13,012 research outputs found
Recommended from our members
Ensuring Access to Safe and Nutritious Food for All Through the Transformation of Food Systems
Testing the nomological network for the Personal Engagement Model
The study of employee engagement has been a key focus of management for over three decades. The academic literature on engagement has generated multiple definitions but there are two primary models of engagement: the Personal Engagement Model of Kahn (1990), and the Work Engagement Model (WEM) of Schaufeli et al., (2002). While the former is cited by most authors as the seminal work on engagement, research has tended to focus on elements of the model and most theoretical work on engagement has predominantly used the WEM to consider the topic.
The purpose of this study was to test all the elements of the nomological network of the PEM to determine whether the complete model of personal engagement is viable. This was done using data from a large, complex public sector workforce. Survey questions were designed to test each element of the PEM and administered to a sample of the workforce (n = 3,103). The scales were tested and refined using confirmatory factor analysis and then the model was tested determine the structure of the nomological network. This was validated and the generalisability of the final model was tested across different work and organisational types.
The results showed that the PEM is viable but there were differences from what was originally proposed by Kahn (1990). Specifically, of the three psychological conditions deemed necessary for engagement to occur, meaningfulness, safety, and availability, only meaningfulness was found to contribute to employee engagement. The model demonstrated that employees experience meaningfulness through both the nature of the work that they do and the organisation within which they do their work. Finally, the findings were replicated across employees in different work types and different organisational types.
This thesis makes five contributions to the engagement paradigm. It advances engagement theory by testing the PEM and showing that it is an adequate representation of engagement. A model for testing the causal mechanism for engagement has been articulated, demonstrating that meaningfulness in work is a primary mechanism for engagement. The research has shown the key aspects of the workplace in which employees experience meaningfulness, the nature of the work that they do and the organisation within which they do it. It has demonstrated that this is consistent across organisations and the type of work. Finally, it has developed a reliable measure of the different elements of the PEM which will support future research in this area
Subsidiary Entrepreneurial Alertness: Antecedents and Outcomes
This thesis brings together concepts from both international business and entrepreneurship to develop a framework of the facilitators of subsidiary innovation and performance. This study proposes that Subsidiary Entrepreneurial Alertness (SEA) facilitates the recognition of opportunities (the origin of subsidiary initiatives). First introduced by Kirzner (1979) in the context of the individual, entrepreneurial alertness (EA) is the ability to notice an opportunity without actively searching. Similarly, to entrepreneurial alertness at the individual level, this study argues that SEA enables the subsidiary to best select opportunities based on resources available. The research further develops our conceptualisation of SEA by drawing on work by Tang et al. (2012) identifying three distinct activities of EA: scanning and search (identifying opportunities unseen by others due to their awareness gaps), association and connection of information, and evaluation and judgement to interpret or anticipate future viability of opportunities. This study then hypothesises that SEA leads to opportunity recognition at the subsidiary level and further hypothesises innovation and performance as outcomes of opportunity recognition. This research brings these arguments together to develop and test a comprehensive theoretical model.
