Over many years, researchers in the field of flotation have developed an in-depth understanding of processes occurring in the pulp phase of flotation machines. Until recently, however, the froth phase has received little attention. The froth phase serves to separate bubble-particle aggregates from suspended slurry in a flotation cell. The mechanism of recovery by entrainment, its relationship to water recovery and particle size dependency is well understood. Froth recovery, (the fraction of particles entering the concentrate launder that entered the froth phase attached to air bubbles), is not well understood. Up until now, there has been doubt over whether this property is dependent on particle size and hydrophobicity. Difficulties in measuring froth recovery had previously prevented researchers from gaining a deeper understanding of the transport of attached particles across the froth phase. A novel device was designed and tested to measure froth recovery by isolating bubble-particle aggregates in the pulp-phase of flotation machines through the determination of the bubble loading in the pulp phase (mass of particles attached per unit volume of air bubbles). This technique can be used with other measurements to investigate froth selectivity by directly comparing these captured particles to those found in the froth phase. Evidence was collected at Red Dog Mine, Alaska and Newmont Golden Grove Operations, Western Australia which showed that the froth phase selectively transported more hydrophobic and smaller sized particles across the froth than less hydrophobic and larger particles. Particles collected in the device were compared to those found in the concentrate stream on a size by mineral by liberation class. Froth recovery was also calculated on a size by mineral by liberation class for two valuable sulphide minerals in a continuous 3m³ flotation cell. These results show that the froth phase is responsible for the upgrading of attached particles across the froth phase as well as for the separation of bubble-particle aggregates from suspended slurry. The pulp phase is responsible for creating bubble-particle aggregates through the attachment of hdyrophobic mineral particles to air bubbles. Many complex factors affect the extent to which this occurs including the size and hdyrophobicity of the particles, the size and number of air bubbles produced by the flotation machine, the rate of collisions between particles and bubbles and the overall chemistry of the system. This measurement of bubble loading presents an opportunity to measure the impact of all these factors on the successful creation of bubble-particle aggregates. Based on a literature review suggesting that there was a high probability of particles being detached at the pulp-froth interface due to the aggregates change in momentum, a three phase description of a flotation cell was proposed. The three phases were: pulp, pulp-froth interface and upper froth zones. A second froth recovery measurement technique (changing froth depth) was used in combination with the bubble load technique to determine the recovery across each of the two froth zones. It was found that the pulp-froth interface appears to be responsible for the selectivity observed across the froth phase as a whole. These findings will enable more in-depth research into the sub-process of the froth phase as well as assisting flotation cell design through a better understanding of the roles of the pulp-froth interface and the upper froth region.

Over many years, researchers in the field of flotation have developed an in-depth understanding of processes occurring in the pulp phase of flotation machines. Until recently, however, the froth phase has received little attention. The froth phase serves to separate bubble-particle aggregates from suspended slurry in a flotation cell. The mechanism of recovery by entrainment, its relationship to water recovery and particle size dependency is well understood. Froth recovery, (the fraction of particles entering the concentrate launder that entered the froth phase attached to air bubbles), is not well understood. Up until now, there has been doubt over whether this property is dependent on particle size and hydrophobicity. Difficulties in measuring froth recovery had previously prevented researchers from gaining a deeper understanding of the transport of attached particles across the froth phase. A novel device was designed and tested to measure froth recovery by isolating bubble-particle aggregates in the pulp-phase of flotation machines through the determination of the bubble loading in the pulp phase (mass of particles attached per unit volume of air bubbles). This technique can be used with other measurements to investigate froth selectivity by directly comparing these captured particles to those found in the froth phase. Evidence was collected at Red Dog Mine, Alaska and Newmont Golden Grove Operations, Western Australia which showed that the froth phase selectively transported more hydrophobic and smaller sized particles across the froth than less hydrophobic and larger particles. Particles collected in the device were compared to those found in the concentrate stream on a size by mineral by liberation class. Froth recovery was also calculated on a size by mineral by liberation class for two valuable sulphide minerals in a continuous 3m³ flotation cell. These results show that the froth phase is responsible for the upgrading of attached particles across the froth phase as well as for the separation of bubble-particle aggregates from suspended slurry. The pulp phase is responsible for creating bubble-particle aggregates through the attachment of hdyrophobic mineral particles to air bubbles. Many complex factors affect the extent to which this occurs including the size and hdyrophobicity of the particles, the size and number of air bubbles produced by the flotation machine, the rate of collisions between particles and bubbles and the overall chemistry of the system. This measurement of bubble loading presents an opportunity to measure the impact of all these factors on the successful creation of bubble-particle aggregates. Based on a literature review suggesting that there was a high probability of particles being detached at the pulp-froth interface due to the aggregates change in momentum, a three phase description of a flotation cell was proposed. The three phases were: pulp, pulp-froth interface and upper froth zones. A second froth recovery measurement technique (changing froth depth) was used in combination with the bubble load technique to determine the recovery across each of the two froth zones. It was found that the pulp-froth interface appears to be responsible for the selectivity observed across the froth phase as a whole. These findings will enable more in-depth research into the sub-process of the froth phase as well as assisting flotation cell design through a better understanding of the roles of the pulp-froth interface and the upper froth region.

