bluuebunny/crossref_metadata_2025 huggingface dataset:
Probabilistic solution and bounds for serial inventory systems with discounted and average costs
Authors: Chao Xiuli , Zhou Sean X.
Published: April 2007

We consider the infinite horizon serial inventory system with both average cost and discounted cost criteria. The optimal echelon base‐stock levels are obtained in terms of only probability distributions of leadtime demands. This analysis yields a novel approach for developing bounds and heuristics for optimal inventory control polices. In addition to deriving the known bounds in literature, we develop several new upper bounds for both average cost and discounted cost models. Numerical studies show that the bounds and heuristic are very close to optimal.© 2007 Wiley Periodicals, Inc. Naval Research Logistics, 2007
Neurodevelopment of C57B/L6 mouse brain assessed by in vivo diffusion tensor imaging
Authors: Chahboune Halima , R. Ment Laura , B. Stewart William , Ma Xiaoxian , Rothman Douglas L. , Hyder Fahmeed
Published: April 2007

Heterogeneous spatiotemporal patterns of C57B/L6 murine brain maturation during the first 7 weeks after birth (i.e. P15 to P45) were assessed in vivo by diffusion tensor imaging (DTI) at 9.4 T. Maps of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were used to assess developmental changes. Because directionally encoded color (DEC) maps provide an efficient and straightforward way to visualize anisotropy direction, they were used to highlight the orientation‐dominant anisotropic tissues. In the corpus callosum, the increases in FA (∼0.4 to ∼0.6 from P15 to P45) were primarily dominant in the medial–lateral direction, whereas the ADC decreased slightly (∼0.8 × 10−3 to ∼0.5 × 10−3 mm2/s from P15 to P45). Similar increases in FA (∼0.3 to ∼0.4 from P15 to P45) and decreases in ADC (∼0.8 × 10−3 to ∼0.5 × 10−3 mm2/s from P15 to P45) were found in the cingulate, but these anisotropic changes were dominant in the anterior–posterior direction. In the caudate putamen, there were significant FA increases (∼0.1 to ∼0.2 from P15 to P45) dominant in the dorsal–ventral and anterior–posterior directions, whereas the ADC increased rapidly early in development (∼0.3 × 10−3 to ∼0.7 × 10−3 mm2/s from P15 to P17). There were no significant changes in tissue anisotropy in the somatosensory regions (whisker, forelimb), but the ADC decreased slightly (∼0.7 × 10−3 to ∼0.5 × 10−3 mm2/s from P15 to P45). Although the major differences in DEC values were mainly observed in white matter pathways, other cortical and subcortical regions showed some potential morphological changes that were consistent with classical histological findings. In summary, these results show that high‐resolution DTI at high magnetic fields allows detection and quantification of brain structures throughout normal development in C57B/L6 mice in vivo. Copyright © 2007 John Wiley & Sons, Ltd.
Developing MR reporter genes: promises and pitfalls
Authors: Gilad Assaf A. , Winnard Paul T. , van Zijl Peter C. M. , Bulte Jeff W. M.
Published: April 2007

MR reporter genes have the potential to monitor transgene expression non‐invasively in real time at high resolution. These genes can be applied to interrogate the efficacy of gene therapy, to assess cellular differentiation, cell trafficking, and specific metabolic activity, and also assess changes in the microenvironment. Efforts toward the development of MR reporter genes have been made for at least a decade, but, despite these efforts, the field is still in its early developmental stage. This reflects the fact that there are potential pitfalls, caused by the low sensitivity of detection, the need for substrates with their associated undesirable pharmacokinetics, and/or the difficult and, in some cases, delayed interpretation of signal changes. Nevertheless, significant progress has been made during the last few years. Whereas enzyme‐based reporters were initially applied to NMR spectroscopic monitoring of changes in phosphor and fluorine metabolism, MRI‐based approaches are now emerging that rely on: (1) enzyme‐based cleavage of functional groups that block water (proton) exchange or protein binding of MR contrast agents; (2) expression of surface receptors that enable binding of specific MR contrast agents; (3) expression of para‐ and anti‐ferromagnetic (metallo)proteins involved with iron metabolism, such as tyrosinase, transferrin receptor, and ferritin. After an introduction to the basic principles of designing promoters, expression vectors, and cloning of transgenes, a fresh look is provided on the use of reporter genes for optical (including bioluminescent) and nuclear imaging, with which MR reporter genes compete. Although progress in the use of MR reporter genes has been slow, newer strategies that use metalloproteins or alternative contrast mechanisms, with no need for substrates, promise rapid growth potential for this field. Copyright © 2007 John Wiley & Sons, Ltd.
MR technology for biological studies in mice
Authors: Nieman Brian J. , Bishop Jonathan , Dazai Jun , Bock Nicholas A. , Lerch Jason P. , Feintuch Akiva , Chen X. Josette , Sled John G. , Henkelman R. Mark
Published: April 2007

