Selection of the initial design for the two-stage continual reassessment method

The continual reassessment method (CRM) was proposed in a Bayesian framework whereby the first patient is assigned to the prior guess of the maximum tolerated dose which is usually not the lowest dose level. This assignment may lead to safety concerns in practice because physicians usually prefer not to skip lower dose levels before escalating to the higher dose levels. The two-stage CRM was proposed to address such concern whereby model based dose escalation is preceded by a pre-specified escalating sequence starting from the lowest dose level. While a theoretical framework to build the two-stage CRM has been proposed, the selection of the initial dose escalating sequence, generally referred to as the initial design, remains arbitrary, either by specifing cohorts of three patients or by trial and error through extensive simulations. Motivated by a currently ongoing oncology dose finding study for which physicians stated their desire to start from the lowest dose even though the maximum tolerated dose was thought to be one of the higher dose levels, we proposed a systematic approach for selecting the initial design for the two-stage CRM. The initial design obtained using the proposed algorithm yields better operating characteristics compared to using a cohort of three initial design with a calibrated CRM. The proposed algorithm simplifies and provides a systematic approach for the selection of initial design for the two-stage CRM. Moreover, initial designs to be used as reference for planning a two-stage CRM are provided

Effect of age on the prognostic value of left ventricular function in patients with acute coronary syndrome:a prospective registry study

Objective: This study aims to study the prognostic impact of LV function on mortality and examine the effect of age on the prognostic value of left ventricular function.  Methods: We examined the Myocardial Ischaemia National Audit Project (MINAP) registry (2006-2010) data with a mean follow up of 2.1 years. LV function was categorized into good (ejection fraction (EF) ≥50%), moderate (EF 30-49%) and poor (EF <30%) categories. Cox-proportional hazards models were constructed to examine the prognostic significance of LV function in different age groups (<65, 65-74, 75-84 and ≥85 years) on all-cause mortality adjusting for baseline variables.  Results: Of 424,848 patients, LV function data available for 123,609. Multiple imputations were used to impute missing values of LV function and the final sample for analyses were drawn from 414,305. After controlling for confounders, 339,887 participants were included in the regression models. For any age group, mortality was higher with worsening degree of LV impairment. Increased age reduced the adverse prognosis associated with reduced LV function (hazard ratios (HRs) of death comparing poor LV function to good LV function were 2.11 95%CI 1.88-2.37 for age <65 years and 1.28 95%CI 1.20-1.36 for age ≥85 years. Older patients had a high mortality risk even in those with good LV function. HRs of mortality for ≥85 compared to <65 years (HR=1.00) within good, moderate and poor ejection fractions groups were 5.89, 4.86 and 3.43, respectively.  Conclusions: In patients with ACS, clinicians should interpret the prognostic value of LV function taking into account patient’s age

A high-dose pulse steroid regimen for controlling active chronic graft-versus-host disease

AbstractCorticosteroids remain essential for controlling active chronic graft-versus-host disease (cGVHD). However, the optimum dose and administration schedule is unknown. We have reviewed our results in 61 patients with severe refractory cGVHD who were treated with a high-dose pulse steroid regimen (PS) consisting of methylprednisolone at 10 mg/kg per day for 4 consecutive days, with subsequent tapering doses. After 4 days, all patients received a course of additional immunosuppressive therapy. The median age of the 56 patients who were evaluable for response was 32 years (range, 0.2-57 years). Patients had failed a median of 2 (range, 1-5) treatments prior to the PS. The median follow-up for 45 surviving patients after PS was 1.5 years. The probability of survival at 1 year and 2 years after PS was 88% (95% confidence interval [CI], 76%-95%) and 81% (95% CI, 65%-91%), respectively. Twenty-seven patients (48%) showed a major response to PS with substantial improvement of cGVHD manifestations, including softening of the skin, increased range of motion, and improved performance status; 15 patients (27%) showed a minor response, defined as improvement in some but not all symptoms of cGVHD. Of the 42 responders, 21 (50%) had progression of their cGVHD afterwards. The median time to progression was 1.9 years. The probability of progression at 1 and 2 years after PS was 36% (95% CI, 23%-53%) and 54% (95% CI, 38%-71%), respectively. The probability of progression at 1 year was 25% (95% CI, 12%-47%) and 55% (95% CI, 32%-81%) for patients who had major and minor response, respectively (hazard ratio, 2.13). Ten of the 42 responders (24%) were able to discontinue all systemic immunosuppressive treatments. The probability of discontinuation at 1 and 2 years after PS was 9% (95% CI, 3%-25%) and 27% (95% CI, 15%-48%), respectively. The treatment was well tolerated with no serious adverse events. Our results suggest that PS is a well-tolerated regimen for achieving rapid clinical response in the majority of patients with cGVHD who failed on multiple previous therapies. Further studies are warranted to maintain the efficacy of this regimen by combining with new active agents in cGVHD.Biol Blood Marrow Transplant 2001;7(9):495-502

