Human organs are the most valuable gifts of life. Until today, through organ transplantation, thousands of lives have been saved and many more blessed with hope and happiness through a better quality of living. However, rapid developments in transplant technology will be meaningless if supply of the needed organs remains scarce and organ transplantation procedures cannot take place accordingly. This global problem of organ shortage is also faced by Malaysia. Despite campaigns and initiatives introduced by the Malaysian authorities, the problem remains unresolved and the situation is worsening. Malaysia is reported to have less than one donor for every one thousand of the population (Lela Yasmin Mansor, 2007). However, statistics from the National Transplant Registry Malaysia confirm a steady increase in the number of registered potential donors each year. This suggests that certain factors must be preventing potential donors from becoming actual donors. Therefore, this study will not only discuss the current scenario of the organ shortage problem in Malaysia, highlighting its underlying factors, but will also scrutinise legal and social factors causing actual donations to remain relatively small, despite the promising number of potential donors registering each year. The study will suggest practical solutions to help solve organ shortages in Malaysia, particularly by utilising brain-dead patients from serious road traffic accidents as a potential source of cadaveric organs. Clarification on the Islamic perspective concerning organ donation is also included, as Islam is the main religion professed in Malaysia.

The forensic toxicologist faces challenges in the detection of drugs and poisons in biological samples due to transformations which occur both during life and after death. For example, changes can result from drug metabolism during life or from the use of formalin solution for post mortem embalming purposes. The former requires the identification of drug metabolites and the latter the identification of chemical reaction products in order to know which substances had been administered. The work described in this thesis was aimed at providing ways of tackling these challenges and was divided into two parts. Part 1 investigated the use of in vitro drug metabolism by human liver microsomes (HLM) to obtain information on drug metabolites and Part 2 investigated the chemical reactions of drugs and a carbamate pesticide with formalin solution and formalin-blood. The initial aim of part I was to develop an in vitro metabolism method using HLM, based on a literature review of previous studies of this type. MDMA was chosen as a model compound to develop the HLM method because its metabolism was known and standards of its metabolites were commercially available. In addition, a sensitive and selective method was developed for the identification and quantitation of hydrophilic phase I drug metabolites using LC/MS/MS with a conventional reverse-phase (C18) column. In order to obtain suitable retention factors for polar drug metabolites on this column, acetyl derivatives were evaluated for converting the metabolites to more lipophilic compounds and an optimal separation system was developed. Acetate derivatives were found to be stable in the HPLC mobile phase and to provide good chromatographic separation of the target analytes. In vitro metabolism of MDMA and, subsequently, of other drugs involved incubation of 4 µg drug substance in pH 7.4 buffer with an NADPH generating system (NGS) at 37oC for 90 min with addition of more NGS after 30 min. The reaction was stopped at 90 min by the addition of acetonitrile before extraction of the metabolites. Acetate derivatives of MDMA metabolites were identified by LC/MS/MS using multiple reaction monitoring (MRM). Three phase I metabolites (both major and minor metabolites) of MDMA were detected in HLM samples. 3,4-dihydroxy-methamphetamine and 4-hydroxy-3-methoxymethamphetamine were found to be major metabolites of MDMA whereas 3,4-methylenedioxyamphetamine was found to be a minor metabolite. Subsequently, ten MDMA positive urines were analysed to compare the metabolite patterns with those produced by HLM. An LC/MS method for MDMA and its metabolites in urine samples was developed and validated. The method demonstrated good linearity, accuracy and precision and insignificant matrix effects, with limits of quantitation of 0.025 µg/ml. Moreover, derivatives of MDMA and its metabolites were quantified in all 10 positive human urine samples. The urine metabolite pattern was found to be similar to that from HLM. The second aim of Part 1 was to use the HLM system to study the metabolism of some new psychoactive substances, whose misuse worldwide has necessitated the development of analytical methods for these drugs in biological specimens. Methylone and butylone were selected as representative cathinones and para-methoxyamphetamine (PMA) was chosen as a representative ring-substituted amphetamine, because of the involvement of these drugs in recent drug-related deaths, because of a relative lack of information on their metabolism, and because reference standards of their metabolites were not commercially available. An LC/MS/MS method for the analysis of methylone, butylone, PMA and their metabolites was developed. Three phase I metabolites of methylone and butylone were detected in HLM samples. Ketone reduction to β-OH metabolites and demethylenation to dihydroxy-metabolites were found to be major phase I metabolic pathways of butylone and methylone whereas N-demethylation to nor-methylone and nor-butylone were found to be minor pathways. Also, demethylation to para-hydroxyamphetamine was found to be a major phase I metabolic pathway of PMA whereas β-hydroxylation to β-OH-PMA was found to be a minor pathway. Formaldehyde is used for embalming, to reduce decomposition and preserve cadavers, especially in tropical countries such as Thailand. Drugs present in the body can be exposed to formaldehyde resulting in decreasing concentrations of the original compounds and production of new substances. The aim of part II of the study was to evaluate the in vitro reactions of formaldehyde with selected drug groups including amphetamines (amphetamine, methamphetamine and MDMA), benzodiazepines (alprazolam and diazepam), opiates (morphine, hydromorphone, codeine and hydrocodone) and with a carbamate insecticide (carbosulfan). The study would identify degradation products to serve as markers for the parent compounds when these were no longer detectable. Drugs standards were spiked in 10% formalin solution and 10% formalin blood. Water and whole blood without formalin were used for controls. Samples were analysed by LC/MS/MS at different times from the start, over periods of up to 30 days. Amphetamine, methamphetamine and MDMA were found to rapidly convert to methamphetamine, DMA and MDDMA respectively, in both formalin solution and formalin blood, confirming the Eschweiler-Clarke reaction between amine-containing compounds and formaldehyde. Alprazolam was found to be unstable whereas diazepam was found to be stable in both formalin solution and water. Both were found to hydrolyse in formalin solution and to give open-ring alprazolam and open-ring diazepam. Other alprazolam conversion products attached to paraformaldehyde were detected in both formalin solution and formalin blood. Morphine and codeine were found to be more stable than hydromorphone and hydrocodone in formalin solution. Conversion products of hydromorphone and hydrocodone attached to paraformaldehyde were tentatively identified in formalin solution. Moreover, hydrocodone and hydromorphone rapidly decreased within 24 h in formalin blood and could not be detected after 7 days. Carbosulfan was found to be unstable in formalin solution and was rapidly hydrolysed within 24 h, whereas in water it was stable up to 48 h. Carbofuran was the major degradation product, plus smaller amounts of other products, 3-ketocarbofuran and 3-hydrocarbofuran. By contrast, carbosulfan slowly hydrolysed in formalin-blood and was still detected after 15 days. It was concluded that HLM provide a useful tool for human drug metabolism studies when ethical considerations preclude their controlled administration to humans. The use of chemical derivatisation for hydrophilic compounds such as polar drug metabolites for analysis by LC/MS/MS with a conventional C18 column is effective and inexpensive, and suitable for routine use in the identification and quantitation of drugs and their metabolites. The detection of parent drugs and their metabolites or conversion and decomposition products is potentially very useful for the interpretation of cases in forensic toxicology, especially when the original compounds cannot be observed.