The theoretical model is tested through a mail survey of the CEOs/MDs of foreign subsidiaries within the Republic of Ireland (an innovative hub for foreign subsidiaries). This method was selected as the best method to reach the targeted respondent, and due to the depth of knowledge the target respondent holds, the survey can answer the desired question more substantially. The results were examined using partial least squares structural equation modelling (PLS-SEM). The study’s findings confirm two critical aspects of subsidiary context, subsidiary brokerage and subsidiary credibility are positively related to SEA. The study establishes a positive link between SEA and both the generation of innovation and the subsidiary’s performance. This thesis makes three significant contributions to the subsidiary literature as it 1) introduces and develops the concept of SEA, 2) identifies the antecedents of SEA, and 3) demonstrates the impact of SEA on subsidiary opportunity recognition. Implications for subsidiaries, headquarters and policy makers are discussed along with the limitations of the study
Hurdles and signposts on the road to virtual control groups—A case study illustrating the influence of anesthesia protocols on electrolyte levels in rats
Introduction: Virtual Control Groups (VCGs) represent the concept of using historical control data from legacy animal studies to replace concurrent control group (CCG) animals. Based on the data curation and sharing activities of the Innovative Medicine Initiatives project eTRANSAFE (enhancing TRANSlational SAFEty Assessment through Integrative Knowledge Management) the ViCoG working group was established with the objectives of i) collecting suitable historical control data sets from preclinical toxicity studies, ii) evaluating statistical methodologies for building adequate and regulatory acceptable VCGs from historical control data, and iii) sharing those control-group data across multiple pharmaceutical companies. During the qualification process of VCGs a particular focus was put on the identification of hidden confounders in the data sets, which might impair the adequate matching of VCGs with the CCG.Methods: During our analyses we identified such a hidden confounder, namely, the choice of the anesthetic procedure used in animal experiments before blood withdrawal. Anesthesia using CO2 may elevate the levels of some electrolytes such as calcium in blood, while the use of isoflurane is known to lower these values. Identification of such hidden confounders is particularly important if the underlying experimental information (e.g., on the anesthetic procedure) is not routinely recorded in the standard raw data files, such as SEND (Standard for Exchange of Non-clinical Data). We therefore analyzed how the replacement of CCGs with VCGs would affect the reproducibility of treatment-related findings regarding electrolyte values (potassium, calcium, sodium, and phosphate). The analyses were performed using a legacy rat systemic toxicity study consisting of a control and three treatment groups conducted according to pertinent OECD guidelines. In the report of this study treatment-related hypercalcemia was reported. The rats in this study were anesthetized with isoflurane.Results: Replacing the CCGs with VCGs derived from studies comprising both anesthetics resulted in a shift of control electrolyte parameters. Instead of the originally reported hypercalcemia the use of VCG led to fallacious conclusions of no observed effect or hypocalcemia.Discussion: Our study highlights the importance of a rigorous statistical analysis including the detection and elimination of hidden confounders prior to the implementation of the VCG concept
Consent and the Construction of the Volunteer: Institutional Settings of Experimental Research on Human Beings in Britain during the Cold War
This study challenges the primacy of consent in the history of human experimentation and argues that privileging the cultural frameworks adds nuance to our understanding of the construction of the volunteer in the period 1945 to 1970. Historians and bio-ethicists have argued that medical ethics codes have marked out the parameters of using people as subjects in medical scientific research and that the consent of the subjects was fundamental to their status as volunteers. However, the temporality of the creation of medical ethics codes means that they need to be understood within their historical context. That medical ethics codes arose from a specific historical context rather than a concerted and conscious determination to safeguard the well-being of subjects needs to be acknowledged. The British context of human experimentation is under-researched and there has been even less focus on the cultural frameworks within which experiments took place. This study demonstrates, through a close analysis of the Medical Research Council's Common Cold Research Unit (CCRU) and the government's military research facility, the Chemical Defence Experimental Establishment, Porton Down (Porton), that the `volunteer' in human experiments was a subjective entity whose identity was specific to the institution which recruited and made use of the subject. By examining representations of volunteers in the British press, the rhetoric of the government's collectivist agenda becomes evident and this fed into the institutional construction of the volunteer at the CCRU. In contrast, discussions between Porton scientists, staff members, and government officials demonstrate that the use of military personnel in secret chemical warfare experiments was far more complex. Conflicting interests of the military, the government and the scientific imperative affected how the military volunteer was perceived
Recommended from our members
The Epidemiology and Genetic Architecture of Vitamin D Deficiency in African Children
Vitamin D deficiency is a common public health problem worldwide. However, little is known about the epidemiology of vitamin D deficiency in Africa. In this thesis, I aimed to determine: 1) the prevalence of and risk factors associated with vitamin D deficiency in studies conducted in Africa; 2) the prevalence and predictors of vitamin D deficiency in African children; 3) the association between vitamin D and iron deficiency in African children; and 4) genetic variants that influence vitamin D status in Africans.
