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Background: Recent developments in CRISPR/Cas9 genome-editing tools have facilitated the introduction of precise alleles, including genetic intervals spanning several kilobases, directly into the embryo. However, the introduction of donor templates, via homology directed repair, can be erroneous or incomplete and these techniques often produce mosaic founder animals. Thus, newly generated alleles must be verified at the sequence level across the targeted locus. Screening for the presence of the desired mutant allele using traditional sequencing methods can be challenging due to the size of the interval to be sequenced, together with the mosaic nature of founders. Methodology/Principal findings: In order to help disentangle the genetic complexity of these animals, we tested the application of Oxford Nanopore Technologies long-read sequencing at the targeted locus and found that the achievable depth of sequencing is sufficient to offset the sequencing error rate associated with the technology used to validate targeted regions of interest. We have assembled an analysis workflow that facilitates interrogating the entire length of a targeted segment in a single read, to confirm that the intended mutant sequence is present in both heterozygous animals and mosaic founders. We used this workflow to compare the output of PCR-based and Cas9 capture-based targeted sequencing for validation of edited alleles. Conclusion: Targeted long-read sequencing supports in-depth characterisation of all experimental models that aim to produce knock-in or conditional alleles, including those that contain a mix of genome-edited alleles. PCR- or Cas9 capture-based modalities bring different advantages to the analysis. Author summary: In this study we investigated the use of long-read sequencing for the analysis of genome editing experiments. We found that Oxford Nanopore Technology sequencing is a superior alternative to Sanger sequencing as it yields a more rapid and comprehensive characterisation of the genotype of both mosaic animals and their progeny. We compared PCR-based and nCATs targeted sequencing modalities and found they have different advantages and applicabilities. [ABSTRACT FROM AUTHOR]

The UK's National Institute for Health and Care Excellence (NICE) recently launched a consultation on the methods it uses to evaluate new health technologies, and has highlighted the issue of how 'modifiers', including equity weights, should be incorporated into its processes. The practice of applying equity weights to specific population subgroups, as a means for increasing the effective cost-effectiveness threshold for some new health technologies, is well established in health technology assessment. It is also the subject of extensive discussion in the academic literature. In this paper, we demonstrate that NICE's current approach to equity weighting has the effect of reducing both population health and equity-weighted population health, a fundamental problem that appears to place NICE in contravention of its principles and obligations. We consider two potential methods for modifying NICE's current approach to address this problem. We also consider the merits of NICE abandoning its current approach to equity weighting and adopting a standard 'net benefit' approach in its place. We find that adopting a standard 'net benefit' approach is the most desirable option, as it provides for the most transparency while avoiding specific issues that arise when attempting to modify NICE's current approach. Regardless of the approach NICE uses for equity weighting, we find that protecting the health of National Health Service patients requires that some new technologies be evaluated using an effective cost-effectiveness threshold lower than the 'supply-side' cost-effectiveness threshold. This poses a particular challenge for NICE, given its obligations under the 2019 'Voluntary Scheme' between the UK pharmaceutical industry, the National Health Service, and the UK Government. We conclude by making some recommendations as to how NICE can move forward with the use of 'modifiers' in its decision making. [ABSTRACT FROM AUTHOR]

Although there have been substantial developments in the analysis of uncertainty in economic evaluations of health care programmes, the development of methods for one-way sensitivity analysis has been notably slower. Conditional incremental net benefit was recently proposed as an approach for implementing probabilistic one-way sensitivity analysis for economic evaluations comparing two strategies. In this paper, we generalise this approach to economic evaluations that compare three or more strategies. We find that 'conditional net benefit' may be used to conduct probabilistic one-way sensitivity analysis for economic evaluations comparing any number of strategies. We also propose the 'conditional net benefit frontier', which may be used to identify the most cost-effective of any number of strategies conditional upon the specific value of a parameter of interest. [ABSTRACT FROM AUTHOR]

Predictive–corrective incompressible smoothed particle hydrodynamics (PCISPH) is a promising variant of the particle-based fluid modeling technique smoothed particle hydrodynamics (SPH). In PCISPH, a dedication prediction–correction scheme is employed which allows for using a larger time step and thereby outperforms other SPH variants by up to one order of magnitude. However, certain characteristics of the PCISPH lead to severe synchronization problems that, thus far, prevented PCISPH from being applied to industrial scenarios where high performance computing techniques need to leveraged in order to simulate in appropriate resolution. In this work, we are for the first time, presenting a highly accelerated PCISPH implementation which employs a distributed multi-GPU architecture. To that end, dedicated optimization techniques are presented that allow to overcome the drawbacks caused by the algorithmic characteristics of PCISPH. Experimental evaluations on a standard dam break test case and an industrial water splash scenario confirm that PCISPH can be efficiently employed to model real-world scenarios involving a large number of particles. [ABSTRACT FROM AUTHOR]

Although probabilistic analysis has become the accepted standard for decision analytic cost-effectiveness models, deterministic one-way sensitivity analysis continues to be used to meet the need of decision makers to understand the impact that changing the value taken by one specific parameter has on the results of the analysis. The value of a probabilistic form of one-way sensitivity analysis has been recognised, but the proposed methods are computationally intensive. Deterministic one-way sensitivity analysis provides decision makers with biased and incomplete information whereas, in contrast, probabilistic one-way sensitivity analysis (POSA) can overcome these limitations, an observation supported in this study by results obtained when these methods were applied to a previously published cost-effectiveness analysis to produce a conditional incremental expected net benefit curve. The application of POSA will provide decision makers with unbiased information on how the expected net benefit is affected by a parameter taking on a specific value and the probability that the specific value will be observed. [ABSTRACT FROM AUTHOR]

