Research misconduct can arise In any area of research and can discredit the findings. Research misconduct at any level is unacceptable, especially in a clinical trial. Because the results from clinical trials are used to decide whether or not treatments are effective, and affect decisions that may influence treatment choices for large numbers of patients, the prevention and detection of scientific misconduct in clinical trials is particularly important. Chapter 1 outlines some definitions of research misconduct, discusses the underlying motivations behind it, and the overall prevalence of research misconduct beyond that occurring in clinical trials. Different ways to detect and prevent research misconduct are also presented. In addition, an initial insight into the types of scientific misconduct that have been reported as occurring in clinical trials, based on a search of the PubMed database between January 2000 and July 2003 is provided. Thirty-eight published reports were found, but they provide no indication of the relative importance of different types of scientific misconduct in clinical trials. Chapter 2 presents a three-round Delphi survey aimed at achieving consensus among experts in clinical trials on what types of scientific misconduct are most likely to occur, and are most likely to influence the results of a clinical trial. This study identified thirteen forms of scientific misconduct for which there was consensus (>50%) that they would be likely or very likely to distort the results and consensus (>50%) that they would be likely or very likely to occur. Of these, the over-interpretation of 'significant' findings in small trials, selective reporting and inappropriate sub-group analyses were the main themes. To prevent such types of misconduct in clinical trials, the issue of selective reporting of outcomes or sub-group analyses and the opportunistic use of the play of chance (inappropriate sub-group analyses) should be addressed. Full details of the primary and secondary outcomes and sub-group analyses need to be specified clearly in protocols. Any sub-group analyses reported without pre-specification in the protocol would need supporting evidence within the publication for them to be justified. Chapter 3 explores selective reporting and inappropriate sub-group analyses within a cohort of randomised trial protocols approved by the Lancet. It determines the prevalence of selective reporting of primary and secondary outcomes and sub-group analyses in published reports of randomised trials. It also examines how sub-group analyses are described in protocols and how sub-group analyses are reported, and whether they match those specified in the protocol. Of 56 accepted protocols, four non-randomized trials were excluded. For the remaining 52, permission to review them was obtained for 48 (92%). Of those 48 trials, 30 (63%) trials were published. This study identifies some shortcomings in the reporting of the results of primary and secondary outcomes and sub-group analyses. It shows at least one unreported primary, secondary or sub-group analysis in 37%, 87%, and 50% of the trials, respectively. It also shows that the pre-specification and reporting of sub-group analyses are often incomplete and inaccurate. The majority of protocols gave hardly any detail on this matter. There was notable deviation from the protocols in reports in several of the trials. Data fabrication and falsification were judged by the experts in the Delphi survey to be unlikely to occur. However, they can have major effects on the outcomes of clinical trials if it they do occur. A systematic review was conducted in chapter 4, to identify the available statistical techniques that could be used for the detection of data fabrication and falsification. Chapter 5 examines the ability of these statistical techniques to detect data fabrication in data from two randomised controlled trials. In one trial, the possibility of fabricated data had been raised by British Medical Journal (BM) referees and the data were considered likely to contain fraudulent elements. For comparison, a second trial, about which there were no such concerns, was analysed using the same techniques, and no hint appeared of any unusual or unexpected features was shown. Finally, chapter 6 contains some concluding remarks, a discussion of the strengths and weaknesses of this research and suggestions for future research.

No description available.

