Isotonic designs for phase I trials

The purpose of a phase I trial in cancer is to determine the level (dose) of the treatment under study that has an acceptable level of adverse effects. Although substantial progress has recently been made in this area using parametric approaches, the method that is widely used is based on treating small cohorts of patients at escalating doses until the frequency of toxicities seen at a dose exceeds a predefined tolerable toxicity rate. This method is popular because of its simplicity and freedom from parametric assumptions. In this payer, we consider cases in which it is undesirable to assume a parametric dose-toxicity relationship. We propose a simple model-free approach by modifying the method that is in common use. The approach assumes toxicity is nondecreasing with dose and fits an isotonic regression to accumulated data. At any point in a trial, the dose given is that with estimated toxicity deemed closest to the maximum tolerable toxicity. Simulations indicate that this approach performs substantially better than the commonly used method and it compares favorably with other phase I designs.

Low-temperature and high-pressure Raman and x-ray studies of pyrochlore Tb2Ti2O7: Phonon anomalies and possible phase transition

We have carried out temperature- and pressure-dependent Raman and x-ray measurements on single crystals of Tb2Ti2O7. We attribute the observed anomalous temperature dependence of phonons to phonon-phonon anharmonic interactions. The quasiharmonic and anharmonic contributions to the temperature-dependent changes in phonon frequencies are estimated quantitatively using mode Grüneisen parameters derived from pressure-dependent Raman experiments and bulk modulus from high-pressure x-ray measurements. Further, our Raman and x-ray data suggest a subtle structural deformation of the pyrochlore lattice at ~9 GPa. We discuss possible implications of our results on the spin-liquid behavior of Tb2Ti2O7.

Structure of the noncubic phase in the ferroelectric state of Pr-substituted SrTiO3

Sr1−xPrxTiO3 has recently been shown to exhibit ferroelectricity at room temperature. In this paper powder x-ray and neutron-diffraction patterns of this system at room temperature have been analyzed to show that the system exhibits cubic (Pm-3m) structure for x<=0.05 and tetragonal (I4/mcm) for x>0.05. The redundancy of the noncentrosymmetric structural model (I4cm) in the ferroelectric state suggests the absence of long-range ordered ferroelectric domains and supports the relaxor ferroelectric model for this system.

Stress-induced martensitic phase transformation in Cu-Zr nanowires

A novel stress-induced martensitic phase transformation in an initial < 100 >/{100} B2-CuZr nanowire is reported for the first time in this letter. Such behavior is observed in a nanowire with cross-sectional dimensions of 19.44 x 19.44 angstrom(2) over a temperature range of 100-400 K and at a strain rate of 1 x 10(9) s(-1) using atomistic simulations. Phase transformation from an initial B2 phase to a BCT (Body-Centered-Tetragonal) phase is observed via nucleation and propagation of {100} twinning plane under high strain rate tensile deformation. (C) 2009 Elsevier B.V. All rights reserved.

Role of Melt Convection on the Thermal Performance of Heat Sinks with Phase Change Material

The role of melt convection oil the performance of beat sinks with Phase Change Material (PCM) is presented in this paper. The beat sink consists of aluminum plate fins embedded in PCM and heat flux is supplied from the bottom. The design of such a heat sink requires optimization with respect to its geometrical parameters. The objective of the optimization is to maximize the heat sink operation time for the prescribed heat flux and the critical chip temperature. The parameters considered for optimization are fin number and fill thickness. The height and base plate thickness of heat sink are kept constant in the present analysis. An enthalpy based CFD model is developed, which is capable Of Simulating phase change and associated melt convection. The CFD model is Coupled with Genetic Algorithm (GA) for carrying out the optimization. Two cases are considered, one without melt convection (conduction regime) and the other with convection. It is found that the geometrical optimizations of heat sinks are different for the two cases, indicating the importance of inch convection in the design of heat sinks with PCMs.

A New Three-Phase Current Source Inverter with Flexible PWM Capability

A new three-phase current source inverter topology is presented, consisting of three single-phase bridge inverters connected in series and feeding the isolated windings of a standard three-phase induction motor. Because a current zero in one phase now does not affect the others, it enables the implementation of a wide range of current PWM patterns for the reduction and selective elimination of torque pulsations. Furthermore, this system allows for very fast control of the fundamental load current through the use of sinusoidal PWM, a method that was not possible to implement on existing inverter topologies.