Mouse models are crucial for the study of genetic factors and processes that influence human disease. In addition to tools for measuring genetic expression and establishing genotype, tools to accurately and comparatively assess mouse phenotype are essential in order to characterize pathology and make comparisons with human disease. MRI provides a powerful means of evaluating various anatomical and functional changes and hence is growing in popularity as a phenotypic readout for biomedical research studies. To accommodate the large numbers of mice needed in most biological studies, mouse MRI must offer high‐throughput image acquisition and efficient image analysis. This article reviews the technology of multiple‐mouse MRI, a method that images multiple mice or specimens simultaneously as a means of enabling high‐throughput studies. Aspects of image acquisition and computational analysis in multiple‐mouse studies are also described. Copyright © 2007 John Wiley & Sons, Ltd.
Non‐invasive MRI of mouse models of atherosclerosis
Authors: Weinreb David B. , Aguinaldo Juan Gilberto S. , Feig Jonathan E. , Fisher Edward A. , Fayad Zahi A.
Published: April 2007

Early detection and characterization of atherosclerotic lesions susceptible to sudden rupture and thrombosis may decrease morbidity and mortality. Plaque development has been extensively studied using MRI in animal models of rapidly progressing atherosclerosis. These transgenic mice develop atherosclerotic plaques in the aortic root by 10 weeks of age and throughout the vasculature thereafter. Transplantation of lesion‐containing segments of the thoracic aorta into wild‐type mice results in nearly total reversal of atherosclerosis, making it possible to study both progression and regression of plaques in this model. MRI permits the non‐invasive accurate assessment of atherosclerotic plaque burden and the differentiation between the lipid and fibrous content of individual plaques, thus providing a non‐invasive approach to serially monitor the evolution of individual plaques in the mouse models. Emergence of novel contrast agents that target a diverse set of molecules within the plaque are now helping to elucidate the changes at the cellular and molecular levels during plaque progression and regression. Copyright © 2007 John Wiley & Sons, Ltd.
Radio frequency coil technology for small‐animal MRI
Authors: Doty F. David , Entzminger George , Kulkarni Jatin , Pamarthy Kranti , Staab John P.
Published: April 2007

A review of the theory, technology, and use of radio frequency (RF) coils for small‐animal MRI is presented. It includes a brief overview of MR signal‐to‐noise (S/N) analysis and discussions of the various coils commonly used in small‐animal MR: surface coils, linear volume coils, birdcages, and their derivatives. The scope is limited to mid‐range coils, i.e. coils where the product (fd) of the frequency f and the coil diameter d is in the range 2–30 MHz‐m. Common applications include mouse brain and body coils from 125 to 750 MHz, rat body coils up to 500 MHz, and small surface coils at all fields. In this regime, all the sources of loss (coil, capacitor, sample, shield, and transmission lines) are important. All such losses may be accurately captured in some modern full‐wave 3D electromagnetics software, and new simulation results are presented for a selection of surface coils using Microwave Studio 2006 by Computer Simulation Technology, showing the dramatic importance of the ‘lift‐off effect’. Standard linear circuit simulators have been shown to be useful in optimization of complex coil tuning and matching circuits. There appears to be considerable potential for trading S/N for speed using phased arrays, especially for a larger field of view. Circuit simulators are shown to be useful for optimal mismatching of ultra‐low‐noise preamps based on the enhancement‐mode pseudomorphic high‐electron‐mobility transistor for optimal coil decoupling in phased arrays. Cryogenically cooled RF coils are shown to offer considerable opportunity for future gains in S/N in smaller samples. Copyright © 2007 John Wiley & Sons, Ltd.
MR in mouse models of cardiac disease
Authors: Epstein Frederick H.
Published: April 2007

Transgenic and knockout mice can be used to study the genes and basic mechanisms involved in heart disease, and have therefore assumed a central role in modern cardiac research. MRI and MRS techniques have recently been developed for mice that enable the quantitative or semi‐quantitative in vivo assessment of cardiac anatomy, function, perfusion, infarction, Ca2+ influx, and metabolism. With these techniques, the normal mouse heart has been shown to be well suited as a model of human cardiac disease. The roles of individual genes in normal cardiac physiology have recently been studied by MR, including the role of neuronal nitric oxide synthase in β‐adrenergic stimulation, the roles of the inducible nitric oxide synthase and myoglobin in function, dilation, and energetics, and the role of cardiac troponin I in contractility. Furthermore, with a mouse model of myocardial infarction, the roles of the angiotensin II type 2 receptor, xanthine oxidase inhibitors, blood coagulation factor XIII, and inducible nitric oxide synthase in post‐infarct function and remodeling have been further elucidated. Non‐invasive in vivo MRI and MRS in mice provide a unique and powerful means for phenotyping genetically engineered mice and can improve our understanding of the roles of specific genes and proteins in cardiac physiology and pathophysiology. Copyright © 2007 John Wiley & Sons, Ltd.
MRI monitoring of focal cerebral ischemia in peroxisome proliferator‐activated receptor (PPAR)‐deficient mice
Authors: Pialat Jean‐Baptiste , Cho Tae‐Hee , Beuf Olivier , Joye Elisabeth , Moucharaffie Samir , Langlois Jean‐Baptiste , Nemoz Chantal , Janier Marc , Berthezene Yves , Nighoghossian Norbert , Desvergne Béatrice , Wiart Marlène
Published: April 2007