Sepsis, a state of deregulated systemic inflammation following an infectious insult, can lead to multi-organ failure. This is the commonest cause of death in the critically ill yet the pathophysiology remains uncertain. Mitochondrial ultrastructural and functional abnormalities are associated with sepsis-induced organ dysfunction. Though cause-and-effect was not yet definitively established, bioenergetic failure appears a plausible factor in the causation of organ failure. Mitochondria are not only involved in energy provision but also intracellular calcium regulation. These aspects may be highly relevant in impaired myocardial function, which is clinically identifiable in 40-50% of septic shock patients and linked with a poor prognosis. In an awake, fluid-resuscitated, clinically relevant rodent faecal peritonitis model, septic cardiomyopathy was characterized in vivo by depressed contractility and cardiac output. In non-survivors echocardiography-derived kinetic energy, an in vivo measure of work, failed to increase in response to inotropes, suggesting failure to sustain adequate levels of energy demand. Hearts isolated from septic animals prognosticated to die based on a 24-hour echocardiography (severe sepsis) presented decreased efficiency, despite preserved basal MvO2. Cardiomyocytes isolated from septic animals showed similar maximal respiration and bioenergetic reserve capacity to controls, suggesting absence of major disturbances in the respiratory chain. On the other hand, in mild sepsis, increased NADH oxidation and tighter coupling between substrate oxidation and ATP synthesis, could support increased contractile efficiency. In summary, these studies demonstrate that, in my fluid resuscitated sepsis model, cardiac mitochondria are not able to adequately respond to high-energy demand. Decreased phosphorylation capacity or disturbances in the supply-demand relationship may be involved. The reversibility of the myocardial depression seen ex vivo suggests the possibility of a circulating myocardial depressant factor(s). Finally, my observations highlight the importance of studying mitochondria with dynamic challenges within physiological boundaries in models that preserve cellular integrity and the cellular milieu.

Myelin in the CNS is produced by oligodendrocytes (OLs), which are themselves produced by oligodendrocyte precursors (OLPs). OLPs are generated during embryonic development and continue to proliferate and give rise to new OLs throughout life. OLPs express a number of ion channels and neurotransmitter receptors, and receive synaptic input from neurons. The role of this synaptic communication has remained elusive. In this Thesis I investigated the developmental role of electrical communication between neurons and OLPs. I examined the expression of glutamate receptors of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic) subclass in cells of the OL lineage. This revealed that OLPs are likely to express three of the four AMPA receptor subunits (GluA2-4). I started to investigate the function of these subunits by generating GluA2/GluA3 single and double knockout mice. This resulted in reduced glutamatergic synaptic signalling to OLPs. The decrease in synaptic input was accompanied by a decrease in the number of OLPs and mature OLs. Thus, glutamatergic synaptic input to OLPs promotes their development. To investigate this question further in the future, I have generated new transgenic mouse lines that should allow manipulation of electrical communication specifically between neurons and OLPs in vivo.

Background: Missing treatment effect estimates for particular outcomes in a study have the potential to affect the conclusions in a meta-analysis (MA), especially if missingness is a result of outcome reporting bias (ORB). ORB comes from the results-based selection for publication of a subset of the original measured outcome variables and can result in overestimating treatment effects, resulting in bias. As well as missing treatment effect estimates at the study level, outcome data may also be missing within studies at the individual participant level. Multivariate meta-analysis (MVMA) of individual participant data (IPD) has the potential to overcome the impact of both these problems, by utilising the correlation between outcomes. Methods: An assessment of ORB was carried out in a cohort of systematic reviews (SR) with a core set of outcomes investigating pharmacological treatments for rheumatoid arthritis (RA). Novel IPD- MVMA methods to borrow strength across correlated outcomes were applied and evaluated through simulation, with the aim to show and quantify how this approach can reduce bias and improve precision of MA results, compared to traditional univariate methods, when there is missing outcome data as a result of both ORB and missing participant data. ORB assessments and the MVMA methods were applied to examples in RA. Results: Of the 167 assessable trials from 21 Cochrane RA reviews, 23% contained high suspicion of ORB in at least one of the core outcomes. Results from the simulations showed that the ‘borrowing of strength’ (BoS) in a multivariate model can reduce the magnitude of bias and increase precision in the pooled estimates. Results showed that when an ORB mechanism is introduced or there was missing IPD, MVMA tends to reduce the bias, increase the precision and improve the coverage when compared to a univariate analysis. In some instances, these benefits observed were also found in applying MVMA to the RA reviews. Conclusions: MVMA is not the solution to all missing data related problems within review meta- analyses, but, informed by this thesis, it can unquestionably be seen as a route to address missing outcome data in SRs. The BoS, reduction in bias and increase in precision can all be seen as promising.

