Field-free control of magnetism in nanostructured materials probed with high resolution X-ray microscopy

Magnetic memories are a backbone of today's digital data storage technology, where the digital information is stored as the magnetic configuration of nanostructured ferromagnetic bits. Currently, the writing of the digital information on the magnetic memory is carried out with the help of magnetic fields. This approach, while viable, is not optimal due to its intrinsically high energy consumption and relatively poor scalability. For this reason, the research for different mechanisms that can be used to manipulate the magnetic configuration of a material is of interest. In this thesis, the control of the magnetization of different nanostructured materials with field-free mechanisms is investigated. The magnetic configuration of these nanostructured materials was imaged directly with high resolution x-ray magnetic microscopy. rnFirst of all, the control of the magnetic configuration of nanostructured ferromagnetic Heusler compounds by fabricating nanostructures with different geometries was analyzed. Here, it was observed that the magnetic configuration of the nanostructured elements is given by the competition of magneto-crystalline and shape anisotropy. By fabricating elements with different geometries, we could alter the point where these two effects equilibrate, allowing for the possibility to tailor the magnetic configuration of these nanostructured elements to the required necessities.rnThen, the control of the magnetic configuration of Ni nanostructures fabricated on top of a piezoelectric material with the magneto-elastic effect (i.e. by applying a piezoelectric strain to the Ni nanostructures) was investigated. Here, the magneto-elastic coupling effect gives rise to an additional anisotropy contribution, proportional to the strain applied to the magnetic material. For this system, a reproducible and reversible control of the magnetic configuration of the nanostructured Ni elements with the application of an electric field across the piezoelectric material was achieved.rnFinally, the control of the magnetic configuration of La0.7Sr0.3MnO3 (LSMO) nanostructures with spin-polarized currents was studied. Here, the spin-transfer torque effect was employed to achieve the displacement of magnetic domain walls in the LSMO nanostructures. A high spin-transfer torque efficiency was observed for LSMO at low temperatures, and a Joule-heating induced hopping of the magnetic domain walls was observed at room temperatures, allowing for the analysis of the energetics of the domain walls in LSMO.rnThe results presented in this thesis give thus an overview on the different field-free approaches that can be used to manipulate and tailor the magnetization configuration of a nanostructured material to the various technological requirements, opening up novel interesting possibilities for these materials.

Development of a model-based transient calibration process for diesel engine electronic control module tables – Part 2: modelling and optimization

This is the second part of a study investigating a model-based transient calibration process for diesel engines. The first part addressed the data requirements and data processing required for empirical transient emission and torque models. The current work focuses on modelling and optimization. The unexpected result of this investigation is that when trained on transient data, simple regression models perform better than more powerful methods such as neural networks or localized regression. This result has been attributed to extrapolation over data that have estimated rather than measured transient air-handling parameters. The challenges of detecting and preventing extrapolation using statistical methods that work well with steady-state data have been explained. The concept of constraining the distribution of statistical leverage relative to the distribution of the starting solution to prevent extrapolation during the optimization process has been proposed and demonstrated. Separate from the issue of extrapolation is preventing the search from being quasi-static. Second-order linear dynamic constraint models have been proposed to prevent the search from returning solutions that are feasible if each point were run at steady state, but which are unrealistic in a transient sense. Dynamic constraint models translate commanded parameters to actually achieved parameters that then feed into the transient emission and torque models. Combined model inaccuracies have been used to adjust the optimized solutions. To frame the optimization problem within reasonable dimensionality, the coefficients of commanded surfaces that approximate engine tables are adjusted during search iterations, each of which involves simulating the entire transient cycle. The resulting strategy, different from the corresponding manual calibration strategy and resulting in lower emissions and efficiency, is intended to improve rather than replace the manual calibration process.