Peroxisome proliferator‐activated receptors (PPARs) are a potential target for neuroprotection in focal ischemic stroke. These nuclear receptors have major effects in lipid metabolism, but they are also involved in inflammatory processes. Three PPAR isotypes have been identified: α, β (or δ) and γ. The development of PPAR transgenic mice offers a promising tool for prospective therapeutic studies. This study used MRI to assess the role of PPARα and PPARβ in the development of stroke. Permanent middle cerebral artery occlusion induced focal ischemia in wild‐type, PPARα‐null mice and PPARβ‐null mice. T2‐weighted MRI was performed with a 7 T MRI scan on day 0, 1, 3, 7 and 14 to monitor lesion growth in the various genotypes. General Linear Model statistical analysis found a significant difference in lesion volume between wild‐type and PPAR‐null mice for both α and β isotypes. These data validate high‐resolution MRI for monitoring cerebral ischemic lesions, and confirm the neuroprotective role of PPARα and PPARβ in the brain. Copyright © 2007 John Wiley & Sons, Ltd.
Association of cell cycle‐related gene products and NF‐kappaB with clinical parameters in Langerhans cell histiocytosis
Authors: Amir Gail , Weintraub Michael
Published: April 2007

Background

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by the accumulation of abnormal Langerhans cells in one or several organs where they cause local tissue damage. The pathophysiology is not well understood. The aim of this study was to examine expression of various gene products that play a role in cell cycle and cell death and to look for an association with the extent of the disease at the time of diagnosis and with “risk bone” involvement.

Procedure

Histologic slides from cases with biopsy proven disease were stained immunohistochemically for Bcl‐2, caspase‐3, Ki‐67, p53, and nuclear factor‐kappaB (NF‐κB) and the results were quantitated and compared with the clinical extent of the disease.

Results

In patients with multisystem disease and “risk” bone involvement, a higher percentage of Langerhans cells stained with the anti‐apoptotic gene product Bcl‐2 (P = 0.0004; P = 0.001 respectively) and a lower percentage of these cells stained with the apoptosis marker caspase‐3 compared to patients with single system disease (P = 0.0001; P = 0.01 respectively). Proliferation marker Ki‐67 was expressed more frequently in multisystem disease compared to single system disease (P = 0.02) but an association with “risk” bone involvement was not found. Expression of p53 and NF‐κB did not discriminate between clinical subgroups.

Conclusions

The findings suggest that cell proliferation and suppression of apoptosis may be mechanisms of cell survival in the more aggressive forms of LCH (multisystem, risk bone involvement). Pediatr Blood Cancer 2008;50:304–307. © 2007 Wiley‐Liss, Inc.
Triple intrathecal therapy without cranial irradiation for central nervous system preventive therapy in childhood acute lymphoblastic leukemia
Authors: Lin Wei‐Ying , Liu Hsi‐Che , Yeh Ting‐Chi , Wang Lin‐Yen , Liang Der‐Cherng
Published: April 2007

Background

To evaluate the treatment results of central nervous system preventive therapy (CNSP) with triple intrathecal therapy (TIT) alone in children with acute lymphoblastic leukemia (ALL).

Methods

We retrospectively studied a cohort of 59 patients with median follow‐up time 50.6 months (range: 27–80 months) at a single institution in Taiwan. Patients with ALL were classified in risk groups at diagnosis. TPOG‐ALL‐93 protocols and TPOG‐ALL‐2002 protocols were used. Both protocols were for multicenter studies in Taiwan and contained protocols for standard‐risk (SR), high‐risk (HR), and very‐high‐risk (VHR) patients. In this study, we used TIT alone for CNSP. In all ALL patients, methotrexate, hydrocortisone, and cytarabine were given at age‐dependent doses.

Results

As of October 2006, patients had a 3‐year event‐free survival and an overall survival 89.4 ± 4.1% (S.E.) and 93.1 ± 3.3%, respectively. Under TIT no patients had complications such as seizure, encephalitis, or infection, and no morbidities like those caused by cranial irradiation. In this study, we used TIT alone for CNSP and had no CNS relapse.

Conclusions

In the context of effective systemic therapy, TIT alone appears to be effective CNSP for most patients with ALL. Pediatr Blood Cancer 2008;50:523–527. © 2007 Wiley‐Liss, Inc.
Essential thrombocythemia in a child with elevated thrombopoietin concentrations and skeletal anomalies
Authors: Robins Edwin B. , Niazi Massoma
Published: April 2007

Essential thrombocythemia is a rare myleoproliferative disorder in pediatrics. This myleoproliferative disorder is characterized by excessive proliferation of megakaryocytes and sustained elevation of platelet count. Reactive thrombocytosis is a more common cause of elevated platelet counts among children. We describe a 2‐year‐old child with essential thrombocythemia, skeletal anomalies, and elevated thrombopoietin concentrations. The child's mother was also subsequently diagnosed with essential thrombocythemia and had elevated thrombopoietin concentrations. Chromosomal studies on the mother, child and other family members were normal. Pediatr Blood Cancer 2008;50:859–861. © 2007 Wiley‐Liss, Inc.
Analysis of outcome for patients with mass lesions of the central nervous system due to Langerhans cell histiocytosis treated with 2‐chlorodeoxyadenosine
Authors: Dhall Girish , Finlay Jonathan L. , Dunkel Ira J. , Ettinger Lawrence J. , Kellie Stewart J. , Allen Jeffrey C. , Egeler R. Maarten , Arceci Robert J.
Published: April 2007

Purpose

To assess the activity and tolerability of 2‐chlorodeoxyadenosine (2‐CDA) in treating mass lesions of the central nervous system (CNS) due to Langerhans cell histiocytosis (LCH).

