Heart failure (HF) is a debilitating chronic illness that afflicts millions of Americans and carries a poor prognosis, likely due to insufficient medication and low-salt diet adherence, which exacerbates HF symptoms and leads to frequent rehospitalizations. Specific reasons underlying non-adherence among HF patients are unclear. Studies investigating reasons for adherence among HF patients have shown that correlates of poor adherence include demographic (i.e., age, income), functional (i.e., NYHA), and psychosocial (i.e., social support, depression) variables. Research studies among individuals with chronic diseases suggest that an individual’s beliefs about medicines may explain adherence, but this research is limited among HF patients. The purpose of this study was to examine how psychosocial variables and beliefs about medicines are related to self-reported medication and low-salt diet adherence among individuals with HF, while controlling for demographic and physical functioning variables. This study had three aims: 1) To examine the relationships between psychosocial variables (e.g., depression, hostility, social support) and adherence; 2) To examine the relationship between beliefs about medicines and adherence; and 3) To investigate whether beliefs about medicines moderate the relationship between psychosocial variables and adherence. An ethnically-diverse sample of 105 HF patients completed several measures assessing depressive symptoms, level of hostility, perceived social support, beliefs about medicines, and medication and low-salt diet adherence. Structural equation modeling revealed that higher depression, higher hostility, and a stronger belief that medications are harmful and/or overused by doctors were significantly related to worse medication adherence. Further, participants who believed that medicines are necessary and had few concerns about them were more likely to adhere to a low-salt diet. Age, income, and number of co-morbid illness also were significantly related to low-salt diet adherence beyond contributions of beliefs about medicines scales and psychosocial variables. Thus, overall it appears that different beliefs about medicines differentially influence medication versus low-salt diet adherence, and psychological disposition may not underlie low-salt diet adherence. These results can inform interventions of health care practitioners in addressing adherence issues with HF patients.

In the past several years, the impact of intellectual property rights (IPRs) on access to medicines and medical technologies has come under increased scrutiny. Motivating this are highly publicized cases where IPRs appear the threaten access to particular medicines and diagnostics. As IPRs become globalized, so does the controversy: In 1998, nearly forty pharmaceutical companies filed a lawsuit against South Africa, citing (among other issues) deprivation of intellectual property. This followed South Africa’s implementation of various measures to enable and encourage the use of generic medicines – a move that was particularly controversial for the newly available (and still patented) HIV medicines. While many historical, legal, economic, and policy analyses of these cases and issues exist, few explicitly normative projects have been undertaken. This thesis utilizes interdisciplinary and explicitly normative philosophical methods to fill this normative void, engaging theoretical work on intellectual property and global distributive justice with each other, and with empirical work on IPR reform. In doing so, it explicitly rejects three mistaken assumptions about the debate over IPRs and access to essential medicines: (i) that this debate reduces to a disagreement about empirical facts; (ii) that intellectual property is normatively justified solely by its ability to “maximize innovation”; and (iii) that this controversy reduces to irresolvable disagreement about global distributive justice. Calling upon the best contemporary approaches to human rights, it argues that these approaches lend normative weight in favor of reforming IPRs – both that they should be reformed, and how – to better enable access to essential medicines. Such reforms might include modifying the present global IPR regime or creating new alternatives to the exclusivity of IPRs, both of which are considered in light of a human right to access to essential medicines. Future work will be needed, however, to better specify the content of a right to “essential medicines” and determine a fair distribution of the costs of fulfilling it. / Dissertation

No description available.