In a systematic review and meta-analyses of previous vitamin D studies in Africa, the average prevalence of low vitamin D status was 18.5%, 34.2% and 59.5% using cut-offs of 25-hydroxyvitamin D (25(OH)D) levels of <30 nmol/L, <50 nmol/L and <75 nmol/L, respectively. Populations at risk of vitamin D deficiency included newborns, women, and people living in high latitudes or urban areas.
In an epidemiological study of young children living in Africa, the prevalence of low vitamin D status was 0.6%, 7.8% and 44.5% using cut-offs of 25(OH)D levels of GC2 variant of the group-specific component (GC) gene, which encodes vitamin D binding protein.
Vitamin D deficiency was also associated with 80% higher odds of iron deficiency in these children. Adjusted regression models revealed that vitamin D deficiency was associated with higher ferritin and hepcidin levels suggesting lower iron status, and reduced sTfR and transferrin levels and increased TSAT and serum iron levels suggesting improved iron status.
Genome-wide association study (GWAS) in Africans revealed genetic variants that influence vitamin D status in vitamin D metabolism genes: DHCR7/NADSYN1, CYP2R1 and GC. However, the majority of SNPs from previous European GWASs did not replicate in the current GWAS.
Findings from this thesis indicate that vitamin D deficiency is prevalent in many African populations and should be considered in public health strategies in Africa
Estudo da remodelagem reversa miocárdica através da análise proteómica do miocárdio e do líquido pericárdico
Valve replacement remains as the standard therapeutic option for aortic
stenosis patients, aiming at abolishing pressure overload and triggering
myocardial reverse remodeling. However, despite the instant hemodynamic
benefit, not all patients show complete regression of myocardial hypertrophy,
being at higher risk for adverse outcomes, such as heart failure. The current
comprehension of the biological mechanisms underlying an incomplete reverse
remodeling is far from complete. Furthermore, definitive prognostic tools and
ancillary therapies to improve the outcome of the patients undergoing valve
replacement are missing. To help abridge these gaps, a combined myocardial
(phospho)proteomics and pericardial fluid proteomics approach was followed,
taking advantage of human biopsies and pericardial fluid collected during
surgery and whose origin anticipated a wealth of molecular information
contained therein.
From over 1800 and 750 proteins identified, respectively, in the myocardium
and in the pericardial fluid of aortic stenosis patients, a total of 90 dysregulated
proteins were detected. Gene annotation and pathway enrichment analyses,
together with discriminant analysis, are compatible with a scenario of increased
pro-hypertrophic gene expression and protein synthesis, defective ubiquitinproteasome system activity, proclivity to cell death (potentially fed by
complement activity and other extrinsic factors, such as death receptor
activators), acute-phase response, immune system activation and fibrosis.
Specific validation of some targets through immunoblot techniques and
correlation with clinical data pointed to complement C3 β chain, Muscle Ring
Finger protein 1 (MuRF1) and the dual-specificity Tyr-phosphorylation
regulated kinase 1A (DYRK1A) as potential markers of an incomplete
response. In addition, kinase prediction from phosphoproteome data suggests
that the modulation of casein kinase 2, the family of IκB kinases, glycogen
synthase kinase 3 and DYRK1A may help improve the outcome of patients
undergoing valve replacement. Particularly, functional studies with DYRK1A+/-
cardiomyocytes show that this kinase may be an important target to treat
cardiac dysfunction, provided that mutant cells presented a different response
to stretch and reduced ability to develop force (active tension).
This study opens many avenues in post-aortic valve replacement reverse
remodeling research. In the future, gain-of-function and/or loss-of-function
studies with isolated cardiomyocytes or with animal models of aortic bandingdebanding will help disclose the efficacy of targeting the surrogate therapeutic
targets. Besides, clinical studies in larger cohorts will bring definitive proof of
complement C3, MuRF1 and DYRK1A prognostic value.A substituição da válvula aórtica continua a ser a opção terapêutica de
referência para doentes com estenose aórtica e visa a eliminação da
sobrecarga de pressão, desencadeando a remodelagem reversa miocárdica.