Over many years, researchers in the field of flotation have developed an in-depth understanding of processes occurring in the pulp phase of flotation machines. Until recently, however, the froth phase has received little attention. The froth phase serves to separate bubble-particle aggregates from suspended slurry in a flotation cell. The mechanism of recovery by entrainment, its relationship to water recovery and particle size dependency is well understood. Froth recovery, (the fraction of particles entering the concentrate launder that entered the froth phase attached to air bubbles), is not well understood. Up until now, there has been doubt over whether this property is dependent on particle size and hydrophobicity. Difficulties in measuring froth recovery had previously prevented researchers from gaining a deeper understanding of the transport of attached particles across the froth phase. A novel device was designed and tested to measure froth recovery by isolating bubble-particle aggregates in the pulp-phase of flotation machines through the determination of the bubble loading in the pulp phase (mass of particles attached per unit volume of air bubbles). This technique can be used with other measurements to investigate froth selectivity by directly comparing these captured particles to those found in the froth phase. Evidence was collected at Red Dog Mine, Alaska and Newmont Golden Grove Operations, Western Australia which showed that the froth phase selectively transported more hydrophobic and smaller sized particles across the froth than less hydrophobic and larger particles. Particles collected in the device were compared to those found in the concentrate stream on a size by mineral by liberation class. Froth recovery was also calculated on a size by mineral by liberation class for two valuable sulphide minerals in a continuous 3m³ flotation cell. These results show that the froth phase is responsible for the upgrading of attached particles across the froth phase as well as for the separation of bubble-particle aggregates from suspended slurry. The pulp phase is responsible for creating bubble-particle aggregates through the attachment of hdyrophobic mineral particles to air bubbles. Many complex factors affect the extent to which this occurs including the size and hdyrophobicity of the particles, the size and number of air bubbles produced by the flotation machine, the rate of collisions between particles and bubbles and the overall chemistry of the system. This measurement of bubble loading presents an opportunity to measure the impact of all these factors on the successful creation of bubble-particle aggregates. Based on a literature review suggesting that there was a high probability of particles being detached at the pulp-froth interface due to the aggregates change in momentum, a three phase description of a flotation cell was proposed. The three phases were: pulp, pulp-froth interface and upper froth zones. A second froth recovery measurement technique (changing froth depth) was used in combination with the bubble load technique to determine the recovery across each of the two froth zones. It was found that the pulp-froth interface appears to be responsible for the selectivity observed across the froth phase as a whole. These findings will enable more in-depth research into the sub-process of the froth phase as well as assisting flotation cell design through a better understanding of the roles of the pulp-froth interface and the upper froth region.

Over many years, researchers in the field of flotation have developed an in-depth understanding of processes occurring in the pulp phase of flotation machines. Until recently, however, the froth phase has received little attention. The froth phase serves to separate bubble-particle aggregates from suspended slurry in a flotation cell. The mechanism of recovery by entrainment, its relationship to water recovery and particle size dependency is well understood. Froth recovery, (the fraction of particles entering the concentrate launder that entered the froth phase attached to air bubbles), is not well understood. Up until now, there has been doubt over whether this property is dependent on particle size and hydrophobicity. Difficulties in measuring froth recovery had previously prevented researchers from gaining a deeper understanding of the transport of attached particles across the froth phase. A novel device was designed and tested to measure froth recovery by isolating bubble-particle aggregates in the pulp-phase of flotation machines through the determination of the bubble loading in the pulp phase (mass of particles attached per unit volume of air bubbles). This technique can be used with other measurements to investigate froth selectivity by directly comparing these captured particles to those found in the froth phase. Evidence was collected at Red Dog Mine, Alaska and Newmont Golden Grove Operations, Western Australia which showed that the froth phase selectively transported more hydrophobic and smaller sized particles across the froth than less hydrophobic and larger particles. Particles collected in the device were compared to those found in the concentrate stream on a size by mineral by liberation class. Froth recovery was also calculated on a size by mineral by liberation class for two valuable sulphide minerals in a continuous 3m³ flotation cell. These results show that the froth phase is responsible for the upgrading of attached particles across the froth phase as well as for the separation of bubble-particle aggregates from suspended slurry. The pulp phase is responsible for creating bubble-particle aggregates through the attachment of hdyrophobic mineral particles to air bubbles. Many complex factors affect the extent to which this occurs including the size and hdyrophobicity of the particles, the size and number of air bubbles produced by the flotation machine, the rate of collisions between particles and bubbles and the overall chemistry of the system. This measurement of bubble loading presents an opportunity to measure the impact of all these factors on the successful creation of bubble-particle aggregates. Based on a literature review suggesting that there was a high probability of particles being detached at the pulp-froth interface due to the aggregates change in momentum, a three phase description of a flotation cell was proposed. The three phases were: pulp, pulp-froth interface and upper froth zones. A second froth recovery measurement technique (changing froth depth) was used in combination with the bubble load technique to determine the recovery across each of the two froth zones. It was found that the pulp-froth interface appears to be responsible for the selectivity observed across the froth phase as a whole. These findings will enable more in-depth research into the sub-process of the froth phase as well as assisting flotation cell design through a better understanding of the roles of the pulp-froth interface and the upper froth region.

