at simulation and by diagnostic imaging was compared. Results: Prescriptions were most commonly to D max 3 cm or 5 cm using 60 Co-6MV photons delivering 8–30 Gy in 1–10 fractions. Mean depths from MRI were: posterior spinal canal, 5.5 cm; anterior spinal canal, 6.9 cm; and anterior vertebral body, 9.6 cm. Application of the prescription parameters from the survey to these measurements showed a wide range in the dose at depth with variation in technique. Depths measured at simulation correlated well with diagnostic imaging. Conclusion: The spinal canal and vertebral body lie >5 cm beneath the skin, and the dose received varies by up to 50% with changes in prescription depth. We suggest a suitable prescription point for vertebral metastases and a method for determining this at simulation.

Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) increase transcription of the gastrin gene, and the gastrin peptide may be phosphorylated by EGF-stimulated tyrosine kinase. Our aims were to compare EGF/TGF-alpha interactions in 2 human gastro-intestinal cell lines: MGLVA1, with a strong gastrin autocrine pathway, and C170HM2, with a weak pathway. Both cell lines expressed the TGF-alpha gene. MGLVA1 expressed TGF-alpha protein as determined by immuno-cytochemistry, which was absent in C170HM2. Both cell lines expressed the same level of EGF receptors, as assessed by flow cytometry; however, MGLVA1 did not have enhanced in vitro proliferation in response to EGF or TGF-alpha, unlike C170HM2. The basal growth of MGLVA1 was inhibited by anti-sera against TGF-alpha, the EGF receptor and G17. C170HM2 was not inhibited by any of the anti-sera. Neutralisation of TGF-alpha resulted in undetectable cell-associated progastrin levels in MGLVA1 (untreated had 391.7 fmol/5 x 10(6) cells). The progastrin level of C170HM2 remained unaffected. Tyrosine kinase activity, as assessed by phosphopeptide concentration, of unstimulated MGLVA1 was 2.6 times higher than that of C170HM2 in the cell membrane fraction (0.097 compared to 0.037 microg/mg protein, p < 0.001) and 4.8 times higher in the cytosolic fraction (0.269 compared to 0.056 microg/mg protein, p < 0.05). Following treatment with EGF, the phosphopeptide concentration increased in both the membrane and cytosolic fractions of both cell lines. Tyrphostin B42, which inhibits autophosphorylation of the EGF receptor, inhibited the basal growth of MGLVA1 (IC(50) 1.3 microM) and C170HM2 (9.5 microM, p < 0.05 from MGLVA1). Herbimycin, which inhibits pp60(c-src) kinase, reduced the basal growth of MGLVA1 (0.67 microM) but not C170HM2. Immunofluorescence studies confirmed the presence of tyrosine-phosphorylated proteins and pp60(c-src) within the cytoplasm of unstimulated MGLVA1 cells. There was no specific immunofluorescence for either parameter in C170HM2 cells until after treatment with EGF.

Outlines some of the questions raised during the course of a qualitative research inquiry into the personal consequences of organisational change for directors who are “drivers” of such change. Links these questions to more general issues and trends in the organisation of work (Handy) and for human resource management priorities (Ulrich). Questions the interpretation of these trends in relation to the role of the developer, arguing that effective development involving a third party developer is always dependent on genuine partnership working. Such a way of working is particularly challenging or even threatening to developers, frequently tempting them into hiding themselves behind fashionable theories, tools and techniques, rather than risking their own learning and development while facilitating that of others. Suggests ten keys to unlocking the development potential in oneself and others and that the application of these keys can be a painful process.

