Reforming the cancer drug fund focus on drugs that might be shown to be cost effective

The Cancer Drug Fund was originally conceived as a temporary measure, until value based pricing for drugs was introduced, to give NHS cancer patients access to drugs not approved by NICE. Spending on these drugs rose from less than the £50m (€63m; $79m) budgeted for the first year in 2010-11 to well over £200m in 2013-14, and the budget for the scheme—now extended for a further two years—will reach £280m by 2016.1 The recent changes to the fund recognise the impossibility, within any sensible budget limit, of providing all the new cancer drugs that offer possible benefit to patients. More radical changes are needed to the working of the fund, given the failure to introduce value based pricing, so that it deals with the underlying problem of inadequate information on the effectiveness and cost effectiveness of new cancer drugs when used in the NHS

Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease

The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 µg compared to powder 18 µg and assess dose-dependency of tiotropium solution pharmacodynamics in comparison to placebo. In total 154 patients with chronic obstructive pulmonary disease (COPD) were included in this multicenter, randomized, double-blind within-solution (1.25, 2.5, 5 µg, and placebo), and open-label powder 18 µg, crossover study, including 4-week treatment periods. Primary end points were peak plasma concentration (Cmax,ss ), and area under the plasma concentration-time profile (AUC0-6h,ss ), both at steady state. The pharmacodynamic response was assessed by serial spirometry (forced expiratory volume in 1 second/forced vital capacity). Safety was evaluated as adverse events and by electrocardiogram/Holter. Tiotropium was rapidly absorbed with a median tmax,ss of 5-7 minutes postdosing for both devices. The gMean ratio of solution 5 µg over powder 18 µg was 81% (90% confidence interval, 73-89%) for Cmax,ss and 76% (70-82%) for AUC0-6h,ss , indicating that bioequivalence was not established. Dose ordering for bronchodilation was observed. Powder 18 µg and solution 5 µg were most effective, providing comparable bronchodilation. All treatments were well tolerated with no apparent relation to dose or device. Comparable bronchodilator efficacy to powder18 µg at lower systemic exposure supports tiotropium solution 5 µg for maintenance treatment of COPD

The developmental influence of primary memory capacity on working memory and academic achievement

In this study, we investigate the development of primary memory capacity among children. Children between the ages of 5-8 completed three novel tasks (split span, interleaved lists, and a modified free recall task) that measured primary memory by estimating the number of items in the focus of attention that could be spontaneously recalled in serial order. These tasks were calibrated against traditional measures of simple and complex span. Clear age- related changes in these primary memory estimates were observed. There were marked individual differences in primary memory capacity but each novel measure was predictive of simple span performance. Among older children, each measure shared variance with reading and mathematics performance, whereas for younger children the interleaved lists task was the strongest single predictor of academic ability. We argue that these novel tasks have considerable potential for the measurement of primary memory capacity and provide new, complementary ways of measuring the transient memory processes that predict academic performance. The interleaved lists task also shared features with interference control tasks, and our findings suggest that young children have a particular difficulty in resisting distraction, and that variance in the ability to resist distraction is also shared with measures of educational attainment

An Individualized, Perception-Based Protocol to Investigate Human Physiological Responses to Cooling

Cold exposure, a known stimulant of the thermogenic effects of brown adipose tissue (BAT), is the most widely used method to study BAT physiology in adult humans. Recently, individualized cooling has been recommended to standardize the physiological cold stress applied across participants, but critical experimental details remain unclear. The purpose of this work was to develop a detailed methodology for an individualized, perception-based protocol to investigate human physiological responses to cooling. Participants were wrapped in two water-circulating blankets and fitted with skin temperature probes to estimate BAT activity and peripheral vasoconstriction. We created a thermoesthesia graphical user interface (tGUI) to continuously record the subject\u27s perception of cooling and shivering status during the cooling protocol. The protocol began with a 15 min thermoneutral phase followed by a series of 10 min cooling phases and concluded when sustained shivering (\u3e1 min duration) occurred. Researchers used perception of cooling feedback (tGUI ratings) to manually adjust and personalize the water temperature at each cooling phase. Blanket water temperatures were recorded continuously during the protocol. Twelve volunteers (ages: 26.2 ± 1.4 years; 25% female) completed a feasibility study to evaluate the proposed protocol. Water temperature, perception of cooling, and shivering varied considerably across participants in response to cooling. Mean clavicle skin temperature, a surrogate measure of BAT activity, decreased (−0.99°C, 95% CI: −1.7 to −0.25°C, P = 0.16) after the cooling protocol, but an increase in supraclavicular skin temperature was observed in 4 participants. A strong positive correlation was also found between thermoesthesia and peripheral vasoconstriction (ρ = 0.84, P \u3c 0.001). The proposed individualized, perception-based protocol therefore has potential to investigate the physiological responses to cold stress applied across populations with varying age, sex, body composition, and cold sensitivity characteristics

What can we learn about immediate memory from the development of children's free recall?