Drawing on the classification of expertise developed by Collins and Evans, this study explores the expertises held by members of NHS Research Ethics Committees (RECs) and how they differ from the ones described by the regulations. The study used Q methodology followed by ten semi-structured interviews with Lay and Expert REC members. The results show that committee members see themselves as part of a team, with individual members making different contributions to a collective task. Viewing REC members in this way allows their different expertises to be formally recognised and leads to the creation of two new membership categories, specialist and generalist, based on these expertises. Specialists have expertises such as statistics and pharmacy that are required by the current legislation and which would be present on recruitment. Generalists possess the other expertises needed by the committee but which not required by statute. These include the clinical expertises possessed by healthcare professionals and the other professional expertises – legal, academic, IT and so on – that are typically found amongst those currently classed as Lay members. All REC members, be they specialist or generalist, would also be trained in the ethical and regulatory expertises required to deliver an ethical review. Emphasising how all REC members, whether specialist or generalise, have expertises that contribute to the ethical review enables recruitment activities to focus on the skills needed by the committee rather than current concerns with population demographics. This provides a solution to many of the recruitment issues identified by participants. In particular, it enables the replacement of skills on a ‘like for like’ basis using clearly defined person specifications. Not only would such a process comply with the Nolan principles it be more likely to maintain the integrity and function of the committee regardless of personnel changes.

Although forensic biology is a powerful tool in criminal investigations, there are a number of capability gaps; namely, the interpretation of low-level DNA mixtures, associating the DNA profile with a body fluid, and the issue of consent in sexual offences. A research strategy was developed that utilises whole genome amplification (WGA), messenger RNA and microRNA analysis, DNA profiling, and clothing damage analysis. An evaluation of a WGA technique – multiple displacement amplification - with and without a macromolecular crowding agent, indicated that this may be of use for DNA samples containing certain mixing ratios; however, for this to be truly of use, knowledge of the nature of the sample preanalysis is required, which is not feasible in a forensic environment. A SYBR Greenbased mRNA gene expression test was developed that was capable of distinguishing between saliva and blood by using relative quantitation on real-time PCR. However, the low specificity of the SYBR Green meant that a higher number of controls were required for this to work at forensic standard. A single channel simultaneous analytical test for DNA and microRNA was also developed, which meant that it could be possible to definitively identify the body fluid origin of a DNA profile. This represented a significant step forward in improving forensic biology capability. Reconstruction studies were carried out in response to a sexual assault case where consent was an issue. This study demonstrated that it was possible to cause significant damage to a bra without causing damage to the hook and eye fastening; thus, negating a hypothesis offered by the defence. A long term research strategy has been developed and significant progress has been made in improving the capability of the operational forensic biologist.

