Effects of SLCO1B1 polymorphism on the pharmacokinetics of the oral antidiabetic drugs repaglinide, nateglinide, rosiglitazone, and pioglitazone

Organic anion-transporting polypeptide 1B1 (OATP1B1), encoded by the SLCO1B1 gene, is an influx transporter expressed on the sinusoidal membrane of human hepatocytes. The common c.521T>C (p.Val174Ala) single-nucleotide polymorphism (SNP) of the SLCO1B1 gene has been associated with reduced OATP1B1 transport activity in vitro and increased plasma concentrations of several of its substrate drugs in vivo in humans. Another common SNP of the SLCO1B1 gene, c.388A>G (p.Asn130Asp), defining the SLCO1B1*1B (c.388G-c.521T) haplotype, has been associated with increased OATP1B1 transport activity in vitro. The aim of this thesis was to investigate the role of SLCO1B1 polymorphism in the pharmacokinetics of the oral antidiabetic drugs repaglinide, nateglinide, rosiglitazone, and pioglitazone. Furthermore, the effect of the SLCO1B1 c.521T>C SNP on the extent of interaction between gemfibrozil and repaglinide as well as the role of the SLCO1B1 c.521T>C SNP in the potential interaction between atorvastatin and repaglinide were evaluated. Five crossover studies with 2-4 phases were carried out, with 20-32 healthy volunteers in each study. The effects of the SLCO1B1 c.521T>C SNP on single doses of repaglinide, nateglinide, rosiglitazone, and pioglitazone were investigated in Studies I and V. In Study II, the effects of the c.521T>C SNP on repaglinide pharmacokinetics were investigated in a dose-escalation study, with repaglinide doses ranging from 0.25 to 2 mg. The effects of the SLCO1B1*1B/*1B genotype on repaglinide and nateglinide pharmacokinetics were investigated in Study III. In Study IV, the interactions of gemfibrozil and atorvastatin with repaglinide were evaluated in relation to the c.521T>C SNP. Plasma samples were collected for drug concentration determinations. The pharmacodynamics of repaglinide and nateglinide was assessed by measuring blood glucose concentrations. The mean area under the plasma repaglinide concentration-time curve (AUC) was ~70% larger in SLCO1B1 c.521CC participants than in c.521TT participants (P ≤ 0.001), but no differences existed in the pharmacokinetics of nateglinide, rosiglitazone, and pioglitazone between the two genotype groups. In the dose-escalation study, the AUC of repaglinide was 60-110% (P ≤ 0.001) larger in c.521CC participants than in c.521TT participants after different repaglinide doses. Moreover, the AUC of repaglinide increased linearly with repaglinide dose in both genotype groups (r > 0.88, P 0.001). The AUC of repaglinide was ~30% lower in SLCO1B1*1B/*1B participants than in SLCO1B1*1A/*1A (c.388AA-c.521TT) participants (P = 0.007), but no differences existed in the AUC of nateglinide between the two genotype groups. In the drug-drug interaction study, the mean increase in the repaglinide AUC by gemfibrozil was ~50% (P = 0.002) larger in c.521CC participants than in c.521TT participants, but the relative (7-8-fold) increases in the repaglinide AUC did not differ significantly between the genotype groups. In c.521TT participants, atorvastatin increased repaglinide peak plasma concentration and AUC by ~40% (P = 0.001) and ~20% (P = 0.033), respectively. In each study, after repaglinide administration, there was a tendency towards lower blood glucose concentrations in c.521CC participants than in c.521TT participants. In conclusion, the SLCO1B1 c.521CC genotype is associated with increased and the SLCO1B1*1B/*1B genotype with decreased plasma concentrations of repaglinide, consistent with reduced and enhanced hepatic uptake, respectively. Inhibition of OATP1B1 plays a limited role in the interaction between gemfibrozil and repaglinide. Atorvastatin slightly raises plasma repaglinide concentrations, probably by inhibiting OATP1B1. The findings on the effect of SLCO1B1 polymorphism on the pharmacokinetics of the drugs studied suggest that in vivo in humans OATP1B1 significantly contributes to the hepatic uptake of repaglinide, but not to that of nateglinide, rosiglitazone, or pioglitazone. SLCO1B1 polymorphism may be associated with clinically significant differences in blood glucose-lowering response to repaglinide, but probably has no effect on the response to nateglinide, rosiglitazone, or pioglitazone.

