A study of potential serum markers for a diagnosis of gram-positive and gram-negative bacterial sepsis

Sepsis continues to be a major cause of morbidity and mortality as it can readily lead tosevere sepsis, septic shock, multiple organ failure and death. The onset can be rapid and difficult to define clinically. Despite the numerous candidate markers proposed in the literature, to date a serum marker for sepsis has not been found. The aim of this study was to assay the serum of clinically diagnosed patients with eithera Gram-negative or Gram- positive bacterial sepsis for elevated levels of nine potentialmarkers of sepsis, using commercially produced enzyme linked immunosorbent assays(ELISA). The purpose was to find a test marker for sepsis that would be helpful toclinicians in cases of uncertain sepsis and consequently expose false positive BC'scaused by skin or environmental contaminants. Nine test markers were assayed including IL-6, IL-I 0, ILI2, TNF-α, lipopolysaccharide binding protein, procalcitonin, sE-selectin, sICAM -1 and a potential differential marker for Gram-positive sepsis- anti-lipid S antibody. A total of 445 patients were enrolled into this study from the Queen Elizabeth Hospital and Selly Oak Hospital (Birmingham). The results showed that all the markers were elevated in patients with sepsis and that patients with a Gram-negative sepsis consistently produced higher median/range serum levels than those with a Gram-positive sepsis. No single marker was able to identify all the septic patients. Combining two markers caused the sensitivities and specificities for a diagnosis of sepsis to increase to within a 90% to 100% range. By a process of elimination the markers that survived into the last phase were IL-6 with sICAM -1, and anti-lipid S IgG assays Defining cut-off levels for a diagnosis of sepsis became problematic and a semi-blind trial was devised to test the markers in the absence of both clinical details and positive blood cultures. Patients with pyrexia of unknown origin and negative BC were included in this phase (4). The results showed that IL-6 with sICAM-l are authentic markers of sepsis. There was 82% agreement between the test marker diagnosis and the clinical diagnosis for sepsis in patients with a Gram-positive BC and 78% agreement in cases of Gram-negative Be. In the PUO group the test markers identified 12 cases of sepsis and the clinical diagnosis 15. The markers were shown to differentiate between early sepsis and sepsis, inflammatory responses and infection. Anti-lipid S with IL-6 proved be a sensitive marker for Gram-positive infections/sepsis.

Developing a model for consumer product safety evaluation

Safety enforcement practitioners within Europe and marketers, designers or manufacturers of consumer products need to determine compliance with the legal test of "reasonable safety" for consumer goods, to reduce the "risks" of injury to the minimum. To enable freedom of movement of products, a method for safety appraisal is required for use as an "expert" system of hazard analysis by non-experts in safety testing of consumer goods for implementation consistently throughout Europe. Safety testing approaches and the concept of risk assessment and hazard analysis are reviewed in developing a model for appraising consumer product safety which seeks to integrate the human factors contribution of risk assessment, hazard perception, and information processing. The model develops a system of hazard identification, hazard analysis and risk assessment which can be applied to a wide range of consumer products through use of a series of systematic checklists and matrices and applies alternative numerical and graphical methods for calculating a final product safety risk assessment score. It is then applied in its pilot form by selected "volunteer" Trading Standards Departments to a sample of consumer products. A series of questionnaires is used to select participating Trading Standards Departments, to explore the contribution of potential subjective influences, to establish views regarding the usability and reliability of the model and any preferences for the risk assessment scoring system used. The outcome of the two stage hazard analysis and risk assessment process is considered to determine consistency in results of hazard analysis, final decisions regarding the safety of the sample product and to determine any correlation in the decisions made using the model and alternative scoring methods of risk assessment. The research also identifies a number of opportunities for future work, and indicates a number of areas where further work has already begun.

