Complete cytogenetic response and major molecular response as surrogate outcomes for overall survival in first-line treatment of chronic myelogenous leukemia: A case study for technology appraisal on the basis of surrogate outcomes evidence

Objectives In 2012, the National Institute for Health and Care Excellence assessed dasatinib, nilotinib, and standard-dose imatinib as first-line treatment of chronic phase chronic myelogenous leukemia (CML). Licensing of these alternative treatments was based on randomized controlled trials assessing complete cytogenetic response (CCyR) and major molecular response (MMR) at 12 months as primary end points. We use this case study to illustrate the validation of CCyR and MMR as surrogate outcomes for overall survival in CML and how this evidence was used to inform National Institute for Health and Care Excellence’s recommendation on the public funding of these first-line treatments for CML. Methods We undertook a systematic review and meta-analysis to quantify the association between CCyR and MMR at 12 months and overall survival in patients with chronic phase CML. We estimated life expectancy by extrapolating long-term survival from the weighted overall survival stratified according to the achievement of CCyR and MMR. Results Five studies provided data on the observational association between CCyR or MMR and overall survival. Based on the pooled association between CCyR and MMR and overall survival, our modeling showed comparable predicted mean duration of survival (21–23 years) following first-line treatment with imatinib, dasatinib, or nilotinib. Conclusions This case study illustrates the consideration of surrogate outcome evidence in health technology assessment. Although it is often recommended that the acceptance of surrogate outcomes be based on randomized controlled trial data demonstrating an association between the treatment effect on both the surrogate outcome and the final outcome, this case study shows that policymakers may be willing to accept a lower level of evidence (i.e., observational association).

Surviving the effects of barotrauma: assessing treatment options and a ‘natural’ remedy to enhance the release survival of line caught pink snapper (Pagrus auratus)

A new technique to ameliorate the effects of barotrauma was tested based on observations of pink snapper, Pagrus auratus (Forster), inadvertently piercing their everted stomach with their teeth and releasing trapped swim bladder gases. This technique was termed buccal venting and involved piercing the everted stomach protruding into the buccal cavity or out of the mouth with a 16-gauge hypodermic needle (a practice previously not encouraged). Short-term (~3 days) survival of buccal-vented fish was not significantly different from laterally vented fish nor untreated controls. Both buccal and lateral venting techniques were shown to cause no harm and allowed fish to return to depth. The short-term (1–3 days) post-release survival of line caught snapper was 88% with no significant difference in survival across three depth ranges tested (37–50, 51–100 and 101–180 m). Survival of sublegal pink snapper (<35 cm TL) was not significantly different (P > 0.05) from that of legal-sized fish (≥35 cm TL). Healing of the swim bladder was observed in 27% of pink snapper dissected after ≤3 days in captivity, and healing of stomachs was observed in 64% of pink snapper that had been buccal vented. Relatively high post-release survival rates of line caught pink snapper may offer some protection for snapper stocks where high fishing pressure and legal size restrictions result in the majority of the catch having to be released.

AC conductivity of a quantum Hall line junction

We present a microscopic model for calculating the AC conductivity of a finite length line junction made up of two counter-or co-propagating single mode quantum Hall edges with possibly different filling fractions. The effect of density-density interactions and a local tunneling conductance (sigma) between the two edges is considered. Assuming that sigma is independent of the frequency omega, we derive expressions for the AC conductivity as a function of omega, the length of the line junction and other parameters of the system. We reproduce the results of Sen and Agarwal (2008 Phys. Rev. B 78 085430) in the DC limit (omega -> 0), and generalize those results for an interacting system. As a function of omega, the AC conductivity shows significant oscillations if sigma is small; the oscillations become less prominent as sigma increases. A renormalization group analysis shows that the system may be in a metallic or an insulating phase depending on the strength of the interactions. We discuss the experimental implications of this for the behavior of the AC conductivity at low temperatures.

Quantitative effects of in-line operations on Campylobacter and Escherichia coli through two Australian broiler processing plants

Campylobacter is an important food borne pathogen, mainly associated with poultry. A lack of through-chain quantitative Campylobacter data has been highlighted within quantitative risk assessments. The aim of this study was to quantitatively and qualitatively measure Campylobacter and Escherichia coli concentration on chicken carcasses through poultry slaughter. Chickens (n = 240) were sampled from each of four flocks along the processing chain, before scald, after scald, before chill, after chill, after packaging and from individual caeca. The overall prevalence of Campylobacter after packaging was 83% with a median concentration of 0.8 log10 CFU/mL. The processing points of scalding and chilling had significant mean reductions of both Campylobacter (1.8 and 2.9 log10 CFU/carcase) and E. coli (1.3 and 2.5 log10 CFU/carcase). The concentration of E. coli and Campylobacter was significantly correlated throughout processing indicating that E. coli may be a useful indicator organism for reductions in Campylobacter concentration. The carriage of species varied between flocks, with two flocks dominated by Campylobacter coli and two flocks dominated by Campylobacter jejuni. Current processing practices can lead to significant reductions in the concentration of Campylobacter on carcasses. Further understanding of the variable effect of processing on Campylobacter and the survival of specific genotypes may enable more targeted interventions to reduce the concentration of this poultry associated pathogen.