Model Predictive Control for Vehicle Stabilization at the Limits of Handling

Recent developments in vehicle steering systems offer new opportunities to measure the steering torque and reliably estimate the vehicle sideslip and the tire-road friction coefficient. This paper presents an approach to vehicle stabilization that leverages these estimates to define state boundaries that exclude unstable vehicle dynamics and utilizes a model predictive envelope controller to bound the vehicle motion within this stable region of the state space. This approach provides a large operating region accessible by the driver and smooth interventions at the stability boundaries. Experimental results obtained with a steer-by-wire vehicle and a proof of envelope invariance demonstrate the efficacy of the envelope controller in controlling the vehicle at the limits of handling.

Dietary intervention induces flow of changes within biomarkers of lipids, inflammation, liver enzymes, and glycemic control

To determine how changes in lipids, liver enzymes, and inflammatory and glycemia markers intercorrelate during prolonged dietary intervention in obese participants with or without type 2 diabetes (T2D).

Au@Hg nanoalloy formation through direct amalgamation: Structural, spectroscopic, and computational evidence for slow nanoscale diffusion

Dynamic core-shell nanoparticles have received increasing attention in recent years. This paper presents a detailed study of Au-Hg nanoalloys, whose composing elements show a large difference in cohesive energy. A simple method to prepare Au@Hg particles with precise control over the composition up to 15 atom% mercury is introduced, based on reacting a citrate stabilized gold sol with elemental mercury. Transmission electron microscopy shows an increase of particle size with increasing mercury content and, together with X-ray powder diffraction, points towards the presence of a core-shell structure with a gold core surrounded by an Au-Hg solid solution layer. The amalgamation process is described by pseudo-zero-order reaction kinetics, which indicates slow dissolution of mercury in water as the rate determining step, followed by fast scavenging by nanoparticles in solution. Once adsorbed at the surface, slow diffusion of Hg into the particle lattice occurs, to a depth of ca. 3 nm, independent of Hg concentration. Discrete dipole approximation calculations relate the UV-vis spectra to the microscopic details of the nanoalloy structure. Segregation energies and metal distribution in the nanoalloys were modeled by density functional theory calculations. The results indicate slow metal interdiffusion at the nanoscale, which has important implications for synthetic methods aimed at core-shell particles.

Variations of the Atlantic meridional overturning circulation in control and transient simulations of the last millennium

The variability of the Atlantic meridional overturing circulation (AMOC) strength is investigated in control experiments and in transient simulations of up to the last millennium using the low-resolution Community Climate System Model version 3. In the transient simulations the AMOC exhibits enhanced low-frequency variability that is mainly caused by infrequent transitions between two semi-stable circulation states which amount to a 10 percent change of the maximum overturning. One transition is also found in a control experiment, but the time-varying external forcing significantly increases the probability of the occurrence of such events though not having a direct, linear impact on the AMOC. The transition from a high to a low AMOC state starts with a reduction of the convection in the Labrador and Irminger Seas and goes along with a changed barotropic circulation of both gyres in the North Atlantic and a gradual strengthening of the convection in the Greenland-Iceland-Norwegian (GIN) Seas. In contrast, the transition from a weak to a strong overturning is induced by decreased mixing in the GIN Seas. As a consequence of the transition, regional sea surface temperature (SST) anomalies are found in the midlatitude North Atlantic and in the convection regions with an amplitude of up to 3 K. The atmospheric response to the SST forcing associated with the transition indicates a significant impact on the Scandinavian surface air temperature (SAT) in the order of 1 K. Thus, the changes of the ocean circulation make a major contribution to the Scandinavian SAT variability in the last millennium.

Slc15a4, a gene required for pDC sensing of TLR ligands, is required to control persistent viral infection

Plasmacytoid dendritic cells (pDCs) are the major producers of type I IFN in response to viral infection and have been shown to direct both innate and adaptive immune responses in vitro. However, in vivo evidence for their role in viral infection is lacking. We evaluated the contribution of pDCs to acute and chronic virus infection using the feeble mouse model of pDC functional deficiency. We have previously demonstrated that feeble mice have a defect in TLR ligand sensing. Although pDCs were found to influence early cytokine secretion, they were not required for control of viremia in the acute phase of the infection. However, T cell priming was deficient in the absence of functional pDCs and the virus-specific immune response was hampered. Ultimately, infection persisted in feeble mice. We conclude that pDCs are likely required for efficient T cell priming and subsequent viral clearance. Our data suggest that reduced pDC functionality may lead to chronic infection.

