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Parametric models are routinely used to estimate the benefit of cancer drugs beyond trial follow-up. The advent of immune checkpoint inhibitors has challenged this paradigm, and emerging evidence suggests that more flexible survival models, which can better capture the shapes of complex hazard functions, might be needed for these interventions. Nevertheless, there is a need for an algorithm to help analysts decide whether flexible models are required and, if so, which should be chosen for testing. This position article has been produced to bridge this gap. A virtual advisory board comprising 7 international experts with in-depth knowledge of survival analysis and health technology assessment was held in summer 2021. The experts discussed 24 questions across 6 topics: the current survival model selection procedure, data maturity, heterogeneity of treatment effect, cure and mortality, external evidence, and additions to existing guidelines. Their responses culminated in an algorithm to inform selection of flexible survival models. The algorithm consists of 8 steps and 4 questions. Key elements include the systematic identification of relevant external data, using clinical expert input at multiple points in the selection process, considering the future and the observed hazard functions, assessing the potential for long-term survivorship, and presenting results from all plausible models. This algorithm provides a systematic, evidence-based approach to justify the selection of survival extrapolation models for cancer immunotherapies. If followed, it should reduce the risk of selecting inappropriate models, partially addressing a key area of uncertainty in the economic evaluation of these agents. • Standard parametric survival models can lack the flexibility to capture the shape of the underlying hazard functions of patients treated with cancer immunotherapies. This can lead to inaccurate long-term survival projections and biased cost-effectiveness estimates. More flexible extrapolation models are being adopted, but their acceptability for healthcare decision making can be an area of contention. Guidance is limited on when flexible models should be used and which, of the many available, should be considered. • An algorithm was developed to supplement existing guidance on extrapolation model selection for economic evaluation. The algorithm recommends an initial review of relevant external evidence identified in a systematic, reproducible way; highlights the need to engage with clinical experts and consider the observed hazard function and how it might change in the future; cautions against overinterpreting observed survival, particularly when data are immature; and recommends that the results of all plausible models are presented. • If followed, this algorithm will provide a systematic and evidence-based approach for flexible survival model selection. This will improve transparency and consistency, reduce the risk of inappropriate model selection, and increase confidence in the results of the cost-effectiveness analysis of cancer immunotherapies. It may also prove useful for other treatments and diseases where more flexible extrapolation models may be warranted. [ABSTRACT FROM AUTHOR]

Regulation of slow fiber-specific genes by muscle TF II-In like repeat domain 1?1 gene, using transgenic mice studies, is presented.

Globally, large carnivores have been heavily affected by habitat loss, fragmentation and persecution, sometimes resulting in local extinctions. With increasing recognition of top-down trophic cascades and complex predator-prey dynamics, reintroductions are of growing interest for restoration of ecosystem functioning. Many reintroductions have however failed, in part due to poor planning and inability to model complex eco-evolutionary processes to give reliable predictions. Using the case study of Eurasian lynx (Lynx lynx), a large predator being considered for reintroduction to Scotland, we demonstrate how an individual-based model that integrates demography with three distinct phases of dispersal (emigration, transfer and settlement) can be used to explore the relative suitability of three geographically-distant potential reintroduction sites, multi-site reintroductions and two founding population sizes. For a single-site reintroduction of 10 lynx, our simulation results show a clear hierarchy of suitability across all metrics. Reintroduction in the Kintyre Peninsula (west coast) consistently performed best, with a probability of population persistence at year 100 of 83%, and the Scottish component of Kielder Forest (southern Scotland) worst, with only a 21% chance of population persistence to year 100. Simultaneous two-site reintroduction in the Kintyre Peninsula and in Aberdeenshire (near the east coast) of 32 lynx gave a 96% persistence at 100 years. Our model was highly sensitive to survival, particularly of adults, highlighting this parameter's importance for reintroduction success. The results strongly indicate the potential viability of Eurasian lynx reintroduction to Scotland given the current cover of suitable woodland habitat. More generally, our work demonstrates how emerging modelling approaches incorporating increased realism in representing species' demography, ecology and dispersal can have high value for quick, inexpensive assessment of likely reintroduction success and for selection between alternative strategies. • IBM's integrating stochastic movement and population dynamics provide greater realism in reintroduction modelling. • This modelling approach enables quick, effective assessments of reintroduction proposals and management scenarios. • Models of this nature could significantly improve the probability of reintroduction successes in large carnivores. • Scotland's existing habitat is suitable for Eurasian lynx reintroduction, but appropriate site selection is key to success. [ABSTRACT FROM AUTHOR]