Consent is a concept used frequently and with great significance in a wide array of legal fields. It serves to regulate relationships, legitimize authority, delimit normality, and entrench idealized ways of being in the world. Yet despite the consequence of these functions, there is very little precision within legal scholarship about just what consent is. Few investigations of its definitional content depart from presumptive statements about personal autonomy. These associations are often described as the ‘common sense’ of consent and serve to secure a foundationalist discourse about what consent is, rendering alternative conceptions of its meaning or functions unintelligible. This is perhaps best evidenced in more critical approaches to consent, where despite widespread acknowledgement of the concept as a legal and political fiction, its status as a signifier of autonomy is maintained. This creates an imperative to move beyond the notion of consent as merely an illusion, to an understanding of it as something more operative. Not only does the story of autonomy that is told about consent obscure the social realities of inequality, difference, and subordination that might threaten a notion of a homogenous citizenry (and thus, governmental action made in its name), but it also conceals the historically specific conditions of existence which have brought consent’s ‘common sense’ story of autonomy into being. This thesis explores how this dominant narrative of consent, while producing certain ‘ideal’ subjectivities, also necessarily produces subjectivities which don’t fall within the ambit of consent. Moreover, this project asks what is achieved when the meaning of consent is positioned as a matter of ‘common sense’? What does its apparent transparency keep obscure? In contrast to conventional approaches to consent, this project positions consent as an historical artefact rather than a concept with doctrinal, cognitive, or communicative certainty and seeks to investigate its operations across legal fields rather than strictly within them. This includes an examination of consent to sex, the doctrine of informed consent in medical jurisprudence, and the defence of consent to assault in professional sporting contexts. Further, the project engages in a ‘juridical genealogy’ of consent, studying its use in three vastly different historical periods in search of how it might perform different socio-political functions than understandings of its role within contemporary medical and criminal law suggest it should. How these counter-narratives of consent serve to challenge the dominant autonomy story are investigated for what they reveal about the frames of cultural and legal intelligibility at work in consent law today.

The thesis consists of two volumes. Volume 1: This volume consists of three chapters. The first chapter is a literature review examining whether there is a link between psychopathy and self-harm. The second chapter is a quantitative study investigating whether scores on the HCR-20 and FAM risk assessment tools predict frequency of self-harm in females within a secure psychiatric hospital. The third chapter comprises a public domain briefing document which provides a plain language summary of the literature review and empirical paper. Volume 2: This volume consists of five Forensic Clinical Practice Reports (FCPRs). The first details the case of a 63-year-old man with depression and paranoid schizophrenia, formulated from both cognitive and psychodynamic perspectives. The second is a service evaluation examining whether scores on the HCR-20 and HoNOS decrease over time for patients detained within a secure psychiatric hospital, and whether individuals’ scores on these measures reflect the level of security in which they reside. The third FCPR documents the case of a 34-year-old man experiencing offence-related anxiety, shame and depression. The fourth FCPR is a single-case experimental design investigating the effectiveness of a trauma-focussed cognitive-behavioural intervention for offence-related PTSD. The fifth FCPR is an abstract of an oral case presentation of a 14-year-old girl experiencing school anxiety. Pseudonyms have been used throughout to ensure anonymity.

Pharmaceuticals have benefitted countless lives. New therapies are being developed every day—many prove effective, but many do not. In order to ensure only safe and effective drugs enter the market, the United States' Food and Drug Administration (FDA) approves each treatment based on data garnered from clinical trials. Clinical trials take time, however, and investigational new drugs (INDs) can demonstrate signs of efficacy long before approval. These cases introduce a fundamental question: should the government limit patient access to a drug that has yet to be proven safe and effective? Or do patients have the right to freedom from governmental intervention in their medical decision-making? In this paper, the history of IND regulation will be explored, followed by an examination of the freedom to access from constitutional, ethical, and infrastructural perspectives. Changes to the current system will then be proposed.