The Constitutional-Judicial Control of the Legislative and Executive Powers in Central and Eastern European Countries

This project looked at the nature, contents, methods, means and legal and political effects of the influence that constitutional courts exercise upon the legislative and executive powers in the newly established democracies of Central and Eastern Europe. The basic hypothesis was that these courts work to provide a limitation of political power within the framework of the principal constitutional values and that they force the legislature and executive to exercise their powers and duties in strict accordance with the constitution. Following a study of the documentary sources, including primarily the relevant constitutional and statutory provisions and decisions of constitutional courts, Mr. Cvetkovski prepared a questionnaire on various aspects of the topics researched and sent it to the respective constitutional courts. A series of direct interviews with court officials in six of the ten countries then served to clarify a large number of questions relating to differences in procedures etc. that arose from the questionnaires. As a final stage, the findings were compared with those described in recent publications on constitutional control in general and in Central and Eastern Europe in particular. The study began by considering the constitutional and political environment of the constitutional courts' activities in controlling legislative and executive powers, which in all countries studied are based on the principles of the rule of law and the separation of powers. All courts are separate bodies with special status in terms of constitutional law and are independent of other political and judicial institutions. The range of matters within their jurisdiction is set by the constitution of the country in question but in all cases can be exercised only with the framework of procedural rules. This gives considerable significance to the question of who sets these rules and different countries have dealt with it in different ways. In some there is a special constitutional law with the same legal force as the constitution itself (Croatia), the majority of countries allow for regulation by an ordinary law, Macedonia gives the court the autonomy to create and change its own rules of procedure, while in Hungary the parliament fixes the rules on procedure at the suggestion of the constitutional court. The question of the appointment of constitutional judges was also considered and of the mechanisms for ensuring their impartiality and immunity. In the area of the courts' scope for providing normative control, considerable differences were found between the different countries. In some cases the courts' jurisdiction is limited to the normative acts of the respective parliaments, and there is generally no provision for challenging unconstitutional omissions by legislation and the executive. There are, however, some situations in which they may indirectly evaluate the constitutionality of legislative omissions, as when the constitution contains provision for a time limit on enacting legislation, when the parliament has made an omission in drafting a law which violates the constitutional provisions, or when a law grants favours to certain groups while excluding others, thereby violating the equal protection clause of the constitution. The control of constitutionality of normative acts can be either preventive or repressive, depending on whether it is implemented before or after the promulgation of the law or other enactment being challenged. In most countries in the region the constitutional courts provide only repressive control, although in Hungary and Poland the courts are competent to perform both preventive and repressive norm control, while in Romania the court's jurisdiction is limited to preventive norm control. Most countries are wary of vesting constitutional courts with preventive norm control because of the danger of their becoming too involved in the day-to-day political debate, but Mr. Cvetkovski points out certain advantages of such control. If combined with a short time limit it can provide early clarification of a constitutional issue, secondly it avoids the problems arising if a law that has been in force for some years is declared to be unconstitutional, and thirdly it may help preserve the prestige of the legislation. Its disadvantages include the difficulty of ascertaining the actual and potential consequences of a norm without the empirical experience of the administration and enforcement of the law, the desirability of a certain distance from the day-to-day arguments surrounding the political process of legislation, the possible effects of changing social and economic