There are well-known and extensive differences in color preferences between individuals, but there are also within-individual differences from one time to another. Despite the seeming independence between these individual and temporal effects, we propose that they have the same underlying cause: people's ecological experiences with color-associated objects and events. Our approach is motivated by the Ecological Valence Theory (EVT; Palmer & Schloss, 2010) which states that preference for a given color is determined by the combined valence (liking/disliking) of all objects and events associated with that color. We define three ecologically-based hypotheses for explaining temporal and individual differences in color preferences concerning: (1) differences in object valences, (2) differences in color-object associations, and (3) differences in object activations in the mind when preferences are measured. We review prior studies that support these hypotheses and raise open research questions about untested predictions. We also extend the computational framework of the EVT by defining a single weighted average equation that captures both individual and temporal differences in color preferences. Finally, we consider other factors that potentially contribute to color preferences, including abstract symbolic associations, color in design, and psychophysical and/or physiological factors. [ABSTRACT FROM AUTHOR]

The urban environment has become the main place that people live and work. As a result it can have profound impacts on our health. While much of the literature has focused on physical health, less attention has been paid to the possible psychological impacts of the urban environment. In order to understand the potential relevance and importance of the urban environment to population mental health, we carried out a systematic review to examine the associations between objective measurements of the urban environment and psychological distress, independently of the individual's subjective perceptions of the urban environment. 11 peer-reviewed papers published in English between January 2000 and February 2012 were identified. All studies were cross-sectional. Despite heterogeneity in study design, the overall findings suggested that the urban environment has measurable associations with psychological distress, including housing with deck access, neighbourhood quality, the amount of green space, land-use mix, industry activity and traffic volume. The evidence supports the need for development of interventions to improve mental health through changing the urban environment. We also conclude that new methods for measuring the urban environment objectively are needed which are meaningful to planners. In particular, future work should look at the spatial-temporal dynamic of the urban environment measured in Geographical Information System (GIS) in relation to psychological distress. [ABSTRACT FROM AUTHOR]

Background: The value of evidence about the performance of a technology and the value of access to a technology are central to policy decisions regarding coverage with, without, or only in research and managed entry (or risk-sharing) agreements.Objectives: We aim to outline the key principles of what assessments are needed to inform "only in research" (OIR) or "approval with research" (AWR) recommendations, in addition to approval or rejection.Methods: We developed a comprehensive algorithm to inform the sequence of assessments and judgments that lead to different types of guidance: OIR, AWR, Approve, or Reject. This algorithm identifies the order in which assessments might be made, how similar guidance might be arrived at through different combinations of considerations, and when guidance might change.Results: The key principles are whether the technology is expected to be cost-effective; whether the technology has significant irrecoverable costs; whether additional research is needed; whether research is possible with approval and whether there are opportunity costs that once committed by approval cannot be recovered; and whether there are effective price reductions. Determining expected cost-effectiveness is only a first step. In addition to AWR for technologies expected to be cost-effective and OIR for those not expected to be cost-effective, there are other important circumstances when OIR should be considered.Conclusions: These principles demonstrate that cost-effectiveness is a necessary but not sufficient condition for approval. Even when research is possible with approval, OIR may be appropriate when a technology is expected to be cost-effective due to significant irrecoverable costs. [ABSTRACT FROM AUTHOR]

Semi-natural agricultural habitats have declined in northern Europe since the 1950s, to the detriment of habitat connectivity and biodiversity. European agri-environmental schemes to restore them should target the habitats most likely to remedy these impacts. We employed a stochastic individual-based simulation model to predict movements of a model species, the European hedgehog (Erinaceus europaeus), across a series of virtual landscapes - digitised from a typical UK lowland agricultural area - in which the abundance of hedgerow, pasture fields and field margin had been manipulated according to a factorial design. The primary landscape determinant of distances that model hedgehogs travelled was the percentage of field boundaries that were hedgerow: doubling this from the status quo resulted in an additional 13% of individuals moving 500 m, 25% 1000 m, 35% 1500 m and 51% 2000 m. Trebling the percentage of hedge yielded no additional benefit over doubling it (mean additional percentage 0.6%). Doubling the landscape percentage of pastures resulted in a 1% increase in model individuals moving 500 m and 1000 m, but decreases for 1500 m and 2000 m (-2% and -4%, respectively). Increasing the percentage of hedged fields that also had field margins led to decreases of -1% to -8% in individuals moving any distance. Agri-environmental scheme options to reinstate or repair hedges that double their percentage in lowland farmland would enhance population connectivity for European hedgehogs. Further work should extend these individual-based models to representative sets of species to explore the extent to which management for one species may benefit others. [ABSTRACT FROM AUTHOR]

