Influence of phytohormones on seed germination of Solanum linnaeanum

The aim of this study was to determine the germination ability and seedling growth of the apple of Sodom by soaking in water, gibberellin (GA3), naphthylacetic acid (NAA), and salicylic acid (SA), separately. The findings showed that NAA at 50 mgL-1 produced superior germination (77.78%), germination speed (1.43 seeds/time interval), hypocotyl length (1.01 cm), hypocotyl diameter (1.13 mm), leaf number (2.66), and root number (17.25), followed by 50 and 100 mgL-1 GA3, particularly in germination percentage. The best root length (5.33 cm) was detected at 100 mgL-1 SA. In contrast, control seeds and water-soaked seeds showed inferior results. The seeds of the apple of Sodom can be germinated successfully as a result of treatment with NAA at 50 mgL-1, followed by GA3 at 50 and 100 mgL-1

Implementing GIS and linear regression models to investigate partial building failures

One of the most dangerous field problems in the civil engineering discipline is the suddenly developed cracks in the building, which could be caused by the swelling of the subsurface soil. Thus, this work has focused on employing a procedure in the geographic information system known as the inverse distance weighted (IDW) technique, to analyze the extent of cracks in a residential complex in the city of Kirkuk in Iraq using the physical and chemical soil data for seven boreholes from the field of the study. Physical soil parameters such as liquid limit (LL), gravel, sand, silt and clay percentages were characterized first, followed by chemical properties such as gypsum content (GYP), total suspended solids (TSS), potential of hydrogen (pH), and organic content (ORG). Furthermore, statistical studies such as plasticity index (PI) and soil characteristics association, linear single, and various linear multi-regression models were used. The data analysis shows that there are significantly positive and negative relationships between PI as a swelling indicator and the physical and chemical soil properties, although weak to moderate correlations were observed between PI and these variables. The PI values were accurately predicted by the proposed linear multi-regression models of the physical and integrated physical and chemical soil characteristics, with multiple R values of 0.92 for both models. As a result, the suggested statistical models can provide complete geographic and mechanical explanations for the crack sources in the investigated residential complex