conditions, and the danger of placing obstacles in the way of rapid reactions to acute situations. In the case of repressive norm control, this can be either abstract or concrete. The former is initiated by the supreme state organs in order to protect abstract constitutional order and the latter is initiated by ordinary courts, administrative authorities or by individuals. Constitutional courts cannot directly oblige the legislature and executive to pass a new law and this remains a matter of legislative and executive political responsibility. In the case of Poland, the parliament even has the power to dismiss a constitutional court decision by a special majority of votes, which means that the last word lies with the legislature. As the current constitutions of Central and Eastern European countries are newly adopted and differ significantly from the previous ones, the courts' interpretative functions should ensure a degree of unification in the application of the constitution. Some countries (Bulgaria, Hungary, Poland, Slovakia and Russia) provide for the constitutional courts' decisions to have a binding role on the constitutions. While their decisions inevitably have an influence on the actions of public bodies, they do not set criteria for political behaviour, which depends rather on the overall political culture and traditions of the society. All constitutions except that of Belarus, provide for the courts to have jurisdiction over conflicts arising from the distribution of responsibilities between different organs and levels in the country, as well for impeachment procedures against the head of state, and for determining the constitutionality of political parties (except in Belarus, Hungary, Russia and Slovakia). All the constitutions studied guarantee individual rights and freedoms and most courts have jurisdiction over complaints of violation of these rights by the constitution. All courts also have some jurisdiction over international agreements and treaties, either directly (Belarus, Bulgaria and Hungary) before the treaty is ratified, or indirectly (Croatia, Czech Republic, Macedonia, Romania, Russia and Yugoslavia). In each country the question of who may initiate proceedings of norm control is of central importance and is usually regulated by the constitution itself. There are three main possibilities: statutory organs, normal courts and private individuals and the limitations on each of these is discussed in the report. Most courts are limited in their rights to institute ex officio a full-scale review of a point of law, and such rights as they do have rarely been used. In most countries courts' decisions do not have any binding force but must be approved by parliament or impose on parliament the obligation to bring the relevant law into conformity within a certain period. As a result, the courts' position is generally weaker than in other countries in Europe, with parliament remaining the supreme body. In the case of preventive norm control a finding of unconstitutionality may act to suspend the law and or to refer it back to the legislature, where in countries such as Romania it may even be overturned by a two-thirds majority. In repressive norm control a finding of unconstitutionality generally serves to take the relevant law out of legal force from the day of publication of the decision or from another date fixed by the court. If the law is annulled retrospectively this may or may not bring decisions of criminal courts under review, depending on the provisions laid down in the relevant constitution. In cases relating to conflicts of competencies the courts' decisions tend to be declaratory and so have a binding effect inter partes. In the case of a review of an individual act, decisions generally become effective primarily inter partes but is the individual act has been based on an unconstitutional generally binding normative act of the legislature or executive, the findings has quasi-legal effect as it automatically initiates special proceedings in which the law or other regulation is to be annulled or abrogated with effect erga omnes. This wards off further application of the law and thus further violations of individual constitutional rights, but also discourages further constitutional complaints against the same law. Thus the success of one individual's complaint extends to everyone else whose rights have equally been or might have been violated by the respective law. As the body whose act is repealed is obliged to adopt another act and in doing so is bound by the legal position of the constitutional court on the violation of constitutionally guaranteed freedoms and rights of the complainant, in this situation the decision of the constitutional court has the force of a precedent.