A biomarker can be used for early diagnosis of a disease, identification of individuals for disease prevention, as a potential drug target, or as a potential marker for a drug response. A biomarker may also limit the use of drug (and therefore costs) to the population of patients for which the drug will be safe and efficacious. A biomarker in reproduction could be used to improve assessment of exposure, identify subgroups susceptible to treatment, predict outcome, and/or differentiate subgroups with potentially different etiologies of disease. Despite many potential uses there is low participation in reproductive biology to develop molecular biomarkers, which may be directly related to the low number of new molecular entities entering clinical trials. As the number of candidate markers in reproductive medicine is increasing, it is important to understand the pathway of development from discovery to clinical utility and recognize that the vast majority of potential markers will not be clinically useful, owing to a variety of pitfalls. Extensive testing, validation, and modification needs to be performed before a biomarker is demonstrated to have clinical utility. New opportunities and partnerships exist and should hasten the development of biomarkers in reproduction. As more biomarkers are moved into practice, a better-educated biomarker consumer will enhance the possibility that biomarker(s) will realize their great potential. [ABSTRACT FROM AUTHOR]

Background: The study aimed to compare the short-term costs and long-term cost-effectiveness of 2 antithrombotics, fondaparinux and enoxaparin, for non–ST-elevation acute coronary syndrome in the United States. Methods: It was based on a large randomized trial of 20,078 patients Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators [OASIS-5] comparing the therapies in these patients. In OASIS-5, fondaparinux patients had about half the rate of major bleeding 9 days after randomization and at least as good clinical outcomes (death, myocardial infarction, major bleeding and stroke) after 6 months of follow-up. Health care resource use and clinical efficacy data from the trial were incorporated into a cost-effectiveness model as applied to a general US health care system both for the time horizon of the study (6 months) and over the longer term. Results: The 180-day cost analysis indicates that fondaparinux would generate a cost saving of $547 per patient (95% CI $207-$924). Sensitivity analysis suggested that savings could vary between $494 and $733. When 180-day cost and clinical results were extrapolated to long-term cost-effectiveness, fondaparinux was dominant (less costly and more effective in terms of quality-adjusted life-years) under most scenarios. Conclusions: Fondaparinux is a more cost-effective antithrombotic agent than enoxaparin in non–ST-elevation acute coronary syndrome. This is true across the range of event risks seen in OASIS-5. [Copyright &y& Elsevier]

Catering businesses continue to be the most common setting for foodborne disease outbreaks. In a study of catering businesses in England and Wales, operational practices relating to the supply, preparation, and service of food in 88 businesses associated with outbreaks were compared with those practices at 88 control businesses. Operational practices did not differ significantly between case and control businesses but larger small medium-size enterprise (SME) businesses were more likely to be associated with foodborne disease outbreaks than were micro-SME businesses. Businesses associated with outbreaks of Salmonella infection were less likely to use local or national suppliers but instead used regional suppliers, especially for eggs. This practice was the only significantly independent operational practice associated with outbreaks of Salmonella infection. Regional egg suppliers also were more likely to be used by businesses associated with outbreaks attributed to food vehicles containing eggs. Businesses associated with egg-associated outbreaks were less likely to use eggs produced under an approved quality assurance scheme, suggesting that the underlying risk associated with using regional suppliers may relate to the use of contaminated eggs. [ABSTRACT FROM AUTHOR]

Despite structured enforcement of food hygiene requirements known to prevent foodbome disease outbreaks, catering businesses continue to be the most common setting for outbreaks in the United Kingdom. In a matched case control study of catering businesses, 148 businesses associated with outbreaks were compared with 148 control businesses. Hazard analysis critical control point systems and/or formal food hygiene training qualifications were not protective. Food hygiene inspection scores were not useful in predicting which catering businesses were associated with outbreaks. Businesses associated with outbreaks were more likely to be larger small and medium-sized enterprises (SMEs) or to serve Chinese cuisine and less likely to have the owner or manager working in the kitchen, but when size of the SME was taken into account these two differences were no longer significant. In larger businesses, case businesses were more likely to be hotels and were more commonly associated with viral foodbome outbreaks, but there was no explanation within the data for this association. [ABSTRACT FROM AUTHOR]