Pharmacogenetics of SLCO1B1: Population genetics and effect on statins

Kohonneiden kolesterolipitoisuuksien alentamisessa käytettävien statiinien hyödyt sydän- ja verisuonisairauksien estossa on vahvasti osoitettu ja niiden käyttö on niin Suomessa kuin muuallakin maailmassa kasvanut voimakkaasti – Suomessa statiininkäyttäjiä on noin 600 000. Statiinilääkitys on pitkäaikaisessakin käytössä melko hyvin siedetty, mutta yleisimpinä haittavaikutuksina voi ilmetä lihasheikkoutta, -kipua ja -kramppeja, jotka voivat edetä jopa henkeä uhkaavaksi lihasvaurioksi. Lihashaittariski suurenee suhteessa statiiniannokseen ja plasman statiinipitoisuuksiin. Statiinien plasmapitoisuuksissa, tehossa ja haittavaikutusten ilmenemisessä on suuria potilaskohtaisia eroja. SLCO1B1-geenin koodaama OATP1B1-kuljetusproteiini kuljettaa monia elimistön omia aineita ja lääkeaineita verenkierrosta solukalvon läpi maksasoluun, mm. statiineja, joiden kolesterolia alentava vaikutus ja poistuminen elimistöstä tapahtuvat pääosin maksassa. Erään SLCO1B1-geenin nukleotidimuutoksen (c.521T>C) tiedetään heikentävän OATP1B1:n kuljetustehoa. Tässä väitöskirjatyössä selvitettiin SLCO1B1-geenin perinnöllistä muuntelua suomalaisilla ja eri väestöissä maailmanlaajuisesti. Lisäksi selvitettiin SLCO1B1:n muunnosten vaikutusta eri statiinien pitoisuuksiin (farmakokinetiikka) ja vaikutuksiin (farmakodynamiikka) sekä kolesteroliaineenvaihduntaan. Näihin tutkimuksiin valittiin SLCO1B1-genotyypin perusteella terveitä vapaaehtoisia koehenkilöitä, joille annettiin eri päivinä kerta-annos kutakin tutkittavaa statiinia: fluvastatiinia, pravastatiinia, simvastatiinia, rosuvastatiinia ja atorvastatiinia. Verinäytteistä määritettiin plasman statiinien ja niiden aineenvaihduntatuotteiden sekä kolesterolin ja sen muodostumista ja imeytymistä kuvaavien merkkiaineiden pitoisuuksia. Toiminnallisesti merkittävien SLCO1B1-geenimuunnosten esiintyvyydessä todettiin suuria eroja eri väestöjen välillä. Suomalaisilla SLCO1B1 c.521TC-genotyypin (geenimuunnos toisessa vastinkromosomissa) esiintyvyys oli noin 32 % ja SLCO1B1 c.521CC-genotyypin (geenimuunnos molemmissa vastinkromosomeissa) esiintyvyys noin 4 %. Globaalisti geenimuunnosten esiintyvyys korreloi maapallon leveyspiirien kanssa siten, että matalaan transportteriaktiivisuuteen johtavat muunnokset olivat yleisimpiä pohjoisessa ja korkeaan aktiivisuuteen johtavat päiväntasaajan lähellä asuvilla väestöillä. SLCO1B1-genotyypillä oli merkittävä vaikutus statiinien plasmapitoisuksiin lukuun ottamatta fluvastatiinia. Simvastatiinihapon plasmapitoisuudet olivat keskimäärin 220 %, atorvastatiinin 140 %, pravastatiinin 90 % ja rosuvastatiinin 70 % suuremmat c.521CC-genotyypin omaavilla koehenkilöillä verrattuna normaalin c.521TT-genotyypin omaaviin. Genotyypillä ei ollut merkittävää vaikutusta minkään statiinin tehoon tässä kerta-annostutkimuksessa, mutta geenimuunnoksen kantajilla perustason kolesterolisynteesinopeus oli suurempi. Tulokset osoittavat, että SLCO1B1 c.521T>C geenimuunnos on varsin yleinen suomalaisilla ja muilla ei-afrikkalaisilla väestöillä. Tämä geenimuunnos voi altistaa erityisesti simvastatiinin, mutta myös atorvastatiinin, pravastatiinin ja rosuvastatiinin, aiheuttamille lihashaitoille suurentamalla niiden plasmapitoisuuksia. SLCO1B1:n geenimuunnoksen testaamista voidaan tulevaisuudessa käyttää apuna valittaessa sopivaa statiinilääkitystä ja -annosta potilaalle, ja näin parantaa sekä statiinihoidon turvallisuutta että tehoa.