Contudo, apesar do benefício hemodinâmico imediato, nem todos os pacientes
apresentam regressão completa da hipertrofia do miocárdio, ficando com maior
risco de eventos adversos, como a insuficiência cardíaca. Atualmente, os
mecanismos biológicos subjacentes a uma remodelagem reversa incompleta
ainda não são claros. Além disso, não dispomos de ferramentas de
prognóstico definitivos nem de terapias auxiliares para melhorar a condição
dos pacientes indicados para substituição da válvula. Para ajudar a resolver
estas lacunas, uma abordagem combinada de (fosfo)proteómica e proteómica
para a caracterização, respetivamente, do miocárdio e do líquido pericárdico
foi seguida, tomando partido de biópsias e líquidos pericárdicos recolhidos em
ambiente cirúrgico.
Das mais de 1800 e 750 proteínas identificadas, respetivamente, no miocárdio
e no líquido pericárdico dos pacientes com estenose aórtica, um total de 90
proteínas desreguladas foram detetadas. As análises de anotação de genes,
de enriquecimento de vias celulares e discriminativa corroboram um cenário de
aumento da expressão de genes pro-hipertróficos e de síntese proteica, um
sistema ubiquitina-proteassoma ineficiente, uma tendência para morte celular
(potencialmente acelerada pela atividade do complemento e por outros fatores
extrínsecos que ativam death receptors), com ativação da resposta de fase
aguda e do sistema imune, assim como da fibrose.
A validação de alguns alvos específicos através de immunoblot e correlação
com dados clínicos apontou para a cadeia β do complemento C3, a Muscle
Ring Finger protein 1 (MuRF1) e a dual-specificity Tyr-phosphoylation
regulated kinase 1A (DYRK1A) como potenciais marcadores de uma resposta
incompleta. Por outro lado, a predição de cinases a partir do fosfoproteoma,
sugere que a modulação da caseína cinase 2, a família de cinases do IκB, a
glicogénio sintase cinase 3 e da DYRK1A pode ajudar a melhorar a condição
dos pacientes indicados para intervenção. Em particular, a avaliação funcional
de cardiomiócitos DYRK1A+/- mostraram que esta cinase pode ser um alvo
importante para tratar a disfunção cardíaca, uma vez que os miócitos mutantes
responderam de forma diferente ao estiramento e mostraram uma menor
capacidade para desenvolver força (tensão ativa).
Este estudo levanta várias hipóteses na investigação da remodelagem reversa.
No futuro, estudos de ganho e/ou perda de função realizados em
cardiomiócitos isolados ou em modelos animais de banding-debanding da
aorta ajudarão a testar a eficácia de modular os potenciais alvos terapêuticos
encontrados. Além disso, estudos clínicos em coortes de maior dimensão
trarão conclusões definitivas quanto ao valor de prognóstico do complemento
C3, MuRF1 e DYRK1A.Programa Doutoral em Biomedicin
A comprehensive review of the current and future role of the microbiome in pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second most common cause of cancer death in the USA by 2030, yet progress continues to lag behind that of other cancers, with only 9% of patients surviving beyond 5 years. Long-term survivorship of PDAC and improving survival has, until recently, escaped our understanding. One recent frontier in the cancer field is the microbiome. The microbiome collectively refers to the extensive community of bacteria and fungi that colonise us. It is estimated that there is one to ten prokaryotic cells for each human somatic cell, yet, the significance of this community in health and disease has, until recently, been overlooked. This review examines the role of the microbiome in PDAC and how it may alter survival outcomes. We evaluate the possibility of employing microbiomic signatures as biomarkers of PDAC. Ultimately this review analyses whether the microbiome may be amenable to targeting and consequently altering the natural history of PDAC
An investigation of the relationship between perioperative characteristics and perioperative anaesthesia on the postoperative systemic inflammatory response and clinical outcome in patients undergoing surgery for colorectal cancer