This thesis consists of three main parts. An introduction to diode-pumped solid-state lasers, thermal modelling of solid-state lasers and rate-equation modelling of solid-state lasers. The first part explains the basic components and operation principles of a typical diode-end-pumped solid-state laser. The stimulated emission process, solid-state laser gain media, various pump geometries and a basic end-pumped laser resonator configuration are among the topics that are explained. Since thermal effects are one of the main limiting factors in the power-scaling of diode-pumped solid-state lasers, the second part of this thesis describes numerical and analytical thermal models that determine the thermal lens and thermally induced stresses in a laser crystal. As a first step, a time-independent numerical thermal model which calculates the three-dimensional temperature distribution in the laser crystal is implemented. In order to calculate the time dependent thermally induced stresses in a laser crystal, a coupled thermal-stress finite element analysis model was implemented. Even though some steady-state analytical solutions for simple crystal geometries do exist, the finite element analysis approach was taken so that the time dependent thermally induced stresses could be calculated for birefringent crystals of various geometries. In order to validate the numerical results, they are compared to experimental data and analytical solutions where possible. In the last part, the population dynamics inside the laser gain medium are described and modelled with a quasi-three-level rate-equation model. A comprehensive spatially resolved rate-equation model is developed and discussed. In order to simplify the implementation of the rate-equation model as a computer simulation, the spatial dependence of the laser parameters is ignored so that the model reduces to a singleelement plane-wave model. The simplified rate-equation model is implemented and solved numerically. The model is applied to a four-level CW and Q-switched Nd:YLF laser as well as a quasi-three-level QCW Tm:GdV04 laser. The models' predictions are thoroughly verified with experimental results and also with analytical solutions where possible. / Thesis (M.Med.Sc.)-University of KwaZulu-Natal, Durban, 2007.

In 2000, Jordan signed the Agreement on Trade-related Aspects of Intellectual Property Rights (the TRIPS Agreement) and a free trade agreement with the US (USJFTA). Both commitments have required Jordan to comply with various obligations, including full compliance with the minimum standards for the protection of intellectual property rights (IPRs) under the TRIPS Agreement and TRIPS-Plus IP standards set out under the terms of the USJFTA. Enticed by views that strong IP protection would create prosperity in the Kingdom by promoting technological innovation and inducing transfer and dissemination of technology to Jordanians, Jordan implemented the provisions of TRIPS and the USJFTA to the letter. However, Jordan focused little attention on important “TRIPS flexibilities”. In particular, Jordan has qualified parallel importation and limited the grounds of compulsory licenses. In addition, Jordan provides pharmaceutical testing data with data exclusivity. This thesis focuses on the Jordanian experience in the pharmaceutical sector. It argues that strong patent protection has not been conducive to the promotion of technological innovation and the transfer and dissemination of technology. Moreover, this protection has resulted in adverse outcomes such as increased drug prices, unavailability of essential medicines in some public hospitals for serious diseases, and a dwindling local pharmaceutical industry, in part, as a consequence of its inability to access advanced, patented technology on reasonable commercial terms. The thesis also investigates the legitimacy of establishing certain grounds of compulsory licensing by Jordan, even in light of the TRIPS-Plus obligations under the USJFTA. It advocates that such grounds contribute to the promotion of technical innovation, lead to the transfer of advanced technology, and above all improve access to affordable medicines. Finally, the thesis explores Jordan’s obligations to protect pharmaceutical testing data under TRIPS and USFTA arguing that neither of these two instruments requires data exclusivity as claimed by Pharmaceutical Research and Manufacturers of America (PhRMA) and some developed countries.

Theophylline is one of the few preparations available for the treatment of apnoea of prematurity. Currently little data is available on the pharmacokinetics and the pharmacokinetic/pharmacodynamic relationships of theophylline for premature neonates during the first few days of life, a time when neonates undergo profound physiological changes and when the drug is most often used. Furthermore, the influence of theophylline on hypoxaemic episodes has not yet been quantified. The study aimed to investigate optimal theophylline dosing in this group by establishing pharmacokinetic parameters, assessing the effectiveness of the drug in abolishing apnoea and hypoxaemic episodes and investigating the concentration/effect relationship. The project was conducted in the neonatal wards of King Edward VIII Hospital, Durban, South Africa. The study group comprised a total of 105 