Separation of Ownership from Control and Discretionary Managerial Behaviour in a Transition Economy

This study was the final stage of a four-year study of managerial behaviour and company performance in Bulgaria and examined the influence of changing ownership and control structures of companies on managerial behaviour and initiative. It provides a theoretical summary of the specific types of ownership, control, governance structures and managerial strategies in the Bulgarian transitional economy during 1992-1996. It combines two theoretical approaches, the property-rights approach to show concentrated property-rights structure and private and majority types of control as determinants of efficient enterprise risk bearing and constrained managerial discretion, and the agency theory approach to reveal the efficient role of direct non-market governance mechanisms over managers. Mr. Peev also used empirical information collected from the Central Statistical office in Bulgaria, three different enterprise investigations of corporatised state-owned enterprises between 1992 and 1994, and his own data base of privatised and private de novo industrial companies in 1996-1996. The project gives a detailed description of the main property-rights structures in Bulgaria at the present time and of the various control structures related to these. It found that there is a strong owner type of control in private and privatised firms, although, contrary to expectations, 100% state -owned enterprises tended to be characterised by a separation of ownership from control, leaving scope for managerial discretion. Mr. Peev predicts that after the forthcoming mass privatisation, many companies will acquire a dispersed ownership structure and there will be a greater separation of ownership from control and potential or inefficient managerial behaviour. The next aspect considered in detail was governance structures and the influence of the generally unstable macroeconomic environment in the country during the period in question. In examining managerial strategies, Mr. Peev divided the years since 1990 into 3 periods. Even in the first period (1990-1992) there were some signs of a more efficient role for managers and between 1992 and 1994 the picture of control structures and different managerial behaviour in state-owned companies became more diversified. Managerial strategies identified included managerial initiatives for privatisation, where managers took initiative in resolving problems of property rights and introducing restructuring measures and privatisation proposals, managerial initiatives for restructuring without privatisation, and passive adjustment and passive management, where managers seek outside services for marketing, finance management, etc. in order to adjust to the new environment. During 1995-1996 some similarities and differences between the managerial behaviour of privatised and state-owned firms emerged. Firstly, the former have undergone many changes in investment and technology, while managers of state-owned companies have changed little in this field, indicating that the private property-rights structure is more efficient for the long-term adaptation of enterprises. In the area of strategies relating to product quality, marketing, and pricing policy there was little difference between managers of private, privatised and state-owned firms. The most passive managerial behaviour was found in non-incorporated state-owned firms, although these have only an insignificant stake in the economy.

Financial analysis of various strategies for the control of Neospora caninum in dairy cattle in Switzerland

The present study was conducted to estimate the direct losses due to Neospora caninum in Swiss dairy cattle and to assess the costs and benefits of different potential control strategies. A Monte Carlo simulation spreadsheet module was developed to estimate the direct costs caused by N. caninum, with and without control strategies, and to estimate the costs of these control strategies in a financial analysis. The control strategies considered were "testing and culling of seropositive female cattle", "discontinued breeding with offspring from seropositive cows", "chemotherapeutical treatment of female offspring" and "vaccination of all female cattle". Each parameter in the module that was considered to be uncertain, was described using probability distributions. The simulations were run with 20,000 iterations over a time period of 25 years. The median annual losses due to N. caninum in the Swiss dairy cow population were estimated to be euro 9.7 million euros. All control strategies that required yearly serological testing of all cattle in the population produced high costs and thus were not financially profitable. Among the other control strategies, two showed benefit-cost ratios (BCR) >1 and positive net present values (NPV): "Discontinued breeding with offspring from seropositive cows" (BCR=1.29, NPV=25 million euros ) and "chemotherapeutical treatment of all female offspring" (BCR=2.95, NPV=59 million euros). In economic terms, the best control strategy currently available would therefore be "discontinued breeding with offspring from seropositive cows".

Beta-D-glucoside utilization by Mycoplasma mycoides subsp. mycoides SC: possible involvement in the control of cytotoxicity towards bovine lung cells