BACKGROUND Thyroid peroxidase antibodies are associated with an increased risk of miscarriage and preterm birth, even when thyroid function is normal. Small trials indicate that the use of levothyroxine could reduce the incidence of such adverse outcomes. METHODS We conducted a double-blind, placebo-controlled trial to investigate whether levothyroxine treatment would increase live-birth rates among euthyroid women who had thyroid peroxidase antibodies and a history of miscarriage or infertility. A total of 19,585 women from 49 hospitals in the United Kingdom underwent testing for thyroid peroxidase antibodies and thyroid function. We randomly assigned 952 women to receive either 50 jig once daily of levothyroxine (476 women) or placebo (476 women) before conception through the end of pregnancy. The primary outcome was live birth after at least 34 weeks of gestation. RESULTS The follow-up rate for the primary outcome was 98.7% (940 of 952 women). A total of 266 of 470 women in the levothyroxine group (56.6%) and 274 of 470 women in the placebo group (58.3%) became pregnant. The live-birth rate was 37.4% (176 of 470 women) in the levothyroxine group and 37.9% (178 of 470 women) in the placebo group (relative risk, 0.97; 95% confidence interval [Cl], 0.83 to 1.14, P=0.74; absolute difference, -0.4 percentage points; 95% Cl, -6.6 to 5.8). There were no significant between-group differences in other pregnancy outcomes, including pregnancy loss or preterm birth, or in neonatal outcomes. Serious adverse events occurred in 5.9% of women in the levothyroxine group and 3.8% in the placebo group (P = 0.14). CONCLUSIONS The use of levothyroxine in euthyroid women with thyroid peroxidase antibodies did not result in a higher rate of live births than placebo. [ABSTRACT FROM AUTHOR]

The article offers information on the scope of costs and benefits for economic evaluations in the field of health. Topics discussed include the use of cost-effectiveness analysis in healthcare and the discussion on the productivity costs; the Second Panel on Cost Effectiveness in Health and Medicine which proposed the use of impact inventories on healthcare; and the health technology assessment processes such as Common Drug Review in Canada, Pharmaceutical Benefits Scheme in Australia.

In addition to excellent scientific and patient care-oriented content, this year's program will also offer ample opportunities for attendees to network and unwind, including the opening welcome reception on Wednesday evening, the DEI networking session on Thursday afternoon, and the ATA attendee meeting party on Friday night. In anticipation of the upcoming revised ATA guidelines on thyroid nodules, cochaired by Susan Mandel, MD, and Lisa Orloff, MD, and on differentiated thyroid cancer, cochaired by Julie Ann Sosa, MD, and Matthew Ringel, MD, the Arthur Bauman Clinical Symposium will offer a sneak peek into changes on the horizon and highlight the main forthcoming recommendations on these topics. We are delighted that the 91st Annual Meeting of the American Thyroid Association (ATA) is almost here!. [Extracted from the article]

Over the past forty years, animal models of focal cerebral ischaemia have allowed us to identify the critical cerebral blood flow thresholds responsible for irreversible cell death, electrical failure, inhibition of protein synthesis, energy depletion and thereby the lifespan of the potentially salvageable penumbra. They have allowed us to understand the intricate biochemical and molecular mechanisms within the ‘ischaemic cascade’ that initiate cell death in the first minutes, hours and days following stroke. Models of permanent, transient middle cerebral artery occlusion and embolic stroke have been developed each with advantages and limitations when trying to model the complex heterogeneous nature of stroke in humans. Yet despite these advances in understanding the pathophysiological mechanisms of stroke-induced cell death with numerous targets identified and drugs tested, a lack of translation to the clinic has hampered pre-clinical stroke research. With recent positive clinical trials of endovascular thrombectomy in acute ischaemic stroke the stroke community has been reinvigorated, opening up the potential for future translation of adjunctive treatments that can be given alongside thrombectomy/thrombolysis. This review discusses the major animal models of focal cerebral ischaemia highlighting their advantages and limitations. Acute imaging is crucial in longitudinal pre-clinical stroke studies in order to identify the influence of acute therapies on tissue salvage over time. Therefore, the methods of identifying potentially salvageable ischaemic penumbra are discussed. This article is part of the Special Issue entitled ‘Cerebral Ischemia’. [ABSTRACT FROM AUTHOR]

The authors discuss the implications of the 2015 proposed revision of the Cancer Drugs Fund (CDF), established to provide a means by which National Health Service (NHS) patients could get cancer drugs that are not available on the NHS in Great Britain. They argues against the threats of the revised scheme on public health. They describe how the revised CDF could maximize the value of the benefit to cancer patients while minimizing its negative impact on the equity and efficiency of the NHS.