Over many years, researchers in the field of flotation have developed an in-depth understanding of processes occurring in the pulp phase of flotation machines. Until recently, however, the froth phase has received little attention. The froth phase serves to separate bubble-particle aggregates from suspended slurry in a flotation cell. The mechanism of recovery by entrainment, its relationship to water recovery and particle size dependency is well understood. Froth recovery, (the fraction of particles entering the concentrate launder that entered the froth phase attached to air bubbles), is not well understood. Up until now, there has been doubt over whether this property is dependent on particle size and hydrophobicity. Difficulties in measuring froth recovery had previously prevented researchers from gaining a deeper understanding of the transport of attached particles across the froth phase. A novel device was designed and tested to measure froth recovery by isolating bubble-particle aggregates in the pulp-phase of flotation machines through the determination of the bubble loading in the pulp phase (mass of particles attached per unit volume of air bubbles). This technique can be used with other measurements to investigate froth selectivity by directly comparing these captured particles to those found in the froth phase. Evidence was collected at Red Dog Mine, Alaska and Newmont Golden Grove Operations, Western Australia which showed that the froth phase selectively transported more hydrophobic and smaller sized particles across the froth than less hydrophobic and larger particles. Particles collected in the device were compared to those found in the concentrate stream on a size by mineral by liberation class. Froth recovery was also calculated on a size by mineral by liberation class for two valuable sulphide minerals in a continuous 3m³ flotation cell. These results show that the froth phase is responsible for the upgrading of attached particles across the froth phase as well as for the separation of bubble-particle aggregates from suspended slurry. The pulp phase is responsible for creating bubble-particle aggregates through the attachment of hdyrophobic mineral particles to air bubbles. Many complex factors affect the extent to which this occurs including the size and hdyrophobicity of the particles, the size and number of air bubbles produced by the flotation machine, the rate of collisions between particles and bubbles and the overall chemistry of the system. This measurement of bubble loading presents an opportunity to measure the impact of all these factors on the successful creation of bubble-particle aggregates. Based on a literature review suggesting that there was a high probability of particles being detached at the pulp-froth interface due to the aggregates change in momentum, a three phase description of a flotation cell was proposed. The three phases were: pulp, pulp-froth interface and upper froth zones. A second froth recovery measurement technique (changing froth depth) was used in combination with the bubble load technique to determine the recovery across each of the two froth zones. It was found that the pulp-froth interface appears to be responsible for the selectivity observed across the froth phase as a whole. These findings will enable more in-depth research into the sub-process of the froth phase as well as assisting flotation cell design through a better understanding of the roles of the pulp-froth interface and the upper froth region.