BACKGROUND: Contagious bovine pleuropneumonia (CBPP) caused by Mycoplasma mycoides subsp. mycoides small-colony type (SC) is among the most serious threats for livestock producers in Africa. Glycerol metabolism-associated H2O2 production seems to play a crucial role in virulence of this mycoplasma. A wide number of attenuated strains of M. mycoides subsp. mycoides SC are currently used in Africa as live vaccines. Glycerol metabolism is not affected in these vaccine strains and therefore it does not seem to be the determinant of their attenuation. A non-synonymous single nucleotide polymorphism (SNP) in the bgl gene coding for the 6-phospho-beta-glucosidase (Bgl) has been described recently. The SNP differentiates virulent African strains isolated from outbreaks with severe CBPP, which express the Bgl isoform Val204, from strains to be considered less virulent isolated from CBPP outbreaks with low mortality and vaccine strains, which express the Bgl isoform Ala204. RESULTS: Strains of M. mycoides subsp. mycoides SC considered virulent and possessing the Bgl isoform Val204, but not strains with the Bgl isoform Ala204, do trigger elevated levels of damage to embryonic bovine lung (EBL) cells upon incubation with the disaccharides (i.e., beta-D-glucosides) sucrose and lactose. However, strains expressing the Bgl isoform Val204 show a lower hydrolysing activity on the chromogenic substrate p-nitrophenyl-beta-D-glucopyranoside (pNPbG) when compared to strains that possess the Bgl isoform Ala204. Defective activity of Bgl in M. mycoides subsp. mycoides SC does not lead to H2O2 production. Rather, the viability during addition of beta-D-glucosides in medium-free buffers is higher for strains harbouring the Bgl isoform Val204 than for those with the isoform Ala204. CONCLUSION: Our results indicate that the studied SNP in the bgl gene is one possible cause of the difference in bacterial virulence among strains of M. mycoides subsp. mycoides SC. Bgl does not act as a direct virulence factor, but strains possessing the Bgl isoform Val204 with low hydrolysing activity are more prone to survive in environments that contain high levels of beta-D-glucosides, thus contributing in some extent to mycoplasmaemia.

Inhibitory control of the human dorsolateral prefrontal cortex during the anti-saccade paradigm--a transcranial magnetic stimulation study

In the anti-saccade paradigm, subjects are instructed not to make a reflexive saccade to an appearing lateral target but to make an intentional saccade to the opposite side instead. The inhibition of reflexive saccade triggering is under the control of the dorsolateral prefrontal cortex (DLPFC). The critical time interval at which this inhibition takes place during the paradigm, however, is not exactly known. In the present study, we used single-pulse transcranial magnetic stimulation (TMS) to interfere with DLPFC function in 15 healthy subjects. TMS was applied over the right DLPFC either 100 ms before the onset of the visual target (i.e. -100 ms), at target onset (i.e. 0 ms) or 100 ms after target onset (i.e. +100 ms). Stimulation 100 ms before target onset significantly increased the percentage of anti-saccade errors to both sides, while stimulation at, or after, target onset had no significant effect. All three stimulation conditions had no significant influence on saccade latency of correct or erroneous anti-saccades. These findings show that the critical time interval at which the DLPFC controls the suppression of a reflexive saccade in the anti-saccade paradigm is before target onset. In addition, the results suggest the view that the triggering of correct anti-saccades is not under direct control of the DLPFC.

THERMAL CHARACTERIZATION OF A GASOLINE TURBOCHARGED DIRECT INJECTION (GTDI) ENGINE UTILIZING LEAN OPERATION AND EXHAUST GAS RECIRCULATION (EGR)

The push for improved fuel economy and reduced emissions has led to great achievements in engine performance and control. These achievements have increased the efficiency and power density of gasoline engines dramatically in the last two decades. With the added power density, thermal management of the engine has become increasingly important. Therefore it is critical to have accurate temperature and heat transfer models as well as data to validate them. With the recent adoption of the 2025 Corporate Average Fuel Economy(CAFE) standard, there has been a push to improve the thermal efficiency of internal combustion engines even further. Lean and dilute combustion regimes along with waste heat recovery systems are being explored as options for improving efficiency. In order to understand how these technologies will impact engine performance and each other, this research sought to analyze the engine from both a 1st law energy balance perspective, as well as from a 2nd law exergy analysis. This research also provided insights into the effects of various parameters on in-cylinder temperatures and heat transfer as well as provides data for validation of other models. It was found that the engine load was the dominant factor for the energy distribution, with higher loads resulting in lower coolant heat transfer and higher brake work and exhaust energy. From an exergy perspective, the exhaust system provided the best waste heat recovery potential due to its significantly higher temperatures compared to the cooling circuit. EGR and lean combustion both resulted in lower combustion chamber and exhaust temperatures; however, in most cases the increased flow rates resulted in a net increase in the energy in the exhaust. The exhaust exergy, on the other hand, was either increased or decreased depending on the location in the exhaust system and the other operating conditions. The effects of dilution from lean operation and EGR were compared using a dilution ratio, and the results showed that lean operation resulted in a larger increase in efficiency than the same amount of dilution with EGR. Finally, a method for identifying fuel spray impingement from piston surface temperature measurements was found. Note: The material contained in this section is planned for submission as part of a journal article and/or conference paper in the future.

