Space-Filling Designs for Multi-Layer Nested Factors

This articles considers computer experiments where levels for continuous factors are selected in sequential order with the level selected for one factor directly a ecting the range of possible levels for the nested factor, and so on for a nite number of factors. In addition, we assume the nested relationships between the factors have no closed form solution. In this paper, we propose an approach for constructing a multi-layer nested factor design, or multi-NFD for short. This space- lling design approach takes advan- tage of the maximin criterion and can be analyzed using a standard Gaussian process model. While the multi-NFD approach can be adapted for future computer experi- ments involving factor relationships of this type, we present results from a particular aerospace computer simulation study

Rationalisering van de dietetiek

Until recently the majority of therapeutic diets prescribed were based almost exclusively on empirism and aimed at symptomatic treatment of certain diseases. This situation has been changing radically in the last few decades. Under the influence of increased knowledge in the field of nutrition on the one hand, the greater insight into the patho- physiology of digestion and the rapid extension of the knowledge of metabolic disorders on the other hand, diet therapy is rapidly developing into a scientifically valid and often causal method of treating diseases.In spite of these developments little attention has so far been paid to definition of terms. The terminology used in the naming and prescribing of diets is extremely confusing and there is no adeauate classification of therapeutic diets. Sometimes the diets are named according to their purpose (cholesterol lowering diet, etc.); in other cases the diet carries the names of the disease (diabetes diet, hepatitis diet, etc.) or of the diseased organ (gastric diet, kidney diet, etc.); in still other cases the (deviating) composition determines the designation (low-protein diet, salt- free diet, fruit diet, etc.) or the diet is named after its "inventor" (Sippy-cure, Meulengracht diet, etc.). Quantity specifications too, are often extremely vague (moderate, limited, low, strict, ascending) and in some cases completely incorrect (e.g. salt-free). Even the definition of the term (therapeutic) diet as such is still a subject of wide-spread disagreement.In practice this confusing nomenclature causes every physician and dietitian to form his own idea of a particular therapeutic diet, based on his personal insight and experience. The contents af a therapeutic diet can therefore vary according to the physician or dietitian and hospital concerned.Whether or to what extent these differences actually rest on medical grounds remains unclear. Directly consequent on this an often unnecessarily large diversity of therapeutic diet meals is prepared, notably in hospitals. Lack of clearity and discrepancies with regard to the procedure and the delimination of physicians' and dietitians' duties can also be traced back to this. The confusing terminology prevents the realization of satisfactory regulations on labelling of foodstuffs (esp. diet products) and compensation for the costs of a therapeutic diet.The original occasion for the research was an experiment carried out in 1972-1973 in two hospitals, in which the production of meals was entirely contracted out to an industry of foodstuffs. This experiment concerned the industrial production of separate, individual mealcomponents, from which the hospital patients, including the dietpatients, could compose their meals as they choose. This necessitated a clear and unambiguous formulation of the medical requirements these therapeutic diet meals had to fulifii. Soon, however, the investigation began to lead a life of its own and was therefore entirely dissociated from the afore mentioned experiment.The research was primarily directed at logical analysing and ordening of therapeutic diets and the procedure followed by physicians and dietitians in prescribing a diet. The main issue was: What is a therapeutic diet? In this way a clearly consistent and coherent stock of concepts was developed (Chapter 2 and 3) on the basis of which rules regarding the prescription and composition of therapeutic diets were drawn up.Besides the respective duties and responsibilities of physicians and dietitians were delimited and a sound model for paramedical delegation was developed (Chapter 4).It is essential that physicians and dietitians employ uniform units and specifications of foodstuffs in prescribing and composing therapeutic diets. National agreements have been reached on this head, which can also constitute the basis of a simple system of labelling and declaration of nutritional values (Chapter 5).About half of all hospital patients are prescribed a therapeutic diet. In Chapter 6 an organization model has been developed for catering in hospitals, applying the results of the preceding chapters. A model according to which diet patients, too, can compose a meal as they choose from the supply of foodstuffs and dishes.By rationalization - the title of the research - we mean the formalization (Chapter 4), normalization (Chapter 5) and organization (Chapter 6) of the prescribing and composing of therapeutic diets, both intramurally and extramurally, by way of logical analysis, definition and ordening (Chapter 2 and 3).The investigation is a composition of basic scientific research (analysis, ordening and definition) and applied scientific research (formalization, normalization and organization). It was carried out in close co-operation with those concerned, notably physicians and dietitians. As regards set-up the investigation can best be described as an action-research. Twenty-eight hospitals took part in the last phase of the research: the diffusion and adoption.We have defined a therapeutic diet as a diet which deviates from a normal diet for medical reasons. By a normal diet we understand an optimal diet; a diet which under physiological conditions contributes towards the best health to be achieved. A normal diet is synonymous with a healthy diet. In this definition Met is the genus proximum. A therapeutic diet differs from a normal diet in two respects (differentiae specificae):- it is a deviating diet- the deviation rests on medical (patho-physioiogical) grounds.Only if both conditions have simultaneously been complied with we can speak of a therapeutic diet or modified diet.