User Satisfaction Evaluation of the EHR4CR Query Builder: A Multisite Patient Count Cohort System.

The Electronic Health Records for Clinical Research (EHR4CR) project aims to develop services and technology for the leverage reuse of Electronic Health Records with the purpose of improving the efficiency of clinical research processes. A pilot program was implemented to generate evidence of the value of using the EHR4CR platform. The user acceptance of the platform is a key success factor in driving the adoption of the EHR4CR platform; thus, it was decided to evaluate the user satisfaction.

Web-based multi-site feasibility questionnaire tool.

The design of clinical trial (CT) study protocols, currently supported by clinicians, is often a slow and cumbersome process. The Electronic Health Records for Clinical Research (EHR4CR) project supports the design of study protocols through a multi-site patient count cohort system. However, there is still a need to improve the process step in which the clinicians are involved.

Efficiency and effectiveness evaluation of an automated multi-country patient count cohort system.

Background: With the increase of clinical trial costs during the last decades, the design of feasibility studies has become an essential process to reduce avoidable and costly protocol amendments. This design includes timelines, targeted sites and budget, together with a list of eligibility criteria that potential participants need to match. The present work was designed to assess the value of obtaining potential study participant counts using an automated patient count cohort system for large multi-country and multi-site trials: the Electronic Health Records for Clinical Research (EHR4CR) system.

Feasibility platform for stroke studies: an online tool to improve eligibility criteria for clinical trials.

Background And Purpose: Eligibility criteria are a key factor for the feasibility and validity of clinical trials. We aimed to develop an online tool to assess the potential effect of inclusion and exclusion criteria on the proportion of patients eligible for an acute stroke trial.

Methods: We identified relevant inclusion and exclusion criteria of acute stroke trials.

Comparison of electronic health record system functionalities to support the patient recruitment process in clinical trials.

Objectives: Reusing data from electronic health records for clinical and translational research and especially for patient recruitment has been tackled in a broader manner since about a decade. Most projects found in the literature however focus on standalone systems and proprietary implementations at one particular institution often for only one singular trial and no generic evaluation of EHR systems for their applicability to support the patient recruitment process does yet exist. Thus we sought to assess whether the current generation of EHR systems in Germany provides modules/tools, which can readily be applied for IT-supported patient recruitment scenarios.

Protocol feasibility workflow using an automated multi-country patient cohort system.

The Electronic Health Record for Clinical Research (EHR4CR) project aims to improve the current process of clinical trials, providing a technological platform that supports the design and execution of trials. For the protocol feasibility scenario, the system currently allows the user to create a set of in-/exclusion criteria to find patients matching these criteria across sites located in several countries. The automated multi-country patient cohort system developed in EHR4CR implies substantial changes on the current protocol feasibility process, which will be reflected in this study.

Towards a trial-ready mobile patient questionnaire system.

Gathering patient-reported data enables physicians to know a patient and his/her health-related needs in a more comprehensive way. One method to collect these data is to let the patient fill out electronic questionnaires on a mobile device, e.g.

Design and multicentric implementation of a generic software architecture for patient recruitment systems re-using existing HIS tools and routine patient data.

Objective: (1) To define features and data items of a Patient Recruitment System (PRS); (2) to design a generic software architecture of such a system covering the requirements; (3) to identify implementation options available within different Hospital Information System (HIS) environments; (4) to implement five PRS following the architecture and utilizing the implementation options as proof of concept.

Methods: Existing PRS were reviewed and interviews with users and developers conducted. All reported PRS features were collected and prioritized according to their published success and user's request.

Patient recruitment workflow with and without a patient recruitment system.

In clinical trials (CTs), the process of patient recruitment (PR) is one of the main risk factors, as almost half of all trial delays are caused by problems in PR. To our knowledge, no publication in this field describes the process of PR. Therefore, weak spots and potential benefits cannot be identified.