Black, apnoeic, premature neonates, with respiratory distress syndrome, who were receiving intravenous theophylline. Serum samples (263), collected from patients during routine care, were analysed for theophylline. Forty-six patients were monitored before and after theophylline therapy with a neonatal capnograph linked to a data acquisition. Apnoea incidents were classified into total (all apnoea <_5 seconds) and pathologic (all apnoea >_20 seconds) and a hypoxaemic episode was defined as a >_10% fall for >10 seconds in peripheral oxygen saturation. Within each of these groups patients were assessed as responders (>_50% reduction in the clinical effect from baseline to the last recording) and non-responders. Patient characteristics were identified as possible markers of non-response to theophylline therapy. The Nonlinear Mixed Effects Model (NONMEM) was used to derive population pharmacokinetic models and parameters for theophylline as well as to assess the concentration-effect relationship. The pharmacokinetic analysis estimated a low clearance and volume of distribution, with oxygen support enhancing clearance. Relatively high inter-individual and residual variability values were obtained prompting testing for inter-occasion variability. This resulted in a decrease of inter-individual variability for clearance and volume of distribution as well as in residual variability. In the theophylline doses used, a significant reduction in total and pathologic apnoea but not in hypoxaemic episodes occurred over the first three days after birth. The most positive improvement was seen on the first day of treatment after the loading dose. A statistically significant increase in the average pulse rate and a decrease in episodes of bradycardia from baseline to all three days of monitoring were recorded. Most patients responded at serum theophylline concentrations of 3 to 9 mg/L. Most serum theophylline concentration measurements were also in this range and it was not possible to clearly define a concentration-effect relationship. The cumulative percentage of non-responders was relatively high for total apnoea (48%) and hypoxaemic episodes (45%), but low for pathological apnoea (13%). Being one of a set of twins was identified as a marker of poor response for both total apnoea and hypoxaemic episodes. Other possible markers for poor response, in terms of total hypoxaemic episodes, were being born by caesarean section and having more than the 75th percentile pathologic apnoea per hour at baseline. It was interesting to note that, with regard to total apnoea, there were some features that seemed to predict a favourable response to theophylline. These were birth weight and 5 minute Apgar score below the 25th percentile, and patients with baseline total apnoea counts above the 75th percentile. The cumulative graphs of the responders and non-responders resembled the fixed effect model, which is the simplest model to explain drug-effect relationships. More sophisticated analysis of the concentration-effect relationship, using NONMEM and the count model proved difficult. None of the models tested were found to be satisfactory, but that which included the influence of a hypothetical respiratory depressant factor gave the most realistic value of EC50. It is suggested that further even more complex modelling may be required to accurately define the concentration-effect relationship (and hence the therapeutic range) for theophylline in neonatal apnoea. / Thesis (Ph.D.)-University of Natal, Durban, 2000.

Introduction: Plasma kallikrein (PK) is a cofactor in blood coagulation and modulates inflammation through the release of bradykinin (BK). Previously it was believed that plasma prekallikrein (PPK), the precursor of PK and a member of the serine protease superfamily, was synthesised exclusively by hepatocytes and secreted into circulation. However, recent studies show that various human tissues contain PPK mRNA. In this study we sought to determine in which human tissues PK is expressed. Methods: Following approval by the Ethics Committee at the University of Natal, tissue samples from the spinal cord, 13 different regions of the brain, 7 different blood vessels and various other organs were collected at autopsy within 24h of death (n =10). Sections were probed using polyclonal antibodies specific for PK. PK concentrations in extracts of these tissues were measured by competitive EllSA. Results: A Western blot analysis demonstrated the monospecificity of the antibody for the PK protein. The presence of immunoreactive PK in cells of the pancreatic islets of Langerhans served as a positive control for each immunolabeling experiment. The hepatocytes, renal distal convoluted tubules and epithelial cells lining the bronchiole and pulmonary alveoli labeled positively for PK. In the gastrointestinal tract tissue, immunoreactive PK was visualised in the acinar cells of the salivary gland, in stromal and glandular duct cells of the oesophagus, and in some chief and glandular cells in the stomach. Some of the above-mentioned tissues contained a few inflammatory cells which stained intensely for PK. Immunoreactive PK was visualised in the endothelial cells and smooth muscle cells of the all the blood vessels examined, except the renal vein. Increased immunolabeling for PK in the endothelial cells, foam cells and