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Detailed, comprehensive, and timely reporting on population health by underlying causes of disability and premature death is crucial to understanding and responding to complex patterns of disease and injury burden over time and across age groups, sexes, and locations. The availability of disease burden estimates can promote evidence-based interventions that enable public health researchers, policy makers, and other professionals to implement strategies that can mitigate diseases. It can also facilitate more rigorous monitoring of progress towards national and international health targets, such as the Sustainable Development Goals. For three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has filled that need. A global network of collaborators contributed to the production of GBD 2021 by providing, reviewing, and analysing all available data. GBD estimates are updated routinely with additional data and refined analytical methods. GBD 2021 presents, for the first time, estimates of health loss due to the COVID-19 pandemic. Methods: The GBD 2021 disease and injury burden analysis estimated years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries using 100 983 data sources. Data were extracted from vital registration systems, verbal autopsies, censuses, household surveys, disease-specific registries, health service contact data, and other sources. YLDs were calculated by multiplying cause-age-sex-location-year-specific prevalence of sequelae by their respective disability weights, for each disease and injury. YLLs were calculated by multiplying cause-age-sex-location-year-specific deaths by the standard life expectancy at the age that death occurred. DALYs were calculated by summing YLDs and YLLs. HALE estimates were produced using YLDs per capita and age-specific mortality rates by location, age, sex, year, and cause. 95% uncertainty intervals (UIs) were generated for all final estimates as the 2·5th and 97·5th percentiles values of 500 draws. Uncertainty was propagated at each step of the estimation process. Counts and age-standardised rates were calculated globally, for seven super-regions, 21 regions, 204 countries and territories (including 21 countries with subnational locations), and 811 subnational locations, from 1990 to 2021. Here we report data for 2010 to 2021 to highlight trends in disease burden over the past decade and through the first 2 years of the COVID-19 pandemic. Findings: Global DALYs increased from 2·63 billion (95% UI 2·44–2·85) in 2010 to 2·88 billion (2·64–3·15) in 2021 for all causes combined. Much of this increase in the number of DALYs was due to population growth and ageing, as indicated by a decrease in global age-standardised all-cause DALY rates of 14·2% (95% UI 10·7–17·3) between 2010 and 2019. Notably, however, this decrease in rates reversed during the first 2 years of the COVID-19 pandemic, with increases in global age-standardised all-cause DALY rates since 2019 of 4·1% (1·8–6·3) in 2020 and 7·2% (4·7–10·0) in 2021. In 2021, COVID-19 was the leading cause of DALYs globally (212·0 million [198·0–234·5] DALYs), followed by ischaemic heart disease (188·3 million [176·7–198·3]), neonatal disorders (186·3 million [162·3–214·9]), and stroke (160·4 million [148·0–171·7]). However, notable health gains were seen among other leading communicable, maternal, neonatal, and nutritional (CMNN) diseases. Globally between 2010 and 2021, the age-standardised DALY rates for HIV/AIDS decreased by 47·8% (43·3–51·7) and for diarrhoeal diseases decreased by 47·0% (39·9–52·9). Non-communicable diseases contributed 1·73 billion (95% UI 1·54–1·94) DALYs in 2021, with a decrease in age-standardised DALY rates since 2010 of 6·4% (95% UI 3·5–9·5). Between 2010 and 2021, among the 25 leading Level 3 causes, age-standardised DALY rates increased most substantially for anxiety disorders (16·7% [14·0–19·8]), depressive disorders (16·4% [11·9–21·3]), and diabetes (14·0% [10·0–17·4]). Age-standardised DALY rates due to injuries decreased globally by 24·0% (20·7–27·2) between 2010 and 2021, although improvements were not uniform across locations, ages, and sexes. Globally, HALE at birth improved slightly, from 61·3 years (58·6–63·6) in 2010 to 62·2 years (59·4–64·7) in 2021. However, despite this overall increase, HALE decreased by 2·2% (1·6–2·9) between 2019 and 2021. Interpretation: Putting the COVID-19 pandemic in the context of a mutually exclusive and collectively exhaustive list of causes of health loss is crucial to understanding its impact and ensuring that health funding and policy address needs at both local and global levels through cost-effective and evidence-based interventions. A global epidemiological transition remains underway. Our findings suggest that prioritising non-communicable disease prevention and treatment policies, as well as strengthening health systems, continues to be crucially important. The progress on reducing the burden of CMNN diseases must not stall; although global trends are improving, the burden of CMNN diseases remains unacceptably high. Evidence-based interventions will help save the lives of young children and mothers and improve the overall health and economic conditions of societies across the world. Governments and multilateral organisations should prioritise pandemic preparedness planning alongside efforts to reduce the burden of diseases and injuries that will strain resources in the coming decades. Funding: Bill & Melinda Gates Foundation

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions

Granulocyte-macrophage colony-stimulating factor: expression and regulation in human immune responses with relevance to multiple sclerosis

Background: Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) is a haematopoietic growth factor and a pro-inflammatory cytokine produced by T cells and other immune cells. Recent evidence suggests that GM-CSF plays an important role in multiple sclerosis (MS) pathogenesis. Few recent studies have detected GM-CSF expression by immune cells in MS. In this thesis, the expression of GM-CSF and its receptor by different subtypes of peripheral blood mononuclear cells (PBMCs) in MS was investigated. In addition, GM-CSF regulation was studied in the above-mentioned cells in MS. Finally, GM-CSF neutralization was performed in a phase Ib clinical trial, and some immune-related effects were investigated. Aims: To evaluate the expression of GM-CSF and its receptor by PBMC subsets in MS; to determine the key factors regulating their expression by PBMC subsets in MS; to detect the differentiation of helper T cells producing GM-CSF (Th-GM) in MS patients, and to detect the frequency of immune cells after GM-CSF neutralization in MS in vivo. Subjects and Methods: Patients were mainly untreated relapsing-remitting MS (RRMS) during remission stage, and some were MS patients during a relapse. Healthy controls were also enrolled. All subjects consented to participation in the study before donating peripheral blood. PBMCs were isolated using Ficoll density gradient centrifugation. Flow cytometry and q-PCR were used to detect the expression of GM-CSF and its receptor. Multiplex bead assay was used to quantify GM-CSF with other pro-inflammatory and anti-inflammatory cytokines. Results: The frequency of stimulated GM-CSF-expressing cells (helper T (Th), cytotoxic T (Tc), monocytes, NK cells, and B cells) is significantly higher in the mixed PBMC population of untreated RRMS patients when compared to healthy volunteers. The frequency of Th1 cells expressing GM-CSF was higher in MS patients than healthy controls. The expression of GM-CSF by isolated and stimulated NK cells was not different in MS patients and controls. PBMC culture supernatants were shown to contain significantly higher concentrations of IL-2, IL-12, IL-1β, and GM-CSF in MS patients than controls. Blocking IL-2 and IL-12 significantly reduced GM-CSF expression by Tc, NK, and B cells in MS patients, but not in healthy controls. MS patients during relapse had significantly higher frequency of Th-GM (CD3+CD8-IL-17-IFN-γ-IL-3+GM-CSF+) cells than healthy controls. EBV infected B cells expressed GM-CSF receptor in less frequency than non-infected B cells. In vivo GM-CSF neutralization in MS patients resulted in significant reduction in the frequency of CD8+ T cells and CD4+CD45RA+CD25++ (naïve) Tregs and an increase in CD4+CD35+foxp3 (total) Tregs. Conclusions: Th1 (and Th in general), Tc, monocytes, NK and B cells are all high producers of GM-CSF in MS. IL-2 and IL-12 are the main regulators of GM-CSF expression by Tc, NK, and B cells in MS patients. GM-CSF and its receptor may not be major survival or proliferation factors for EBV infected B cells. The newly identified Th-GM cells were detected in higher frequency in MS patients during relapse, which may suggest a new source for GM-CSF production in MS. The recent safety, tolerability, and immune-related results of GM-CSF neutralization in MS are encouraging. Therefore, GM-CSF is a potential therapeutic target in MS