Obstructive sleep apnoea (OSA) is a common condition characterized by recurrent complete and partial upper airway obstruction. OSA sufferers have been shown to have a significantly smaller upper airway lumen compared to non-OSA sufferers. However, non-anatomical factors of sleep stage, arousability and neuromechanical responses to airway occlusion and chemosensitivity are likely to play a significant part in influencing OSA severity across the night. An exploration of these non-anatomical factors forms the basis for the experiments in this thesis. In the first experimental chapter presented in this thesis, a detailed retrospective epoch by epoch analysis of nocturnal polysomnography in 253 patients referred to a clinical sleep service was performed to examine differences in sleep apnoea severity and arousal indices across the different stages of sleep, while controlling for posture. Both patients with and without OSA demonstrated significant reductions in respiratory and arousal event frequencies from stage 1 to 4 with intermediate frequencies in REM sleep. Lateral posture was also associated with significant improvements in OSA and arousal frequencies, with an effect size comparable to that of sleep stage. The majority of patients showed significant reductions in OSA severity during slow wave sleep. In non-REM sleep, there was a strong correlation between OSA severity and arousal frequency. These results confirm in a large group of patients, a strong sleep stage dependence of both OSA and arousal frequencies. The second study in this thesis explores the development of a CO2 stabilising or ‘clamp’ device to enable the provision of positive airway pressure, and by proportional rebreathing, the maintenance of relatively constant end-tidal CO2 despite significant hyperventilation. Healthy volunteers performed brief periods of significant voluntary hyperventilation at 2 levels of CPAP with the rebreathing function off and with active CO2 clamping in randomized order. Compared to CPAP alone, the device substantially attenuated hypocapnia associated with hyperventilation. The third study of the thesis was designed to investigate if increasing and stabilizing end-tidal CO2 could improve obstructive breathing patterns during sleep. 10 patients with severe OSA underwent rapid CPAP dialdown from therapeutic to a sub-therapeutic level to experimentally induce acute, partial upper airway obstruction over 2 minute periods repeated throughout the night. The CO2 clamp device developed and validated in Study 2 was used to determine whether during periods of partial upper airway obstruction with severe flow limitation, (1) increased end-tidal CO2 resulted in improved airflow and ventilation and (2) clamping end-tidal CO2 lessened post-arousal ventilatory undershoot. Three conditions were studied in random order: no clamping of CO2, clamping of end-tidal CO2 3-4 mmHg above eucapnic levels during the pre-dialdown baseline period only, and clamping of CO2 above eucapnia during both baseline and dialdown periods. Elevated CO2 in the baseline period alone or in the baseline and dialdown periods together resulted in significantly higher peak inspiratory flows and ventilation compared to the no clamp condition. Breath-by-breath analysis immediately pre- and post-arousal showed higher end-tidal CO2 despite hyperventilation immediately post-arousal and attenuation of ventilatory undershoot in CO2 versus non-CO2 clamped conditions. These results support that modulation of ventilatory drive by changes in pre- and post-arousal CO2 are likely to importantly influence upper airway and ventilatory stability in OSA. The fourth study was designed to explore several possible pathophysiological mechanisms whereby obstructive sleep apnoea is improved in stages 3 & 4 (slow wave) versus stage 2 sleep. 10 patients with severe OSA who demonstrated significant reductions in OSA frequency during slow wave sleep on diagnostic investigation were studied. Patients underwent rapid dialdowns from therapeutic CPAP to 3 different pre-determined sub-therapeutic pressures to induce partial airway obstruction and complete airway occlusions in a randomised sequence during the night in both stage 2 and slow wave sleep. Partial airway obstructions and complete occlusions were maintained until arousal occurred or until 2 minutes had elapsed, whichever came first. After airway occlusions, time to arousal, peak pre-arousal negative epiglottic pressure and the rate of ventilatory drive augmentation were significantly greater, suggesting a higher arousal threshold and ventilatory responsiveness to respiratory stimuli during slow wave compared to stage 2 sleep. Post dialdowns, the likelihood of arousal was lower with less severe dialdowns and in slow wave compared to stage 2 sleep. Respiratory drive measured by epiglottic pressure progressively increased post-dialdown, but did not translate into increases in peak flow or ventilation pre-arousal and was not different between sleep stages. These data suggest that while arousal time and propensity following respiratory challenge are altered by sleep depth, there is little evidence to support that upper airway and ventilatory compensation responses to respiratory load are fundamentally improved in slow wave compared to stage 2 sleep. In summary, sleep stage, arousal threshold and chemical drive appear to strongly influence upper airway and ventilatory stability in OSA and are suggestive of important non-anatomical pathogenic mechanisms in OSA.