Evaluation of data completeness in the electronic health record for the purpose of patient recruitment into clinical trials: a retrospective analysis of element presence.

Background: Computerized clinical trial recruitment support is one promising field for the application of routine care data for clinical research. The primary task here is to compare the eligibility criteria defined in trial protocols with patient data contained in the electronic health record (EHR). To avoid the implementation of different patient definitions in multi-site trials, all participating research sites should use similar patient data from the EHR.

Multilingual Medical Data Models in ODM Format: A Novel Form-based Approach to Semantic Interoperability between Routine Healthcare and Clinical Research.

Background: Semantic interoperability between routine healthcare and clinical research is an unsolved issue, as information systems in the healthcare domain still use proprietary and site-specific data models. However, information exchange and data harmonization are essential for physicians and scientists if they want to collect and analyze data from different hospitals in order to build up registries and perform multicenter clinical trials. Consequently, there is a need for a standardized metadata exchange based on common data models.

The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane.

Persistently hyperphosphorylated Akt contributes to human oncogenesis and resistance to therapy. Triciribine (TCN) phosphate (TCN-P), the active metabolite of the Akt phosphorylation inhibitor TCN, is in clinical trials, but the mechanism by which TCN-P inhibits Akt phosphorylation is unknown. Here we show that in vitro, TCN-P inhibits neither Akt activity nor the phosphorylation of Akt S473 and T308 by mammalian target of rapamycin or phosphoinositide-dependent kinase 1.

MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons.

Microtubule-dependent transport of vesicles and organelles appears saltatory because particles switch between periods of rest, random Brownian motion, and active transport. The transport can be regulated through motor proteins, cargo adaptors, or microtubule tracks. We report here a mechanism whereby microtubule associated proteins (MAPs) represent obstacles to motors which can be regulated by microtubule affinity regulating kinase (MARK)/Par-1, a family of kinases that is known for its involvement in establishing cell polarity and in phosphorylating tau protein during Alzheimer neurodegeneration.

MARK4 is a novel microtubule-associated proteins/microtubule affinity-regulating kinase that binds to the cellular microtubule network and to centrosomes.

The MARK protein kinases were originally identified by their ability to phosphorylate a serine motif in the microtubule-binding domain of tau that is critical for microtubule binding. Here, we report the cloning and expression of a novel human paralog, MARK4, which shares 75% overall homology with MARK1-3 and is predominantly expressed in brain. Homology is most pronounced in the catalytic domain (90%), and MARK4 readily phosphorylates tau and the related microtubule-associated protein 2 (MAP2) and MAP4.

Crystallization of a macromolecular ring assembly of tubulin liganded with the anti-mitotic drug podophyllotoxin.

The interaction of the anti-cancer drug podophyllotoxin with a high-molecular-weight assembly of tubulin has been employed to produce three-dimensional crystals from avian erythrocyte tubulin as well as from pig brain tubulin. Avian erythrocyte tubulin crystals belong to the space group C2 with unit cell dimensions a = 740 A, b = 330 A, c = 460 A, beta = 128 degrees. The basis of these crystals is ring oligomers with a molecular mass of approximately 6 x 10(6) Da.

Tau regulates the attachment/detachment but not the speed of motors in microtubule-dependent transport of single vesicles and organelles.

We have performed a real time analysis of fluorescence-tagged vesicle and mitochondria movement in living CHO cells transfected with microtubule-associated protein tau or its microtubule-binding domain. tau does not alter the speed of moving vesicles, but it affects the frequencies of attachment and detachment to the microtubule tracks. Thus, tau decreases the run lengths both for plus-end and minus-end directed motion to an equal extent.

Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer's disease.

The neuronal microtubule-associated protein tau plays an important role in establishing cell polarity by stabilizing axonal microtubules that serve as tracks for motor-protein-driven transport processes. To investigate the role of tau in intracellular transport, we studied the effects of tau expression in stably transfected CHO cells and differentiated neuroblastoma N2a cells. Tau causes a change in cell shape, retards cell growth, and dramatically alters the distribution of various organelles, known to be transported via microtubule-dependent motor proteins.