Granulocyte-macrophage colony-stimulating factor: expression and regulation in human immune responses with relevance to multiple sclerosis

Background: Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) is a haematopoietic growth factor and a pro-inflammatory cytokine produced by T cells and other immune cells. Recent evidence suggests that GM-CSF plays an important role in multiple sclerosis (MS) pathogenesis. Few recent studies have detected GM-CSF expression by immune cells in MS. In this thesis, the expression of GM-CSF and its receptor by different subtypes of peripheral blood mononuclear cells (PBMCs) in MS was investigated. In addition, GM-CSF regulation was studied in the above-mentioned cells in MS. Finally, GM-CSF neutralization was performed in a phase Ib clinical trial, and some immune-related effects were investigated. Aims: To evaluate the expression of GM-CSF and its receptor by PBMC subsets in MS; to determine the key factors regulating their expression by PBMC subsets in MS; to detect the differentiation of helper T cells producing GM-CSF (Th-GM) in MS patients, and to detect the frequency of immune cells after GM-CSF neutralization in MS in vivo. Subjects and Methods: Patients were mainly untreated relapsing-remitting MS (RRMS) during remission stage, and some were MS patients during a relapse. Healthy controls were also enrolled. All subjects consented to participation in the study before donating peripheral blood. PBMCs were isolated using Ficoll density gradient centrifugation. Flow cytometry and q-PCR were used to detect the expression of GM-CSF and its receptor. Multiplex bead assay was used to quantify GM-CSF with other pro-inflammatory and anti-inflammatory cytokines. Results: The frequency of stimulated GM-CSF-expressing cells (helper T (Th), cytotoxic T (Tc), monocytes, NK cells, and B cells) is significantly higher in the mixed PBMC population of untreated RRMS patients when compared to healthy volunteers. The frequency of Th1 cells expressing GM-CSF was higher in MS patients than healthy controls. The expression of GM-CSF by isolated and stimulated NK cells was not different in MS patients and controls. PBMC culture supernatants were shown to contain significantly higher concentrations of IL-2, IL-12, IL-1β, and GM-CSF in MS patients than controls. Blocking IL-2 and IL-12 significantly reduced GM-CSF expression by Tc, NK, and B cells in MS patients, but not in healthy controls. MS patients during relapse had significantly higher frequency of Th-GM (CD3+CD8-IL-17-IFN-γ-IL-3+GM-CSF+) cells than healthy controls. EBV infected B cells expressed GM-CSF receptor in less frequency than non-infected B cells. In vivo GM-CSF neutralization in MS patients resulted in significant reduction in the frequency of CD8+ T cells and CD4+CD45RA+CD25++ (naïve) Tregs and an increase in CD4+CD35+foxp3 (total) Tregs. Conclusions: Th1 (and Th in general), Tc, monocytes, NK and B cells are all high producers of GM-CSF in MS. IL-2 and IL-12 are the main regulators of GM-CSF expression by Tc, NK, and B cells in MS patients. GM-CSF and its receptor may not be major survival or proliferation factors for EBV infected B cells. The newly identified Th-GM cells were detected in higher frequency in MS patients during relapse, which may suggest a new source for GM-CSF production in MS. The recent safety, tolerability, and immune-related results of GM-CSF neutralization in MS are encouraging. Therefore, GM-CSF is a potential therapeutic target in MS