Mature and post-translational precursor gastrin forms are growth factors for colorectal tumours. The immunogen Gastrimmune is composed of the amino terminus of gastrin-17 linked to diphtheria toxoid and raises antibodies in situ which neutralise amidated and glycine-extended gastrin-17. The aim of the study was to determine the effect of treatment with 5-fluorouracil(5-FU)/leucovorin on the antibody titres induced by Gastrimmune and the effect of combination therapy on the growth of the rat colon tumour DHDK12. Gastrimmune was administered to rats s.c. at 3 weekly intervals. The rat colon tumour line DHDK12 was injected into the abdominal wall of BDIX rats. Combinations of 5-FU/leucovorin were injected i.v. on days 1, 3 and 5, with the cycle repeated every 4 weeks. Antibody titres were measured by an ELISA technique. Antibody titres were followed for 40 weeks after Gastrimmune (500 microg.ml(-1)) immunization, with titres peaking between 10 and 20 weeks after a single immunisation and falling by week 30. At termination, no effect was observed on either the histological appearance of the gastro-intestinal tract or the proliferation of the colonic mucosa. Pre- and post-treatment with 5-FU/leucovorin (30 mg.kg(-1)) had no effect on the kinetics and level of antibody response to Gastrimmune. Gastrimmune (200 microg.ml(-1)) and 5-FU/leucovorin combinations (12.5 and 20 mg.kg(-1)) increased the therapeutic effects on the in vivo growth of DHDK12 tumors when compared to the agents given singly. Gastrimmune immunisation may be a therapeutic option for the treatment of colorectal cancer in combination with 5-FU/leucovorin.

OBJECTIVES Calcitonin gene-related peptide (CGRP) is a smooth muscle relaxant with potent vasodilating properties. To investigate its inhibitory effects on human myometrial contractions, we obtained excised human myometria from term pregnant, with and without spontaneous labor, and nonpregnant patients. METHODS Myometrial strips were mounted in tissue baths in which contractile activity was recorded. Spontaneously contracting tissues in vitro were exposed to increasing concentrations of CGRP (10(-11)-10(-7) mol/L). Tissues without spontaneous contractions were induced to contract with either oxytocin or KCl before being exposed to CGRP. The IC25 (CGRP concentration required to inhibit contractility by 25%) was used as comparison between groups. RESULTS Tissues with spontaneous or oxytocin-induced in vitro contractions responded equally to CGRP relaxation. Tissues induced to contract with KCl in vitro required approximately 2000 times more CGRP for equal relaxation. In tissues with spontaneous or oxytocin-induced in vitro contractions, those from pregnant unlabored patients were 60 times more sensitive to CGRP than those from pregnant labored or nonpregnant patients. The letter two groups responded equally to CGRP. CONCLUSIONS The sensitivity of myometrial tissues to CGRP relaxation in vitro is increased from the nonpregnant to the pregnant term state. This increased sensitivity is lost once patients develop spontaneous term labor. The relative ineffectiveness of CGRP in relaxing KCl-induced in vitro contractions probably reflects its known mechanism of action, namely the hyperpolarization of cell membrane potentials via activation of membrane potassium channels.

Describes a process of management learning and development involving over 100 senior public sector managers in the States of Guernsey and covering a period of six years. Details the programme’s content and action learning approach which had much in common with many other management development processes. However, highlights the fact that it involved the whole spectrum of public sector activity (from policy making, service purchasing and service providing to utilities trading) and that more than 20 chief executives and their senior management teams participated in the process, which makes it somewhat unusual. Reports that, in the wake of the programme, a fundamental shift in the “doing of management” would appear to have taken place, involving a willingness to share resources, to break out of silos and to experiment across previously well‐defended boundaries; and notes that it has also generated a healthy appetite for further learning.

The neutralising ability of rabbit anti-gastrin-17 (G17) antiserum raised by Gastrimmune, an immunogen constructed of the N-terminal portion of human G17 conjugated to diptheria toxoid (DT), was evaluated. The anti-serum (denoted anti-G17: DT) was shown to displace 125[I] G17 from the gastrin receptors on AR42J cells. The therapeutic effect of the rabbit anti-G17:DT anti-serum was evaluated on a freshly derived human colorectal cancer cell line, AP5, which was shown to express both gastrin receptors and gastrin immunoreactivity as assessed by immunocytochemistry. Rabbit anti-G17:DT anti-serum was shown to block basal in vitro growth of AP5 cells when used at an antigen binding capacity of 3.75 x 10(-9) M. The same dilution of anti-serum completely reversed growth stimulated by human G17 at concentrations of 1 x 10(-10) and 1 x 10(-9) M but did not inhibit growth at 1 x 10(-8) M G17. When AP5 was grown as a xenograft in nude mice, the sensitivity to the proliferative effect of human G17 was maintained. In addition, the basal growth of AP5 xenografts was significantly reduced by i.v. infusion of rabbit anti-G17:DT anti-serum when compared to treatment with rabbit anti:DT control anti-serum. Thus anti-G17:DT antibodies raised by Gastrimmune may be of clinical value in gastrin-sensitive tumours.