macrophages was observed in arteries with atheromatous plaques. In neural tissue immunoreactive PK was observed in neurons, ependymal cells, fibre tracts, and in secretory cells of the anterior pituitary gland. Immunolabeling for PK was visualised in some neurons of the spinal cord and in different brain regions viz. hypothalamus, cerebral cortex, thalamus, brain stem and hippocampus. In sections of the hypothalamus and spinal cord, we observed immunolabeling for PK in ependymal cells lining the third ventricle and central canal respectively. Positive labeling for PK was evident in fibre tracts of the pons, medulla and hippocampus. No immunoreactive PK was visualised in the choroid plexus or cerebellum. High amounts of PK were measured by competitive ELlSA in extracts of the pancreas (12.94 ± 2.04 /-lg/ml), the pons (1.67 ± 1.46 /-lg/ml) and aorta (0.44 ± 0.14 /-lg/ml). The basilar artery (0.09 ± 0.07 /-lg/ml) and spinal cord (0.09 ± 0.04 /-lg/ml) had the least PK concentrations. Discussion and Conclusions: We have shown that the PPK mRNA demonstrated in various human tissues is most likely translated into protein by the immunolocalisation of PK within specific cells in the different tissues examined. The actions of PK within these tissues may be two fold, firstly by its kininogenase activity it may release BK from high molecular weight kininogen, or alternatively, PK may act as a proteolytic enzyme on other proteins. With respect to the latter) PK may be involved in the processing of protein precursors, for example precursors of the digestive enzymes found in saliva and in gastric secretion, insulin precursors in the pancreas, and hormonal precursors in the pituitary gland. The localisation of PK and B1 and B2 kinin receptors in the kidney, lung, stomach, blood vessels and brain suggests that the effects of PK in these tissues are mediated by BK-receptor interaction. These may include the regulation of glucose uptake in the pancreas, water and ion transport in the kidney, and local and systemic blood pressure in the cardiovascular system. The presence of immunoreactive PK in neurons suggests that BK-receptor mediated interaction may regulate neurophysiological processes such as synaptic transmission. Immunolabeling for PK in polymorphonuclear leukocytes observed in some of these tissue sections suggests the potential to mediate the inflammatory process. / Thesis (M.Med.Sc.)-University of Natal, Durban, 2000

Introduction Angiogenesis, the growth of new blood vessels from the pre-existing vasculature, is a pre-requisite for tumour growth and metastasis. Tumour-angiogenesis is regulated by various pro- and anti-angiogenic factors released by both endothelial and tumour cells, as well as by the micro-environment. Numerous studies have implicated various systems in the acquisition of the angiogenic phenotype. The present study sought to investigate the role of the kallikrein-kinin system (KKS) in tumour-angiogenesis. The kallikreins consist of two serine proteases, plasma and tissue kallikrein (TK), involved in the release of kinin peptides by enzymatic cleavage of kininogens. Stimulation of the cognate bradykinin receptors (BKR), B1R and B2R, mediates the mitogenic and vasoactive properties of kinins. In addition, TK activates matrix metallo-proteinases (MMPs) involved in extracellular matrix (ECM) degradation. The expression profiles of TK and kinins have been found to be dys-regulated in numerous human cancers, and several studies have demonstrated the involvement of the KKS in growth and metastasis of prostate tumours. Further, previous in vitro models in our laboratory have established an association between the KKS and prostate tumour-angiogenesis. In those studies it was postulated that the up-regulated TK (produced by endothelial and tumour cells) stimulated endothelial cell proliferation. Thus, the aim of the present study was to define the effects of the KKS and seek a direct correlation with angiogenesis using in vitro models with tumour conditioned medium (CM), kinin receptor agonists and antagonists. Methods Ethical approval for this project was granted by the Biomedical Research Ethics Committee, University of KwaZulu-Natal (reference number BE152/08). Micro-vascular endothelial cells represent a suitable in vitro angiogenic model and dermal micro-vascular endothelial cells (dMVECs) were obtained commercially for this purpose. The tumour model used in this study was an immortalised prostate cancer (DU145) cell line. The CM model involves the treatment of one cell line with the metabolites of another. In the angiogenic model, dMVECs were exposed to increasing concentrations of DU145 CM. Stimulation was further augmented with BKR agonists. Specific BKR antagonists were used to test the specificity of stimulation. In addition, vascular endothelial growth factor (VEGF) was tested as a positive proliferation control. The potential of these agents to induce proliferation and migration was determined using the 3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay and a modified Boyden chamber assay, respectively. Previous studies investigating the pro-angiogenic effects of CM differed, in many respects, in terms of their models and methodologies. In an attempt to fully explore the pro-mitogenic effects of CM on endothelial cells, various modifications, as well