Development of a new flexor tendon repair technique performed with bioabsorbable poly-L/D-lactide (PLDLA) suture

Sormen koukistajajännevamman korjauksen jälkeisen aktiivisen mobilisaation on todettu johtavan parempaan toiminnalliseen lopputulokseen kuin nykyisin yleisesti käytetyn dynaamisen mobilisaation. Aktiivisen mobilisaation ongelma on jännekorjauksen pettämisriskin lisääntyminen nykyisten ommeltekniikoiden riittämättömän vahvuuden vuoksi. Jännekorjauksen lujuutta on parannettu kehittämällä monisäieommeltekniikoita, joissa jänteeseen tehdään useita rinnakkaisia ydinompeleita. Niiden kliinistä käyttöä rajoittaa kuitenkin monimutkainen ja aikaa vievä tekninen suoritus. Käden koukistajajännekorjauksessa käytetään yleisesti sulamattomia ommelmateriaaleja. Nykyiset käytössä olevat biohajoavat langat heikkenevät liian nopeasti jänteen paranemiseen nähden. Biohajoavan laktidistereokopolymeeri (PLDLA) 96/4 – langan vetolujuuden puoliintumisajan sekä kudosominaisuuksien on aiemmin todettu soveltuvan koukistajajännekorjaukseen. Tutkimuksen tavoitteena oli kehittää välittömän aktiivisen mobilisaation kestävä ja toteutukseltaan yksinkertainen käden koukistajajännekorjausmenetelmä biohajoavaa PLDLA 96/4 –materiaalia käyttäen. Tutkimuksessa analysoitiin viiden eri yleisesti käytetyn koukistajajänneompeleen biomekaanisia ominaisuuksia staattisessa vetolujuustestauksessa ydinompeleen rakenteellisten ominaisuuksien – 1) säikeiden (lankojen) lukumäärän, 2) langan paksuuden ja 3) ompeleen konfiguraation – vaikutuksen selvittämiseksi jännekorjauksen pettämiseen ja vahvuuteen. Jännekorjausten näkyvän avautumisen todettiin alkavan perifeerisen ompeleen pettäessä voima-venymäkäyrän myötöpisteessä. Ydinompeleen lankojen lukumäärän lisääminen paransi ompeleen pitokykyä jänteessä ja suurensi korjauksen myötövoimaa. Sen sijaan paksumman (vahvemman) langan käyttäminen tai ompeleen konfiguraatio eivät vaikuttaneet myötövoimaan. Tulosten perusteella tutkittiin mahdollisuuksia lisätä ompeleen pitokykyä jänteestä yksinkertaisella monisäieompeleella, jossa ydinommel tehtiin kolmen säikeen polyesterilangalla tai nauhamaisen rakenteen omaavalla kolmen säikeen polyesterilangalla. Nauhamainen rakenne lisäsi merkitsevästi ompeleen pitokykyä jänteessä parantaen myötövoimaa sekä maksimivoimaa. Korjauksen vahvuus ylitti aktiivisen mobilisaation jännekorjaukseen kohdistaman kuormitustason. PLDLA 96/4 –langan soveltuvuutta koukistajajännekorjaukseen selvitettiin tutkimalla langan biomekaanisia ominaisuuksia ja solmujen pito-ominaisuuksia staattisessa vetolujuustestauksessa verrattuna yleisimmin jännekorjauksessa käytettävään punottuun polyesterilankaan (Ticron®). PLDLA –langan todettiin soveltuvan hyvin koukistajajännekorjaukseen, sillä se on polyesterilankaa venymättömämpi ja solmujen pitävyys on parempi. Viimeisessä vaiheessa tutkittiin PLDLA 96/4 –langasta valmistetulla kolmisäikeisellä, nauhamaisella jännekorjausvälineellä tehdyn jännekorjauksen kestävyyttä staattisessa vetolujuustestauksessa sekä syklisessä kuormituksessa, joka simuloi staattista testausta paremmin mobilisaation toistuvaa kuormitusta. PLDLA-korjauksen vahvuus ylitti sekä staattisessa että syklisessä kuormituksessa aktiivisen mobilisaation edellyttämän vahvuuden. Nauhamaista litteää ommelmateriaalia ei aiemmin ole tutkittu tai käytetty käden koukistajajännekorjauksessa. Tässä tutkimuksessa ommelmateriaalin nauhamainen rakenne paransi merkitsevästi jännekorjauksen vahvuutta, minkä arvioidaan johtuvan lisääntyneestä kontaktipinnasta jänteen ja ommelmateriaalin välillä estäen ompeleen läpileikkautumista jänteessä. Tutkimuksessa biohajoavasta PLDLA –materiaalista valmistetulla rakenteeltaan nauhamaisella kolmisäikeisellä langalla tehdyn jännekorjauksen vahvuus saavutti aktiivisen mobilisaation edellyttämän tason. Lisäksi uusi menetelmä on helppokäyttöinen ja sillä vältetään perinteisten monisäieompeleiden tekniseen suoritukseen liittyvät ongelmat.