(There is no completely correct English equivalent for the Dutch word "dieet". Instead of therapeutic diet a better translation would be modified diet).As in theoretical nutrition we define a diet as a set of nutrients. A therapeutic or modified diet is a diet in which the amount of one more nutrients deviates - for medical reasons - from what would be a normal quantity for the patient in question under physiological conditions.Proceeding from this definition the therapeutic (modified) diets have been divided into four categories:1. nutrient-limited diets: diets in which the quantity of one or more nu trients is less than normal2. nutrient-enriched diets: diets in which the quantity of one or more nutrients is more than normal3. nutrient-eliminated (or-free) diets: diets in which one or more nutrients do not occur at all4. nutrient-substituted diets: diets in which one or more macro-nutrients are replaced by an equivalent set of micro-nutrients. Substitution is always a combination of limitation or elimination and enrichment.If the quantity of only one nutrient diverges from the normal amount we speak of single modified diets. If the quantity of two or more nutrients deviates from the normal we speak of multiple modified diets or combina tion-diets. A multiple modified Met is a combination of two or more single modified diets.This classification constitutes the basis of a clear, unambiguous and consistent method of naming and prescribing therapeutic diets. In order to keep classification and terminology as simple as possible a distinction has been made between the main characteristics of a modified diet and the derived characteristics. By a main characteristic we mean a modification directly proceeding from the clinial picture of the patient in question. A derived characteristic is a characteristic which is a consequence of a main characteristic and as such is related only indirectly to the patient's disease.A therapeutic diet is named - exclusively - after its main characteristic(s).A diet-prescription is correct and complete if it states:a. the main characteristic(s) of a diet; i.e. the name;b. the degree in which the quantity ties of nutrients should deviate from the normal: i.e. the quantities of nutrients permitted or required per 24 hours. (Energy and proteins are indicated preferably in quantities per kg body weight and fats and carbohydrates in per cent of energy).Drawing up such a diet-prescription is part of the duties and responsibili ties of the physician. To promote uniformity and clarity in the method of prescribing (not: the contents) we have developed a modelform on which physicians can, in a simple manner, record the diet-prescription. This diet-prescriptionform at the same time serves as a means of delegation, when patients are referred to a dietitian by the physician.Theoretical nutrition and dietetics are concerned with diet as a set of nutrients. Applied nutrition and dietetics concern diet as a set of foodstuffs. Foodstuffs are (consumable) products containing one or more nutrients. The diet prescription specifies the limiting conditions with which the diet as a set of foodstuffs should comply. Theoretically the problem of composing a therapeutic diet can be completely solved if the nutritional values of all foodstuffs are known, in particular the content of nutrients relevant to that therapeutic diet. In that respect there is no essential difference between composing normal and therapeutic (modified) diets. In both cases the foodstuffs should be selected in such a way that the daily diet complies with the required content of nutrients, on the understanding that in the case of therapeutic diets the quantity of one or more nutrients should be more or less than the normal quantity. Most modified diets too leave a lot of room for combination and variation.But in practice dietitians follow another procedure, taking into account the eating habits (the meal- and menu-pattern) of the patient in question. The patient's customary diet is correced and adapted to the diet prescription bya. prohibiting (in nutrient-limited and -eliminated diets) or requiring (in nutrient-enriched and -substituted diets) the use of particular kinds of foodstuffs per component of the menu:and/or byb. prescribing the use of a maximum quantity (in nutrient-limited diets) or minumum quantity (in nutrient-enriched diets) of particular kinds of foodstuffs per component of the menu.By quantities we understand the number of consumption-units, i.e. the number of slices, spoonfuls, cups, etc. The determining factor with respect to the kind of foodstuff is the quantity of one ore more nutrient(s) the food stuff contains per consumption unit. Similar foodstuffs are foodstuffs containing approximately, i.e. within certain limits, the same amount of a particular, relevant nutrient.The instructions drawn up by a dietitian in this way for a specific patient are called: dietetic-advice. Dietetic-advice is the translation in terms of foodstuffs of the diet- prescription, expressed in terms of nutrients.Dietetic-advice is also the nature of a prescription with regard to the patient, but it is attuned to the requirements and eating habits of the individual patient. Dietetic-advice can be continually adapted even when the prescription remains the same, and its contents can be entirely different for two different patients, even though the diet prescription is identical in both cases.To promote uniformity and clarity with respect to the dietetic advice the foodstuffs are divided into 14 menu groups, on the basis of the meal- and menu-pattern customary in the Netherlands. Each group corresponds with a fixed component of a meal. All foodstuffs belonging to a particular menu group have the same function in the composing of a meal or daily diet. In addition all foodstuffs have been divided into (at most) five kinds per nutrient: nutrient-free, nutrient-limited, nutrient-average, high-nutrient and nutrient-extreme.The classification-matrix, obtained in this way, serves as the basis for drawing up by far the greater proportion of all dietetic advices. With the dietitians and catering managers of the 28 hospitals taking part in our investigation agreements were made about:a. the size of the composition units of the most frequently occurring food stuffs (i.e. the number of grams),b. the limits (i.e. the amount of nutrients per consumption unit) within which foodstuffs are of the same kind (e.g. low-, high-, etc.)That is what we called: normalization.All practical problems, with respect to the prescribing, advising and composing of therapeutic diets, are all indirectly caused wholly or to a considerable extent by the fact that so far little attention has been paid to definition and terminology. Problems accordingly, which have all become wholly solvable thanks to the research.Nevertheless the investigation is first and foremost a basic scientific research. Definition is the basis of every science. The terminology and classification, of therapeutic diets which we have developed serve as a paradigm; a terminological model, for structuring a professional language by means of which implicit skill can be transformed into explicit - and thus verifiable and transmissible - knowledge. A paradigm which, at the same time, serves as a hypothesis for discerning gaps in existing scientific dietetic knowledge.The definition of a therapeutic modified diets constitutes the foundation of the entire research. A definition by wich modified diets have been restricted to the field of medicine in the pure sense of the word. This is not merely a question of definition, but is theoretically fundamental. Dietetics concerns itself with the relation disease -->diet; a relation which is of an entirely different nature and order from the relation diet --->health, with which nutrition concerns itself.</p