As the use of knowledge capture and reuse becomes more prevalent in industry, the research into how the capture process can be automated is also increasing. In this paper, research is presented on how basic design knowledge, such as design decisions and best practice, in a virtual reality-based cable harness design system can be automatically captured and represented. By automated and unobtrusive logging of a user as a design task is carried out, the resulting log file is parsed and various representations of the captured design processes are automatically generated. A user trial involving industrial collaborators was conducted to find out which of the representations were the most effective and preferred. It was discovered that users had a preference for representations that contain more visual information. Future work will involve utilising the captured knowledge to develop training tools which will aid new users performing similar design tasks.Copyright © 2010 by ASME

Why are so many highly experienced and competent leaders caught out and taken by surprise by unexpected events for which they are unprepared, with the consequence that they then do things that seriously damage their organizations and themselves? Why do they fail to notice the alarm signals that are so often shown to have been sounding long before the specific event that did them so much harm actually occurred? What was it that during 2008 caused the leaders of many of the world’s long-established and highly respected financial institutions to lead these institutions to self-destruction, dragging the global economy down with them?

In the previous chapter we stated that the ways in which organizations respond to unexpected events is largely determined by its prevalent mindset. An organization’s prevailing mindset, in turn, is shaped by the values, attitudes and behaviors of its leaders and reflected in the way it deals with mistakes. For example, it may result in their being perceived as a fact of life for which allowances must be made or as failures, the perpetrators of which need to be discovered, humiliated and punished. It may encourage errors to be hidden, denied and covered up. It may mean that blame is the name of the game or encourage people to freely acknowledge when they have made a mistake so that both they and the organization may learn from them. Whatever complexion an organization’s mindset may develop, its tone is significantly influenced by its leadership.

As an organizational leader you are operating at the interface between the past, the present and the future. If you are to manage this interface effectively, you are going to need the ability to appreciate the past, to understand the present and to anticipate, plan for and shape the future. A core message of this book is that the plans that you make for that future will be constantly and increasingly buffeted by unexpected events with the potential to knock such plans for six.

Just who is responsible for the current mess in which we find ourselves? People like us; like you and like me. That’s uncomfortable.

Throughout this book we have stressed how important it is for leaders of businesses or organizations to be aware of what is going on in the wider environment within which their business or organization is situated. The leader must be constantly on the lookout for signals and cues for possible changes or developing trends that may give rise to events that could be significant for the organization and its performance. We have discussed the importance of generating “memories of the future” through the use of techniques such as scenario planning so that the organization as a whole may become sensitive to such wider environmental trends and their possible implications. The use of such techniques and getting their messages into the organization’s bloodstream by means of the myths and stories that are told within it greatly increase the chances that signals, even weak ones, that cue the arrival of the unexpected will be picked up and that the organization will respond appropriately.

At the beginning of this book we asserted that leading an organization, whether as its CEO, managing or divisional director or general manager, whatever the particular leadership label you happen to bear, carries with it a number of obligations. Some of these will be set out in your letter of appointment, your service contract or laid down as the statutory responsibilities of anyone taking on the role of a director of a limited company. We believe that there are others, less formal, but just as important.

In this chapter we discuss two contrasting ways of thinking. Business leaders need to employ these in a balanced way when developing the goals that they wish their organizations to pursue and as they seek to gain the commitment of those upon whom they will depend if those goals are to become reality. The first of these modes of thinking owes much to the contribution that science, engineering and technology have made to the success of industrial societies over the past 250 years or so. This mode tends to be formally structured, emphasizes and favors the logical, the analytical and the objective and is popularly termed “left Brain” thinking.