PhD / Introduction Kidney transplantation confers both survival and quality of life advantages over dialysis for most people with end-stage kidney disease (ESKD). The mortality rate on dialysis is 10-15% per year, compared with 2-4% per year post-transplantation. Short-term graft survival is related to control of the acute rejection process, requiring on-going immunosuppression. Most current immunosuppressive algorithms include one of the calcineurin inhibitors (CNI: cyclosporin or tacrolimus), an anti-metabolite (azathioprine or mycophenolate) and corticosteroids, with or without antibody induction agents (Ab) given briefly peri-transplantation. Despite this approach, between 15-35% of recipients undergo treatment for an episode of acute rejection (AR) within one year of transplantation. Transplantation is not without risk, and relative mortality rates for kidney recipients after the first post-transplant year remain 4-6 times that of the general population. Longer-term transplant and recipient survival are related to control of chronic allograft nephropathy (rooted in the interplay of AR, non-immunological factors, and the chronic nephrotoxicity of CNI) and limitation of the complications of chronic ESKD and long-term immunosuppression: cardiovascular disease, cancer and infection, which are responsible for 22%, 39% and 21% of deaths respectively. This thesis is presented as published works on the theme of immunosuppression and cancer after kidney transplantation. The work presented in the first chapters of this thesis has striven to identify, evaluate, synthesise and distil the entirety of evidence available of new and established immunosuppressive drug agents through systematic review of randomised trial data, with particular emphasis on quantifying harms of treatment. The final chapters use inception cohort data from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), which is first validated then used to explore the risk of cancer in more detail than was possible from trial data alone. Interleukin 2 receptor antagonists Interleukin-2 receptor antagonists (IL2Ra, commercially available as basiliximab and daclizumab) are humanised or chimeric IgG monoclonal antibodies to the alpha subunit of the IL2 receptor present only on activated T lymphocytes, and the rationale for their use has been as induction agents peri-transplantation. Introduced in the mid-1990s, IL2Ra use has increased globally, and by 2003 38% of new kidney transplant recipients in the United States and 25% in Australasia received an IL2Ra. This study aimed to systematically identify and synthesise the evidence of effects of IL2Ra as an addition to standard therapy, or as an alternative to other induction agents. We identified 117 reports from 38 randomised trials involving 4893 participants. Where IL2Ra were compared with placebo (17 trials; 2786 patients), graft loss was not different at one (Relative Risk -RR 0.84; 0.64 to 1.10) or 3 years (RR 1.08; 0.71 to1.64). AR was reduced at 6 months (RR 0.66; 0.59 to 0.74) and at 1 year (RR 0.66; 0.59 to 0.74) but cytomegalovirus (CMV) disease (RR 0.82; CI 0.65 to 1.03) and malignancy (RR 0.67; 0.33 to1.36) were not different. Where IL2Ra were compared with other antibody therapy no significant differences in treatment effects were demonstrated, but IL2Ra had significantly fewer side effects. Given a 40% risk of rejection, 7 patients would need treatment with IL2Ra in addition to standard therapy, to prevent 1 patient having rejection, with no definite improvement in graft or patient survival. There was no apparent difference between basiliximab and daclizumab. Tacrolimus versus cyclosporin for primary immunosuppression There are pronounced global differences in CNI use; 63% of new kidney transplant recipients in the USA but only 22% in Australia receive tacrolimus as part of the initial immunosuppressive regimen. The side effects of CNI differ: tacrolimus is associated more with diabetes and neurotoxicity, but less with hypertension and dyslipidaemia than cyclosporin, with uncertainty about equivalence of nephrotoxicity or how these relate to patient and graft survival, or impact on patient compliance and quality of life. This study aimed to systematically review and synthesise the positive and negative effects of tacrolimus and cyclosporin as initial therapy for renal transplant recipients. We identified 123 reports from 30 randomised trials involving 4102 participants. At 6 months graft loss was reduced in tacrolimus-treated recipients (RR 0•56; 0•36 to 0•86), and this effect persisted for 3 years. The relative reduction in graft loss with tacrolimus diminished with higher levels of tacrolimus (P=0.04), but did not vary with cyclosporin formulation (P=0.97) or cyclosporin level (P=0.38). At 1 year, tacrolimus patients suffered less AR (RR 0•69; 0•60 to 0•79), and less steroid-resistant AR (RR 0•49; 0•37 to 0•64), but more insulin-requiring diabetes (RR 1•86; 1•11 to 3•09), tremor, headache, diarrhoea, dyspepsia and vomiting. The relative excess in diabetes increased with higher levels of tacrolimus (P=0.003). Cyclosporin-treated recipients experienced significantly more constipation and cosmetic side-effects. We demonstrated no differences in infection or malignancy. Treating 100 recipients with tacrolimus instead of cyclosporin for the 1st year post-transplantation avoids 12 suffering acute rejection and 2 losing their graft but causes an extra 5 to become insulin dependent diabetics, thus optimal drug choice may vary among patients. Target of rapamycin inhibitors for primary immunosuppression Target of rapamycin inhibitors (TOR-I) are among the newest immunosuppressive agents and have a novel mode of action but uncertain clinical role. Sirolimus is a macrocyclic