Strike Hard, Strike Sure - Operation Musketeer : British Military Planning during the Suez Crisis, 1956

This study analyses British military planning and actions during the Suez Crisis in 1956. It seeks to find military reasons for the change of concepts during the planning and compares these reasons with the tactical doctrines of the time. The thesis takes extensive advantage of military documents preserved in the National Archives, London. In order to expand the understanding of the exchange of views during the planning process, the private papers of high ranking military officials have also been consulted. French military documents preserved in the Service Historique de la Defence, Paris, have provided an important point of comparison. The Suez Crisis caught the British armed forces in the middle of a transition phase. The main objective of the armed forces was to establish a credible deterrence against the Soviet Union. However, due to overseas commitments the Middle East playing a paramount role because of its economic importance the armed forces were compelled to also prepare for Limited War and the Cold War. The armed forces were not fully prepared to meet this demand. The Middle Eastern garrison was being re-organised after the withdrawal from the Canal Base and the concept for a strategic reserve was unimplemented. The tactical doctrines of the time were based on experiences from the Second World War. As a result, the British view of amphibious operations and the subsequent campaigns emphasised careful planning, mastery of the sea and the air, sufficient superiority in numbers and firepower, centralised command and extensive administrative preparations. The British military had realized that Nasser could nationalise the Suez Canal and prepared an outline plan to meet this contingency. Although the plan was nothing more than a concept, it was accepted as a basis for further planning when the Canal was nationalised at the end of July. This plan was short-lived. The nominated Task Force Commanders shifted the landing site from Port Said to Alexandria because it enabled faster expansion of the bridgehead. In addition, further operations towards Cairo the hub of Nasser s power would be easier to conduct. The operational concept can be described as being traditional and was in accordance with the amphibious warfare doctrine. This plan was completely changed at the beginning of September. Apparently, General Charles Keightley, the Commander-in-Chief, and the Chairman of the Chiefs of Staff Committee developed the idea of prolonged aerial operations. The essence of the concept was to break the Egyptian will to resist by attacking the oil facilities, the transportation system and the armed forces. This victory through air concept would be supported by carefully planned psychological operations. This concept was in accordance with the Royal Air Force doctrine, which promoted a bomber offensive against selected target categories. General Keightley s plan was accepted despite suspicions at every planning level. The Joint Planning Staff and the Task Force Commanders opposed the concept from the beginning to the end because of its unpredictability. There was no information that suggested the bombing would persuade the Egyptians to submit. This problem was worsened by the fact that British intelligence was unable to provide reliable strategic information. The Task Force Commanders, who were responsible for the tactical plans, were not able to change Keightley s mind, but the concept was expanded to include a traditional amphibious assault on Port Said due to their resistance. The bombing campaign was never tested as the Royal Air Force was denied authorisation to destroy the transportation and oil targets. The Chiefs of Staff and General Keightley were too slow to realise that the execution of the plan depended on the determination of the Prime Minister. However, poor health, a lack of American and domestic support and the indecisiveness of the military had ruined Eden s resolve. In the end, a very traditional amphibious assault, which was bound to succeed at the tactical level but fail at the strategic level, was launched against Port Said.

ESR Studies of Phase Transitions in Double Propionates: Dicalcium Barium Propionate Ca2Ba(C2H5COO)6

Single crystal [(111) and (100) planes], and powder ESR of Mn2+ (substituting for Ca2+) in Ca2Ba(C2H5COO)6 in the temperature range 220°C to -160°C shows (i) a doubling of both the physically and chemically inequivalent sites, and a change in the magnitude (150 G at -6°C to 170 G at -8°C) as well as the orientation of the D tensor across the -6°C transition and (ii) an inflection point in the D vs T plot across the -75°C transition. The oxygen octahedra around the Ca2+ sites are inferred to undergo alternate rotations, showing the participation of the carboxyl oxygens in the -6°C transition. A relation of the type D=D0(1+αT+βT2) seems to fit the D variation satisfactorily.

