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 purpose of the present research was to address gaps in the video based modeling (VBM) literature through the use of meta-analytic techniques to provide clarity and specificity regarding the practical utility of VBM for participants with disabilities. Two meta-analyses of published single-case VBM research were conducted. Improvement rate difference, an effect size measure, was utilized to analyze the fifty-six single-case studies. The purpose of study one was to determine if differential effects occurred based on the type of model utilized and variations in procedural implementation. In addition, the quality of research was evaluated. The purpose of study two was to determine if participant characteristics, intervention components by participant characteristics, and targeted outcome moderated the effectiveness of video modeling with other as model (VMO). Results of Study One indicated moderate to strong effects for both VMO and video self-modeling, however, when further disaggregated based on type of model utilized, VMO with adult as model demonstrated statistically significant superiority in terms of outcome effects. Results also indicated VBM with reinforcement demonstrated greater effects than when delivered alone or as part of a package. Additionally, the evaluation of quality of research indicated a tendency of the previously published VBM research not to evaluate treatment integrity. Study Two found that age and diagnosis moderate the effectiveness of VMO, although strong effects were found across levels for both moderators. VMO was found to be more effective for elementary age participants and participants with autism spectrum disorders. Additionally, VMO with reinforcement demonstrated statistically significant stronger effects for participants with ASD than when it is delivered alone or as part of a package. However, VMO delivered as part of a package was more potent for participants with developmental disabilities. Considering targeted outcomes, the results indicated strong effects across skill areas, however, VMO was found to be most impactful when utilized to improve play skills versus other measured skills. Implications related to the practical application of VBM for individuals with disabilities particularly in regards to treatment decision making were discussed. Additionally, implications for future research were addressed.

Antiplatelet therapy with clopidogrel is widely used in patients with coronary artery disease, but the recent development of the new P2Y12 receptor antagonists prasugrel and ticagrelor will increase treatment options. An overview of systematic reviews was performed to summarize available evidence on clopidogrel. Current data on prasugrel and ticagrelor were identified by a systematic review and used for an indirect treatment comparison (ITC) of the drugs against each other and versus placebo in the absence of head-to-head clinical trials. Adjusted indirect comparison according to Bucher, Bayesian methods for mixed treatment comparisons using Winbugs, and generalized linear mixed models using SAS were employed for ITC, yielding almost identical results: prasugrel was favored regarding stent thrombosis and ticagrelor regarding major bleeding. However, substantial differences in trial design were identified, demanding caution when interpreting these results. On the basis of the obtained results, a randomized controlled trial was designed within the gap of current evidence.

The effect of temperature on predator and herbivore consumption is an important factor for predicting the effects of climate warming on ecosystems. The Metabolic Theory of Ecology (MTE) describes the temperature dependence of biological and ecological rates and states that metabolism is the fundamental biological mechanism that governs most observed patterns in ecology. This statement has been criticized empirically for a number of organismal traits and systematic deviations have been found. Here, a meta-analysis is performed on published temperature responses of ectotherm consumption. The mean effect of temperature on consumption was higher than the mean value predicted by proponents of the MTE and was highly variable. Some of this variation is explained by habitat type, where the consumption rates of marine organisms displayed stronger temperature dependence than for terrestrial and freshwater organisms. The frequency distribution of temperature dependencies is right skewed for consumption. Here, this skewness is explained by a methodological artefact as values close to “no effect” are more unlikely to be sampled than others when fitting the Arrhenius equation. In conclusion, the assumptions of the MTE do not hold for rates of consumption and marine organisms display a stronger temperature dependence compared to terrestrial and freshwater organisms.

