Individual patient data meta-analysis of diagnostic and prognostic studies in obstetrics, gynaecology and reproductive medicine

BACKGROUND: In clinical practice a diagnosis is based on a combination of clinical history, physical examination and additional diagnostic tests. At present, studies on diagnostic research often report the accuracy of tests without taking into account the information already known from history and examination. Due to this lack of information, together with variations in design and quality of studies, conventional meta-analyses based on these studies will not show the accuracy of the tests in real practice. By using individual patient data (IPD) to perform meta-analyses, the accuracy of tests can be assessed in relation to other patient characteristics and allows the development or evaluation of diagnostic algorithms for individual patients. In this study we will examine these potential benefits in four clinical diagnostic problems in the field of gynaecology, obstetrics and reproductive medicine. METHODS/DESIGN: Based on earlier systematic reviews for each of the four clinical problems, studies are considered for inclusion. The first authors of the included studies will be invited to participate and share their original data. After assessment of validity and completeness the acquired datasets are merged. Based on these data, a series of analyses will be performed, including a systematic comparison of the results of the IPD meta-analysis with those of a conventional meta-analysis, development of multivariable models for clinical history alone and for the combination of history, physical examination and relevant diagnostic tests and development of clinical prediction rules for the individual patients. These will be made accessible for clinicians. DISCUSSION: The use of IPD meta-analysis will allow evaluating accuracy of diagnostic tests in relation to other relevant information. Ultimately, this could increase the efficiency of the diagnostic work-up, e.g. by reducing the need for invasive tests and/or improving the accuracy of the diagnostic workup. This study will assess whether these benefits of IPD meta-analysis over conventional meta-analysis can be exploited and will provide a framework for future IPD meta-analyses in diagnostic and prognostic research.

Subclinical thyroid dysfunction and cardiovascular outcomes among prospective cohort studies

The association between subclinical thyroid dysfunction and cardiovascular outcomes has been recently clarified with the publication of three individual participant data (IPD) analyses from the Thyroid Studies Collaboration. We identified original cohort studies with a systematic review and pooled individual data from over 70'000 participants to obtain a more precise estimate of the risks of cardiovascular outcomes associated with subclinical thyroid dysfunction. Subclinical hypothyroidism and subclinical hyperthyroidism, defined as normal thyroxine (FT4) levels with increased or decreased Thyroid-Stimulating Hormones (TSH or thyrotropin) respectively, are associated with increased risk of cardiovascular outcomes compared to euthyroid state, particularly in those with a more pronounced thyroid dysfunction. Specifically, subclinical hypothyroidism is associated with an increased risk of coronary heart disease (CHD) events, CHD mortality and heart failure (HF) events in individuals with higher TSH levels, particularly in those with TSH levels ≥10.0 mIU/L. Conversely, subclinical hyperthyroidism is associated with an increased risk of total mortality, CHD mortality, HF and atrial fibrillation, particularly in those with suppressed TSH levels <0.10 mIU/L. Pending ongoing randomized controlled trials, these observational findings allow identifying potential TSH thresholds for thyroid medication initiation based on risk of clinical outcomes, although clinical decision based solely on observational data need caution. The impact of thyroid replacement among the elderly with subclinical hypothyroidism is currently studied in a multicenter international randomized controlled trial (Thyroid Hormone Replacement for Subclinical Hypothyroidism Trial, TRUST trial).

Serotype epidemiology of invasive pneumococcal disease in Swiss adults: A nationwide population-based study.