Evolution of crystallographic texture and microstructure in the orthorhombic phase of a two-phase alloy Ti-22Al-25Nb

Evolution of crystallographic texture in the orthorhombic phase of a two-phase alloy Ti–22Al–25Nb (at%), consisting of orthorhombic (O) and bcc (β/B2) phases, was studied. The material was subjected to deformation in two-phase field as well as in the single β phase field. The resulting evolution of microstructure and crystallographic texture were recorded using scanning electron microscopy and X-ray diffraction. The orthorhombic phase underwent change in morphology (from platelets to equiaxed) on rolling in the two-phase field with the texture getting sharper with the amount of deformation. Rolling above β transus temperature led to hot deformation of single β phase microstructure and its subsequent cooling produced transformed coarse platelets of orthorhombic phase with texture in orientation relation with the high temperature deformed β phase.

A precision apparatus, with solid phase micro-extraction monitoring capability, for incorporation studies of gaseous precursors into insect-derived metabolites

An apparatus is described that facilitates the determination of incorporation levels of isotope labelled, gaseous precursors into volatile insect-derived metabolites. Atmospheres of varying gas compositions can be generated by evacuation of a working chamber followed by admission of the required levels of component gases, using a precision, digitised pressure read-out system. Insects such as fruit-flies are located initially in a small introduction chamber, from which migration can occur downwards into the working chamber. The level of incorporation of labelled precursors is continuously assayed by the Solid Phase Micro Extraction (SPME) technique and GC-MS analyses. Experiments with both Bactrocera species (fruit-flies) and a parasitoid wasp, Megarhyssa nortoni nortoni (Cresson) and oxygen-18 labelled dioxygen illustrate the utility of this system. The isotope effects of oxygen-18 on the carbon-13 NMR spectra of 1,7- dioxaspiro[5,5]undecane are also described.

Phase transition in ammonium aluminium and ammonium chromium alums-A high pressure EPR study

An investigation of the phase transitions at high pressures in the alums mentioned in the title has been carried out using EPR of the Cr3+ ion (at the trivalent metal ion site). It is observed that at ambient as well as at high pressures there is a change of slope in the linear variations of the zero field splitting with temperature and that the low temperature phase is characterised by a large number of lines in the EPR spectra. The transition temperature shows a large positive shift with pressure, for both the alums. All these facts are explained in terms of our model of the origin of the trigonal field at the trivalent metal ion site as well as the details of the motion of NH4+ ion.

Use of 45° pulse pair as a filter for pure-phase two-dimensional NMR spectroscopy

Conventionally two-dimensional NMR spectra are recorded in the absolute-intensity mode (1-4). It has recently been demonstrated that absorption-mode 2D spectra have much higher resolution and are the preferred mode of presentation, especially for 2D spectra of biomolecules (5-7). Indeed, any experimental scheme which yields phasemixed lineshapes is subject to modification to yield pure-phase spectra, even at the expense of intensity and anomalous multiplet structure (8-10). For this purpose two types of filters are already known: the z filter (9, 20) and the purging pulse (8, 10). In this note, we propose a 45” pulse pair as a filter for obtaining pure-phase 2D spectra, mainly for experiments in which the above filters do not yield pure-phase spectra.

Association of a second phase of mortality in cucumber seedlings with a rapid rate of metalaxyl biodegradation in greenhouse soils

A study was undertaken from 2004 to 2007 to investigate factors associated with decreased efficacy of metalaxyl to manage damping-off of cucumber in Oman. A survey over six growing seasons showed that growers lost up to 14.6% of seedlings following application of metalaxyl. No resistance to metalaxyl was found among Pythium isolates. Damping-off disease in the surveyed greenhouses followed two patterns. In most (69%) greenhouses, seedling mortality was found to occur shortly after transplanting and decrease thereafter (Phase-I). However, a second phase of seedling mortality (Phase-II) appeared 9-14 d after transplanting in about 31% of the surveyed greenhouses. Analysis of the rate of biodegradation of metalaxyl in six greenhouses indicated a significant increase in the rate of metalaxyl biodegradation in greenhouses, which encountered Phase-II damping-off. The half-life of metalaxyl dropped from 93 d in soil, which received no previous metalaxyl treatment to 14 d in soil, which received metalaxyl for eight consecutive seasons, indicating an enhanced rate of metalaxyl biodegradation after repeated use. Multiple applications of metalaxyl helped reduce the appearance of Phase-II damping-off. This appears to be the first report of rapid biodegradation of metalaxyl in greenhouse soils and the first report of its association with appearance of a second phase of mortality in cucumber seedlings.