Background: The use of meta-analysis to combine the results of observational studies is controversial. Despite its common use, methodological work in this area is lacking. Because of the diversity of study designs, exposure and outcome measures, and differential adjustment for confounding variables, the identification of sources of heterogeneity among study effect estimates is particularly important when combining data from observational studies. This thesis presents the results of a study that examines the relative ability of individual participant data (IPD) meta-analysis (which was considered a “gold standard”) and traditional aggregate data (AD) meta-analysis to identify sources of heterogeneity among studies examining mechanical exposure and low back pain (LBP) in workers. Materials and Methods: A systematic literature search was conducted to identify relevant articles. The corresponding author of each article was contacted to request their individual-level data. Because the outcome definitions and exposure measures were not uniform across studies, two sub-studies were conducted 1) to identify sets of outcome definitions that could be combined in a meta-analysis and 2) to develop methods to translate mechanical exposure onto a common metric. IPD analyses were conducted using generalized estimating equation (GEE) regression to identify variables that acted as strong confounders and effect modifiers. Traditional AD meta-analysis was also conducted and potential sources of heterogeneity were tested using meta-regression. Key Findings: (1) Overall, we found an association between both forces and postures on LBP, although the magnitude varied depending on the exposure-outcome combination. Among the outcomes, the ORs tended to be highest for sick leave due to LBP. (2) There was very little evidence of strong confounders in the relationship between mechanical exposure and LBP; thus differential adjustment for confounders in studies would not likely be an important source of heterogeneity in an AD meta-analysis. (3) AD meta-analysis was able to identify the same study-level effect modifiers as IPD meta-analysis, but did not consistently identify individual-level effect modifiers. Both individual-level characteristics (older age and being male), and study-level characteristics (population-based studies and self-reported mechanical exposure), were associated with an increased OR for many of the LBP outcome and mechanical exposure combinations. Conclusion: AD meta-analysis is likely sufficient to detect heterogeneity for study-level factors but is not sufficient to identify individual-level effect modifiers. When the primary source of evidence in a research area is observational studies and when there is controversy despite several systematic reviews, IPD meta-analysis can be used to better understand sources of heterogeneity and provide context

Background: The relationship between average alcohol consumption and heart disease is well researched, showing a substantial cardioprotective association. This dissertation examined the epidemiological evidence for an effect of heavy episodic drinking (HED) over and above the effect of average alcohol consumption on heart disease. Methods: Electronic databases were systematically searched for epidemiological studies on the effect of HED on heart disease and identified articles were quantitatively summarized in a meta-analysis. Meta-regression models were used to examine the effect of characteristics of primary studies. Using individual-level data, semi-parametric Cox regression models were used to investigate HED exposure within narrow categories of average alcohol consumption in a US national population sample (n = 9,937) in relation to heart disease mortality in an 11-22 year follow-up. Frequency of heavy drinking episodes was used to identify latent classes of drinking history using growth mixture modeling in a sub-sample of this US cohort. Retrieved classes were used as independent variables in Cox regression models with heart disease mortality as the outcome event. Results: A pooled relative risk of 1.45 (95% confidence interval (CI): 1.24-1.70) for HED compared with non-HED drinkers with average alcohol consumption between 0.1-60 g/day was derived in a meta-analysis. A strong and consistent association with HED was found among current drinkers consuming an average of 1-2 drinks per day in the US cohort. There was no evidence of increased heart disease mortality resulting from the frequency of heavy drinking episodes before the age of forty. Conclusions: There is reasonable and consistent evidence for an association of HED and heart disease in current drinkers, negating any beneficial effect from alcohol consumption on heart health. History of frequency of heavy drinking episodes, however, showed no evidence for such an effect modification.

This research is a meta-analytic review of the effects of transformational school leadership (TSL)-- a systematic, comprehensive synthesis of the quantitative research on transformational school leadership. The review method used in this research is standard meta-analysis supplemented by narrative synthesis and vote-counting methods. The types of effect sizes involved in meta-analytical calculations are correlation coefficients rs. The evidence reviewed was provided exclusively by unpublished theses or dissertations that were completed between 1996 and 2008. This study identified 33 dimensions of transformational leadership as developed by various scholars and captured by a variety of leadership measures, which were synthesized into 11 core leadership dimensions. This study meta-analyzed the effects of transformational school leadership and its dimensions on a large range of school outcomes, including 17 school conditions (e.g., school culture, shared decision-making processes), 23 teacher-related outcomes (e.g., teacher satisfaction), and five types of student outcomes. Transformational school leadership was most influential on teachers’ emotions and inner states. TSL had large effects on teachers’ individual inner states and their practices while it had small effects on their group inner states. Leaders effectively influence teachers’ psychological inner states and practices mainly through modeling good practices themselves, providing support and intellectual stimulation to teachers individually and setting shared school goals. TSL was also very influential on school conditions. It had large effects on four key school conditions. This review detected significant, positive small direct effects of TSL on student achievements. The indirect effects of TSL on student learning vary when different school or teacher variables are controlled. This review identified seven important moderators and three mediators that significantly contributed to student learning along with TSL. Specific leadership practices that effectively influenced school and student outcomes were also examined and discussed. Regarding the moderating effects of contextual and methodological factors, school level and leadership measures were found to moderate leadership impacts significantly in some cases. The findings of this study provide guidance for school administrators and policy makers who want to improve school leadership as a means of improving school quality.