Short-term survival of discarded pearl perch (Glaucosoma scapulare Ramsay, 1881) caught by hook-and-line in Queensland, Australia

Post-release survival of line-caught pearl perch (Glaucosoma scapulare) was assessed via field experiments where fish were angled using methods similar to those used by commercial, recreational and charter fishers. One hundred and eighty-three individuals were caught during four experiments, of which >91 survived up to three days post-capture. Hook location was found to be the best predictor of survival, with the survival of throat- or stomach-hooked pearl perch significantly (P < 0.05) lower than those hooked in either the mouth or lip. Post-release survival was similar for both legal (≥35 cm) and sub-legal (<35 cm) pearl perch, while those individuals showing no signs of barotrauma were more likely to survive in the short term. Examination of the swim bladders in the laboratory, combined with observations in the field, revealed that swim bladders rupture during ascent from depth allowing swim bladder gases to escape into the gut cavity. As angled fish approach the surface, the alimentary tract ruptures near the anus allowing swim bladder gases to escape the gut cavity. As a result, very few pearl perch exhibit barotrauma symptoms and no barotrauma mitigation strategies were recommended. The results of this study show that pearl perch are relatively resilient to catch-and-release suggesting that post-release mortality would not contribute significantly to total fishing mortality. We recommend the use of circle hooks, fished actively on tight lines, combined with minimal handling in order to maximise the post-release survival of pearl perch.

Line tension of a two dimensional gas-liquid interface

In two dimensional (2D) gas-liquid systems, the reported simulation values of line tension are known to disagree with the existing theoretical estimates. We find that while the simulation erred in truncating the range of the interaction potential, and as a result grossly underestimated the actual value, the earlier theoretical calculation was also limited by several approximations. When both the simulation and the theory are improved, we find that the estimate of line tension is in better agreement with each other. The small value of surface tension suggests increased influence of noncircular clusters in 2D gas-liquid nucleation, as indeed observed in a recent simulation.

Isotope shifts and hyperfine structure in the 555.8-nm S-1(0) -> P-3(1) line of Yb

We apply our technique of using a Rb-stabilized ring-cavity resonator to measure the frequencies of various spectral components in the 555.8-nm 1S0-->3P1 line of Yb. We determine the isotope shifts with 60 kHz precision, which is an order-of-magnitude improvement over the best previous measurement on this line. There are two overlapping transitions, 171Yb(1/2-->3/2) and 173Yb(5/2-->3/2), which we resolve by applying a magnetic field. We thus obtain the hyperfine constants in the 3P1 state of the odd isotopes with a significantly improved precision. Knowledge of isotope shifts and hyperfine structure should prove useful for high-precision calculations in Yb necessary to interpret ongoing experiments testing parity and time-reversal symmetry violation in the laws of physics.

A Modified Dubins Method for Optimal Path Planning of a Miniature Air Vehicle Converging to a Straight Line Path

This paper presents a Dubins model based strategy to determine the optimal path of a Miniature Air Vehicle (MAV), constrained by a bounded turning rate, that would enable it to fly along a given straight line, starting from an arbitrary initial position and orientation. The method is then extended to meet the same objective in the presence of wind which has a magnitude comparable to the speed of the MAV. We use a modification of the Dubins' path method to obtain the complete optimal solution to this problem in all its generality.

Autonomous Line Scanning for SPC Telephone Switching Systems

An Autonomous Line Scanning Unit (ALSU) for completely autonomous detection of call originations in the SPC Telephone Switching System is described. Through its own memories, ALSU maintains an up-to-date record of subscribers' statuses, detects call originations, performs 'hit timing check' and informs the Switching System of the identity of calling subscribers. The ALSU needs minimum interaction with the Central Processor, resulting in increased call handling capacity

On the elimination of DC in reconstructed wavefronts from in-line holograms

New experimental results to demonstrate that the annoying DC in the reconstructed wavefronts from in-line holograms could be successfully eliminated are presented in this paper. The complete elimination of DC has been achieved by making proper use of a Mach-Zehnder interferometer. The results for an in-line hololens and an in-line Fourier transform hologram are discussed.

Kinetic characterization of rat brain type IIA sodium channel alpha-subunit stably expressed in a somatic cell line

1. The rat brain type IIA Na+ channel alpha-subunit was stably expressed in Chinese hamster ovary (CHO) cells. Current through the expressed Na+ channels was studied using the whole-cell configuration of the patch clamp technique. The transient Na+ current was sensitive to TTX and showed a bell-shaped peak current vs. membrane potential relation. 2. Na+ current inactivation was better described by the sum of two exponentials in the potential range -30 to +40 mV, with. a dominating fast component and a small slower component. 3. The steady-state inactivation, h(infinity), was related to potential by a Boltzmann distribution, underlying thr ee states of the inactivation gate. 4. Recovery of the channels from inactivation at different potentials in the range -70 to -120 mV were characterized by al? initial delay which decreased with hyperpolarization. The time course was well fitted by the sum of two exponentials. In this case the slower exponential was the major component, and both time constants decreased with hyperpolarization. 5. For a working description of the Na+ channel inactivation in this preparation, with a minimal deviation from the Hodgkin-Huxley model, a three-state scheme of the form O reversible arrow I-1 reversible arrow I-2 was proposed, replacing the original two-state scheme of the Hodgkin-Huxley model, and the rate constants are reported. 6. The instantaneous current-voltage relationship showed marked deviation from linearity and was satisfactorily fitted by the constant-field equation. 7. The time course of activation was described by an m(x) model. However, the best-fitted value of x varied with the membrane potential and had a mean value of 2. 8. Effective gating charge was determined to be 4.7e from the slope of the activation plot, plotted on a logarithmic scale. 9. The rate constants of activation, alpha(m) and beta(m), were determined. Their functional dependence on the membrane potential was investigated.