Breast cancer is the second most common cancer worldwide and the leading cause of cancer death in women, with incidence rates that continue to rise. The heterogeneity of the disease makes breast cancer exceptionally difficult to treat, particularly for those patients with triple-negative disease. To address the therapeutic complexity of these tumours, new strategies for diagnosis and treatment are urgently required. The ability of lactating and malignant breast cells to uptake and transport iodide has led to the hypothesis that radioiodide therapy could be a potentially viable treatment for many breast cancer patients. Understanding how iodide is transported, and the factors regulating the expression and function of the proteins responsible for iodide transport, is critical for translating this hypothesis into reality. This review covers the three known iodide transporters -- the sodium iodide symporter, pendrin and the sodium-coupled monocarboxylate transporter -- and their role in iodide transport in breast cells, along with efforts to manipulate them to increase the potential for radioiodide therapy as a treatment for breast cancer. [ABSTRACT FROM AUTHOR]

Background Acute ischemic stroke is common and disabling, but there remains a paucity of acute treatment options and available treatment (thrombolysis) is underutilized. Advanced brain imaging, designed to identify viable hypoperfused tissue (penumbra), could target treatment to a wider population. Existing magnetic resonance imaging and computed tomography-based technologies are not widely used pending validation in ongoing clinical trials. T2* oxygen challenge magnetic resonance imaging, by providing a more direct readout of tissue viability, has the potential to identify more patients likely to benefit from thrombolysis - irrespective of time from stroke onset - and patients within and beyond the 4·5 h thrombolysis treatment window who are unlikely to benefit and are at an increased risk of hemorrhage. Aims This study employs serial multimodal imaging and voxel-based analysis to develop optimal data processing for T2* oxygen challenge penumbra assessment. Tissue in the ischemic hemisphere is compartmentalized into penumbra, ischemic core, or normal using T2* oxygen challenge (single threshold) or T2* oxygen challenge plus cerebral blood flow (dual threshold) data. Penumbra defined by perfusion imaging/apparent diffusion coefficient mismatch (dual threshold) is included for comparison. Methods Permanent middle cerebral artery occlusion was induced in male Sprague- Dawley rats ( n = 6) prior to serial multimodal imaging: T2* oxygen challenge, diffusion-weighted and perfusion imaging (cerebral blood flow using arterial spin labeling). Results Across the different methods evaluated, T2* oxygen challenge combined with perfusion imaging most closely predicted 24 h infarct volume. Penumbra volume declined from one to four-hours post-stroke: mean ± SD, 77 ± 44 to 49 ± 37 mm3 (single T2* oxygen challenge-based threshold); 55 ± 41 to 37 ± 12 mm3 (dual T2* oxygen challenge/cerebral blood flow); 84 ± 64 to 42 ± 18 mm3 (dual cerebral blood flow/apparent diffusion coefficient), as ischemic core grew: 155 ± 37 to 211 ± 36 mm3 (single apparent diffusion coefficient threshold); 178 ± 56 to 205 ± 33 mm3 (dual T2* oxygen challenge/cerebral blood flow); 139 ± 30 to 168 ± 38 mm3 (dual cerebral blood flow/apparent diffusion coefficient). There was evidence of further lesion growth beyond four-hours (T2-defined edema-corrected infarct, 231 ± 19 mm3). Conclusions In conclusion, T2* oxygen challenge combined with perfusion imaging has advantages over alternative magnetic resonance imaging techniques for penumbra detection by providing serial assessment of available penumbra based on tissue viability. [ABSTRACT FROM AUTHOR]

The authors reflect on the article by S. Eckermann and B. Pekarsky which challenges several concepts including the methods of determining cost-effectiveness threshold for assessing the potential health technology in public healthcare system. They discuss the National Institute forHealth and Care Excellence (NICE) in Great Britain, the quality-adjusted life years (QALY), and disinvestment.

Despite high expectations of economic returns, large investments in regenerative medicine technology have yet to materialize, partly due to a lack of proven business and investment models, regulatory hurdles, and a greater focus on cost-effectiveness for reimbursement decisions by payors. Adoption of new economic modeling methods will better link investment decisions to value-based criteria of health systems. [ABSTRACT FROM AUTHOR]

Healthcare systems are increasingly under pressure to provide funding for innovative technologies. These technologies tend to be characterized by their potential to make valued contributions to patient health in areas of relative unmet need, and have high acquisition costs and uncertainty within the evidence base on their actual impact on health. Decision makers are increasingly interested in linking reimbursement strategies to the degree of uncertainty in the evidence base and, as a result, reimbursement for innovative technologies is frequently linked to some form of patient access or risk-sharing scheme. As the dominant methods of economic evaluation report final outcomes only at the time horizon of the analysis, they present only aggregated information. This omits much of the information available on how net benefit is distributed within the time horizon. In this article, we introduce the Net Benefit Probability Map (NBPM), which maps net health benefit versus time to identify how certain decision makers can be about the benefit of technologies at multiple time points. Using an illustrative example, we show how the NBPM can inform decision makers about how long it will take for innovative technologies to 'pay off', how methodological choices on discount rates affect results and how alternative payment mechanisms can reduce the risk for decision makers facing innovative technologies. [ABSTRACT FROM AUTHOR]

The construction of mapping models is an increasingly popular mechanism for obtaining health state utility data to inform economic evaluations in health care. There is great variation in the sophistication of the methods utilized but to date very little discussion of the appropriate theoretical framework to guide the design and evaluation of these models. In this paper, we argue that recognizing mapping models as a form of indirect health state valuation allows the use of the framework described by Dolan for the measurement of social preferences over health. Using this framework, we identify substantial concerns with the method for valuing health states that is implicit in indirect utility models (IUMs), the conflation of two sets of respondents' values in such models, and the lack of a structured and statistically reasonable approach to choosing which states to value and how many observations per state to require in the estimation dataset. We also identify additional statistical challenges associated with clustering and censoring in the datasets for IUMs, additional to those attributable to the descriptive systems, and a potentially significant problem with the systematic understatement of uncertainty in predictions from IUMs. Whilst recognizing that IUMs appear to meet the needs of reimbursement organizations that use quality-adjusted life years in their appraisal processes, we argue that current proposed quality standards are inadequate and that IUMs are neither robust nor appropriate mechanisms for estimating utilities for use in cost-effectiveness analyses. [ABSTRACT FROM AUTHOR]