Patients and Methods

The records of eight children and four adults with CNS LCH who were treated with 2‐CDA were reviewed. The pattern of CNS disease included involvement of the hypothalamic‐pituitary axis, gadolinium enhancing parenchymal as well as dural and choroid plexus based mass lesions, and atrophy. 2‐CDA (5–13 mg/m2/day) was given on 3–5 consecutive days and repeated every 2–8 weeks for a period ranging from 3 to 12 months.

Results

Eight patients demonstrated a complete radiographic response to 2‐CDA with resolution of all enhancing mass lesions and four patients showed a sustained, partial radiographic response. One patient died from a non‐treatment related cause without evidence of LCH on autopsy. With a follow‐up ranging from 2 to 10 years after completion of therapy, the 11 surviving patients remain in continuous remission or are progression free. Prolonged bone marrow suppression was the most common toxicity (four patients). Permanent sequelae of CNS LCH, such as panhypopituitarism, diabetes insipidus (DI) and neurocognitive dysfunction, were not found to be reversible with 2‐CDA therapy.

Conclusions

2‐CDA is an active agent in patients with CNS LCH, with the possible exception of neurodegenerative disease, and should be further evaluated in a prospective multi‐center clinical trial for LCH patients with enhancing mass lesions of the CNS. Pediatr Blood Cancer 2008;50:72–79. © 2007 Wiley‐Liss, Inc.
Bone marrow assessment in Langerhans cell histiocytosis
Authors: Minkov Milen , Pötschger Ulrike , Grois Nicole , Gadner Helmut , Dworzak Michael N.
Published: April 2007

Background

Bone marrow changes and their relation to blood cytopenia in patients with Langerhans cell histiocytosis (LCH) have not been extensively studied to date. The aim of the present study was to characterize the bone marrow changes in LCH patients and to ascertain their relation to disease severity.

Methods

Fifty‐seven marrow samples of LCH patients were studied by conventional cytology, immunocytochemistry (ICC) and flow cytometry (FCM).

Results

On conventional cytology there was no significant difference between LCH cases and controls with respect to cellularity, number of monocytes and progenitor cells, and presence of histiocytes and hemophagocytosis. The numbers of nucleated cells, CD34pos cells, and CD14pos cells on FCM did not differ, either. The CD1a staining by ICC was positive in 14/41 LCH samples, and was consistently negative in controls. FCM staining for CD1a was positive in 12/54 samples, but also in 5/35 controls. The number of the CD1apos cells in LCH marrows was usually very low (<10–20 cells/slide by ICC, or <0.5% of the leukocytes by FCM). The CD1a staining was more frequently positive and more pronounced in patients with severe disease.

Conclusions

The combination of conventional aspirate cytology with ICC (CD1a staining) appears to be the most reliable tool for bone marrow assessment in LCH. Pediatr Blood Cancer 2007;49:694–698. © 2007 Wiley‐Liss, Inc.
Initial testing of the VEGFR inhibitor AZD2171 by the pediatric preclinical testing program
Authors: Maris John M. , Courtright Joshua , Houghton Peter J. , Morton Christopher L. , Gorlick Richard , Kolb E. Anders , Lock Richard , Tajbakhsh Mayamin , Reynolds C. Patrick , Keir Stephen T. , Wu Jianrong , Smith Malcolm A.
Published: April 2007

Background

Inhibition of vascular endothelial growth factor mediated signaling shows promise as an antiangiogenic strategy for solid tumors. AZD2171 is a potent and relatively selective inhibitor of the vascular endothelial growth factor (VEGF) receptor family that is orally bioavailable. This study was designed to screen for antitumor activity of AZD2171 against the in vitro and in vivo childhood cancer preclinical models of the Pediatric Preclinical Testing Program (PPTP).

Procedures

AZD2171 was tested at concentrations from 0.1 nM to 1.0 µM against the in vitro panel and was tested against the in vivo tumor panels using a 6‐week exposure to daily gavage administration of AZD2171 (3 or 6 mg/kg) or vehicle.

Results

One of 22 cell lines evaluated was sensitive to AZD2171 in vitro (maximum concentration 1 µM). Evidence of in vivo antitumor activity (primarily tumor growth delay) was observed in 78% of solid tumor xenografts (3/3 rhabdoid, 2/3 Wilms', 3/3 Ewing's, 5/5 rhabdomyosarcoma, 1/3 medulloblastoma, 2/4 glioblastoma, 5/6 neuroblastoma, 4/5 osteosarcoma). Objective responses (both complete responses) were observed in two of 32 (6%) solid tumor xenografts (a rhabdoid xenograft and an osteosarcoma xenograft). No activity was observed against 7 acute lymphoblastic leukemia models.