The legalization of medical marijuana has been a complicated and confusing process. The drug is used for medical purposes yet is only semi-legal and not approved by the federal government. This piece will observe the legal medical history of this drug in the United States. It will analyze the growth of the medical marijuana movement up to the present with a special emphasis to the importance of federal, state and local supremacy. It will observe important court cases that have been decisive in defining the reach of federal power under the Commerce Clause and the 1970 Controlled Substance Act. This analysis will look at the current legal standing of medical marijuana as well as the legal hurdles to achieve full legal status and medical recognition from state federal and local levels of government. A special focus will be given to the state of California because it has the largest medical marijuana market and has taken center stage in the movement to legalize marijuana as a medicine. This paper will also cover the growth of the state condoned medical marijuana black market and the complications that arise from taxing, and licensing semi-legal businesses. This paper will assess the monetary and personal costs of this movement and the political elements of resisting the medical development and scientific understanding of this drug. It will seek to suggest a solution to the current impasse and explain why medical marijuana in this instance has been bad medicine and dangerous policy.

This study examines the utility of the MMPI-2 in predicting responsibility in pre-trial forensic patients, using a post hoc sample of 94 offenders from Sterkfontein Psychiatric Hospital in Gauteng. Firstly, the overall characteristics of the pre-trial forensic patients are discussed, following an analysis of demographic, clinical, criminal and MMPI-2 pre-trial data, as well as an overview of the Megargee typological classification of offenders. The sample is classified into Criminally Responsible (CR), Diminished Criminal Responsibility (DCR) and Not Criminally Responsible (NCR), and the CR and DCR groups are collapsed (CR/DCR) for many of the analyses when comparing them to the NCR group. Secondly, the variance of variables with responsibility is discussed, after examining one-way ANOVA’s of demographic, clinical, criminal and MMPI-2 variables, as well as an overview of high point pairs. Thirdly, discriminant analyses were conducted of demographic, clinical and MMPI-2 variables. When comparing the collapsed CR/DCR group to the NCR group, psychiatric diagnosis, presence of psychosis, the MMPI-2 Pa and Es scales, as well as race and substance abuse each had unique predictive power and created a substantial discriminative equation (F (6,70) = 45.732, p <0.0005) with a successful prediction rate of 96%. Using only MMPI-2 variables to predict responsibility showed significant unique contributions for the Pa, Es, MAC-R and Mf scales, with the BIZ scale not quite significant, and a fairly significant overall discriminant equation (F (5,73) = 6.474, p < 0.0005), with an overall successful prediction rate of 82%, with the MMPI-2 variables adding an additional 3% to the predictive power of the demographic and clinical variables. Similarly, when examining the more complex 3 group responsibility classification of CR, DCR and NCR, it was found that the demographic, clinical and MMPI-2 variables of psychiatric diagnosis, psychosis, race, substance abuse, and the Pa, Es and Ma scales all had significant contributions to a powerful discriminant analysis (F (14, 136) = 19.758, p < 0.0005) that was capable of correctly reclassifying almost 95% of the sample, and the MMPI-2 variables providing an increase in predictive power of 8%. Differences in responsible and not responsible pre-trial forensic patients are discussed, as well as the role of the MMPI-2 in assessing these differences, and the fact that it is highly likely that it adds more to the forensic assessment of responsibility than a 3% (CR/DCR versus NCR) or 8% (CR versus DCR versus NCR) increase in predictive power. Limitations of the study are discussed, together with recommendations for future research with the MMPI-2 for assessment of criminal responsibility. The suggestion is made that the MMPI-2 can become a valuable tool in South African forensic settings, not only in the assessment of responsibility and malingering, but also in the placement, management, follow-up and treatment of offenders, to maximize the limited resources in South Africa allocated for the rehabilitation of offenders, and minimize the risk of recidivism or rehospitalization.

Due to concerns about international differences in treatment effectiveness, many countries are reluctant to extrapolate overseas clinical data to form the basis of guideline recommendations and intervention approval processes. The evidence on which these concerns are based, however, comes from a limited dataset, with few studies directly assessing international differences in treatment effectiveness. This study aims to assess differences in the results of cardiovascular trials between Europe, North America, and Asia using the panoramic meta-analysis approach. All meta-analyses containing randomised control trials for the treatment or prevention of cardiovascular diseases were searched for in The Cochrane Library (2000 to 2008) and Medline (2005-2008). Analysis was then conducted within and over the included meta-analyses by performing pair-wise comparisons of the trial results between Europe and North America, Europe and Asia, and North America and Asia and a universal comparison of all three continents’ trial results together. All analyses were conducted over fatal and non-fatal endpoints. The findings suggested that for both endpoints, interventions performed best in Asian trials. For fatal endpoints, a high proportion of positive trial results were observed for Japan. Further investigation showed that between-continent differences in treatment effect could be explained by between-continent differences in trial quality. However, the types of intervention prone to inter-continental differences could not be identified for fatal or non-fatal endpoints. These findings suggest that those developing guidelines and approving interventions should be cautious when extrapolating overseas data. In particular, this study highlights the importance of taking trial quality into account when extrapolating and interpreting clinical trial data from different regions.