Mediators of gram-positive septic shock

Septic shock can occur as a result of Gram-negative or Gram-positive infection and involves a complex interaction between bacterial factors and the host immune system producing a systemic inflammatory state that may progress to multiple organ failure and death. Gram-positive bacteria are increasingly becoming more prevalent especially Staphylococcus epidermidis in association with indwelling devices. Lipopolysaccaride (LPS) is the key Gram-negative component involved in this process, but it is not clear which components of Gram-positive bacteria are responsible for progression of this often fatal disease. The aim of this thesis was to investigate the effect of bacterial components on the immune systems. Lipid S, a short chain form of lipoteichoic acid (LTA) found to be excreted from bacteria during growth in culture medium was examined along with other Gram-positive cell wall components: LTA, peptidoglycan (PG) and wall teichoic acids (WTA) and LPS from Gram-negative bacteria. Lipid S, LTA, PG and LPS but not WTA all stimulated murine macrophages and cell lines to produce significant amounts of NO, TNF-a, IL-6 and IL-1 and would induce fever and tissue damage seen in inflammatory diseases. Lipid S proved to be the most potent out of the Gram-positive samples tested. IgG antibodies in patients serum were found to bind to and cross react with lipid S and LTA. Anti-inflammatory antibiotics, platelet activating factor (PAF), PAF receptor antagonists and monoclonal antibodies (mAbs) directed to LTA, CD14 and toll-like receptors were utilised to modulate cytokine and NO production. In cell culture the anti-LTA and the anti-CD14 mAbs failed to markedly attenuate the production of NO, TNF-a, IL-6 or IL-1, the anti-TLR4 antibody did greatly inhibit the ability of LPS to stimulate cytokine production but not lipid S. The tetracyclines proved to be the most effective compounds, many were active at low concentrations and showed efficacy to inhibit both lipid S and LPS stimulated macrophages to produce NO.

Investigation of assessment methods for final year optometry undergraduates

This retrospective study was designed to investigate the factors that influence performance in examinations comprised of multiple-choice questions (MCQs), short-answer questions (SAQs), and essay questions in an undergraduate population. Final year optometry degree examination marks were analyzed for two separate cohorts. Direct comparison found that students performed better in MCQs than essays. However, forward stepwise regression analysis of module marks compared with the overall score showed that MCQs were the least influential, and the essay or SAQ mark was a more reliable predictor of overall grade. This has implications for examination design.

Developments in assessment and teaching methodologies in modern languages in England and France in response to educational reform (1975-1985)

This comparative study considers the main causative factors for change in recent years in the teaching of modern languages in England and France and seeks to contribute, in a general sense, to the understanding of change in comparable institutions. In England by 1975 the teaching of modern languages in the comprehensive schools was seen to be inappropriate to the needs of children of the whole ability-range. A combination of the external factor of the Council of Europe initiative in devising a needs-based learning approach for adult learners, and the internal factor of teacher-based initiatives in developing a graded-objectives learning approach for the less-able, has reversed this situation to some extent. The study examines and evaluates this reversal, and, in addition, assesses teachers' attitudes towards, and understanding of, the changes involved. In France the imposition of `la reforme Haby' in 1977 and the creation of `le college unique' were the main external factors for change. The subsequent failure of the reform and the socialist government's support of decentralisation policies returning the initiative for renewal to schools are examined and evaluated, as are the internal factors for changes in language-teaching - `groupes de niveau' and the creation of `equipes pedagogiques'. In both countries changes in the function of examinations at 15/16 plus are examined. The final chapter compared the changes in both education systems.

The development and operation of the effective interpersonal relationship skills relevant to career development problems from staff assessment at an industrial research laboratory

This study concerns the application of a model of effective interpersonal relationships to problems arising from staff assessment at I.C.I. Ltd. Corporate Laboratory between 1972 and 1974. In collaboration with academic and industrial supervision, the study commenced with a survey of management and supervisor opinions about the effectiveness of current staff (work) relationships, with particular reference to the problem of recognising and developing creative potential. This survey emphasised a need to improve the relationships between staff in the staff assessment context. A survey of research into creativity emphasised the importance of the interpersonal environment for obtaining creative behaviour in an organisation context. A further survey of theories of how inter­personal behaviour related to personal creativity (therapeutic psychology) provided a model of effective interpersonal behaviour (Carkhuff, 1969) that could be applied to the organisation context of staff assessment. The objective of the project was redefined as a need to improve the conditions of interpersonal behaviour in relation to certain (career development) problems arising from staff assessment practices. In order to demonstrate the application of the model of effective interpersonal behaviour, the research student recorded interviews between himself and members of staff designed to develop and operate the dimensions of the model. Different samples of staff were used to develop the 'facilitative' and the 'action oriented' dimensions of bahaviour, and then for the operation of a helping programme (based on vocational guidance tests). These interactions have been analysed, according to the scales of measurement in the model ana the results are presented in case study form in this thesis. At each stage of the project, results and conclusions were presented to the sponsoring organisation (e.g. industrial supervisor) in order to assess their (subjective) opinion of relevance to the organ­ isation. Finally, recommendations on further actions towards general improvement of the work relationships in the laboratory were presented in a brief report to the sponsor.