lactone antibiotic and everolimus is a derivative of sirolimus. Both prevent DNA synthesis resulting in arrest of the cell cycle. Animal models suggested TOR-I would provide synergistic immunosuppression when combined with CNI, but early clinical studies demonstrated synergistic nephrotoxicity. Since then diverse trials have explored strategies that avoid this interaction and investigated other potential benefits. The aim of this study was to systematically identify and synthesise available evidence of sirolimus and everolimus when used in initial immunosuppressive regimens for kidney recipients. We identified 142 reports from 33 randomised trials involving 7114 participants, with TOR-I evaluated in four different primary immunosuppressive algorithms: as replacement for CNI, as replacement for antimetabolites, in combination with CNI at low and high dose, and with variable dose of CNI. When TOR-I replaced CNI (8 trials, 750 participants), there was no difference in AR (RR 1.03; 0.74 to 1.44), but creatinine was lower (WMD -18.31 umol/l; -30.96 to -5.67), and bone marrow more suppressed (leucopoenia RR 2.02; 1.12 to 3.66, thrombocytopenia RR 6.97; 2.97 to 16.36, anaemia RR 1.67; 1.27 to 2.20). When TOR-I replaced antimetabolites (11 trials, 3966 participants), AR and CMV were reduced (RR 0.84; 0.71 to 0.99 and RR 0.49; 0.37 to 0.65) but hypercholesterolaemia was increased (RR 1.65; 1.32 to 2.06). When low was compared to high-dose TOR-I, with equal CNI dose (10 trials, 3175 participants), AR was increased (RR 1.23; 1.06 to 1.43) but GFR higher (WMD 4.27 ml/min; 1.12 to 7.41). When low-dose TOR-I and standard-dose CNI were compared to higher-dose TOR-I and reduced CNI AR was reduced (RR 0.67; 0.52 to 0.88), but GFR also reduced (WMD -9.46 ml/min; -12.16 to -6.76). There was no significant difference in mortality, graft loss or malignancy risk demonstrated for TOR-I in any comparison. Generally surrogate endpoints for graft survival favoured TOR-I (lower risk of acute rejection and higher GFR) and surrogate endpoints for patient outcomes were worsened by TOR-I (bone marrow suppression, lipid disturbance). Long-term hard-endpoint data from methodologically robust randomised trials are still needed. Monoclonal and polyclonal antibody therapy for treating acute rejection Strategies for treating AR include pulsed steroids, an antibody (Ab) preparation, the alteration of background immunosuppression, or combinations of these options. In 2002, in the USA 61.4% of patients with AR received steroids, 20.4% received Ab and 18.2% received both. The Ab available for AR are not new: horse and rabbit derived polyclonal antibodies (ATG and ALG) have been used for 35 years, and a mouse monoclonal antibody (muromonab-CD3) became available in the late 1980s. These preparations remove the functional T-cell population from circulation, producing powerful saturation immunosuppression which is useful for AR but which may be complicated by immediate toxicity and higher rates of infection and malignancy. The aim of this study was to systematically evaluate and synthesise all evidence available to clinicians for treating AR in kidney recipients. We identified 49 reports from 21 randomised trials involving 1394 participants. Outcome measures were inconsistent and incompletely defined across trials. Fourteen trials (965 patients) compared therapies for 1st AR episodes (8 Ab versus steroid, 2 Ab versus another Ab, 4 other comparisons). In treating first rejection, Ab was better than steroid in reversing AR (RR 0.57; CI 0.38 to 0.87) and preventing graft loss (RR 0.74; CI 0.58 to 0.95) but there was no difference in preventing subsequent rejection (RR 0.67; CI 0.43 to 1.04) or death (RR 1.16; CI 0.57 to 2.33) at 1 year. Seven trials (422 patients) investigated Ab treatment of steroid-resistant rejection (4 Ab vs another Ab, 1 different doses Ab, 1 different formulation Ab, 2 other comparisons). There was no benefit of muromonab-CD3 over ATG or ALG in reversing rejection (RR 1.32; CI 0.33 to 5.28), preventing subsequent rejection (RR 0.99; CI 0.61 to 1.59), graft loss (RR 1.80; CI 0.29 to 11.23) or death (RR 0.39; CI 0.09 to 1.65). Given the clinical problem caused by AR, comparable data are sparse, and clinically important differences in outcomes between widely used interventions have not been excluded. Standardised reproducible outcome criteria are needed. Validity of cancer data in an end stage kidney disease registry Registries vary in whether the data they collect are given voluntarily or as a requirement of law, the completeness of population coverage, the breadth of data collected and whether data are assembled directly or indirectly through linkage to other databases. Data quality is crucial but difficult to measure objectively. Formal audit of ANZDATA cancer records has not previously taken place. The aim of this study was to assess agreement of records of incident cancer diagnoses held in ANZDATA (voluntary reporting system) with those reported under statute to the New South Wales (NSW) state Central Cancer Registry (CCR), to explore the strengths and weaknesses of both reporting systems, and to measure the impact of any disagreement on results of cancer analyses. From 1980-2001, 9453 residents received dialysis or transplantation in NSW. Records from ANZDATA registrants were linked to CCR using probabilistic matching and agreement between registries for patients with 1 or more cancers, all cancers and site-specific cancer was estimated using the kappa-statistic (κ). ANZDATA recorded 867 cancers in 779 (8.2%) registrants; CCR 867 cancers in 788 (8.3%), with κ =0.76. ANZDATA had sensitivity 77.3% (CI 74.2 to 80.2), specificity 98.1% (CI 97.7 to 98.3) if CCR records were regarded as the reference