BACKGROUND In Switzerland, the heptavalent (PCV7) and 13-valent pneumococcal conjugate vaccine (PCV13) were recommended for all infants aged <2 years in 2007 and 2011, respectively. Due to herd effects, a protective impact on the invasive pneumococcal disease (IPD) rates in adults had been expected. METHODS Within this study, data from the nationwide mandatory surveillance was analyzed for all adult patients ≥16 years with IPD of known serotype/serogroup during 2003-2012. Trend (for IPD cases from 2003 to 2012) and logistic regression analyses (2007-2010) were performed to identify changes in serotype distribution and to identify the association of serotypes with age, clinical manifestations, comorbidities and case fatality, respectively. FINDINGS The proportion of PCV7 serotypes among all IPD cases (n=7678) significantly declined in adults from 44.7% (2003) before to 16.7% (2012) after the recommendation of PCV7 (P<0.001). In contrast, the proportion of non-PCV7 serogroup/serotypes increased for non-PCV13 but also PCV13 serotypes (not included in PCV7) at the same time. Serotype distribution varied significantly across ages, clinical manifestations and comorbidities. Serotype was furthermore associated with case fatality (P=0.001). In a multivariable logistic regression model, analyzing single serotypes showed that case-fatality was increased for the serotypes 3 (P=0.008), 19A (P=0.03) and 19F (P=0.005), compared to serotype 1 and 7F. CONCLUSION There was a significant decline in PCV7 serotypes among adults with IPD in Switzerland after introduction of childhood vaccination with PCV7. Pneumococcal serotypes were associated with case fatality, age, clinical manifestation and comorbidities of IPD in adults. These results may prove useful for future vaccine recommendations for adults in Switzerland.

Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis.

BACKGROUND Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC. METHODS AND FINDINGS Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15-49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24-1.83) for DMPA use, 1.24 (95% CI 0.84-1.82) for NET-EN use, and 1.03 (95% CI 0.88-1.20) for COC use. Between-study heterogeneity was mild (I2 < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23-1.67) and NET-EN use (aHR 1.32, 95% CI 1.08-1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99-1.50; for NET-EN use 0.67, 95% CI 0.47-0.96; and for COC use 0.91, 95% CI 0.73-1.41) compared to those at higher risk of bias (pinteraction = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC-HIV relationship. CONCLUSIONS This IPD meta-analysis found no evidence that COC or NET-EN use increases women's risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.

Cognitive-Behavioural Analysis System of Psychotherapy (CBASP), a drug, or their combination: differential therapeutics for persistent depressive disorder: a study protocol of an individual participant data network meta-analysis.

INTRODUCTION Despite important advances in psychological and pharmacological treatments of persistent depressive disorders in the past decades, their responses remain typically slow and poor, and differential responses among different modalities of treatments or their combinations are not well understood. Cognitive-Behavioural Analysis System of Psychotherapy (CBASP) is the only psychotherapy that has been specifically designed for chronic depression and has been examined in an increasing number of trials against medications, alone or in combination. When several treatment alternatives are available for a certain condition, network meta-analysis (NMA) provides a powerful tool to examine their relative efficacy by combining all direct and indirect comparisons. Individual participant data (IPD) meta-analysis enables exploration of impacts of individual characteristics that lead to a differentiated approach matching treatments to specific subgroups of patients. METHODS AND ANALYSIS We will search for all randomised controlled trials that compared CBASP, pharmacotherapy or their combination, in the treatment of patients with persistent depressive disorder, in Cochrane CENTRAL, PUBMED, SCOPUS and PsycINFO, supplemented by personal contacts. Individual participant data will be sought from the principal investigators of all the identified trials. Our primary outcomes are depression severity as measured on a continuous observer-rated scale for depression, and dropouts for any reason as a proxy measure of overall treatment acceptability. We will conduct a one-step IPD-NMA to compare CBASP, medications and their combinations, and also carry out a meta-regression to identify their prognostic factors and effect moderators. The model will be fitted in OpenBUGS, using vague priors for all location parameters. For the heterogeneity we will use a half-normal prior on the SD. ETHICS AND DISSEMINATION This study requires no ethical approval. We will publish the findings in a peer-reviewed journal. The study results will contribute to more finely differentiated therapeutics for patients suffering from this chronically disabling disorder. TRIAL REGISTRATION NUMBER CRD42016035886.