Hypertension is associated with cerebral small vessel disease (SVD) and with diffuse white matter hyperintensities (WMH) on T2-weighted magnetic resonance imaging (MRI). We tested whether stroke-prone spontaneously hypertensive rats (SHRSP), a model of chronic hypertension, exhibit WMH. Male SHRSP (age 10 months) without stroke symptoms were compared with age-matched male WKY rats. Stroke-prone spontaneously hypertensive rats exhibited no WMH on MRI scans (T2, T2*, diffusion tensor imaging) and no neuropathological lesions. While leptomeningeal arteries exhibited fibrohyaline wall thickening, with decreased smooth muscle actin relative to WKY, deep penetrating arterioles within the caudate nuclei had no vasculopathy. We conclude that WMH are not an obligate feature of stroke-free SHRSP aged up to 10 months. [ABSTRACT FROM AUTHOR]

We summarise and evaluate Harris' criticisms of cost-effectiveness analysis (CEA) and the alternative processes he commends to health care decision makers. In contrast to CEA, Harris' asserts that individuals have a right to life-saving treatment that cannot be denied on the basis of their capacity to benefit. We conclude that, whilst Harris' work has challenged the proponents of CEA and quality-adjusted life years to be explicit about the method's indirect discriminatory characteristics, his arguments ignore important questions about what 'lives saved' mean. Harris also attempts to avoid opportunity cost by advocating the same chance of treatment for every person desiring treatment. Using a simple example, we illustrate that an 'equal chances' lottery is not in the interest of any patient, as it reduces the chance of treatment for all patients by leaving some of the health budget unspent. [ABSTRACT FROM AUTHOR]

Arterial spin labelling (ASL) is increasingly available for noninvasive cerebral blood flow (CBF) measurement in stroke research. Here, a pseudo-continuous ASL technique (pCASL) was evaluated against 99mTc-D, L-hexamethylpropyleneamine oxime (99mTc-HMPAO) autoradiography in a rat stroke model. The 99mTc-HMPAO was injected (intravenously, 225 MBq) during pCASL acquisition. The pCASL and 99mTc-HMPAO autoradiography CBF measures, relative to the contralateral hemisphere, were in good agreement across the spectrum of flow values in normal and ischemic tissues. The pCASL-derived quantitative regional CBF values (contralateral: 157 to 177 mL/100 g per minute; ipsilateral: 9 to 104 mL/100 g per minute) were consistent with the literature values. The data show the potential utility of pCASL for CBF assessment in a rat stroke model. [ABSTRACT FROM AUTHOR]

Background Multi-parameter genomic tests identify patients with early-stage breast cancer who are likely to derive little benefit from adjuvant chemotherapy. These tests can potentially spare patients the morbidity from unnecessary chemotherapy and reduce costs. However, the costs of the test must be balanced against the health benefits and cost savings produced. This economic evaluation compared genomic test–directed chemotherapy using the Oncotype DX 21-gene assay with chemotherapy for all eligible patients with lymph node–positive, estrogen receptor–positive early-stage breast cancer. Methods We performed a cost–utility analysis using a state transition model to calculate expected costs and benefits over the lifetime of a cohort of women with estrogen receptor–positive lymph node–positive breast cancer from a UK perspective. Recurrence rates for Oncotype DX–selected risk groups were derived from parametric survival models fitted to data from the Southwest Oncology Group 8814 trial. The primary outcome was the incremental cost-effectiveness ratio, expressed as the cost (in 2011 GBP) per quality-adjusted life-year (QALY). Confidence in the incremental cost-effectiveness ratio was expressed as a probability of cost-effectiveness and was calculated using Monte Carlo simulation. Model parameters were varied deterministically and probabilistically in sensitivity analysis. Value of information analysis was used to rank priorities for further research. Results The incremental cost-effectiveness ratio for Oncotype DX–directed chemotherapy using a recurrence score cutoff of 18 was £5529 (US $8852) per QALY. The probability that test-directed chemotherapy is cost-effective was 0.61 at a willingness-to-pay threshold of £30 000 per QALY. Results were sensitive to the recurrence rate, long-term anthracycline-related cardiac toxicity, quality of life, test cost, and the time horizon. The highest priority for further research identified by value of information analysis is the recurrence rate in test-selected subgroups. Conclusions There is substantial uncertainty regarding the cost-effectiveness of Oncotype DX–directed chemotherapy. It is particularly important that future research studies to inform cost-effectiveness–based decisions collect long-term outcome data. [ABSTRACT FROM PUBLISHER]