Corporate Governance and Financial Disclosures: Bangladesh Perspective

Financial reporting disclosures are very essential to the shareholders of a company because they frequently use these disclosures for their economic decisions about the business enterprise.  Board of directors, corporate management and external auditor may have an influence on financial reporting disclosures. From this perspective, the study investigates the influence of corporate governance on financial reporting disclosures. The results show that corporate governance is significantly associated with the extent of financial reporting disclosures. External auditor, multilisting and profitability are significantly (5 per cent level) associated with overall financial reporting disclosures index. Keywords: Bangladesh, financial reporting disclosure, corporate governanc

In vivo pharmacokinetics of a gentamicin-loaded collagen sponge in acute periprosthetic infection - Serum values in 19 patients

Background The in vivo pharmacokinetics of gentamycin- loaded collagen fleeces in humans have not been described in the current literature. We therefore analyzed in vivo pharmacokinetics of these fleeces when used in the treatment of periprosthetic infections. Patients and methods Gentamycin concentrations were measured in 19 consecutive patients with an acute periprosthetic infection. Each patient received 2-5 fleeces (130 mg gentamycin/fleece). Results Initially, the blood concentration increased to 3.2-7.2 mg/L, depending on the number of fleeces that were applied. The serum peak concentrations resulted in peak/MIC ratios of 2.5-36 for P. aeruginosa, S. aureus, and Klebsiella spp. Subsequently, the serum values decreased almost linearly below 0.3 mg/L in 18 to 62 hours. After 24 hours, the serum levels of gentamicin dropped below 2 mg/L, the toxicity threshold. Interpretation The application of 2 to 5 130-mg gentamycin-loaded collagen fleeces may be useful as an adjuvant treatment for implant-related infections, since no toxic concentrations were measured 24 hours postoperatively