Burden of invasive pneumococcal disease in Harris County, Texas (2003--2010) and the implication for enhanced public health surveillance of isolates

Invasive pneumococcal disease (IPD) causes significant health burden in the US, is responsible for the majority of bacterial meningitis, and causes more deaths than any other vaccine preventable bacterial disease in the US. The estimated National IPD rate is 14.3 cases per 100,000 population with a case-fatality rate of 1.5 cases per 100,000 population. Although cases of IPD are routinely reported to the local health department in Harris County Texas, the incidence (IR) and case-fatality (CFR) rates have not been reported. Additionally, it is important to know which serotypes of S. pneumoniae are circulating in Harris County Texas and to determine if ‘replacement disease’ is occurring. ^ This study reported incidence and case-fatality rates from 2003 to 2009, and described the trends in IPD, including the IPD serotypes circulating in Harris County Texas during the study period, particularly in 2008 and 2010. Annual incidence rates were calculated and reported for 2003 to 2009, using complete surveillance-year data. ^ Geographic information system (GIS) software was used to create a series of maps of the data reported during the study period. Cluster and outlier analysis and hot spot analysis were conducted using both case counts by census tract and disease rate by census tract. ^ IPD age- and race-adjusted IR for Harris County Texas and their 95% confidence intervals (CIs) were 1.40 (95% CI 1.0, 1.8), 1.71 (95% CI 1.24, 2.17), 3.13 (95% CI 2.48, 3.78), 3.08 (95% CI 2.43, 3.74), 5.61 (95% CI 4.79, 6.43), 8.11 (95% CI 7.11, 9.1), and 7.65 (95% CI 6.69, 8.61) for the years 2003 to 2009, respectively (rates were age- and race-adjusted to each year's midyear US population estimates). A Poisson regression model demonstrated a statistically significant increasing trend of about 32 percent per year in the IPD rates over the course of the study period. IPD age- and race-adjusted case-fatality rates (CFR) for Harris County Texas were also calculated and reported. A Poisson regression model demonstrated a statistically significant increasing trend of about 26 percent per year in the IPD case-fatality rates from 2003 through 2009. A logistic regression model associated the risk of dying from IPD to alcohol abuse (OR 4.69, 95% CI 2.57, 8.56) and to meningitis (OR 2.42, 95% CI 1.46, 4.03). ^ The prevalence of non-vaccine serotypes (NVT) among IPD cases with serotyped isolates was 98.2 percent. In 2008, the year with the sample more geographically representative of all areas of Harris County Texas, the prevalence was 96 percent. Given these findings, it is reasonable to conclude that ‘replacement disease’ is occurring in Harris County Texas, meaning that, the majority of IPD is caused by serotypes not included in the PCV7 vaccine. Also in conclusion, IPD rates increased during the study period in Harris County Texas.^

Elaboración de un Índice de Privaciones para los Departamentos de la Provincia de Mendoza

Conocer las realidades departamentales es un factor primordial para la eficacia de las políticas públicas. Actualmente la divergencia que existe entre el accionar del Estado y las reales necesidades y preferencias de los ciudadanos se debe en gran parte a la falta de información acerca de ellas. El presente trabajo tiene como objetivo acortar esa brecha a través del cálculo del Índice de Privaciones Departamentales (IPD) para el periodo 2001 a 2010, ampliando y profundizando el estudio de las carencias departamentales iniciado en “Pobreza y Distribución del Ingreso en Mendoza: 1980 – 2008". Con esta investigación se pretende entonces describir y comparar las situaciones de cada municipio y establecer pautas que ayuden a optimizar y focalizar más adecuadamente la elaboración de políticas públicas destinadas a reducir las carencias de cada departamento. El IPD está basado en el Índice de Desarrollo Humano (en adelante, IDH) que mide Naciones Unidas y que considera tres aspectos básicos para el desarrollo: vida larga y saludable, educación y nivel de vida digno. El Índice aquí calculado buscará reflejar estos aspectos pero bajo la forma de carencias, involucrando una mayor cantidad de variables, de manera que permitan perfeccionar el análisis y brindar información más amplia y certera.