Continuous retinal vessel diameter m easurements: the future in retinal vessel assessment?

PURPOSE. To establish an alternative method, sequential and diameter response analysis (SDRA), to determine dynamic retinal vessel responses and their time course in serial stimulation compared with the established method of averaged diameter responses and standard static assessment. METHODS. SDRA focuses on individual time and diameter responses, taking into account the fluctuation in baseline diameter, providing improved insight into reaction patterns when compared with established methods as delivered by retinal vessel analyzer (RVA) software. SDRA patterns were developed with measurements from 78 healthy nonsmokers and subsequently validated in a group of 21 otherwise healthy smokers. Fundus photography and retinal vessel responses were assessed by RVA, intraocular pressure by contact tonometry, and blood pressure by sphygmomanometry. RESULTS. Compared with the RVA software method, SDRA demonstrated a marked difference in retinal vessel responses to flickering light (P 0.05). As a validation of that finding, SDRA showed a strong relation between baseline retinal vessel diameter and subsequent dilatory response in both healthy subjects and smokers (P 0.001). The RVA software was unable to detect this difference or to find a difference in retinal vessel arteriovenous ratio between smokers and nonsmokers (P 0.243). However, SDRA revealed that smokers’ vessels showed both an increased level of arterial baseline diameter fluctuation before flicker stimulation (P 0.005) and an increased stiffness of retinal arterioles (P 0.035) compared with those in nonsmokers. These differences were unrelated to intraocular pressure or systemic blood pressure. CONCLUSIONS. SDRA shows promise as a tool for the assessment of vessel physiology. Further studies are needed to explore its application in patients with vascular diseases.

A scoring system for early prognostic assessment after neonatal seizures

OBJECTIVE: The aim of this study was to devise a scoring system that could aid in predicting neurologic outcome at the onset of neonatal seizures. METHODS: A total of 106 newborns who had neonatal seizures and were consecutively admitted to the NICU of the University of Parma from January 1999 through December 2004 were prospectively followed-up, and neurologic outcome was assessed at 24 months’ postconceptional age. We conducted a retrospective analysis on this cohort to identify variables that were significantly related to adverse outcome and to develop a scoring system that could provide early prognostic indications. RESULTS: A total of 70 (66%) of 106 infants had an adverse neurologic outcome. Six variables were identified as the most important independent risk factors for adverse outcome and were used to construct a scoring system: birth weight, Apgar score at 1 minute, neurologic examination at seizure onset, cerebral ultrasound, efficacy of anticonvulsant therapy, and presence of neonatal status epilepticus. Each variable was scored from 0 to 3 to represent the range from “normal” to “severely abnormal.” A total composite score was computed by addition of the raw scores of the 6 variables. This score ranged from 0 to 12. A cutoff score of =4 provided the greatest sensitivity and specificity. CONCLUSIONS: This scoring system may offer an easy, rapid, and reliable prognostic indicator of neurologic outcome after the onset of neonatal seizures. A final assessment of the validity of this score in routine clinical practice will require independent validation in other centers.

Assessment of different formulations of oral Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccine in rodent models for immunogenicity and protection against aerosol challenge with M-bovis

Bovine tuberculosis (bTB) caused by infection with Mycobacterium bovis is causing considerable economic loss to farmers and Government in the United Kingdom as its incidence is increasing. Efforts to control bTB in the UK are hampered by the infection in Eurasian badgers (Metes metes) that represent a wildlife reservoir and source of recurrent M. bovis exposure to cattle. Vaccination of badgers with the human TB vaccine, M. bovis Bacille Calmette-Guerin (BCG), in oral bait represents a possible disease control tool and holds the best prospect for reaching badger populations over a wide geographical area. Using mouse and guinea pig models, we evaluated the immunogenicity and protective efficacy, respectively, of candidate badger oral vaccines based on formulation of BCG in lipid matrix, alginate beads, or a novel microcapsular hybrid of both lipid and alginate. Two different oral doses of BCG were evaluated in each formulation for their protective efficacy in guinea pigs, while a single dose was evaluated in mice. In mice, significant immune responses (based on lymphocyte proliferation and expression of IFN-gamma) were only seen with the lipid matrix and the lipid in alginate microcapsular formulation, corresponding to the isolation of viable BCG from alimentary tract lymph nodes. In guinea pigs, only BCG formulated in lipid matrix conferred protection to the spleen and lungs following aerosol route challenge with M. bovis. Protection was seen with delivery doses in the range 10(6)-10(7) CFU, although this was more consistent in the spleen at the higher dose. No protection in terms of organ CFU was seen with BCG administered in alginate beads or in lipid in alginate microcapsules, although 10(7) in the latter formulation conferred protection in terms of increasing body weight after challenge and a smaller lung to body weight ratio at necropsy. These results highlight the potential for lipid, rather than alginate, -based vaccine formulations as suitable delivery vehicles for an oral BCG vaccine in badgers.