standard. Agreement was similar for diagnoses whilst receiving dialysis (κ =0.78) or after transplantation (κ =0.79), but varied by cancer type. Melanoma (κ =0.61) and myeloma (κ =0.47) were less good; lymphoma (κ =0.80), leukaemia (κ =0.86) and breast cancer (κ =0.85) were very good. Artefact accounted for 20.8% non-concordance but error and misclassification did occur in both registries. Cancer risk did not differ in any important way whether estimated using ANZDATA or CCR records. Quality of cancer records in ANZDATA are high, differences largely explicable, and seem unlikely to alter results of analyses. Risk of cancer after kidney transplantation Existing data on the magnitude of excess risk of cancer across different kidney recipient groups are sparse. Quantifying an individual transplant candidate’s cancer risk informs both pre-transplant counselling, treatment decisions and has implications for monitoring, screening and follow-up after transplantation. The aims of this study were firstly to establish the risk of cancer in the post-transplant population compared to that experienced by the general population, and secondly to quantify how excess risk varied within the transplanted population, seeking to establish meaningful absolute risk estimates for post-transplant cancer based on unalterable recipient characteristics known a priori at the time of transplantation. 15,183 residents of Australia and New Zealand had a transplant between 1963 and 2004, and were followed for a median of 7.2 years (130,186 person-years), with 1642 (10.8%) developing cancer. Overall, kidney recipients had 3 times the cancer risk, with risk inversely related to age (Standardised Incidence Ratio of 15 to 30 in children reducing to 2 in people > 65 years). Female recipients aged 25 -29 had rates of cancer (779.2/100,000) equivalent to women aged 55 - 59 from the general population. The risk pattern of lymphoma, colorectal and breast cancer was similar to the overall age trend, melanoma showed less variability across ages and prostate cancer showed no risk increase. Within the transplanted population cancer risk was affected by age differently for each sex (P=0.007), and was elevated for recipients with prior non-skin malignancy (Hazard Ratio: HR 1.40; 1.03 to 1.89), of white race (HR 1.36; 1.12 to 1.89), but reduced for those with diabetic ESKD (HR 0.67; 0.50 to 0.89) Rates of cancer in kidney recipients were similar to non-transplanted people 20 -30 years older, but risk differed across patient groups. Men aged 45 - 54 at transplantation with graft function at 10 years had a risk of cancer that varied from 1 in 13 (non-white, diabetic ESKD, no prior cancer) to 1 in 5 (white, prior cancer, ESKD from other causes).

The gas dispersion characteristics in mechanical flotation cells have a significant effect on the overall flotation performance. Three major properties that can be measured in characterising the gas dispersion in a flotation cell are bubble size, gas hold-up, and superficial gas velocity. Another property that is equally important in flotation is bubble surface area flux which is calculated from bubble size and superficial gas velocity. Despite the importance of gas dispersion in flotation, not much work has been reported previously in this area. Moreover, the study of gas dispersion in flotation has typically considered only a few points in a flotation cell and the average values were assumed to represent the gas dispersion characteristics in the entire volume of the cell. It is known however, that the gas dispersion characteristics are not uniformly distributed in a mechanical flotation cell. This thesis seeks to understand better the gas dispersion characteristics in mechanical flotation cells with a view to optimisation, modelling, cell comparison and selection. The main aim of this thesis was to measure comprehensively the gas dispersion characteristics in a mechanical flotation cell, analyse the behaviour in the entire volume of the cell, and develop a methodology for modelling the gas dispersion characteristics in the whole volume of the cell as well as develop the models themselves. For this purpose, a fully instrumented 3 m³ glass rectangular flotation cell at the Julius Kruttschnitt Mineral Research Centre (JKMRC) at the University of Queensland was used. The cell was fitted with a Dorr-Oliver impeller-stator mechanism and was provided with facilities to change impeller speed and gas flow rate. Sensors to measure the gas dispersion characteristics were also acquired and modified. This cell could only be operated in a two-phase (air-water) system but the opportunity was taken to make some comparative measurements in an operating plant in a three-phase slurry to compare the gas dispersion characteristics in two and three-phase systems. The comprehensive measurements of the gas dispersion characteristics (i.e. bubble size, gas hold-up, and superficial gas velocity, with subsequent calculation of bubble surface area flux) throughout the entire volume of the 3 m³ rectangular flotation cell show that the properties do vary with distance from the impeller, the cell bottom, and the walls. Statistical analysis to test the homogeneity of the properties in the cell confirmed that the differences (variation with distance) were real. It was found that the gas dispersion was poor in the corners of a rectangular flotation cell. These corners are referred to as dead zones. It can be interpreted that in these zones, flotation is less effective compared to other zones in a cell. The results of mapping the gas dispersion characteristics throughout the entire volume of the flotation cell were used to determine the best location to measure gas dispersion characteristics in a flotation cell in