The endogenous and cell cycle-dependent phosphorylation of tau protein in living cells: implications for Alzheimer's disease.

In Alzheimer's disease the neuronal microtubule-associated protein tau becomes highly phosphorylated, loses its binding properties, and aggregates into paired helical filaments. There is increasing evidence that the events leading to this hyperphosphorylation are related to mitotic mechanisms. Hence, we have analyzed the physiological phosphorylation of endogenous tau protein in metabolically labeled human neuroblastoma cells and in Chinese hamster ovary cells stably transfected with tau.

Phosphorylation of microtubule-associated proteins MAP2 and MAP4 by the protein kinase p110mark. Phosphorylation sites and regulation of microtubule dynamics.

The phosphorylation of microtubule-associated proteins (MAPs) is thought to be a key factor in the regulation of microtubule stability. We have shown recently that a novel protein kinase, termed p110 microtubule-affinity regulating kinase ("MARK"), phosphorylates microtubule-associated protein tau at the KXGS motifs in the region of internal repeats and causes the detachment of tau from microtubules (Drewes, G., Trinczek, B.

Structure, microtubule interactions, and phosphorylation of tau protein.

This paper summarizes recent structural and functional studies on tau protein, its interactions with microtubules, its self-assembly into paired helical filaments (PHF)-like fibers, and its modification by phosphorylation. The structure of tau in solution resembles that of a random coil. Both tau and Alzheimer PHFs have very little secondary structure, making it improbable that the assembly of tau into PHFs is based on interacting beta sheets.

Domains of tau protein, differential phosphorylation, and dynamic instability of microtubules.

The dynamic instability of microtubules is thought to be regulated by MAPs and phosphorylation. Here we describe the effect of the neuronal microtubule-associated protein tau by observing the dynamics of single microtubules by video microscopy. We used recombinant tau isoforms and tau mutants, and we phosphorylated tau by the neuronal kinases MARK (affecting the KXGS motifs within tau's repeat domain) and cdk5 (phosphorylating Ser-Pro motifs in the regions flanking the repeats).

Tau domains, phosphorylation, and interactions with microtubules.

We consider the interactions of tau protein with microtubules from two points of view, phosphorylation and domain structure. Tau can be phosphorylated at many sites and by several kinases, notably by proline-directed kinases (MAPK, GSK-3, cdk5) which generate Alzheimer-like antibody epitopes. Other kinases phosphorylate Ser 262, a site that has a particularly pronounced influence on the affinity of tau for microtubules.

Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262.

Aberrant phosphorylation of the microtubule-associated protein tau is one of the pathological features of neuronal degeneration in Alzheimer's disease. The phosphorylation of Ser-262 within the microtubule binding region of tau is of particular interest because so far it is observed only in Alzheimer's disease (Hasegawa, M., Morishima-Kawashima, M.

Domains of tau protein and interactions with microtubules.

The role of the neuronal microtubule-associated protein tau has been studied by generating a series of tau constructs differing in one or several of its subdomains: length and composition of the repeat domains, extensions of the repeats in the N- or C-terminal direction, constructs without repeats, assembly vs projection domain, and number of N-terminal inserts. The interaction of the mutant tau proteins with microtubules was judged by several independent methods. (i) Direct binding assays between tau and taxol-stabilized microtubules yield dissociation constants and stoichiometries.

Dynamics of microtubules from erythrocyte marginal bands.

Microtubules can adjust their length by the mechanism of dynamic instability, that is by switching between phases of growth and shrinkage. Thus far this phenomenon has been studied with microtubules that contain several components, that is, a mixture of tubulin isoforms, with or without a mixture of microtubule-associated proteins (MAPs), which can act as regulators of dynamic instability. Here we concentrate on the influence of the tubulin component.