Accurate identification of ischemic penumbra will improve stroke patient selection for reperfusion therapies and clinical trials. Current magnetic resonance imaging (MRI) techniques have limitations and lack validation. Oxygen challenge T2* MRI (T2* OC) uses oxygen as a biotracer to detect tissue metabolism, with penumbra displaying the greatest T2* signal change during OC. [14C]2-deoxyglucose (2-DG) autoradiography was combined with T2* OC to determine metabolic status of T2*-defined penumbra. Permanent middle cerebral artery occlusion was induced in anesthetized male Sprague-Dawley rats (n=6). Ischemic injury and perfusion deficit were determined by diffusion- and perfusion-weighted imaging, respectively. At 147±32 minutes after stroke, T2* signal change was measured during a 5-minute 100% OC, immediately followed by 125 μCi/kg 2-DG, intravenously. Magnetic resonance images were coregistered with the corresponding autoradiograms. Regions of interest were located within ischemic core, T2*-defined penumbra, equivalent contralateral structures, and a region of hyperglycolysis. A T2* signal increase of 9.22%±3.9% (mean±s.d.) was recorded in presumed penumbra, which displayed local cerebral glucose utilization values equivalent to contralateral cortex. T2* signal change was negligible in ischemic core, 3.2%±0.78% in contralateral regions, and 1.41%±0.62% in hyperglycolytic tissue, located outside OC-defined penumbra and within the diffusion abnormality. The results support the utility of OC-MRI to detect viable penumbral tissue following stroke. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI) with oxygen challenge (T2* OC) uses oxygen as a metabolic biotracer to define penumbral tissue based on CMRO2 and oxygen extraction fraction. Penumbra displays a greater T2* signal change during OC than surrounding tissue. Since timely restoration of cerebral blood flow (CBF) should salvage penumbra, T2* OC was tested by examining the consequences of reperfusion on T2* OC-defined penumbra. Transient ischemia (109±20 minutes) was induced in male Sprague-Dawley rats (n=8). Penumbra was identified on T2*-weighted MRI during OC. Ischemia and ischemic injury were identified on CBF and apparent diffusion coefficient maps, respectively. Reperfusion was induced and scans repeated. T2 for final infarct and T2* OC were run on day 7. T2* signal increase to OC was 3.4% in contralateral cortex and caudate nucleus and was unaffected by reperfusion. In OC-defined penumbra, T2* signal increased by 8.4%±4.1% during ischemia and returned to 3.25%±0.8% following reperfusion. Ischemic core T2* signal increase was 0.39%±0.47% during ischemia and 0.84%±1.8% on reperfusion. Penumbral CBF increased from 41.94±13 to 116.5±25 mL per 100 g per minute on reperfusion. On day 7, OC-defined penumbra gave a normal OC response and was located outside the infarct. T2* OC-defined penumbra recovered when CBF was restored, providing further validation of the utility of T2* OC for acute stroke management. [ABSTRACT FROM AUTHOR]

Abstract: In order to decide whether a new treatment should be used in patients, a robust estimate of efficacy and toxicity is no longer sufficient. As a result of increasing healthcare costs across the globe healthcare payers and providers now seek estimates of cost-effectiveness as well. Most trials currently being designed still only consider the need for prospective efficacy and toxicity data during the development life-cycle of a new intervention. Hence the cost-effectiveness estimates are inevitably less precise than the clinical data on which they are based. Methods based on decision theory are being developed by health economists that can contribute to the design of clinical trials in such a way that they can more effectively lead to better informed drug funding decisions on the basis of cost-effectiveness in addition to clinical outcomes. There is an opportunity to apply these techniques prospectively in the design of future clinical trials. This article describes the problems encountered by those responsible for drug reimbursement decisions as a consequence of the current drug development pathway. The potential for decision theoretic methods to help overcome these problems is introduced and potential obstacles in implementation are highlighted. [Copyright &y& Elsevier]

As tensions between payers, responsible for ensuring prudent and principled use of scarce resources, and both providers and patients, who legitimately want access to technologies from which they could benefit, continue to mount, interest in approaches to managing the uncertainty surrounding the introduction of new health technologies has heightened. The purpose of this project was to compile an inventory of various types of 'access with evidence development' (AED) schemes, examining characteristics of the technologies to which they have been applied, the uncertainty they sought to address, the terms of arrangements of each scheme, and the policy outcomes. It also aimed to identify issues related to such schemes, including advantages and disadvantages from the perspectives of various stakeholder groups. A comprehensive search, review and appraisal of peer-reviewed and 'grey' literature were performed, followed by a facilitated workshop of academics and decision makers with expertise in AED schemes. Information was extracted and compiled in tabular form to identify patterns or trends. To enhance the validity of interpretations made, member checking was performed. Although the concept of AED is not new, evaluative data are sparse. Despite varying opinions on the 'right' answers to some of the questions raised, there appears to be consensus on a 'way forward' - development of methodological guidelines. All stakeholders seemed to share the view that AEDs offer the potential to facilitate patient access to promising new technologies and encourage innovation while ensuring effective use of scarce healthcare resources. There is no agreement on what constitutes 'sufficient evidence', and it depends on the specific uncertainty in question. There is agreement on the need for 'best practice' guidelines around the implementation and evaluation of AED schemes. This is the first attempt at a comprehensive analysis of methods that have been used to address uncertainty concerning a new drug or other technology. The analysis reveals that, although various approaches have been experimented with, many of them have not achieved the ostensible goal of the approach. This article outlines challenges related to AED schemes and issues that remain unresolved. [ABSTRACT FROM AUTHOR]