Implementing GIS and linear regression models to investigate partial building failures

One of the most dangerous field problems in the civil engineering discipline is the suddenly developed cracks in the building, which could be caused by the swelling of the subsurface soil. Thus, this work has focused on employing a procedure in the geographic information system known as the inverse distance weighted (IDW) technique, to analyze the extent of cracks in a residential complex in the city of Kirkuk in Iraq using the physical and chemical soil data for seven boreholes from the field of the study. Physical soil parameters such as liquid limit (LL), gravel, sand, silt and clay percentages were characterized first, followed by chemical properties such as gypsum content (GYP), total suspended solids (TSS), potential of hydrogen (pH), and organic content (ORG). Furthermore, statistical studies such as plasticity index (PI) and soil characteristics association, linear single, and various linear multi-regression models were used. The data analysis shows that there are significantly positive and negative relationships between PI as a swelling indicator and the physical and chemical soil properties, although weak to moderate correlations were observed between PI and these variables. The PI values were accurately predicted by the proposed linear multi-regression models of the physical and integrated physical and chemical soil characteristics, with multiple R values of 0.92 for both models. As a result, the suggested statistical models can provide complete geographic and mechanical explanations for the crack sources in the investigated residential complex

Students Deviant Behavior Views of Dormitories in Sites of Iran University of Medical Sciences in Tehran - 2005

Objective: this research was conducted to determine the attitude of dormitory students in the university of IRAN medical medical sciences a bout existing deviant behavior in dormitories. Materials & Methods: The present study is a descriptive and cross sectional one, which was completed in the year 1383. The ultimate goal of the research is determining of the attitude of dormitory students regarding the existence of Deviant behavior among the students. In order to achieve the main objective, 325 students were selected through random sampling out of 2014 students (183 boys and 187 girls). Results: The results are as follows: More than 50% of the students believe that, living in dormitory is one of the best period of their whole life. 41.7% found dormitory as a place to take rest after the class. 53.4% believe that marriage can fulfill firstly the affection needs and secondly the sexual needs as well. 86.3% thing that roommate from different provinces leads to maladjustment. Conclusion: There are some other factors to raise deviant behavior such as: - Limitation in social relation among the students in the university in 55.7%. - Existing social problems in the social structure which prevent marriage in 40.9%. - Family Conflicts and quarrels in 65.6%. - Deprivation of having relation with opposite gender in 79.3%

Anidulafungin for the treatment of candidaemia caused by Candida parapsilosis: Analysis of pooled data from six prospective clinical studies

Concerns with echinocandin use for infections caused by Candida parapsilosis complex species have driven the need for data to support echinocandin clinical efficacy in such patients. Data from six prospective studies were pooled to assess efficacy and safety of anidulafungin in patients with candidaemia caused by C. parapsilosis. Patient-level data were pooled from patients with microbiologically confirmed candidaemia due to C. parapsilosis treated with anidulafungin. Patients received a 200 mg intravenous (IV) loading dose of anidulafungin (day 1) and 100 mg daily thereafter. IV treatment could be switched to oral azole therapy after 655 or 6510 days. Primary endpoint was global response at end of IV therapy (EOIVT). Seventy patients had candidaemia caused by C. parapsilosis. Global response was 77.1% (95% CI: 67.3, 87.0) at EOIVT and 70.0% (95% CI: 59.3, 80.7) at end of treatment. Three of 55 isolates (with MICs available) were resistant to anidulafungin (MIC 658 mg/L). All-cause mortality was 5.7% (n=4/70) by day 14 and 14.3% (n=10/70) by day 28. IV anidulafungin was effective for the treatment of C. parapsilosis candidaemia in this population, consistent with efficacy previously demonstrated for other Candida species. (ClinicalTrials.gov identifiers: NCT00496197, NCT00548262, NCT00537329, NCT00689338, NCT00806351, NCT00805740)