Conclusions

AZD2171 demonstrated broad tumor growth inhibition against the PPTP's solid tumor xenografts and much less commonly induced tumor regression. This pattern of in vivo activity, combined with the disassociation of in vitro and in vivo efficacy, are consistent with AZD2171 inhibiting growth of the PPTP's solid tumor xenografts primarily through an anti‐angiogenesis mechanism of action. Pediatr Blood Cancer 2008;50:581–587. © 2007 Wiley‐Liss, Inc.
Fetus in fetu—from prenatal ultrasound and MRI diagnosis to postnatal confirmation
Authors: Hui Pui Wah , Lam Tina Poy Wing , Chan Kwong Leung , Lee Chin Peng
Published: April 2007

We report a case of fetus in fetu presented as a complex intra‐abdominal heterogeneous cystic lesion during ultrasound examination of the fetus at 25 weeks of gestation. Progressive growth of this mass was noted in the prenatal period. Fetal magnetic resonance imaging provided additional information to aid in the prenatal diagnosis. This allows proper counselling for the parents and helps to plan the postnatal management. Surgical excision was carried out in the early neonatal period and the diagnosis of fetus in fetu was confirmed. Copyright © 2007 John Wiley & Sons, Ltd.
Characteristics and quality of adverse drug reaction reports by pharmacists in Norway
Authors: Gedde‐Dahl Ane , Harg Pernille , Stenberg‐Nilsen Hanne , Buajordet Marit , Granas Anne Gerd , Horn Anne Marie
Published: April 2007

Purpose

To evaluate the characteristics and quality of adverse drug reaction (ADR) reports submitted by pharmacists, and thereby assess the possible contribution of pharmacists to the spontaneous reporting system for ADRs in Norway.

Methods

An open, prospective study was conducted where dispensing pharmacists from 39 pharmacies were encouraged to report ADRs over a 3‐month period. The submitted ADR reports were compared to reports by physicians from the same time period. All reports were evaluated for selected characteristics, that is distribution of Anatomical Therapeutic Chemical (ATC) classification codes of suspected drugs, distribution of ADRs according to system‐organ classes and the quality of the reports.

Results

A total of 118 reports covering 274 ADRs received from the pharmacists were compared to 109 ADR reports with 304 ADRs submitted by physicians. Pharmacists more often reported ADRs related to cardiovascular drugs, alimentary tract and metabolism drugs and respiratory drugs, whereas physicians more frequently reported ADRs related to musculoskeletal drugs and antineoplastic and immunomodulating agents. ADRs reported by pharmacists more frequently described gastrointestinal reactions while physicians reported more ADRs in relation to the cardiovascular and blood system. Whereas 68% of the physicians' reports were classified as serious, only 5% of the pharmacists' reports were serious. More than 50% of the reports submitted by pharmacists concerned ADRs following a generic substitution, in contrast to only 2% of the physicians' reports. The pharmacists' reports were found to be of a lower documentation grade. However, there was no substantial difference in a subjective assessment of the quality of information in the reports submitted by the two categories of health professionals.

Conclusions

Pharmacists submit valuable ADR reports which provide information complimentary to physicians' reports. This emphasises that pharmacist ADR reporting might constitute an important addition to the spontaneous reporting system. Copyright © 2007 John Wiley & Sons, Ltd.
Hydrogels as smart biomaterials
Authors: Kopeček Jindřich , Yang Jiyuan
Published: April 2007

Hydrogels were the first biomaterials rationally designed for human use. Beginning with the pioneering work of Wichterle and Lím on three‐dimensional polymers that swell in water, we review the design, synthesis, properties, and applications of hydrogels. The field of hydrogels has moved forward at a dramatic pace. The development of suitable synthetic methods encompassing traditional chemistry to molecular biology has been used in the design of hydrogels mimicking basic processes of living systems. Stimuli‐sensitive hydrogels, hydrogels with controlled degradability, genetically engineered poly(amino acid) polymers reversibly self‐assembling in precisely defined three‐dimensional structures, and hybrid polymers composed of two distinct classes of molecules are just some examples of these exciting novel biomaterials. The biocompatibility of hydrogels and their applications from implants to nanomaterials are also reviewed. Copyright © 2007 Society of Chemical Industry
Hard yet Tough Nanocomposite Coatings – Present Status and Future Trends
Authors: Zhang Sam , Wang Hui Li , Ong Soon‐Eng , Sun Deen , Bui Xuan Lam
Published: April 2007

Toughness and hardness are important aspects for coating applications in manufacturing industry. Extensive theoretical and experimental efforts have been made to synthesize and study nanocomposite coatings with super hardness and high toughness. The materials can be hardened through various or combined hardening mechanisms. However, for engineering applications, coating toughness is as important as, if not more than, super hardness. At present, there is neither a standard test procedure, nor a standalone methodology for the assessment of thin film toughness. The determination of the toughness is still a difficult task, and very much a fully open problem. In this article, we review the hardening and toughening mechanisms of nanocomposite films, and the toughness characterization techniques. Based on these reviews, an outlook will be presented in the concluding remarks.

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Atmospheric‐Pressure Plasmas for Wide‐Area Thin‐Film Deposition and Etching
Authors: Hopfe Volkmar , Sheel David W.
Published: April 2007

The present paper is focused on coating technologies compatible with industrial requirements, particularly on atmospheric pressure plasma technologies which are compatible with scaling to wide substrate widths (≥0.5 m). The AP‐PECVD reactors are designed for continuous air‐to‐air processing, and can be used for deposition of non‐oxide films. Two thermal methods for atmospheric pressure processing are considered: microwave CVD and DC ArcJet‐CVD. Typical thin film growth rates for PECVD are in the range of 5–100 nm · s−1 (static) and up to 2 nm · m · s−1 (dynamic). The rates for plasma chemical etching are typically 10 times higher. A complimentary lower energy plasma source based on dielectric barrier glow discharge plasma CVD has also been explored. Developments are underway to explore uses for the coating technology, for example scratch resistant coatings on metals, barrier layers, self‐clean functional surfaces and antireflective coatings. Coating materials range from silica, titania, aluminium oxide, metal composite layers, carbon and silicon nitride. Layer properties are close to data known from low pressure PECVD. Plasma chemical etching has been developed for crystalline silicon photovoltaics. The surface textures strongly change with the precursors and the plasma parameters used.