Modeling of magnetostrictive materials and structures

The constitutive model for a magnetostrictive material and its effect on the structural response is presented in this article. The example of magnetostrictive material considered is the TERFENOL-D. As like the piezoelectric material, this material has two constitutive laws, one of which is the sensing law and the other is the actuation law, both of which are highly coupled and non-linear. For the purpose of analysis, the constitutive laws can be characterized as coupled or uncoupled and linear or non linear. Coupled model is studied without assuming any explicit direct relationship with magnetic field. In the linear coupled model, which is assumed to preserve the magnetic flux line continuity, the elastic modulus, the permeability and magneto-elastic constant are assumed as constant. In the nonlinear-coupled model, the nonlinearity is decoupled and solved separately for the magnetic domain and the mechanical domain using two nonlinear curves, namely the stress vs. strain curve and the magnetic flux density vs. magnetic field curve. This is performed by two different methods. In the first, the magnetic flux density is computed iteratively, while in the second, the artificial neural network is used, where in the trained network will give the necessary strain and magnetic flux density for a given magnetic field and stress level. The effect of nonlinearity is demonstrated on a simple magnetostrictive rod.

Quality assessment of CdZnTe (Zn similar to 4 %) crystals

We have studied the as grown and annealed CdZnTe (Zn similar to 4 %) crystals for the assessment of their crystalline quality. As grown crystals suffer from tellurium precipitates and cadmium vacancies, which are inherent, due to retrograde solid solubility curve in the phase diagram. This is reflected in the Fourier transform infrared (FTIR) spectra over the 400 - 4500 cm(-1) range by a strong absorption around 2661 cm(-1) which corresponds to the band gap of tellurium confirming their presence, where-as a monotonic decrease in the transmission with the decrease in wave number indicates the presence of cadmium vacancies. Obviously the presence of Cd vacancies lead to the formation of tellurium precipitates confirming their presence. Annealed samples under cadmium + zinc ambient at 650 degrees C for 6 hours show an improvement in the transmission over the same range. This can be attributed to thermo-migration of tellurium precipitates and hence bonding with Cd or Zn to form CdZnTe. This is further supported by the reduced full width at half maximum in the X-ray diffraction rocking curve of these CdZnTe crystals. Cadmium annealing although can passivate Cd vacancy related defects and reduce the Te precipitates, as is observed in our low temperature Photoluminescence (PL) spectra, alone may not be sufficient possibly due to the loss of Zn. Vacuum annealing at 650 degrees C for 6 hours further deteriorated the material quality as is reflected in the low temperature PL spectra by the introduction of a new defect band around 0.85 eV and reduced IR transmission.