as alternate endothelial and tumour cell types, were employed in the present study. The mitogenic and migratory effect of BKR agonists and antagonists on DU145 cells was also assessed. Further, the tumour model was expanded to investigate the autocrine potential of the KKS, by investigating the effect of DU145 CM on DU145 migration. Results In the angiogenic model, although the addition of DU145 CM elicited a statistically significant increase in micro-vascular endothelial cell proliferation, this increase was very small (<10%) and not dose-dependent. Pre-incubation of dMVECs with a B1R or B2R antagonist did not influence this small effect of CM on proliferation. In addition, neither B1R nor B2R agonists, at any concentration, produced any significant proliferative effect on endothelial cells. In contrast to these findings VEGF, a well-known mitogen, was able to stimulate proliferation of dMVECs. Migration assays revealed that DU145 CM failed to stimulate endothelial cell motility. Further, neither BKR agonist displayed any chemo-attractant potential in those assays. The most important finding was in the tumour model, where stimulation with a B1R agonist significantly enhanced proliferation and especially migration of DU145 cells. In addition, pre-treatment with a B1R antagonist abolished both these effects. B2R agonists could not produce the same positive effect as the B1R agonist on growth and migration of prostate tumour cells. DU145 CM did not prove to be a migratory stimulus for DU145 cells at any concentration. Discussion Previous studies in our laboratory have shown prostate-tumour CM to promote proliferation of endothelial cells and have postulated that TK up-regulation may be the reason for this. However, the present study could not reproduce this effect of CM. Further, BKR antagonists had no notable or consistent effect on the minimal promotion of proliferation that had been produced by DU145 CM. In addition, selective BKR agonists failed to induce proliferation or migration of endothelial cells, key events in the angiogenic cascade. Although in contrast to some studies, the present study was unable to implicate the KKS in angiogenesis, tumour neo-vascularisation is a consequence of several angiogenic factors functioning together as opposed to a single, isolated factor. For example, we were able to demonstrate a positive mitogenic effect of VEGF on endothelial cells and it may be this as well as other factors in the CM that are responsible for the small proliferation we observed. Up-regulation of kallikreins and kinins in tumours may enhance fundamental events in tumourigenesis in an autocrine manner, and bradykinin (BK) has previously been shown to promote tumour growth in mouse models. Our study supported the involvement of the KKS in tumourigenesis. Although CM from DU145 cells did not self-stimulate the migration of these cells, a B1R agonist enhanced both proliferation and migration, an effect that was also abrogated by the relevant antagonist, indicating a role for kinins. In contrast to the findings of another study, stimulation of the B2R failed to significantly promote tumour growth or motility. However, this is not an unexpected finding because it is thought that the ubiquitous B2R mediates physiological effects in the prostate while the inducible B1R plays a role in prostate cancer pathology. In summary, this study lends support to the ongoing exploration of BKR antagonists as possible candidates in the development of alternate approaches to cancer therapy. This may be particularly beneficial to hormone-independent tumours, such as those of the prostate, for which there exists few effective treatment options. / Thesis (M.Med.)-University of KwaZulu-Natal, Durban, 2012.

Aminoglycoside antibacterial agents, such as amikacin, continue to play an important role in the treatment of Gram-negative infections. However, although extremely effective, they are not without potential adverse events, the most important of which being nephro- and ototoxicity. Research into factors thought to influence both the efficacy and toxicity, has challenged the rationale upon which these agents have classically been dosed. Various studies in adult patients have found that a new approach to dosing (use of single daily administration) has equal or greater efficacy or safety compared to the standard multiple daily dosing of these agents. Similar studies comparing regimens in children are few, and as yet no comparative investigation has been performed using amikacin in children (as a separate and distinct group). Additionally, in evaluating the impact of altering dose regimens, it is imperative that the documented age-related aminoglycoside pharmacokinetic alterations, be taken into account. Amikacin pharmacokinetic parameters (determined using traditional methods) have been previously published for various (usually small) groups of children. However, population parameters are not currently available for South African children . This study therefore aimed to investigate optimal amikacin dosing in children by studying: a) the comparative efficacy and toxicity of two dosing regimens, and b) the population pharmacokinetic parameters derived using one of the alternative approaches capable of utilising routine, sparse serum drug concentration time data. This investigation was