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The value of latent class analysis in medical diagnosis
Authors: Rindskopf David , Rindskopf Wallace
Published: April 2007

Assessment of the value of diagnostic indicators such as symptoms and laboratory tests results from calculation of the sensitivity and specificity of the indicators. Knowledge of the rate of occurrence of the disease allows for additional calculations of the error rates in using an indicator. These calculations are accurate only when the data on which they are based are reliable. If the diagnosis, which is used as the criterion for computing the sensitivity and specificity, is not accurate, then the resulting calculations will be in error. We show how a statistical method, latent class analysis, allows for the estimation of the characteristics of indicators even when an accurate diagnosis is unavailable. In addition, the method deals with several indicators at once, and provides a way to combine the information from all the indicators to make a diagnosis.
Cause‐deleted proportional mortality analysis and the healthy worker effect
Authors: Walter S. D.
Published: April 2007

This paper evaluates the relationships between various indices of proportional mortality, used in occupational and other settings where denominator data are unavailable. In particular, we examine the necessary conditions for validity of the proportional mortality ratio (PMR) and mortality odds ratio (MOR) as estimates of the standardized mortality ratio (SMR), in general and for the situation where one considers only a subset of deaths, with certain causes of death deleted from the data. We may exclude data in this way to avoid the inflationary effect on the PMRs for some causes of death (e.g. cancer) that results from a ‘healthy worker effect’ for other causes of death (e.g. heart disease). We find that cause‐deleted PMRs and MORs may be unbiased estimates of their corresponding SMR, and these indices appear most useful for specific hazards of employment or relatively infrequent causes of death.
Assessment of stratum‐covariate interactions in Cox's proportional hazards regression model
Authors: Thall Peter F. , Lachin John M.
Published: April 2007

We assess stratum (e.g. treatment) interactions with covariates and with the baseline hazard function in the proportional hazards (PH) regression model for lifetime data. We consider models incorporating stratum interactions both with and without stratification of the risk sets in the likelihood function, and describe likelihood ratio statistics for tests of the presence of these interactions. We also present step‐down methods for building reduced models which include stratum‐specific parameters corresponding to covariates which interact with treatment. We apply PH models with such interactions to a clinical trial of DES in the treatment of prostate cancer to determine optimal treatment conditional on each patient's covariates.
Use of an international data bank to compare outcome following severe head injury in different centres
Authors: Murray G. D.
Published: April 2007

The advantages and drawbacks of basing treatment comparisons on observational data are discussed. Recommendations are made for minimizing bias when basing comparisons on computerized data banks. A specific example is given concerning treatment following severe head injury.
Case‐control studies for estimation of the natural history of preclinical disease from screening data
Authors: Brookmeyer R. , Day N. E. , Moss S.
Published: April 2007

The duration of the detectable preclinical phase of disease, which we call the sojourn time, is an important quantity to consider when recommending frequency of screens and investigating the natural history of the disease. In this paper, we propose a matched case‐control methodology for screening data for joint estimation of the sojourn time distribution and the false negative rate of the screening test. The approach is based on a conditional likelihood for matched sets that involves a comparison of the screening histories of cases and controls. We illustrate the methodology with the data from the Aberdeen screening programme for cervical cancer by the Pap smear. We consider a number of different parametric forms for the sojourn time distribution.
The use of an extended baseline period in the evaluation of treatment in a longitudinal duchenne muscular dystrophy trial
Authors: Madsen K. S. , Miller J. P. , Province M. A.
Published: April 2007

A trial of Duchenne muscular dystrophy involved tracking boys of all ages through a one‐year baseline period, followed by a one‐year trial of leucine versus placebo treatment. In this paper we develop a model for a total‐muscle‐strength score that uses the data of the extended baseline period in the evaluation of the leucine treatment. The model is based on a polynomial growth curve in age whose coefficients can vary according to treatment or phase. Maximum likelihood estimates of the parameters of the model are obtained from use of the EM algorithm. We propose tests for the adequacy of the model as well as for treatment effects. A quadratic model appears the most parsimonious fit to the data and there is no evidence of any leucine effect on scores. We examine the asymptotic power of the test for treatment effect and compare it with that of a simpler analysis.
Censoring distributions as a measure of follow‐up in survival analysis
Authors: Korn Edward L.
Published: April 2007

The mean or median of the follow‐up times as a measure of the quality or completeness of the follow‐up in a survival analysis can sometimes be misleading—a more severe disease will have shorter follow‐up times because of earlier deaths. We suggest here that estimates of the censoring distribution provide a more useful measure of the follow‐up. This paper gives estimation procedures for both grouped‐time (cohort) data and continuous data, and provides an application.
Considerations of statistical power in the shared‐haplotypes test
Authors: Ewens W. J.
Published: April 2007