Targeting platelet receptor function in thrombus formation: The risk of bleeding

In this review, we presume that the process of thrombus formation, as assessed in whole blood flow studies and in experimental (murine) thrombosis studies, reflects the platelet responses in human haemostasis and thrombosis. Following this concept, we give an up-to-date overview of the main platelet receptors and signalling pathways that contribute to thrombus formation and are used as targets in (pre)clinical intervention studies to prevent cardiovascular disease. Discussed are receptors for thrombin, thromboxane, ADP, ATP, prostaglandins, von Willebrand factor, collagen, CLEC-2 ligand, fibrinogen and laminin. Sketched are the consequences of receptor deficiency or blockage for haemostasis and thrombosis in mouse and man. Recording of bleeding due to (congenital) platelet dysfunction or (acquired) antiplatelet treatment occurs according to different protocols, while common laboratory methods are used to determine platelet function

Rate-limiting roles of the tenase complex of factors VIII and IX in platelet procoagulant activity and formation of platelet-fibrin thrombi under flow

The importance of factor Xa generation in thrombus formation has not been studied extensively so far. Here, we used mice deficient in either factor VIII or factor IX to determine the role of platelet-stimulated tenase activity in the formation of platelet-fibrin thrombi on collagen. With tissue factor present, deficiency in factor VIII or IX markedly suppressed thrombus growth, fibrin formation and platelet procoagulant activity (phosphatidylserine exposure). In either case, residual fibrin formation was eliminated in the absence of tissue factor. Effects of factor deficiencies were antagonized by supplementation of the missing coagulation factor. In wild-type thrombi generated under flow, phosphatidylserine-exposing platelets bound (activated) factor IX and factor X, whereas factor VIII preferentially co-localized at sites of von Willebrand factor binding. Furthermore, proteolytic activity of the generated activated factor X and thrombin was confined to the sites of phosphatidylserine exposure. With blood from a hemophilia A or B patient, the formation of platelet-fibrin thrombi was greatly delayed and reduced, even in the presence of high concentrations of tissue factor. A direct activated factor X inhibitor, rivaroxaban, added to human blood, suppressed both thrombin and fibrin formation. Together, these data point to a potent enforcement loop in thrombus formation due to factor X activation, subsequent thrombin and fibrin generation, causing activated factor X-mediated stimulation of platelet phosphatidylserine exposure. This implies that the factor VIII/factor IX-dependent stimulation of platelet procoagulant activity is a limiting factor for fibrin formation under flow conditions, even at high tissue factor concentrations

Platelet-Associated Matrix Metalloproteinases Regulate Thrombus Formation and Exert Local Collagenolytic Activity

Objective Platelets are increasingly implicated in processes beyond hemostasis and thrombosis, such as vascular remodeling. Members of the matrix metalloproteinase (MMP) family not only remodel the extracellular matrix but also modulate platelet function. Here, we made a systematic comparison of the roles of MMP family members in acute thrombus formation under flow conditions and assessed platelet-dependent collagenolytic activity over time. Approach and Results Pharmacological inhibition of MMP-1 or MMP-2 (human) or deficiency in MMP-2 (mouse) suppressed collagen-dependent platelet activation and thrombus formation under flow, whereas MMP-9 inhibition/deficiency stimulated these processes. The absence of MMP-3 was without effect. Interestingly, MMP-14 inhibition led to the formation of larger thrombi, which occurred independently of its capacity to activate MMP-2. Platelet thrombi exerted local collagenolytic activity capable of cleaving immobilized dye-quenched collagen and fibrillar collagen fibers within hours, with loss of the majority of the platelet adhesive properties of collagen as a consequence. This collagenolytic activity was redundantly mediated by platelet-associated MMP-1, MMP-2, MMP-9, and MMP-14 but occurred independently of platelet -granule release (Nbeal2(-/-) mice). The latter was in line with subcellular localization experiments, which indicated a granular distribution of MMP-1 and MMP-2 in platelets, distinct from -granules. Whereas MMP-9 protein could not be detected inside platelets, activated platelets did bind plasma-derived MMP-9 to their plasma membrane. Overall, platelet MMP activity was predominantly membrane-associated and influenced by platelet activation status. Conclusions Platelet-associated MMP-1, MMP-2, MMP-9, and MMP-14 differentially modulate acute thrombus formation and at later time points limit thrombus formation by exerting collagenolytic activity