There is an inevitable tension between robust reimbursement processes and providing speedy access to new and novel technologies, given uncertainties about key pieces of evidence and subsequent concerns regarding their overall efficiency. The public perception of these treatments as 'breakthrough', combined with substantial clinical pressure, has led to healthcare payers looking for schemes that allow the new technology to be made available to (some) patients, while (at least partially) protecting the principles of their reimbursement decision-making processes. Current literature on these schemes is almost completely descriptive and provides little help in planning future schemes. We propose a framework for evaluating current schemes and informing the design of future schemes. We examine the value of the framework using the UK Multiple Sclerosis Risk-Sharing Scheme as a case study. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the cost-effectiveness of disease-modifying therapies (DMTs) for the management of multiple sclerosis (MS) compared to best supportive care in the United States. Methods: Cost-effectiveness analysis was undertaken using a state transition model of disease natural history and the impact of DMTs for the representative Medicare beneficiary with MS. Costs and outcomes were evaluated from the health-care payer perspective using a 50-year time horizon. Natural history data were drawn from a longitudinal cohort study. The effectiveness of the DMTs was evaluated through a systematic review. Utility data were taken from a study of patients with clinically definite MS in Nova Scotia. Resource use and cost data were derived from the Sonya Slifka database and associated literature. Results: When based on placebo-controlled evidence, the marginal cost-effectiveness of interferon beta (IFNβ) and glatiramer acetate compared to best supportive care is expected to be in excess of $100,000 per quality-adjusted life-year gained. When evidence from head-to-head trials is incorporated into the model, the cost-effectiveness of 6 MIU IFNβ-1a is expected to be considerably less favorable. Treatment discontinuation upon progression to Expanded Disability Status Scale 7.0 is expected to improve the cost-effectiveness of all DMTs. Conclusions: Further research is required to examine the long-term clinical effectiveness and cost-effectiveness of these therapies. There is no definitive guidance in the United States concerning discontinuation of DMTs; this study suggests that the prudent use of a treatment discontinuation rule may considerably improve the cost-effectiveness of DMTs. [ABSTRACT FROM AUTHOR]

The National Institute for Health and Clinical Excellence (NICE) has been using a cost-effectiveness threshold range between £20 000 and £30 000 for over 7 years. What the cost-effectiveness threshold represents, what the appropriate level is for NICE to use, and what the other factors are that NICE should consider have all been the subject of much discussion. In this article, we briefly review these questions, provide a critical assessment of NICE’s utilization of the incremental cost-effectiveness ratio (ICER) threshold to inform its guidance, and suggest ways in which NICE’s utilization of the ICER threshold could be developed to promote the efficient use of health service resources.We conclude that it is feasible and probably desirable to operate an explicit single threshold rather than the current range; the threshold should be seen as a threshold at which ‘other’ criteria beyond the ICER itself are taken into account; interventions with a large budgetary impact may need to be subject to a lower threshold as they are likely to displace more than the marginal activities; reimbursement at the threshold transfers the full value of an innovation to the manufacturer.Positive decisions above the threshold on the grounds of innovation reduce population health; the value of the threshold should be reconsidered regularly to ensure that it captures the impact of changes in efficiency and budget over time; the use of equity weights to sustain a positive recommendation when the ICER is above the threshold requires knowledge of the equity characteristics of those patients who bear the opportunity cost. Given the barriers to obtaining this knowledge and knowledge about the characteristics of typical beneficiaries of UK NHS care, caution is warranted before accepting claims from special pleaders; uncertainty in the evidence base should not be used to justify a positive recommendation when the ICER is above the threshold. The development of a programme of disinvestment guidance would enable NICE and the NHS to be more confident that the net health benefit of the Technology Appraisal Programme is positive. [ABSTRACT FROM AUTHOR]

GADD34 is expressed in the ischaemic brain and reverses protein synthesis shutdown. Consequently, GADD34 could have neuroprotective potential in stroke. BHK medium, a replication-deficient HSV viral vector (HSV1716) with no insert or containing full-length GADD34, the N terminal or a conserved portion of the gene, was injected into mouse brain before stroke. Infarct size was 1.0±0.26, 1.19±0.36, 1.5±0.36, 1.3±0.36, and 1.1±0.28 mm3, respectively. The increase in infarct size with full-length GADD34 was statistically significant (P<0.05). Immunohistochemistry confirmed viral protein expression. Tissue culture studies revealed GADD34 gene restored virulence in HSV1716, suggesting that HSV virulence, rather than increased GADD34, exacerbated ischaemic damage.Journal of Cerebral Blood Flow & Metabolism (2008) 28, 747–751; doi:10.1038/sj.jcbfm.9600565; published online 10 October 2007 [ABSTRACT FROM AUTHOR]

Abstract: A key issue in health state valuation modelling is the choice of functional form. The two most frequently used preference based instruments adopt different approaches; one based on multi-attribute utility theory (MAUT), the other on statistical analysis. There has been no comparison of these alternative approaches in the context of health economics. We report a comparison of these approaches for the health utilities index mark 2. The statistical inference model predicts more accurately than the one based on MAUT. We discuss possible explanations for the differences in performance, the importance of the findings, and implications for future research. [Copyright &y& Elsevier]

Abstract: In this paper we report the estimation of conditional logistic regression models for the Health Utilities Index Mark 2 and the SF-6D, using ordinal preference data. The results are compared to the conventional regression models estimated from standard gamble data, and to the observed mean standard gamble health state valuations. For both the HUI2 and the SF-6D, the models estimated using ordinal data are broadly comparable to the models estimated on standard gamble data and the predictive performance of these models is close to that of the standard gamble models. Our research indicates that ordinal data have the potential to provide useful insights into community health state preferences. However, important questions remain. [Copyright &y& Elsevier]

