Adaptive protocols based on predictions from a mechanistic model of the effect of IL7 on CD4 counts

In human immunodeficiency virus–infected patients, antiretroviral therapy suppresses the viral replication, which is followed in most patients by a restoration of CD4+ T cells pool. For patients who fail to do so, repeated injections of exogenous interleukin 7 (IL7) are experimented. The IL7 is a cytokine that is involved in the T cell homeostasis and the INSPIRE study has shown that injections of IL7 induced a proliferation of CD4+ T cells. Phase I/II INSPIRE 2 and 3 studies have evaluated a protocol in which a first cycle of three IL7 injections is followed by a new cycle at each visit when the patient has less than 550 CD4 cells/μL. Restoration of the CD4 concentration has been demonstrated, but the long-term best adaptive protocol is yet to be determined. A mechanistic model of the evolution of CD4 after IL7 injections has been developed, which is based on a system of ordinary differential equations and includes random effects. Based on the estimation of this model, we use a Bayesian approach to forecast the dynamics of CD4 in new patients. We propose four prediction-based adaptive protocols of injections to minimize the time spent under 500 CD4 cells/μL for each patient, without increasing the number of injections received too much. We show that our protocols significantly reduce the time spent under 500 CD4 over a period of two years, without increasing the number of injections. These protocols have the potential to increase the efficiency of this therapy.     

A Review of Clinical Trials With an Adaptive Design and Health Economic Analysis

Objective

An adaptive design uses data collected as a clinical trial progresses to inform modifications to the trial. Hence, adaptive designs and health economics aim to facilitate efficient and accurate decision making. Nevertheless, it is unclear whether the methods are considered together in the design, analysis, and reporting of trials. This review aims to establish how health economic outcomes are used in the design, analysis, and reporting of adaptive designs.

Dosimetric and geometric evaluation of the use of deformable image registration in adaptive intensity-modulated radiotherapy for head-and-neck cancer

The aim of this study was to carry out geometric and dosimetric evaluation of the usefulness of a deformable image registration algorithm utilized for adaptive head-and-neck intensity-modulated radiotherapy. Data consisted of seven patients, each with a planning CT (pCT), a rescanning CT (ReCT) and a cone beam CT (CBCT). The CBCT was acquired on the same day (±1 d) as the ReCT (i.e. at Fraction 17, 18, 23, 24 or 29). The ReCT served as ground truth. A deformed CT (dCT) with structures was created by deforming the pCT to the CBCT. The geometrical comparison was based on the volumes of the deformed, and the manually delineated structures on the ReCT. Likewise, the center of mass shift (CMS) and the Dice similarity coefficient were determined. The dosimetric comparison was performed by recalculating the initial treatment plan on the dCT and the ReCT. Dose–volume histogram (DVH) points and a range of conformity measures were used for the evaluation. We found a significant difference in the median volume of the dCT relative to that of the ReCT. Median CMS values were ∼2–5 mm, except for the spinal cord, where the median CMS was 8 mm. Dosimetric evaluation of target structures revealed small differences, while larger differences were observed for organs at risk. The deformed structures cannot fully replace manually delineated structures. Based on both geometrical and dosimetrical measures, there is a tendency for the dCT to overestimate the need for replanning, compared with the ReCT.     

Behavioural Excesses and Deficits Associated with Dementia in Adults who have Down Syndrome

Background Informant‐based assessment of behavioural change and difference in dementia in Down syndrome can aid diagnosis and inform service delivery. To date few studies have examined the impact of different types of behavioural change. Methods The Assessment for Adults with Developmental Disabilities (AADS), developed for this study, assesses behavioural excesses (11 items) and deficits (17 items) associated with dementia. Inter‐informant reliability, internal consistency and concurrent validity were evaluated and found to be robust. Results A comparison of the AADS subscale scores for three groups (n = 12) of adults with Down syndrome demonstrated more frequent deficits and excesses and greater management difficulty and effects on the individual in a dementia group than age comparable and younger groups. Conclusion The AADS is a promising dementia specific measure for people with intellectual disability. Further research should evaluate change as dementia progresses and the nature of management difficulty and effects on the individual.     

Scaling expectations for the time to establishment of complex adaptations

Although the vast majority of research in evolutionary biology is focused on adaption, a general theory for the population-genetic mechanisms by which complex adaptations are acquired remains to be developed. The issue explored here is the procurement of novel traits that specifically require multiple mutations to achieve a fitness advantage. By highlighting the roles played by the forces of mutation, recombination, and random genetic drift, and drawing from observations on the joint constraints on these factors, the ways in which rates of acquisition of specific types of adaptations scale with population size are explored. These general results provide insight into a number of ongoing controversies regarding the molecular basis of adaptation, including the adaptive utility of recombination and the role of drift in the passage through adaptive valleys.     

Power law relationships between health care utilization and symptom assessment among people with panic attacks

Rationale Although people with panic attacks are high utilizers of health care, the role of symptom assessment in care‐seeking is unclear. Previous studies suggest that symptom perceptions are linearly related to utilization but panic appraisal is not. The purpose of this study was to determine whether the relationships between symptom assessment and utilization are non‐linear, displaying power law distributions. Methods This community‐based study of 97 subjects with panic attacks assessed utilization of family doctor offices, total ambulatory utilization, and hospitalizations as well as symptom perceptions and panic appraisals. Matrices of symptom assessment versus utilization were created, and log–log plots were constructed. To minimize the risk of overestimation of power law distributions, linear, quadratic and cubic regression models were computed. Results None of the utilization versus symptom perceptions displayed power law distributions. However, all three measures of utilization showed power law relationships with panic appraisals, but in unique patterns. Conclusions Although power law relationships were not found between symptom perceptions and utilization, unique patterns of power laws were identified between panic appraisals and all three measures of utilization.     

Limits of spherical blur determined with an adaptive optics mirror

We extended an earlier study (Vision Research, 45, 1967–1974, 2005) in which we investigated limits at which induced blur of letter targets becomes noticeable, troublesome and objectionable. Here we used a deformable adaptive optics mirror to vary spherical defocus for conditions of a white background with correction of astigmatism; a white background with reduction of all aberrations other than defocus; and a monochromatic background with reduction of all aberrations other than defocus. We used seven cyclopleged subjects, lines of three high-contrast letters as targets, 3–6 mm artificial pupils, and 0.1–0.6 logMAR letter sizes. Subjects used a method of adjustment to control the defocus component of the mirror to set the 'just noticeable', 'just troublesome' and 'just objectionable' defocus levels. For the white-no adaptive optics condition combined with 0.1 logMAR letter size, mean 'noticeable' blur limits were ±0.30, ±0.24 and ±0.23 D at 3, 4 and 6 mm pupils, respectively. White-adaptive optics and monochromatic-adaptive optics conditions reduced blur limits by 8% and 20%, respectively. Increasing pupil size from 3–6 mm decreased blur limits by 29%, and increasing letter size increased blur limits by 79%. Ratios of troublesome to noticeable, and of objectionable to noticeable, blur limits were 1.9 and 2.7 times, respectively. The study shows that the deformable mirror can be used to vary defocus in vision experiments. Overall, the results of noticeable, troublesome and objectionable blur agreed well with those of the previous study. Attempting to reduce higher-order aberrations or chromatic aberrations, reduced blur limits to only a small extent.