BMP-2 liberated from biomimetic implant coatings induces and sustains direct ossification in an ectopic rat model

INTRODUCTION: Using a rat model, we evaluated the kinetics and histomorphometry of ectopic bone formation in association with biomimetic implant coatings containing BMP-2. MATERIALS AND METHODS: One experimental and three control groups were set up: titanium-alloy discs coated with a biomimetically co-precipitated layer of calcium phosphate and BMP-2 [1.7 microg per disc (incorporated-BMP group)]; uncoated discs (control); discs biomimetically coated with a layer of calcium phosphate alone (control); and discs biomimetically coated with a layer of calcium phosphate bearing superficially adsorbed BMP-2 [0.98 microg per disc (control)]. Discs (n = 6 per group) were implanted subcutaneously in rats and retrieved at 7-day intervals over a period of 5 weeks for kinetic, histomorphometrical, morphological and histochemical analyses. RESULTS: In the incorporated-BMP-2 group, osteogenic activity was first observed 2 weeks after implantation and thereafter continued unabated until the end of the monitoring period. The net weekly rates of bone formation per disc were 5.8 mm3 at 2 weeks and 3.64 mm3 at 5 weeks. The total volumes of bone formed per disc at these junctures were 5.8 mm3 and 10.3 mm3, respectively. Bone tissue, which was formed by a direct ossification mechanism, was deposited at distances of up to 340 microm from the implant surfaces. The biomimetic coatings were degraded gradually, initially by foreign body giant cells alone and then also by osteoclasts. Forty percent of the coating material (and thus presumably of the incorporated BMP-2) remained at the end of the monitoring period. Hence, 60% of the incorporated BMP-2 had been released. At this 5-week juncture, no bone tissue was associated with any of the control implants. CONCLUSION: BMP-2 incorporated into biomimetic calcium phosphate coatings is capable not only of inducing bone formation at an ectopic site in vivo but also of doing so with a very high potency at a low pharmacological level, and of sustaining this activity for a considerable period of time. The sustainment of osteogenic activity is of great clinical importance for the osseointegration of dental and orthopedic implants.

Better conduct of clinical trials: the control group in critical care trials

OBJECTIVE: To review trial design issues related to control groups. DESIGN: Review of the literature with specific reference to critical care trials. MAIN RESULTS AND CONCLUSIONS: Performing randomized controlled trials in the critical care setting presents specific problems: studies include patients with rapidly lethal conditions, the majority of intensive care patients suffer from syndromes rather than from well-definable diseases, the severity of such syndromes cannot be precisely assessed, and the treatment consists of interacting therapies. Interactions between physiology, pathophysiology, and therapies are at best marginally understood and may have a major impact on study design and interpretation of results. Selection of the right control group is crucial for the interpretation and clinical implementation of results. Studies comparing new interventions with current ones or different levels of current treatments have the problem of the necessity of defining "usual care." Usual care controls without any constraints typically include substantial heterogeneity. Constraints in the usual therapy may help to reduce some variation. Inclusion of unrestricted usual care groups may help to enhance safety. Practice misalignment is a novel problem in which patients receive a treatment that is the direct opposite of usual care, and occurs when fixed-dose interventions are used in situations where care is normally titrated. Practice misalignment should be considered in the design and interpretation of studies on titrated therapies.