Assessment of national health systems performance in the WHO African region

There is growing peer and donor pressure on African countries to utilize available resources more efficiently in a bid to support the ongoing efforts to expand coverage of health interventions with a view to achieving the health-related Millennium Development Goals. The purpose of this study was to estimate the technical and scale efficiency of national health systems in African continent. Methods The study applied the Data Envelopment Analysis approach to estimate the technical efficiency and scale efficiency among the 53 countries of the African Continent. Results Out of the 38 low-income African countries, 12 countries national health systems manifested a constant returns to scale technical efficiency (CRSTE) score of 100%; 15 countries had a VRSTE score of 100%; and 12 countries had a SE score of one. The average variable returns to scale technical efficiency (VRSTE) score was 95% and the mean scale efficiency (SE) score was 59%; meaning that while on average the degree of inefficiency was only 5%, the magnitude of scale inefficiency was 41%. Of the 15 middle-income countries, 5 countries, 9 countries and 5 countries had CRSTE, VRSTE and SE scores of 100%. Ten countries, six countries and 10 countries had CRSTE, VRSTE and SE scores of less than 100%; and thus, they were deemed inefficient. The average VRSTE (i.e. pure efficiency) score was 97.6%. The average SE score was 49.9%. Conclusion There are large unmet need for health and health-related services among countries of the African Continent. Thus, it would not be advisable for health policy-makers address NHS inefficiencies through reduction in excess human resources for health. Instead, it would be more prudent for them to leverage health promotion approaches and universal access prepaid (tax-based, insurance-based or mixtures) health financing systems to create demand for under utilised health services/interventions with a view to increasing ultimate health outputs to efficient target levels.

Medical students' personal experience of high-stakes failure:case studies using interpretative phenomenological analysis

Abstract (provisional): Background Failing a high-stakes assessment at medical school is a major event for those who go through the experience. Students who fail at medical school may be more likely to struggle in professional practice, therefore helping individuals overcome problems and respond appropriately is important. There is little understanding about what factors influence how individuals experience failure or make sense of the failing experience in remediation. The aim of this study was to investigate the complexity surrounding the failure experience from the student’s perspective using interpretative phenomenological analysis (IPA). Methods The accounts of 3 medical students who had failed final re-sit exams, were subjected to in-depth analysis using IPA methodology. IPA was used to analyse each transcript case-by-case allowing the researcher to make sense of the participant’s subjective world. The analysis process allowed the complexity surrounding the failure to be highlighted, alongside a narrative describing how students made sense of the experience. Results The circumstances surrounding students as they approached assessment and experienced failure at finals were a complex interaction between academic problems, personal problems (specifically finance and relationships), strained relationships with friends, family or faculty, and various mental health problems. Each student experienced multi-dimensional issues, each with their own individual combination of problems, but experienced remediation as a one-dimensional intervention with focus only on improving performance in written exams. What these students needed to be included was help with clinical skills, plus social and emotional support. Fear of termination of the their course was a barrier to open communication with staff. Conclusions These students’ experience of failure was complex. The experience of remediation is influenced by the way in which students make sense of failing. Generic remediation programmes may fail to meet the needs of students for whom personal, social and mental health issues are a part of the picture.

Quality planning based on risk assessment

Product quality planning is a fundamental part of quality assurance in manufacturing. It is composed of the distribution of quality aims over each phase in product development and the deployment of quality operations and resources to accomplish these aims. This paper proposes a quality planning methodology based on risk assessment and the planning tasks of product development are translated into evaluation of risk priorities. Firstly, a comprehensive model for quality planning is developed to address the deficiencies of traditional quality function deployment (QFD) based quality planning. Secondly, a novel failure knowledge base (FKB) based method is discussed. Then a mathematical method and algorithm of risk assessment is presented for target decomposition, measure selection, and sequence optimization. Finally, the proposed methodology has been implemented in a web based prototype software system, QQ-Planning, to solve the problem of quality planning regarding the distribution of quality targets and the deployment of quality resources, in such a way that the product requirements are satisfied and the enterprise resources are highly utilized. © Springer-Verlag Berlin Heidelberg 2010.