This paper considers statistical power properties of a test of whether a disease is caused by a recessive gene, using data on HLA sharing properties of affected sibs. It is found that the test has very poor power characteristics, and in particular we are sometimes just as likely to accept the hypothesis that the gene is recessive when it is dominant as when it is truly recessive.
A method for combining results from several prospective epidemiologic studies
Authors: Dyer Alan R.
Published: April 2007

An approach to the problem of a single study lacking adequate power to examine an important question is to combine the data from several studies to allow a more powerful test of the hypothesis in question. The present paper describes a method used by the International Collaborative Group to pool data on 54,492 men aged 40–69 from 10 population studies in 7 countries to examine the association between cholesterol level and risk of death from cancer. Furthermore, there was a suggestion that the inverse association observed in some studies might be the result of an effect of undetected cancer on cholesterol level, rather than an increase in cancer risk resulting from low cholesterol levels. This paper describes the process for selection of the method used to evaluate this possibility over other potential approaches and the results obtained in the analysis of the International Collaborative Group data that support this hypothesis. This report also indicates how one might expect some of the analyses described to compare with analyses based on a discrete version of the Cox proportional hazards model.
Estimation of normal ranges of clinical laboratory data
Authors: Tango Toshiro
Published: April 2007

This paper proposes a new procedure for estimating normal ranges of clinical laboratory tests, which can be applied to data with possibly more than one outlier from healthy subjects. The proposed procedure determines the optimal model among a class of models in which it is assumed that (1) an observed distribution of ‘normal values’ can be transformed to the Gaussian form by one of several specified transformations, and (2) if there exist outliers among the data, then each of the transformed outliers also follows a Gaussian distribution with different mean from, but the same variance as, the transformed distribution of normal values. The optimal model is defined as the best combination of the transformation to normality and the number of outliers identified, and is selected by the Akaike information criterion (AIC). Our procedure is illustrated with data from 200 healthy male subjects on 25 laboratory tests.
Discrimination and other statistical intervals for the interpretation of in vivo patient monitoring data
Authors: Kost Gerald J.
Published: April 2007

A calibration line is used to define the relationship between a new clinical technique and a standard in vitro laboratory methodology. Discrimination intervals quantify the reliability of inverse estimates obtained from the calibration line. Applied to transcutaneous P monitoring, a new in vivo measurement, discrimination intervals for inverse estimates of arterial P range in size from 10 to 50 torr (1.33–6.67 kPa), or more, depending on the values of statistical parameters selected. Discrimination interval analysis shows that the inverse estimates are more reliable near the means. Also, it indicates that the primary value of transcutaneous P monitoring lies not in providing accurate inverse estimates of arterial P, but instead, in monitoring short‐term clinical trends.
The use of glim and the bootstrap in assessing a clinical trial of two drugs
Authors: Mapleson W. W.
Published: April 2007

An approach is described for estimating the dose of a new drug which is equipotent to an established dose of an old drug. The approach is basically that of the parallel‐line assay but it can allow for concomitant variables and, by exploiting the facilities available in the statistical computer package GLIM (generalized linear interactive modelling), the approach can be applied when the residuals conform to one of a number of distributions and, with suitable safeguards, to continuous, discrete and even ‘scored’ responses. In some circumstances, it is necessary to obtain confidence limits by Efron's ‘bootstrap’ technique. The method is illustrated with results from a trial of two premedicant drugs in children.
A simulation study of three sequential methods for the comparison of two treatment groups when the response criterion is censored
Authors: Benichou Jacques , Chastang Claude
Published: April 2007

Three recent sequential methods, group sequential analysis (GSA), the sequential probability ratio test (SPRT) and the triangular test (TT) are well suited to randomized clinical trials with a censored response criterion, as they do not require matched pairs of patients.

We undertook a simulation study to investigate their statistical properties and to compare these three methods with the fixed‐sample design. Our results suggest that (i) the three methods have the expected statistical properties for size and power; (ii) they allow an important reduction of the average number of events before stopping, except with GSA when there is no treatment difference; (iii) the triangular test (closed design) appears the optimal design, as the variance of the number of events is smaller than with the sequential probability ratio test (open design) and (iv) analysis after every twenty new events does not alter the statistical properties of these sequential methods and enhances their usefulness.
Assessing the performance and clinical impact of a computerized prognostic system in severe head injury
Authors: Murray G. D. , Murray L. S. , Barlow P. , Teasdale G. M. , Jennett W. B.
Published: April 2007

The ability to predict outcome in the early stages of severe head injury would have several uses. A computerized system which has been developed in Glasgow to assist clinicians in this task, based on information from over 2500 severely head‐injured patients, is described, with particular attention to the testing of the statistical properties of the system, and, more importantly, the assessment of its clinical impact.
Application of statistical decision theory to treatment choices: Implications for the design and analysis of clinical trials
Authors: Simes R. J.
Published: April 2007

This paper explores the application of statistical decision theory to treatment choices in cancer which involve difficult value judgements in weighing beneficial and deleterious outcomes of treatment. Strengths and weaknesses of using decision theory are illustrated by considering the problem of selecting chemotherapy in advanced ovarian cancer. The paper includes an assessment of individual preferences in 27 volunteers and a discussion of some problems in utility assessment. An alternative approach, using threshold analysis, is presented in which the results of the decision analysis are expressed as a function of utility parameters. By knowing what sets of utilities favour each treatment, the assessment of patient preferences can then be focused on important differences of treatment options. The implications of these results for the design and analysis of clinical trials are discussed.
A counting process approach to the analysis of the course of non‐Hodgkin's lymphoma
Authors: Mau Jochen , Steinke Berthold
Published: April 2007