We ask the question: Which aspects of immediate memory performance improve with age? In two studies, we reexamine the widely held view that primary memory capacity estimates derived from children's immediate free recall are age invariant. This was done by assessing children's immediate free-recall accuracy while also measuring the order in which they elected to recall items (Experiment 1) and by encouraging children to begin free recall with items from towards the end of the presented list (Experiment 2). Across samples aged between 5 and 8 years we replicated the previously reported age-related changes in free-recall serial position functions when aggregated across all trials of the standard task, including an absence of age differences in the recency portion of this curve. However, we also show that this does not reflect the fact that primary memory capacity is constant across age. Instead, when we incorporate order of report information, clear age differences are evident in the recall of list-final items that are output at the start of a participant's response. In addition, the total amount that individuals recalled varied little across different types of free-recall tasks. These findings have clear implications for the use of immediate free recall as a means of providing potential indices of primary memory capacity and in the study of the development of immediate memory

Cold exposure induces dynamic, heterogeneous alterations in human brown adipose tissue lipid content

Brown adipose tissue undergoes a dynamic, heterogeneous response to cold exposure that can include the simultaneous synthesis, uptake, and oxidation of fatty acids. The purpose of this work was to quantify these changes in brown adipose tissue lipid content (fat-signal fraction (FSF)) using fat-water magnetic resonance imaging during individualized cooling to 3 °C above a participant’s shiver threshold. Eight healthy men completed familiarization, perception-based cooling, and MRI-cooling visits. FSF maps of the supraclavicular region were acquired in thermoneutrality and during cooling (59.5 ± 6.5 min). Brown adipose tissue regions of interest were defined, and voxels were grouped into FSF decades (0–10%, 10–20%…90–100%) according to their initial value. Brown adipose tissue contained a heterogeneous morphology of lipid content. Voxels with initial FSF values of 60–100% (P \u3c 0.05) exhibited a significant decrease in FSF while a simultaneous increase in FSF occurred in voxels with initial FSF values of 0–30% (P \u3c 0.05). These data suggest that in healthy young men, cold exposure elicits a dynamic and heterogeneous response in brown adipose tissue, with areas initially rich with lipid undergoing net lipid loss and areas of low initial lipid undergoing a net lipid accumulation

Perceptual Grouping and Distance Estimates in Typical and Atypical Development: Comparing Performance across Perception, Drawing and Construction Tasks

Perceptual grouping is a pre-attentive process which serves to group local elements into global wholes, based on shared properties. One effect of perceptual grouping is to distort the ability to estimate the distance between two elements. In this study, biases in distance estimates, caused by four types of perceptual grouping, were measured across three tasks, a perception, a drawing and a construction task in both typical development (TD; Experiment 1) and in individuals with Williams syndrome (WS; Experiment 2). In Experiment 1, perceptual grouping distorted distance estimates across all three tasks. Interestingly, the effect of grouping by luminance was in the opposite direction to the effects of the remaining grouping types. We relate this to differences in the ability to inhibit perceptual grouping effects on distance estimates. Additive distorting influences were also observed in the drawing and the construction task, which are explained in terms of the points of reference employed in each task. Experiment 2 demonstrated that the above distortion effects are also observed in WS. Given the known deficit in the ability to use perceptual grouping in WS, this suggests a dissociation between the pre-attentive influence of and the attentive deployment of perceptual grouping in WS. The typical distortion in relation to drawing and construction points towards the presence of some typical location coding strategies in WS. The performance of the WS group differed from the TD participants on two counts. First, the pattern of overall distance estimates (averaged across interior and exterior distances) across the four perceptual grouping types, differed between groups. Second, the distorting influence of perceptual grouping was strongest for grouping by shape similarity in WS, which contrasts to a strength in grouping by proximity observed in the TD participants

Challenges in valuing and paying for combination regimens in oncology: reporting the perspectives of a multi‐stakeholder, international workshop

Background It is increasingly common for two or more treatments for cancer to be combined as a single regimen. Determining value and appropriate payment for such regimens can be challenging. This study discusses these challenges, and possible solutions. Methods Stakeholders from around the world attended a 2-day workshop, supported by a background paper. This study captures key outcomes from the discussion, but is not a consensus statement. Results Workshop attendees agreed that combining on-patent treatments can result in affordability and value for money challenges that delay or deny patient access to clinically effective treatments in many health systems. Options for addressing these challenges include: (i) Increasing the value of combination therapies through improved clinical development; (ii) Willingness to pay more for combinations than for single drugs offering similar benefit, or; (iii) Aligning the cost of constituent therapies with their value within a regimen. Workshop attendees felt that (i) and (iii) merited further discussion, whereas (ii) was unlikely to be justifiable. Views differed on the feasibility of (i). Key to (iii) would be systems allowing different prices to apply to different uses of a drug. Conclusions Common ground was identified on immediate actions to improve access to combination regimens. These include an exploration of the legal challenges associated with price negotiations, and ensuring that pricing systems can support implementation of negotiated prices for specific uses. Improvements to clinical development and trial design should be pursued in the medium and longer term

Algorithmic Complexity for Short Binary Strings Applied to Psychology: A Primer

Since human randomness production has been studied and widely used to assess executive functions (especially inhibition), many measures have been suggested to assess the degree to which a sequence is random-like. However, each of them focuses on one feature of randomness, leading authors to have to use multiple measures. Here we describe and advocate for the use of the accepted universal measure for randomness based on algorithmic complexity, by means of a novel previously presented technique using the the definition of algorithmic probability. A re-analysis of the classical Radio Zenith data in the light of the proposed measure and methodology is provided as a study case of an application.Comment: To appear in Behavior Research Method