On the mechanical behavior of compacted pack ice : A theoretical and numerical investigation

Pack ice is an aggregate of ice floes drifting on the sea surface. The forces controlling the motion and deformation of pack ice are air and water drag forces, sea surface tilt, Coriolis force and the internal force due to the interaction between ice floes. In this thesis, the mechanical behavior of compacted pack ice is investigated using theoretical and numerical methods, focusing on the three basic material properties: compressive strength, yield curve and flow rule. A high-resolution three-category sea ice model is applied to investigate the sea ice dynamics in two small basins, the whole Gulf Riga and the inside Pärnu Bay, focusing on the calibration of the compressive strength for thin ice. These two basins are on the scales of 100 km and 20 km, respectively, with typical ice thickness of 10-30 cm. The model is found capable of capturing the main characteristics of the ice dynamics. The compressive strength is calibrated to be about 30 kPa, consistent with the values from most large-scale sea ice dynamic studies. In addition, the numerical study in Pärnu Bay suggests that the shear strength drops significantly when the ice-floe size markedly decreases. A characteristic inversion method is developed to probe the yield curve of compacted pack ice. The basis of this method is the relationship between the intersection angle of linear kinematic features (LKFs) in sea ice and the slope of the yield curve. A summary of the observed LKFs shows that they can be basically divided into three groups: intersecting leads, uniaxial opening leads and uniaxial pressure ridges. Based on the available observed angles, the yield curve is determined to be a curved diamond. Comparisons of this yield curve with those from other methods show that it possesses almost all the advantages identified by the other methods. A new constitutive law is proposed, where the yield curve is a diamond and the flow rule is a combination of the normal and co-axial flow rule. The non-normal co-axial flow rule is necessary for the Coulombic yield constraint. This constitutive law not only captures the main features of forming LKFs but also takes the advantage of avoiding overestimating divergence during shear deformation. Moreover, this study provides a method for observing the flow rule for pack ice during deformation.

Scattering and Refraction as Contrast Mechanisms in X-Ray Imaging

Differentiation of various types of soft tissues is of high importance in medical imaging, because changes in soft tissue structure are often associated with pathologies, such as cancer. However, the densities of different soft tissues may be very similar, making it difficult to distinguish them in absorption images. This is especially true when the consideration of patient dose limits the available signal-to-noise ratio. Refraction is more sensitive than absorption to changes in the density, and small angle x-ray scattering on the other hand contains information about the macromolecular structure of the tissues. Both of these can be used as potential sources of contrast when soft tissues are imaged, but little is known about the visibility of the signals in realistic imaging situations. In this work the visibility of small-angle scattering and refraction in the context of medical imaging has been studied using computational methods. The work focuses on the study of analyzer based imaging, where the information about the sample is recorded in the rocking curve of the analyzer crystal. Computational phantoms based on simple geometrical shapes with differing material properties are used. The objects have realistic dimensions and attenuation properties that could be encountered in real imaging situations. The scattering properties mimic various features of measured small-angle scattering curves. Ray-tracing methods are used to calculate the refraction and attenuation of the beam, and a scattering halo is accumulated, including the effect of multiple scattering. The changes in the shape of the rocking curve are analyzed with different methods, including diffraction enhanced imaging (DEI), extended DEI (E-DEI) and multiple image radiography (MIR). A wide angle DEI, called W-DEI, is introduced and its performance is compared with that of the established methods. The results indicate that the differences in scattered intensities from healthy and malignant breast tissues are distinguishable to some extent with reasonable dose. Especially the fraction of total scattering has large enough differences that it can serve as a useful source of contrast. The peaks related to the macromolecular structure come to angles that are rather large, and have intensities that are only a small fraction of the total scattered intensity. It is found that such peaks seem to have only limited usefulness in medical imaging. It is also found that W-DEI performs rather well when most of the intensity remains in the direct beam, indicating that dark field imaging methods may produce the best results when scattering is weak. Altogether, it is found that the analysis of scattered intensity is a viable option even in medical imaging where the patient dose is the limiting factor.