Hypsographic demography: The distribution of human population by altitude

The global distribution of the human population by elevation is quantified here. As of 1994, an estimated 1.88 × 109 people, or 33.5% of the world’s population, lived within 100 vertical meters of sea level, but only 15.6% of all inhabited land lies below 100 m elevation. The median person lived at an elevation of 194 m above sea level. Numbers of people decreased faster than exponentially with increasing elevation. The integrated population density (IPD, the number of people divided by the land area) within 100 vertical meters of sea level was significantly larger than that of any other range of elevations and represented far more people. A significant percentage of the low-elevation population lived at moderate population densities rather than at the highest densities of central large cities. Assessments of coastal hazards that focus only on large cities may substantially underestimate the number of people who could be affected.

Types of evolutionary stability and the problem of cooperation.

The evolutionary stability of cooperation is a problem of fundamental importance for the biological and social sciences. Different claims have been made about this issue: whereas Axelrod and Hamilton's [Axelrod, R. & Hamilton, W. (1981) Science 211, 1390-1398] widely recognized conclusion is that cooperative rules such as "tit for tat" are evolutionarily stable strategies in the iterated prisoner's dilemma (IPD), Boyd and Lorberbaum [Boyd, R. & Lorberbaum, J. (1987) Nature (London) 327, 58-59] have claimed that no pure strategy is evolutionarily stable in this game. Here we explain why these claims are not contradictory by showing in what sense strategies in the IPD can and cannot be stable and by creating a conceptual framework that yields the type of evolutionary stability attainable in the IPD and in repeated games in general. Having established the relevant concept of stability, we report theorems on some basic properties of strategies that are stable in this sense. We first show that the IPD has "too many" such strategies, so that being stable does not discriminate among behavioral rules. Stable strategies differ, however, on a property that is crucial for their evolutionary survival--the size of the invasion they can resist. This property can be interpreted as a strategy's evolutionary robustness. Conditionally cooperative strategies such as tit for tat are the most robust. Cooperative behavior supported by these strategies is the most robust evolutionary equilibrium: the easiest to attain, and the hardest to disrupt.

Integrated construction project delivery system in the U.S. public sector: An information modeling framework

Integrated project delivery (IPD) method has recently emerged as an alternative to traditional delivery methods. It has the potential to overcome inefficiencies of traditional delivery methods by enhancing collaboration among project participants. Information and communication technology (ICT) facilitates IPD by effective management, processing and communication of information within and among organizations. While the benefits of IPD, and the role of ICT in realizing them, have been generally acknowledged, the US public construction sector is very slow in adopting IPD. The reasons are - lack of experience and inadequate understanding of IPD in public owner as confirmed by the results of the questionnaire survey conducted under this research study. The public construction sector should be aware of the value of IPD and should know the essentials for effective implementation of IPD principles - especially, they should be cognizant of the opportunities offered by advancements in ICT to realize this.^ In order to address the need an IPD Readiness Assessment Model (IPD-RAM) was developed in this research study. The model was designed with a goal to determine IPD readiness of a public owner organization considering selected IPD principles, and ICT levels, at which project functions were carried out. Subsequent analysis led to identification of possible improvements in ICTs that have the potential to increase IPD readiness scores. Termed as the gap identification, this process was used to formulate improvement strategies. The model had been applied to six Florida International University (FIU) construction projects (case studies). The results showed that the IPD readiness of the organization was considerably low and several project functions can be improved by using higher and/or advanced level ICT tools and methods. Feedbacks from a focus group comprised of FIU officials and an independent group of experts had been received at various stages of this research and had been utilized during development and implementation of the model. Focus group input was also helpful for validation of the model and its results. It was hoped that the model developed would be useful to construction owner organizations in order to assess their IPD readiness and to identify appropriate ICT improvement strategies.^

Time, Cost, and Environmental Impact Analysis for Sustainable Design at Multiple Building Levels