In UK, colorectal cancer (CRC) is the fourth most common cancer and the second most common cause of cancer death. Until now, surgical resection remains the cornerstone for the management of CRC in all stages, however, stress response elicit from surgery may cause different changes through multiple systems in human body including neural, endocrine, metabolic, inflammatory, and immunological changes. In addition, other perioperative factors such as volatile anaesthetic and opioids may induce the immunosuppression. There is a proportional correlation between the stress response and the magnitude of the inflammatory immune response, invasiveness, and duration of surgery. The pre-operative and post-operative status of patients are important when considering the prognosis. The systemic inflammatory response (SIR) has been recognised to correlate with tumour progression and the prognosis of CRC. An exaggerated postoperative SIR is associated with postoperative infective complications and poor survival. Several predictive markers of the SIR have been used, such as the neutrophil to lymphocyte ratio (NLR), serum C-reactive protein (CRP) level, and Glasgow prognostic score (GPS). Some evidence reported that general anaesthesia (GA) combined with regional anaesthesia (RA) are better than the single use of general anaesthesia in reducing the post-operative immuno-suppression in some degrees. Furthermore, the peri-operative inflammatory process may be affected by the choice of anaesthetic technique, with propofol reported to have anti-inflammatory effect by targeting neutrophil activity. Up to now, there is insufficient evidence to recommend any specific anaesthetic or analgesic technique for patients undergoing surgery for tumour resection based on inflammatory response, recurrence, and metastasis. The work presented in this thesis further examines the relationship between the perioperative characteristics, perioperative anaesthesia, and the postoperative systemic inflammatory response following surgery for colorectal cancer. Several preoperative medications along with anaesthesia might influence the postoperative systemic inflammatory response but the question is whether the post-operative systemic inflammatory response affected by the administration of different types of anaesthesia or not following surgery for colorectal cancer. Chapter 1 discusses the epidemiology, aetiology, carcinogenesis, risk factors of colorectal cancer, pro-carcinogenic factors, anti-carcinogenic agents, inflammation and cancer, the post-operative systemic inflammatory response, tumour staging, screening, and diagnosis of colorectal cancer. Chapter 2 discusses the treatment of colorectal cancer. Chapter 3 discusses different anaesthetic techniques and agents. Chapter 4 provides summary and aims of the thesis. Chapter 5 represents findings from a systematic review and meta-analysis about the effect of anaesthesia on the postoperative systemic inflammatory response in patients undergoing surgery. The results conclude that there was some evidence that anaesthetic regimens may reduce the magnitude of the post-operative SIR. However, the studies identified in this systematic review were heterogeneous and generally of low quality. Chapter 6 represents a retrospective cohort study about the relationship between anaesthetic technique, clinicopathological characteristics and the magnitude of the postoperative systemic inflammatory response in patients undergoing elective surgery for colon cancer. The results show that the type of anaesthesia varied over time and appears to influence the magnitude of the postoperative SIR on post-operative day 2 for those patients who underwent for open surgery but not laparoscopic surgery. Chapter 7 represents a prospective cohort study about the effect of anaesthesia on the magnitude of the postoperative systemic inflammatory response in patients undergoing elective surgery for colorectal cancer in the context of an enhanced recovery pathway. The results show that there was a modest but an independent association between regional anaesthesia (RA) and a lower magnitude of the postoperative SIR. Chapter 8 represents the relationship between pre-operative medications, the type of anaesthesia and post-operative sequelae in patients undergoing surgery for colorectal cancer. The results show that there was no association between the preoperative administration of aspirin, statins and ACE inhibitors and anaesthesia. Chapter 9 represents the relationship between nutritional status, anaesthetic approach, and peri-operative characteristics of patients undergoing surgery for colorectal cancer. The results show that there was no significant association between measures of nutritional status and anaesthetic approach. Chapter 10 represents the relationship between opioid administration, type of anaesthesia and clinicopathological characteristics in patients undergoing surgery for colorectal cancer. The results show that opioid administration was independently associated with both anaesthetic and operative factors. Chapter 11 represents the main findings of the thesis and some recommendation for a future work
- …