Novel fluorescence detection technique for non-contact temperature sensing in microchip PCR

DNA amplification using Polymerase Chain Reaction (PCR) in a small volume is used in Lab-on-a-chip systems involving DNA manipulation. For few microliters of volume of liquid, it becomes difficult to measure and monitor the thermal profile accurately and reproducibly, which is an essential requirement for successful amplification. Conventional temperature sensors are either not biocompatible or too large and hence positioned away from the liquid leading to calibration errors. In this work we present a fluorescence based detection technique that is completely biocompatible and measures directly the liquid temperature. PCR is demonstrated in a 3 ILL silicon-glass microfabricated device using non-contact induction heating whose temperature is controlled using fluorescence feedback from SYBR green I dye molecules intercalated within sensor DNA. The performance is compared with temperature feedback using a thermocouple sensor. Melting curve followed by gel electrophoresis is used to confirm product specificity after the PCR cycles. (c) 2007 Elsevier B.V. All rights reserved.

Phase Diagram for the System RuO2-TiO2 in Air

There are conflicting reports in the literature regarding solid solubility in the system RuO2-TiO2. To resolve this issue a few experiments were conducted in air at 1673, 1723, and 1773 K. The results show limited terminal solid solubility. There is an extended solid-state miscibility gap that intersects the decomposition curve for the RuO2-rich solid solution generating a peritectoid reaction at 1698 K. The measured equilibrium compositions of the solid solutions are used to develop a thermodynamic description of the oxide solid solution with rutile structure. Using the subregular solution model, the enthalpy of mixing can be represented by the expression, Delta H-M/J center dot mol(-1) = XTiO2XRuO2 ( 34,100X(TiO2) + 30,750X(RuO2)). The binodal and spinodal curves and T-X phase diagram in air are computed using this datum and Gibbs energy of formation of RuO2 available in the literature. The computed results suggest that equilibrium was not attained during solubility measurements at lower temperatures reported in the literature.

Phase-Field Simulation of Fusion Interface Events during Solidification of Dissimilar Welds: Effect of Composition Inhomogeneity

We investigate the events near the fusion interfaces of dissimilar welds using a phase-field model developed for single-phase solidification of binary alloys. The parameters used here correspond to the dissimilar welding of a Ni/Cu couple. The events at the Ni and the Cu interface are very different, which illustrate the importance of the phase diagram through the slope of the liquidus curves. In the Ni side, where the liquidus temperature decreases with increasing alloying, solutal melting of the base metal takes place; the resolidification, with continuously increasing solid composition, is very sluggish until the interface encounters a homogeneous melt composition. The growth difficulty of the base metal increases with increasing initial melt composition, which is equivalent to a steeper slope of the liquidus curve. In the Cu side, the initial conditions result in a deeply undercooled melt and contributions from both constrained and unconstrained modes of growth are observed. The simulations bring out the possibility of nucleation of a concentrated solid phase from the melt, and a secondary melting of the substrate due to the associated recalescence event. The results for the Ni and Cu interfaces can be used to understand more complex dissimilar weld interfaces involving multiphase solidification.

Simulation blocks for TOSSIM-T2

We develop several hardware and software simulation blocks for the TinyOS-2 (TOSSIM-T2) simulator. The choice of simulated hardware platform is the popular MICA2 mote. While the hardware simulation elements comprise of radio and external flash memory, the software blocks include an environment noise model, packet delivery model and an energy estimator block for the complete system. The hardware radio block uses the software environment noise model to sample the noise floor. The packet delivery model is built by establishing the SNR-PRR curve for the MICA2 system. The energy estimator block models energy consumption by Micro Controller Unit(MCU), Radio, LEDs, and external flash memory. Using the manufacturerpsilas data sheets we provide an estimate of the energy consumed by the hardware during transmission, reception and also track several of the MCUs states with the associated energy consumption. To study the effectiveness of this work, we take a case study of a paper presented in [1]. We obtain three sets of results for energy consumption through mathematical analysis, simulation using the blocks built into PowerTossim-T2 and finally laboratory measurements. Since there is a significant match between these result sets, we propose our blocks for T2 community to effectively test their application energy requirements and node life times.