The aims of this study were to determine if endothelin-1 (ET-1) under normal and ischaemic conditions exhibits a direct arrhythmogenic effect that is independent of its ability to cause coronary vasoconstriction, and to determine the contribution of the ET(A) and ET(B) receptor subtype. ET(A/B) (with ET-1) and ET(A) (ET-1 in the presence of BQ-788) receptor activation resulted in a significant reduction in both epi- and endocardial monophasic action potential duration (MAPD(90)). ET(A) receptor activation reduced both epi- and endocardial effective refractory period (ERP). This MAPD(90) and ERP shortening were associated with a reduction in coronary flow, myocardial contractility and induction of ventricular fibrillation (VF) during ERP measurement. The ET(B) agonist sarafotoxin (S6c) had no marked, or concentration-dependent, effect on MAPD(90), ERP, myocardial contractility or induction of arrhythmias. Neither ET-1 nor S6c, given prior to coronary artery occlusion, significantly changed the ischaemia-induced dispersion of MAPD(90), ERP or the % incidence of VF. In conclusion, neither ET(A) nor ET(B) receptor stimulation has a direct arrhythmogenic effect in isolated rabbit hearts under normal or ischaemic conditions. The ET-1-induced arrhythmogenic effect observed in nonischaemic hearts is likely to be the result of the associated coronary vasoconstriction caused by ET(A) receptor stimulation resulting in myocardial ischaemia. [ABSTRACT FROM AUTHOR]

Since the grant of the first Commercial Mobile Radio Service ("CMRS") license over twenty years ago. the wireless industry has grown from a service of convenience to one that is indispensable. What once was a device used for sporadic phone calls now is viewed by many Americans as a source of invaluable communication and security. As the wireless industry matured, government officials turned to the mobile phone as a way to make the United States safer. E-911, the Communications Assistance for Law Enforcement Act ("CALEA"), Wireless Priority Service ("WPS"), and Outage Reporting all were initiated on the wireless platform in the name of safety. The FCC implementation proceedings for each of these initiatives have differed markedly. In an advanced technology area such as wireless, government goals may best be achieved by relying on industry experts, because the technology is so sophisticated and constantly developing that the legislative and regulatory process at times cannot keep pace. This Article reviews wireless public safety and Homeland Security initiatives in three phases and explores the evolution of Homeland Security regulation of the wireless industry. [ABSTRACT FROM AUTHOR]

In a recent leading article in PharmacoEconomics, Nuijten described some methods for incorporating uncertainty into health economic models and for utilising the information on uncertainty regarding the cost effectiveness of a therapy in resource allocation decision-making. His proposals are found to suffer from serious flaws in statistical and health economic reasoning.Nuijten's suggestions for incorporating uncertainty: (a) wrongly interpret the p-value as the probability that the null hypothesis is true; (b) represent this probability wrongly by truncating the input distribution; and (c) in the specific example of an antiparkinsonian drug uses a completely inappropriate p-value of 0.05 when the null hypothesis would, in reality, be emphatically disproved by the data.His suggestions regarding minimum important differences in cost effectiveness: (a) introduce areas of indifference that suggest inappropriate reliance on cost minimisation while failing to recognise that decisions should be based on expected costs versus benefits; and (b) offer no guidance on how the probabilities associated with these areas could be used in decision-making. Furthermore, Nuijten's model for Parkinson's disease is over-simplified to the point of providing a bad example of modelling practice, which may mislead the readers of PharmacoEconomics. The rationale for this paper is to ensure that readers do not apply inappropriate analyses as a result of following the proposals contained in Nuijten's paper. In addition to a detailed critique of Nuijten's proposals, we provide brief summaries of the currently accepted best practice in cost-effectiveness decision-making under uncertainty. [ABSTRACT FROM AUTHOR]

The authors discuss the study by M. Frank and T. Mittendorf on the cost effectiveness of pharmacogenomic profiling prior to colorectal cancer treatment. The authors explain that the study demonstrated that predictive biomarkers in colorectal cancer serves as the standards for establishing evidence on cost-effectiveness of treatment. The authors also emphasize that the study suggests that harmonise methods and increase modelling transparency are needed in the evaluation of biomarkers.

The article investigates the reasons for not reducing the prices of interferon and glatiramer acetate despite evidence noting their ineffectiveness. The multiple sclerosis risk sharing scheme, which was implemented in Great Britain to examine the cost effectiveness of interferon and glatiramer acetate, revealed that such drugs are not effective. However, the monitoring team suggested that reducing the prices of the drugs is still not appropriate and further analyses are needed. The author highlights the factors that might have influenced the decision not to reduce the prices of interferon and glatiramer acetate despite their cost ineffectiveness.

Information about the topics discussed at the Banf Summit in Alberta is presented. Topics include healthcare insurance reimbursements policies as well as access with developmental approaches (AEDs) and its objectives. The summit featured several health economics experts from Great Britain and the U.S. including Devidas Menon, Christopher J. McCabe and Tania Stafinski.