conducted in the paediatric surgical and burns wards of King Edward VIII Hospital , Durban. Study patients (0.6-12 years) received amikacin either once daily (15mg/kg) or twice daily (7.5 mg/kg) by slow intravenous bolus. Concomitant medication was given as prescribed. Regimen efficacy (favourable, unfavourable or indeterminate outcome) was assessed by patient temperatures, clinical improvement and white cell counts. Clinical nephrotoxicity was evaluated by changes in serum creatinine, and renal tubular damage (investigated in a small subgroup of patients) was indicated by detection of urinary low molecular weight proteins. Ototoxicity (cochleotoxicity) was assessed by pure tone audiometry. Pertinent demographic and treatment details (amikacin concentration time data) were recorded for the population pharmacokinetic analysis. The Nonlinear Mixed Effects Model (NONMEM) programme was used to derive appropriate models describing clearance (CL) and volume of distribution (V), as well as mean values of these pharmacokinetic parameters for this population. Fifty four patients were entered into the regimen assessment. Patients in the single daily regimen (n=27) had significantly greater (p<0.05) mean (SO) peak (±0.5 hour post-dose) serum amikacin levels (37.7 (6.9) mg/L) as well as cumulative dose (91.5 (26.5) mg/kg) and duration of therapy (5.7 (1 .5) days) when compared with those of the twice daily group (19.5 (3.7) mg/L, 70.1 (26.1) mg/kg and 4.6 (1 .6) days respectively). No statistically significant differences were found between the groups in terms of outcome (18/24 and 22/25 patients in the once and twice daily dosing groups had favourable outcomes; there were no unfavourable outcomes). Pure tone audiometry (evaluated post-therapy , in 20 patients from each dosing regimen) revealed no statistically significant differences between the number of patients in the two groups with possible drug-related ototoxicity. None of the patients assessed (including an additional 14 patients with burn injury) developed clinical nephrotoxicity. Urinalysis was performed in 17 amikacin treated patients (9 and 8 from the once and twice daily dosing regimens respectively) and 9 control subjects. Low molecular weight proteinuria was absent in all of the latter patients except one, in whom pre-existing renal disease was suspected. Tubular dysfunction ascribed to possible drug effect was detected in similar numbers of patients in the two treatment groups (3 and 2 patients in the once and twice daily dosing groups respectively). In the pharmacokinetic assessment (156 serum levels from 82 patients) using a one compartment model, the final models which best described the data were as follows : CL (Uhr) = 0.271 x age(yrs) + 2.46 x body surface areatrrr'), V (L) = 7.34 x body surface areatrn") Other fixed effects tested, which did not render the data more probable, included serum creatinine measurements at the start of treatment, gender, presence of burn injury and drug regimen. Interpatient variation was 15% and 18% for CL and V respectively, with intrapatient variation or residual error of 10%. The weight adjusted population parameter estimates (95% Confidence Interval) for this group were CL =0.180 (0.175 ,0.185) Uhr/kg and V =0.293 (0.286, 0.300) Ukg, which are within the range of values published previously for other children of similar ages. The findings of this investigation , consistent with those of other similar studies, indicate that daily amikacin administration (in combination with a B-lactam), to children with normal renal function, has similar efficacy to, and no greater toxicity than multiple daily dosing. However, the role, if any, of the significantly greater cumulative dose and duration of therapy in the daily dosing group is unknown. As uncertainty remains regarding the precise duration of certain post-exposure events (and hence, the ideal duration of the interdose interval), and with the rapid drug clearance in this group of patients , future in vitro and in vivo investigations may shed even further light on the optimal dosing approach in these patients. / Thesis (M.Med.)-University of Natal, Durban, 1996.

The purpose of this research was to understand an indigenous perspective on the development and commercialization of non-timber forest products, such as medicines and foods, in Pikangikum First Nation, Northwestern Ontario, Canada. Framed by a research agreement between Pikangikum First Nation and the University of Manitoba, this collaborative research was based on participant observation, field trips, semi-structured interviews, and community workshops. The appropriate development and commercialization of Anishinaabe mushkeekeeh (medicine) and meecheem (food) requires the guidance of community Elders, Anishinaabe knowledge, and traditional teachings. The community is cautiously interested in developing collaborative, diligent, and culturally respectful partnerships that interface knowledge systems. Benefit sharing means the joint ownership of intellectual property and financial benefits, developing employment and capacity-building opportunities for community members, and planning products for community use. This thesis offers a community perspective on how NTFPs might be researched, developed and commercialized in joint and mutually beneficial partnerships with a First Nation.