Natural or Artificial? Habitat-Use by the Bull Shark, Carcharhinus leucas

BACKGROUND: Despite accelerated global population declines due to targeted and illegal fishing pressure for many top-level shark species, the impacts of coastal habitat modification have been largely overlooked. We present the first direct comparison of the use of natural versus artificial habitats for the bull shark, Carcharhinus leucas, an IUCN ‘Near-threatened’ species - one of the few truly euryhaline sharks that utilises natural rivers and estuaries as nursery grounds before migrating offshore as adults. Understanding the value of alternate artificial coastal habitats to the lifecycle of the bull shark is crucial for determining the impact of coastal development on this threatened but potentially dangerous species. METHODOLOGY/FINDINGS: We used longline surveys and long-term passive acoustic tracking of neonate and juvenile bull sharks to determine the ontogenetic value of natural and artificial habitats to bull sharks associated with the Nerang River and adjoining canals on the Gold Coast, Australia. Long-term movements of tagged sharks suggested a preference for the natural river over artificial habitat (canals). Neonates and juveniles spent the majority of their time in the upper tidal reaches of the Nerang River and undertook excursions into adjoining canals. Larger bull sharks ranged further and frequented the canals closer to the river mouth. CONCLUSIONS/SIGNIFICANCE: Our work suggests with increased destruction of natural habitats, artificial coastal habitat may become increasingly important to large juvenile bull sharks with associated risk of attack on humans. In this system, neonate and juvenile bull sharks utilised the natural and artificial habitats, but the latter was not the preferred habitat of neonates. The upper reaches of tidal rivers, often under significant modification pressure, serve as nursery sites for neonates. Analogous studies are needed in similar systems elsewhere to assess the spatial and temporal generality of this research

Dynamics and Pattern Formation in Large Systems of Spatially-Coupled Oscillators with Finite Response Times

We consider systems of many spatially distributed phase oscillators that interact with their neighbors. Each oscillator is allowed to have a different natural frequency, as well as a different response time to the signals it receives from other oscillators in its neighborhood. Using the ansatz of Ott and Antonsen (Ref. \cite{OA1}) and adopting a strategy similar to that employed in the recent work of Laing (Ref. \cite{Laing2}), we reduce the microscopic dynamics of these systems to a macroscopic partial-differential-equation description. Using this macroscopic formulation, we numerically find that finite oscillator response time leads to interesting spatio-temporal dynamical behaviors including propagating fronts, spots, target patterns, chimerae, spiral waves, etc., and we study interactions and evolutionary behaviors of these spatio-temporal patterns

Modelling semi-attributable toxicity in dual-agent phase I trials with non-concurrent drug administration.

In oncology, combinations of drugs are often used to improve treatment efficacy and/or reduce harmful side effects. Dual-agent phase I clinical trials assess drug safety and aim to discover a maximum tolerated dose combination via dose-escalation; cohorts of patients are given set doses of both drugs and monitored to see if toxic reactions occur. Dose-escalation decisions for subsequent cohorts are based on the number and severity of observed toxic reactions, and an escalation rule. In a combination trial, drugs may be administered concurrently or non-concurrently over a treatment cycle. For two drugs given non-concurrently with overlapping toxicities, toxicities occurring after administration of the first drug yet before administration of the second may be attributed directly to the first drug, whereas toxicities occurring after both drugs have been given some present ambiguity; toxicities may be attributable to the first drug only, the second drug only or the synergistic combination of both. We call this mixture of attributable and non-attributable toxicity semi-attributable toxicity. Most published methods assume drugs are given concurrently, which may not be reflective of trials with non-concurrent drug administration. We incorporate semi-attributable toxicity into Bayesian modelling for dual-agent phase I trials with non-concurrent drug administration and compare the operating characteristics to an approach where this detail is not considered. Simulations based on a trial for non-concurrent administration of intravesical Cabazitaxel and Cisplatin in early-stage bladder cancer patients are presented for several scenarios and show that including semi-attributable toxicity data reduces the number of patients given overly toxic combinations. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.G.M. Wheeler and A.P. Mander are supported by the Medical Research Council (grant number G0800860). M.J. Sweeting is supported by a European Research Council Advanced Investigator Award: EPIC-Heart (grant number 268834), the UK Medical Research Council (grant number MR/L003120/1), the British Heart Foundation and the Cambridge National Institute for Health Research Biomedical Research Centre. S.M. Lee is supported by the American Cancer Society (grant number MRSG-13-146-01-CPHPS).This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/sim.691

The Formation and Evolution of Wide-orbit Stellar Multiples In Magnetized Clouds

Stars rarely form in isolation. Nearly half of the stars in the Milky Way have a companion, and this fraction increases in star-forming regions. However, why some dense cores and filaments form bound pairs while others form single stars remains unclear. We present a set of three-dimensional, gravo-magnetohydrodynamic simulations of turbulent star-forming clouds, aimed at understanding the formation and evolution of multiple-star systems formed through large-scale (greater than or similar to 10(3) au) turbulent fragmentation. We investigate three global magnetic field strengths, with global mass-to-flux ratios of mu(phi) = 2, 8, and 32. The initial separations of protostars in multiples depend on the global magnetic field strength, with stronger magnetic fields (e.g., mu(phi)= 2) suppressing fragmentation on smaller scales. The overall multiplicity fraction (MF) is between 0.4 and 0.6 for our strong and intermediate magnetic field strengths, which is in agreement with observations. The weak field case has a lower fraction. The MF is relatively constant throughout the simulations, even though stellar densities increase as collapse continues. While the MF rarely exceeds 60% in all three simulations, over 80% of all protostars are part of a binary system at some point. We additionally find that the distribution of binary spin misalignment angles is consistent with a randomized distribution. In all three simulations, several binaries originate with wide separations and dynamically evolve to less than or similar to 10(2) au separations. We show that a simple model of mass accretion and dynamical friction with the gas can explain this orbital evolution.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]