order to represent the overall values. It was established that this location in a flotation cell is about halfway between the impeller and the wall, and halfway between the bottom of the flotation cell and the pulp-froth interface. Statistical analysis also showed that there is “quarter symmetry”, i.e. there is no significant difference between equivalent positions in different quarters in a horizontal plane. In any future work, therefore, measurements of the gas dispersion characteristics need only be made in one quarter, and symmetry in the rest of the cell can be assumed. Following from the statistical analysis that established quarter symmetry in the 3 m³ glass rectangular flotation cell, a methodology to model gas dispersion characteristics in the entire volume of a rectangular mechanical flotation cell was developed, based on an experimental design known as CCRD (central composite rotatable design) which then modified. Using the methodology, models to predict bubble size, gas hold-up, superficial gas velocity and bubble surface area flux in the entire volume of a rectangular flotation cell were developed as a function of air flow rate and impeller speed. The validity of the models was tested using a predictive (cross) validation method, from where it was concluded that the models were valid. These models were then used to analyse the gas dispersion characteristics in detail in the flotation cell, as a function of flow rate, impeller speed, and location in the cell. Finally, a comparison of gas dispersion characteristics in two and three-phase systems in flotation cells was made. Comprehensive measurements of gas dispersion characteristics were performed in a three-phase slurry in an industrial OK 38 m³ rectangular flotation cell at the PT Freeport Indonesia concentrator, and the results were compared to those measured previously in the two-phase system in the 3 m³ rectangular cell. It was found that the profiles of gas dispersion were generally similar in both cells but the magnitude of the gas dispersion properties differed between the two systems. The presence of solid particles had greater effect on the bubble size than on gas hold-up and superficial gas velocity.

Over many years, researchers in the field of flotation have developed an in-depth understanding of processes occurring in the pulp phase of flotation machines. Until recently, however, the froth phase has received little attention. The froth phase serves to separate bubble-particle aggregates from suspended slurry in a flotation cell. The mechanism of recovery by entrainment, its relationship to water recovery and particle size dependency is well understood. Froth recovery, (the fraction of particles entering the concentrate launder that entered the froth phase attached to air bubbles), is not well understood. Up until now, there has been doubt over whether this property is dependent on particle size and hydrophobicity. Difficulties in measuring froth recovery had previously prevented researchers from gaining a deeper understanding of the transport of attached particles across the froth phase. A novel device was designed and tested to measure froth recovery by isolating bubble-particle aggregates in the pulp-phase of flotation machines through the determination of the bubble loading in the pulp phase (mass of particles attached per unit volume of air bubbles). This technique can be used with other measurements to investigate froth selectivity by directly comparing these captured particles to those found in the froth phase. Evidence was collected at Red Dog Mine, Alaska and Newmont Golden Grove Operations, Western Australia which showed that the froth phase selectively transported more hydrophobic and smaller sized particles across the froth than less hydrophobic and larger particles. Particles collected in the device were compared to those found in the concentrate stream on a size by mineral by liberation class. Froth recovery was also calculated on a size by mineral by liberation class for two valuable sulphide minerals in a continuous 3m³ flotation cell. These results show that the froth phase is responsible for the upgrading of attached particles across the froth phase as well as for the separation of bubble-particle aggregates from suspended slurry. The pulp phase is responsible for creating bubble-particle aggregates through the attachment of hdyrophobic mineral particles to air bubbles. Many complex factors affect the extent to which this occurs including the size and hdyrophobicity of the particles, the size and number of air bubbles produced by the flotation machine, the rate of collisions between particles and bubbles and the overall chemistry of the system. This measurement of bubble loading presents an opportunity to measure the impact of all these factors on the successful creation of bubble-particle aggregates. Based on a literature review suggesting that there was a high probability of particles being detached at the pulp-froth interface due to the aggregates change in momentum, a three phase description of a flotation cell was proposed. The three phases were: pulp, pulp-froth interface and upper froth zones. A second froth recovery measurement technique (changing froth depth) was used in combination with the bubble load technique to determine the recovery across each of the two froth zones. It was found that the pulp-froth interface appears to be responsible for the selectivity observed across the froth phase as a whole. These findings will enable more in-depth research into the sub-process of the froth phase as well as assisting flotation cell design through a better understanding of the roles of the pulp-froth interface and the upper froth region.

Thesis (M.S.)--University of Michigan, 1986.