Surface spin glass behavior in sol–gel derived La0.7Ca0.3MnO3 nanotubes

We report the fabrication of La0.7Ca0.3MnO3 nanotubes (LCMONTs) with a diameter of about 200 nm, by a modified sol-gel method utilizing nanochannel alumina templates. High resolution transmission electron microscopy confirmed that the obtained LCMONTs are made up of nanoparticles (8-12 nm), which are randomly aligned in the wall of the nanotubes. The strong irreversibility between zero field cooling (ZFC) and field cooling (FC) magnetization curves as well as a cusplike peak in the ZFC curve gives strong support for surface spin glass behavior.

A unified construction of space-time codes with optimal rate-diversity tradeoff

The problem of constructing space-time (ST) block codes over a fixed, desired signal constellation is considered. In this situation, there is a tradeoff between the transmission rate as measured in constellation symbols per channel use and the transmit diversity gain achieved by the code. The transmit diversity is a measure of the rate of polynomial decay of pairwise error probability of the code with increase in the signal-to-noise ratio (SNR). In the setting of a quasi-static channel model, let n(t) denote the number of transmit antennas and T the block interval. For any n(t) <= T, a unified construction of (n(t) x T) ST codes is provided here, for a class of signal constellations that includes the familiar pulse-amplitude (PAM), quadrature-amplitude (QAM), and 2(K)-ary phase-shift-keying (PSK) modulations as special cases. The construction is optimal as measured by the rate-diversity tradeoff and can achieve any given integer point on the rate-diversity tradeoff curve. An estimate of the coding gain realized is given. Other results presented here include i) an extension of the optimal unified construction to the multiple fading block case, ii) a version of the optimal unified construction in which the underlying binary block codes are replaced by trellis codes, iii) the providing of a linear dispersion form for the underlying binary block codes, iv) a Gray-mapped version of the unified construction, and v) a generalization of construction of the S-ary case corresponding to constellations of size S-K. Items ii) and iii) are aimed at simplifying the decoding of this class of ST codes.

Appendiceal sonography in children: A retrospective analysis as a platform for potential implementation of diagnostic categories

- Background Sonography is an important diagnostic tool in children with suspected appendicitis. Reported accuracy and appendiceal visualisation rates vary significantly, as does the management of equivocal ultrasound findings. The aim of this study was to audit appendiceal sonography at a tertiary children's hospital, and provide baseline data for a future prospective study. - Summary of work Records of children who underwent ultrasound studies for possible appendicitis between January 2008 and December 2010 were reviewed. Variables included patient demographics, sonographic appendix characteristics, and secondary signs. Descriptive statistics and analysis using ANOVA, Mann-Whitney U test, and ROC curves were performed. Mater Human Research Ethic Committee approval was granted. - Summary of results There were 457 eligible children. Using a dichotomous diagnostic model (including equivocal results), sensitivity was 89.6%, specificity 91.6%, and diagnostic yield of 40.7%. ROC curve analysis of a 6mm diameter cut-off was 0.88 AUC (95% CI 0.80 to 0.95). - Discussion and conclusions Sonography is an accurate test for acute appendicitis in children, with a high sensitivity and negative predictive value. A diameter of 6mm as an absolute cut-off in a binary model can lead to false findings. Results were compared with available literature. Recent publications propose categorising diameter1 and integrating secondary signs2 to improve accuracy and provide more meaningful results to clinicians. This study will be a benchmark for future studies with multiple diagnostic categorisation.

Fracture analysis of stiffened panels under combined tensile, bending, and shear loads

The objective is to present the formulation of numerically integrated modified virtual crack closure integral technique for concentrically and eccentrically stiffened panels for computation of strain-energy release rate and stress intensity factor based on linear elastic fracture mechanics principles. Fracture analysis of cracked stiffened panels under combined tensile, bending, and shear loads has been conducted by employing the stiffened plate/shell finite element model, MQL9S2. This model can be used to analyze plates with arbitrarily located concentric/eccentric stiffeners, without increasing the total number of degrees of freedom, of the plate element. Parametric studies on fracture analysis of stiffened plates under combined tensile and moment loads have been conducted. Based on the results of parametric,studies, polynomial curve fitting has been carried out to get best-fit equations corresponding to each of the stiffener positions. These equations can be used for computation of stress intensity factor for cracked stiffened plates subjected to tensile and moment loads for a given plate size, stiffener configuration, and stiffener position without conducting finite element analysis.