Construction projects are complex endeavors that require the involvement of different professional disciplines in order to meet various project objectives that are often conflicting. The level of complexity and the multi-objective nature of construction projects lend themselves to collaborative design and construction such as integrated project delivery (IPD), in which relevant disciplines work together during project conception, design and construction. Traditionally, the main objectives of construction projects have been to build in the least amount of time with the lowest cost possible, thus the inherent and well-established relationship between cost and time has been the focus of many studies. The importance of being able to effectively model relationships among multiple objectives in building construction has been emphasized in a wide range of research. In general, the trade-off relationship between time and cost is well understood and there is ample research on the subject. However, despite sustainable building designs, relationships between time and environmental impact, as well as cost and environmental impact, have not been fully investigated. The objectives of this research were mainly to analyze and identify relationships of time, cost, and environmental impact, in terms of CO2 emissions, at different levels of a building: material level, component level, and building level, at the pre-use phase, including manufacturing and construction, and the relationships of life cycle cost and life cycle CO2 emissions at the usage phase. Additionally, this research aimed to develop a robust simulation-based multi-objective decision-support tool, called SimulEICon, which took construction data uncertainty into account, and was capable of incorporating life cycle assessment information to the decision-making process. The findings of this research supported the trade-off relationship between time and cost at different building levels. Moreover, the time and CO2 emissions relationship presented trade-off behavior at the pre-use phase. The results of the relationship between cost and CO2 emissions were interestingly proportional at the pre-use phase. The same pattern continually presented after the construction to the usage phase. Understanding the relationships between those objectives is a key in successfully planning and designing environmentally sustainable construction projects.

Caracterización de un modelo murino de glaucoma: implicación funcional de la señalización del receptor P2X7 en procesos neurodegenerativos de la retina

El glaucoma es una de las causas más comunes de discapacidad visual y una de las enfermedades neurodegenerativas oculares más frecuentes de pérdida irreversible de visión. La afectación originada en la retina se caracteriza por la degeneración de las células ganglionares y la pérdida de axones. La presión intraocular es un factor de riesgo importante en el glaucoma, entre otros factores, implicando mecanismos bioquímicos que desencadenan la muerte de las células ganglionares. El ratón DBA/2J es un modelo de hipertensión ocular y de degeneración de las células ganglionares de la retina (CGR). Las características principales de éste son la dispersión del pigmento del iris (IPD) y la atrofia del estroma del iris (ISA) que conducen a la patogénesis del glaucoma. Los mecanismos bioquímicos que comprometen al sistema purinérgico en procesos patológicos como la degeneración glaucomatosa han sido estudiados en los últimos años, siendo de gran relevancia como posibles dianas farmacológicas para el tratamiento de diferentes neuropatías. Los receptores P2X comprenden una familia de siete canales iónicos de membrana activados por ligando (P2X1-7) que se activan por el ATP extracelular (ATPe). En particular, los receptores P2X7 podrían estar involucrados en la regulación de la transmisión sináptica y la muerte neuronal en la retina. Además, la excitotoxicidad mediada por ATP a través de la activación del receptor P2X7 sugiere su posible implicación en la degeneración neuronal y la pérdida de la función visual en las retinas glaucomatosas. Tan importante como la presencia de este receptor purinérgico es estudiar los niveles de ATP extracelular de la retina, así como evaluar los cambios en la expresión del transportador de nucleótidos vesicular (VNUT) y los niveles de ecto-nucleotidasa (E-NPP1) en este modelo murino de glaucoma durante el desarrollo de la enfermedad...