Background: The use of meta-analysis to combine the results of observational studies is controversial. Despite its common use, methodological work in this area is lacking. Because of the diversity of study designs, exposure and outcome measures, and differential adjustment for confounding variables, the identification of sources of heterogeneity among study effect estimates is particularly important when combining data from observational studies. This thesis presents the results of a study that examines the relative ability of individual participant data (IPD) meta-analysis (which was considered a “gold standard”) and traditional aggregate data (AD) meta-analysis to identify sources of heterogeneity among studies examining mechanical exposure and low back pain (LBP) in workers. Materials and Methods: A systematic literature search was conducted to identify relevant articles. The corresponding author of each article was contacted to request their individual-level data. Because the outcome definitions and exposure measures were not uniform across studies, two sub-studies were conducted 1) to identify sets of outcome definitions that could be combined in a meta-analysis and 2) to develop methods to translate mechanical exposure onto a common metric. IPD analyses were conducted using generalized estimating equation (GEE) regression to identify variables that acted as strong confounders and effect modifiers. Traditional AD meta-analysis was also conducted and potential sources of heterogeneity were tested using meta-regression. Key Findings: (1) Overall, we found an association between both forces and postures on LBP, although the magnitude varied depending on the exposure-outcome combination. Among the outcomes, the ORs tended to be highest for sick leave due to LBP. (2) There was very little evidence of strong confounders in the relationship between mechanical exposure and LBP; thus differential adjustment for confounders in studies would not likely be an important source of heterogeneity in an AD meta-analysis. (3) AD meta-analysis was able to identify the same study-level effect modifiers as IPD meta-analysis, but did not consistently identify individual-level effect modifiers. Both individual-level characteristics (older age and being male), and study-level characteristics (population-based studies and self-reported mechanical exposure), were associated with an increased OR for many of the LBP outcome and mechanical exposure combinations. Conclusion: AD meta-analysis is likely sufficient to detect heterogeneity for study-level factors but is not sufficient to identify individual-level effect modifiers. When the primary source of evidence in a research area is observational studies and when there is controversy despite several systematic reviews, IPD meta-analysis can be used to better understand sources of heterogeneity and provide context

This research is a meta-analytic review of the effects of transformational school leadership (TSL)-- a systematic, comprehensive synthesis of the quantitative research on transformational school leadership. The review method used in this research is standard meta-analysis supplemented by narrative synthesis and vote-counting methods. The types of effect sizes involved in meta-analytical calculations are correlation coefficients rs. The evidence reviewed was provided exclusively by unpublished theses or dissertations that were completed between 1996 and 2008. This study identified 33 dimensions of transformational leadership as developed by various scholars and captured by a variety of leadership measures, which were synthesized into 11 core leadership dimensions. This study meta-analyzed the effects of transformational school leadership and its dimensions on a large range of school outcomes, including 17 school conditions (e.g., school culture, shared decision-making processes), 23 teacher-related outcomes (e.g., teacher satisfaction), and five types of student outcomes. Transformational school leadership was most influential on teachers’ emotions and inner states. TSL had large effects on teachers’ individual inner states and their practices while it had small effects on their group inner states. Leaders effectively influence teachers’ psychological inner states and practices mainly through modeling good practices themselves, providing support and intellectual stimulation to teachers individually and setting shared school goals. TSL was also very influential on school conditions. It had large effects on four key school conditions. This review detected significant, positive small direct effects of TSL on student achievements. The indirect effects of TSL on student learning vary when different school or teacher variables are controlled. This review identified seven important moderators and three mediators that significantly contributed to student learning along with TSL. Specific leadership practices that effectively influenced school and student outcomes were also examined and discussed. Regarding the moderating effects of contextual and methodological factors, school level and leadership measures were found to moderate leadership impacts significantly in some cases. The findings of this study provide guidance for school administrators and policy makers who want to improve school leadership as a means of improving school quality.

Antiplatelet therapy with clopidogrel is widely used in patients with coronary artery disease, but the recent development of the new P2Y12 receptor antagonists prasugrel and ticagrelor will increase treatment options. An overview of systematic reviews was performed to summarize available evidence on clopidogrel. Current data on prasugrel and ticagrelor were identified by a systematic review and used for an indirect treatment comparison (ITC) of the drugs against each other and versus placebo in the absence of head-to-head clinical trials. Adjusted indirect comparison according to Bucher, Bayesian methods for mixed treatment comparisons using Winbugs, and generalized linear mixed models using SAS were employed for ITC, yielding almost identical results: prasugrel was favored regarding stent thrombosis and ticagrelor regarding major bleeding. However, substantial differences in trial design were identified, demanding caution when interpreting these results. On the basis of the obtained results, a randomized controlled trial was designed within the gap of current evidence.