The Declaration of Helsinki (DoH) is a set of normative ethical guidelines developed by the World Medical Association (WMA) for doctors participating in medical research. Arguably the best known and most authoritative of such ethical guidelines, the DoH has roots in the Nuremberg Code (1947). First adopted in 1964, the DoH, by 2000, had been revised 5 times. The 5th (Edinburgh, 2000) revision gave rise to great controversy evidenced by the unprecedented step of the WMA issuing Notes of Clarification to the 2 most controversial paragraphs. This thesis considers in detail the text of the 5th (Edinburgh, 2000) revision. Beginning with a review of the historical evolution of the text, there follows description of the controversial issues, discussion of why controversy ensued and what may be the future of the text. Then a detailed paragraph-by-paragraph analysis details exactly what changed in the text and identifies the most significant changes. Seven major areas of change to the text were identified: use of placebos in research, postresearch duty of care to individual participants, duties to ensure reasonable likelihood of benefit to communities involved in research, ethical issues related to publication, the addition of observational research to the scope of the document, the DoH's enhanced statement of its own authority, an enhanced duty to conduct research as well as an 8th major change, a logical re-structuring of the document removing the category of "Non-Therapeutic Research". Based on observation of WMA meetings and archival research a "behind the scenes" analysis is undertaken - asking how the most controversial paragraphs came to take their form in the 5th revision and considering what lessons may be learned from the drafting process itself. Further, the DoH exists in three official languages (English, French and Spanish) and important differences were discovered. There follows a comparison of the three official language versions - investigating concerns as to how differences may lead to uneven application of the DoH but also asking how the differences may help in understanding the controversial paragraphs. This detailed analysis of the text of the 5th revision leads to the central thesis question: "Is the DoH providing adequate guidance as a set of normative ethical standards across the broad spectrum of those involved in the global medical research endeavour as evidenced by reasonable coherence of their interpretations of the DoH?" Or, on the other hand, are the interpretations so diverse that the DoH cannot be considered a source of clear guidance. Or, put another way and incorporating the symbolism inherent in the title of this thesis: "Does the DoH function adequately to map the 'landscape of medical research'"? Semi-structured interviews were constructed based on the 8 major changes identified above and 57 experts drawn from 3 major categories: the "Authors" (15 people involved in the drafting process); the "Medical Researchers" (21 interviewees directly involved in conduct or application of medical research) and the "Expert Commentators" (21 with expertise in other aspects of drafting documents such as the DoH but not directly involved in either of the above) were interviewed. The interpretation process as illustrated in the transcript of the interviews is analysed with a view to determining whether the 5th revision has been effective in achieving a workable agreement among interpretations. Analysis of the results showed the DoH to be variously successful in depicting the landscape of medical research between and amongthe above three groups of interviewees. During the course of this study a further revision of the DoH took place in 2008 and the WMA invited a submission from this author as part of the consultation process. This response is presented and some discussion of the possible influence of this ensues. Finally the summary and conclusions ask what has changed in the 2008 text in the critical parts of the DoH identified above before summing up and considering possible future trajectories for this globally important document addressing the ethical conduct of medical research.