Integrated Construction Project Delivery System in the U.S. Public Sector: An Information Modeling Framework

Integrated project delivery (IPD) method has recently emerged as an alternative to traditional delivery methods. It has the potential to overcome inefficiencies of traditional delivery methods by enhancing collaboration among project participants. Information and communication technology (ICT) facilitates IPD by effective management, processing and communication of information within and among organizations. While the benefits of IPD, and the role of ICT in realizing them, have been generally acknowledged, the US public construction sector is very slow in adopting IPD. The reasons are - lack of experience and inadequate understanding of IPD in public owner as confirmed by the results of the questionnaire survey conducted under this research study. The public construction sector should be aware of the value of IPD and should know the essentials for effective implementation of IPD principles - especially, they should be cognizant of the opportunities offered by advancements in ICT to realize this. In order to address the need an IPD Readiness Assessment Model (IPD-RAM) was developed in this research study. The model was designed with a goal to determine IPD readiness of a public owner organization considering selected IPD principles, and ICT levels, at which project functions were carried out. Subsequent analysis led to identification of possible improvements in ICTs that have the potential to increase IPD readiness scores. Termed as the gap identification, this process was used to formulate improvement strategies. The model had been applied to six Florida International University (FIU) construction projects (case studies). The results showed that the IPD readiness of the organization was considerably low and several project functions can be improved by using higher and/or advanced level ICT tools and methods. Feedbacks from a focus group comprised of FIU officials and an independent group of experts had been received at various stages of this research and had been utilized during development and implementation of the model. Focus group input was also helpful for validation of the model and its results. It was hoped that the model developed would be useful to construction owner organizations in order to assess their IPD readiness and to identify appropriate ICT improvement strategies.

The institutional design of intra-party democracy through legal instruments: Turkish case

The importance of political parties for contemporary representative democracies is beyond dispute. Despite their significance for state-level democracy, political parties continue to be regarded as oligarchical and to be criticised because of their internal practices. For this reason, intra-party democracy (IPD) warrants in-depth analysis. This thesis investigates IPD in Turkey, primarily from the perspective of participatory democracy, with the purpose of suggesting reforms to the Turkish Political Parties Law (TPPL). Turkish political parties and Turkish party regulation provide an interesting case because there is a significant difference between mature democracies and Turkey regarding IPD regulation. IPD in established democracies has always been regarded as a private concern of parties and has been left unregulated. IPD in Turkey, by contrast, is provided for both by the constitution and the TPPL. Although IPD is a constitutional and legal requirement in Turkey, however, political parties in fact display a high level of non-democratic administration. The main reason is that the TPPL only pays lip service to the idea of IPD and requires no specific measures apart from establishing a party congress with a representative form of democracy. By establishing and holding party congresses, political parties are perceived as conforming to the requirements of IPD under the law. In addition, the contested nature of democracy as a concept has impeded the creation of efficacious legal principles. Thus, the existing party law fails to tackle the lack of IPD within political parties and, for this reason, is in need of reform. Furthermore, almost every Turkish party’s own constitution highlights the importance of IPD and promises IPD. However, these declared commitments to IPD in their constitutions alone, especially in countries where the democratic culture is weak, are unlikely to make much difference in practice. Accordingly, external regulation is necessary to ensure the protection of the rights and interests of the party members with regards to their participation in intra-party decision-making processes. Nevertheless, in spite of a general consensus in favour of reforming the TPPL, a lack of consensus exists as to what kind of reforms should be adopted. This thesis proposes that reforming the TPPL in line with an approach based on participatory democracy could provide better IPD within Turkish political parties, citing as evidence comparative case studies of the participatory practices for policy-making, leadership selection and candidate selection in mature democracies. This thesis also analyses membership registration and the effect of state funding on IPD, which are highly problematic in Turkey and represent impediments to the flourishing of IPD.