Non‐Hodgkin's lymphoma is a neoplastic disease with a course including remission and relapse. Therefore, a mortality analysis of overall survival time alone may conceal important differences between the forces of mortality (hazard functions) associated with distinct states of active disease, for example pre‐remission state and first relapse. Further, prognostic factors for overall survival time may fail to contribute significantly to the pre‐remission force of mortality. Our approach to analysis is based on a non‐homogeneous Markov illness‐death process as a stochastic model of the course of disease. It exploits the statistical theory of counting processes.
Selection of variables using ‘independence bayes’ in computer‐aided diagnosis of upper gastrointestinal bleeding
Authors: Ohmann C. , Künneke M. , Zaczyk R. , Thon K. , Lorenz W.
Published: April 2007

In this paper two problems of computer‐aided diagnosis with ‘independence Bayes’ were investigated: selection of variables and monotonicity in performance as the number of measurements is increased. Using prospective data from patients with upper gastrointestinal bleeding, the stepwise forward selection approach maximizing the apparent diagnostic accuracy was analysed with respect to different kinds of bias in estimation of the true diagnostic accuracy and to the stability of the number and type of variables selected. The results of this study suggest first that the selection of variables should be evaluated against the estimated true diagnostic accuracy obtained using all variables, and secondly that the results of a single selected sequence may be severely biased.
Some experiments with factors that might affect the response of mothers to a postal questionnaire
Authors: Cartwright Ann
Published: April 2007

The effects of a number of controllable factors on the response rate of mothers to a postal questionnaire were assessed by a series of experiments. In one a factorial design was used to look at seven factors with a random sample of 1600 mothers. The main findings were that the responses to questionnaires of 8,16 or 24 pages were similar, but that rather more mothers replied when the questionnaires contained only factual questions than when they covered both facts and attitudes. Another experiment, based on a similar sample, compared the response rates when the questionnaires were sent out by a government organization or by the Institute for Social Studies in Medical Care, and found no difference. The final experiment looked at the effect of precoding the answers or asking respondents to tick boxes beside their replies and again found no difference in response rates. The overall response rate was 79 per cent, but this varied between 66 and 87 per cent in the ten randomly selected study areas‐a much greater variation than that found with any of the experimental factors.
Sensitivity of Fisher's exact test to minor perturbations in 2 × 2 contingency tables
Authors: Dupont William D.
Published: April 2007

The two tailed Fisher's exact P value is extremely sensitive to small perturbations in 2 × 2 contingency tables. An example indicates that a 1 per cent increase in the denominator of one treatment group results in a 32 per cent drop in the exact P value, but a mere 0.1 per cent decrease in the treatment success rate. This is equivalent to the increase in significance obtained by a 20 per cent increase in the sample size of both treatments without changing the observed success rates. This drop results from small changes in the probabilities of unobserved events. A systematic evaluation of 920 pairs of similar contingency tables shows that these fluctuations occur frequently over a wide range of sample sizes and significance levels. Doubling the one tailed exact P value provides a more consistent measure of inferential strength. We discuss various chi‐squared continuity corrections.
Prognostic factors, models and related statistical problems in the survival of end‐stage renal disease patients on hemodialysis
Authors: Umen Andrew J. , Le Chap T.
Published: April 2007

We investigate factors associated with the survival of end‐stage renal disease patients on hemodialysis. A model derived for non‐diabetics includes five significant prognostic factors: age at initiation of dialysis, arteriosclerotic heart disease, cerebrovascular accident, cancer and chronic obstructive pulmonary disease. For diabetics, age at initiation of dialysis was the only significant prognostic factor.

We also show that (i) a simple exponential model adequately represents hemodialysis survival data, (ii) the relationship between age and survival hazard is not log‐linear and (iii) data for diabetics require independent analysis or inclusion of interaction terms. In this paper, we chose the first approach.
Effect of covariate measurement error in randomized clinical trials
Authors: Morgan Timothy M. , Elashoff Robert M.
Published: April 2007

Prognostic factors often appear as covariates in clinical trials designed to estimate treatment effects. These factors are usually subject to measurement error and lead to decreased efficiency in the estimation of the treatment effect. We use Weibull regression models and asymptotic theory to derive the efficiency of estimation obtained by adjusting for one dichotomous and one continuous covariate measured with error. An application to a clinical trial involving advanced lung cancer patients illustrates the results.
Small sample behaviour of hypothesis tests related to indirect standardized rates: A Monte Carlo study
Authors: Bean Judy A. , Wiltse Curtis G. , Woolson Robert E.
Published: April 2007

Different distributions of confounding variables in populations complicate any comparison of the relative frequency of an event. To resolve this, methods for fitting statistical models to tables of rates have recently been developed. One such model is the multiplicative model. We performed a Monte Carlo study of the multiplicative model for a 4 × 3 table of rates. For small samples the likelihood ratio test statistic was conservative for small expected cell counts, liberal for moderate expected counts, and performed well for large expected counts. The weighted least squares test statistic was generally more conservative and less powerful than both the likelihood ratio statistic and the Pearson statistic.