Advances in technology have now made it possible to monitor heart rate, body temperature and sleep patterns; continuously track movement; record brain activity; and sequence DNA in the jungle --- all using devices that fit in the palm of a hand. These and other recent developments have sparked interest in privacy-preserving methods: computational approaches which are able to utilise the data without leaking subjects' personal information. Classical encryption techniques have been used very successfully to protect data in transit and in storage. However, the process of encrypting data also renders it unusable in computation. Recently developed fully homomorphic encryption (FHE) techniques improve on this substantially. Unlike classical methods, which require the data to be decrypted prior to computation, homomorphic methods allow data to be simultaneously stored or transfered securely, and used in computation. However, FHE imposes serious constraints on computation, both arithmetic (e.g., no divisions can be performed) and computational (e.g., multiplications become much slower), rendering traditional statistical algorithms inadequate. In this thesis we develop statistical and machine learning methods for outsourced, privacy-preserving analysis of sensitive information under FHE. Specifically, we tackle two problems: (i) classification, using a semiparametric approach based on the naive Bayes assumption and modeling the class decision boundary directly using an approximation to univariate logistic regression; (ii) regression, using two approaches; an accelerated method for least squares estimation based on gradient descent, and a cooperative framework for Bayesian regression based on recursive Bayesian updating in a multi-party setting. Taking into account the constraints imposed by FHE, we analyse the potential of different algorithmic approaches to provide tractable solutions to these problems and give details on several computational costs and performance trade-offs.

Single neurons form the fundamental information processing units of the brain. Yet despite our growing knowledge of the electrophysiological and molecular properties of single neurons and their dendrites, little is known about their contribution to information processing in vivo, which depends strongly on the patterns of synaptic input and the way in which they engage active dendritic mechanisms. Here, I address the input-output function of single neurons in vivo and the role played by active dendrites in pyramidal neurons of mouse primary visual cortex using a dual modelling and experimental approach. First, I developed and tested new experimental techniques to map functional synaptic input in vivo: I have established an ultrastructural method to label active synapses received by the dendrites of an identified neuron during sensory processing in vivo, while measuring its output with somatic whole-cell recording. I show how to use the styryl dye FM1-43FX as an activity-dependent in vivo label which can be read out using focused ion-beam electron microscopy (FIBSEM) and I developed a pipeline for the semi-automated segmentation of the resulting FIBSEM volumes. Second, to study dendritic computation and the role of dendritic spikes in vivo, I have constructed a detailed biophysical model of a layer 2/3 pyramidal neuron, and a model of the synaptic input it receives during visual stimulation in vivo. Both models are tightly constrained by experimental data from the literature, including direct patch-clamp recordings from layer 2/3 dendrites in vivo. My work answers longstanding questions about the synaptic input patterns received by single neurons in vivo and the computations implemented by their integration in active dendrites: I provide a detailed biophysical mechanism for the transformation of synaptic inputs, via dendritic nonlinearities, to somatic output and elucidate the role of active dendrites for the function of the neuron.

This thesis uses transgenic approaches to alter expression of candidate mechanosensors in physiological and pathological conditions to determine their contribution to the sensations of touch and pain. Transient receptor potential (TRP) ion channels have highly conserved roles in sensory function and a great deal of evidence implicates them in the process of mechanotransduction. Their propensity to form heteromeric complexes as well as the functional redundancy they exhibit makes them difficult to study. We used animals with global deletion of multiple canonical TRP (TRPC) channels to minimise the effects of these features and found that TRPC1, TRPC3, TRPC5 and TRPC6 have a modality specific and combinatorial role in innocuous mechanosensation. Next, we looked at the role of TRPC channels and TRPA1 and TRPV1 in mechanical hypersensitivity in the monosodium-iodoacetate (MIA) model of Osteoarthritis (OA). The results show TRPC3, TRPC6 and TRPV1 do not contribute to mechanical hypersensitivity in OA. However, TRPA1 appears to be necessary for the full manifestation of OA induced mechanical hypersensitivity. We also investigated the role of Annexin A6 in mechanosensation and OA. The Annexin A6 protein binds to NMB-1, a blocker of mechanically activated currents. We found that it negatively regulates mechanosensation and that by overexpressing the protein using a gene therapy approach we are able to partially attenuate mechanical hypersensitivity in the MIA model of OA. Finally, we investigated the role of ASIC4 in pain and mechanosensation through generation and behavioural characterisation of a global knockout mouse. The function of ASIC4 is largely unknown but in vitro it regulates expression and function of other ASIC subunits, some of which have roles in noxious and mechanosensory processes. We found a role for ASIC4 in formalin induced pain and in visceral inflammation which is the first report of a somatosensory function for this poorly understood protein.

No description available.