Tenecteplase and alteplase in acute ischaemic stroke thrombolysis: clinical and imaging study

Introduction: Intravenous thrombolysis in acute ischaemic stroke with alteplase improves clinical outcomes, but it has limited efficacy and is associated with increased risk of intracranial haemorrhage. An improved tissue plasminogen activator, tenecteplase, was evidenced to be at least equally effective with lower risk of haemorrhage in acute myocardial infarction thrombolysis. To date, two completed phase II randomised controlled studies comparing tenecteplase and alteplase in acute ischaemic strokes showed variable results. Methods: A literature review of thrombolytic agents used in myocardial infarction and acute ischaemic stroke was performed, followed by a retrospective investigation of the bolus-to- infusion delay of alteplase administration. The main focus of this thesis is the report of our single centre phase II randomised controlled trial that compared tenecteplase (0.25mg/kg, maximum 25mg) and alteplase (0.9mg/kg, maximum 90mg, 10% as the initial bolus, following by one hour infusion with the rest of the dose) in acute ischaemic stroke thrombolysis using advanced imaging as biomarkers. Imaging comprised baseline computed tomography (CT), CT perfusion (CTP) and CT angiography (CTA), and CT+CTA at 24-48 hours. The primary end-point was penumbral salvage (CTP-defined penumbra volume minus follow-up CT infarct volume). A sub-study of coagulation and fibrinolysis analysis of the two agents was performed by comparing a group of coagulation variables measured pre-treatment, 3-12 hours, and 24±3 hours post thrombolysis. An individual patient data (IPD) meta-analysis was carried out using all three completed tenecteplase/alteplase comparison studies in stroke thrombolysis. We compared clinical outcomes including modified Rankin scale at 3 months, early neurological improvement at 24 hours, intracerebral haemorrhage rate and mortality at 3 months between all three tenecteplase doses (0.1mg/kg, 0.25 mg/kg, and 0.4mg/kg) examined and standard alteplase. Imaging outcomes including penumbra salvage, recanalisation rates were also compared using the data from the two studies that had advance imaging carried out. Results: Delay between the initial bolus and the subsequent infusion in administration of alteplase is common. This may reduce the likelihood of achieving a good functional outcome. Among the 104 patients recruited in ATTEST trial, 71 contributed to the imaging primary outcome. No significant differences were observed for penumbral salvage [68 (SD 28) % tenecteplase vs 68 (SD 23) % alteplase], mean difference 1% (95% confidence interval -10%, 12%, p=0·81) or for any secondary end-point. The SICH incidence (1/52, 2% vs 2/51, 4%, by SITS-MOST definition, p=0·55; by ECASS-2 definition, 3/52, 6% tenecteplase vs 4/51, 8% alteplase, p=0.59) did not differed significantly. There was a trend towards lower ICH risk in the tenecteplase group (8/52 tenecteplase, 15% vs 14/51 alteplase, 29%, p=0·091). Compared to baseline, alteplase caused significant hypofibrinogenaemia (p=0.002), prolonged Prothrombin Time (PT) (p=0.011), hypoplasminogenaemia (p=0.001) and lower Factor V (p=0.002) at 3-12 hours after administration with persistent hypofibrinogenaemia at 24h (p=0.011), while only minor hypoplasminogenaemia (P=0.029) was seen in the tenecteplase group. Tenecteplase consumed less plasminogen (p<0.001) and fibrinogen (p=0.002) compared with alteplase. In a pooled analysis, tenecteplase 0.25mg/kg had the greatest odds to achieve early neurological improvement (OR [95%CI] 3.3 [1.5, 7.2], p=0.093), excellent functional outcome (mRS 0-1) at three months (OR [95%CI] 1.9 [0.8, 4.4], p= 0.28), with reduced odds of ICH (OR [95%CI] 0.6 [0.2, 1.8], P=0.43) compared with alteplase. Only 19 patients were treated with tenecteplase 0.4mg/kg, which showed increased odds of SICH compared with alteplase (OR [95% CI] 6.2 [0.7, 56.3]). In the two studies where advanced imaging was performed, the imaging outcomes did not differ in the IPD analysis. Conclusion: Tenecteplase 0.25 mg/kg has the potential to be a better alternative to alteplase. It can be given as a single bolus, does not cause disruption to systemic coagulation, and is possibly safer and more effective in clot lysis. Further phase III study to compare tenecteplase and alteplase in acute ischaemic stroke is warranted.