There has been much speculation about whether the National Institute for Health and Clinical Excellence (NICE) has, or ought to have, a 'threshold' figure for the cost of an additional quality-adjusted life-year above which a technology will not be recommended for use. We argue that it is not constitutionally appropriate for NICE to set such a threshold, which is properly the business of parliament. Instead, the task for NICE is as a 'threshold-searcher' – to seek to identify an optimal threshold incremental cost-effectiveness ratio, at the ruling rate of expenditure, that is consistent with the aim of the health service to maximize population health. This will involve the identification of technologies currently made available by the National Health Service that have incremental cost-effectiveness ratios above the threshold, and alternative uses for those resources in the shape of technologies not currently provided that fall below the threshold. [ABSTRACT FROM AUTHOR]

This study aimed to assess whether recently proposed alternatives to the quality-adjusted life-year (QALY), intended to address concerns about discrimination, are suitable for informing resource allocation decisions. We consider 2 alternatives to the QALY: the health years in total (HYT), recently proposed by Basu et al, and the equal value of life-years gained (evLYG), currently used by the Institute for Clinical and Economic Review. For completeness we also consider unweighted life-years (LYs). Using a hypothetical example comparing 3 mutually exclusive treatment options, we consider how calculations are performed under each approach and whether the resulting rankings are logically consistent. We also explore some further challenges that arise from the unique properties of the HYT approach. The HYT and evLYG approaches can result in logical inconsistencies that do not arise under the QALY or LY approaches. HYT can violate the independence of irrelevant alternatives axiom, whereas the evLYG can produce an unstable ranking of treatment options. HYT have additional issues, including an implausible assumption that the utilities associated with health-related quality of life and LYs are "separable," and a consideration of "counterfactual" health-related quality of life for patients who are dead. The HYT and evLYG approaches can result in logically inconsistent decisions. We recommend that decision makers avoid these approaches and that the logical consistency of any approaches proposed in future be thoroughly explored before considering their use in practice. • A common criticism of the quality-adjusted life-year (QALY) is that life extensions generate fewer QALYs for those with poorer health-related quality of life. The equal value of life-years gained (evLYG) approach addresses this by assigning equal value to life extensions of similar length; however, this does not incentivize development of technologies that also improve health-related quality of life during life extension. The recently proposed health years in total (HYT) approach attempts to overcome both these issues. • We assess whether these recently proposed alternatives to the QALY are suitable for informing healthcare resource allocation decisions. Using a hypothetical example comparing 3 mutually exclusive treatment options, we consider how calculations are performed under each approach and whether the resulting rankings satisfy some basic tenets of rational choice theory. We also explore some further challenges that arise from the unique properties of the HYT approach. • We find that the HYT and evLYG approaches can result in logical inconsistencies that do not arise when using QALYs. HYT can violate the "independence" axiom, whereas the evLYG can produce an unstable ranking of treatment options. We recommend that policy makers exercise caution and avoid adopting any approaches that violate fundamental principles of rational decision making or that rely upon assumptions that lack credibility. [ABSTRACT FROM AUTHOR]

Background: Health care system decision makers face challenges in allocating resources for screening, diagnosis and treatment of hepatitis C. Approximately 240,000 individuals are infected with the hepatitis C virus (HCV) in Canada. Populations most affected by HCV include Indigenous people, people who inject drugs, immigrants and homeless or incarcerated populations as well as those born between 1946 and 1965. Curative but expensive drug regimens of novel direct acting antivirals (DAAs) are available. We aim to identify social values from academic literature for inclusion in health technology assessments.Methods: We conducted a scoping review of academic literature to identify and analyze the social values and evidence-based recommendations for screening, diagnosis and treatment of HCV in Canada. After applying inclusion/exclusion criteria, we abstracted: type of intervention(s), population(s) affected, study location, screening methods, diagnostics and treatments. We then abstracted and applied qualitative codes for social values. We extracted social value statements and clustered them into one of 4 categories: (1) equity and justice, (2) duty to provide care, (3) maximization of population benefit, and (4) individual versus community interests.Results: One hundred and eighteen articles met our inclusion criteria on screening, diagnosis and treatment of HCV in Canada. Of these, 54 (45.8%) discussed screening, 4 (3.4%) discussed diagnosis and 60 (50.8%) discussed treatment options. Most articles discussed the general population and other non-vulnerable populations. Articles that discussed vulnerable populations focused on people who inject drugs. We coded 1243 statements, most of which fell into the social value categories of equity and justice, duty to provide care and maximization of population benefit.Conclusion: The academic literature identified an expanded set of social values to be taken into account by resource allocation decision makers in financially constrained environments. In the context of hepatitis C, authors called for greater consideration of equity and justice and the duty to provide care in making evidence-based recommendations for screening, diagnosis and treatment for different populations and in different settings that also account for individual and community interests. [ABSTRACT FROM AUTHOR]

The authors comment on a study which explored the use of protein markers galectin-3 and monoclonal antibody HBME-1 in detecting thyroid nodules malignancy. Information on guidelines for the clinical management of these nodules is provided. According to the authors, risk stratification would benefit patients with indeterminate lesions. They cite molecular testing for common somatic mutations in some oncogenes as an alternative to immunohistochemical marker expression.

The authors discuss a survey among the general Norwegian population on whether society should pay more to treat rare diseases, by A. S. Desser and colleagues, published within the issue. The survey found that people support equal access to health care but oppose providing care for people with rare diseases if such care could negatively affect care for people with common diseases. The authors argue that, based on the survey results, decision makers should ensure that the benefits offered to people with rare diseases will not harm the general population.

The author advocates the use of targeted therapies in thyroid cancer. He notes that differentiated thyroid cancer has simple treatment options and expresses a sodium-iodide symporter that can be used for targeted treatment and ablation. He adds that formation of papillary thyroid carcinoma has been mapped to mitogen-activated protein kinase (MAPK) signal transduction pathway making tumors readily identified and targeted. He calls for the development of more reliable markers of individual tumor because of the variety of the disease.