Background: Background: The glycoprotein IIb/IIIa antagonists (GPAs) represent a new class of drugs to prevent platelet aggregation in the acute treatment of non-ST-elevation acute coronary syndromes (NSTE-ACS). Systematic reviews have identified serious limitations in published cost-effectiveness analyses, including a lack of UK-specific studies and an absence of studies comparing different protocols for the use of GPAs. Methods: A model was developed to assess the cost effectiveness of a variety of protocols employing GPAs for patients presenting with NSTE-ACS in the UK. The perspective of the UK National Health Service was adopted, with outcomes in terms of quality-adjusted life-years (QALYs). Four treatment strategies were evaluated: GPAs as part of initial medical management (Strategy 1); GPAs in patients with planned percutaneous coronary interventions (PCIs; Strategy 2); GPAs as an adjunct to the PCI procedure (Strategy 3); and no GPAs (Strategy 4). Baseline event rates and costs were taken from a UK observational study of ACS patients and relative risk reductions from GPAs were taken from a meta analysis of trials. Long-term costs and QALYs were estimated using data from a UK longitudinal study. Results: The most cost-effective use of GPAs is likely to be Strategy 1, with an incremental cost per QALY gained of between £4605 to £10,343. Focusing this use of GPAs only on the subgroup of patients at high risk appears to represent the most cost-effective use of NHS resources. Conclusions: Medical management of patients with NSTE-ACS using GPAs is the most cost-effective use of resources, particularly if targeted to higher risk subgroups. [Copyright &y& Elsevier]

Objectives: Partitioned survival models (PSMs) are routinely used to inform reimbursement decisions for oncology drugs. We discuss the appropriateness of PSMs compared to the most common alternative, state transition models (STMs).Methods: In 2017, we published a National Institute for Health and Care Excellence (NICE) Technical Support Document (TSD 19) describing and critically reviewing PSMs. This article summarizes findings from TSD 19, reviews new evidence comparing PSMs and STMs, and reviews recent NICE appraisals to understand current practice.Results: PSMs evaluate state membership differently from STMs and do not include a structural link between intermediate clinical endpoints (eg, disease progression) and survival. PSMs directly consider clinical trial endpoints and can be developed without access to individual patient data, but limit the scope for sensitivity analyses to explore clinical uncertainties in the extrapolation period. STMs facilitate these sensitivity analyses but require development of robust survival models for individual health-state transitions. Recent work has shown PSMs and STMs can produce substantively different survival extrapolations and that extrapolations from STMs are heavily influenced by specification of the underlying survival models. Recent NICE appraisals have not generally included both model types, reviewed individual clinical event data, or scrutinized life-years accrued in individual health states.Conclusions: The credibility of survival predictions from PSMs and STMs, including life-years accrued in individual health states, should be assessed using trial data on individual clinical events, external data, and expert opinion. STMs should be used alongside PSMs to support assessment of clinical uncertainties in the extrapolation period, such as uncertainty in post-progression survival. [ABSTRACT FROM AUTHOR]

To determine whether TOP5300, a novel oral follicle-stimulating hormone (FSH) receptor (FSHR) allosteric agonist, elicits a different cellular response than recombinant human FSH (rh-FSH) in human granulosa cells from patients undergoing in vitro fertilization. Basic science research with a preclinical allosteric FSHR agonist. University hospital. Patients with infertility at a single academic fertility clinic were recruited under an Institutional Review Board-approved protocol. Primary granulosa cell cultures were established for 41 patients, of whom 8 had normal ovarian reserve (NOR), 17 were of advanced reproductive age (ARA), 12 had a diagnosis of polycystic ovary syndrome (PCOS), and 4 had a combination of diagnoses, such as ARA and PCOS. Primary granulosa-lutein (GL) cell cultures were treated with rh-FSH, TOP5300, or vehicle. Estradiol (E 2) production using enzyme-linked immunosorbent assay, steroid pathway gene expression of StAR and aromatase using quantitative polymerase chain reaction, and FSHR membrane localization using immunofluorescence were measured in human GL cells. TOP5300 consistently stimulated E 2 production among patients with NOR, ARA, and PCOS. Recombinant FSH was the more potent ligand in GL cells from patients with NOR but was ineffective in cells from patients with ARA or PCOS. The lowest level of FSHR plasma membrane localization was seen in patients with ARA, although FSHR localization was more abundant in cells from patients with PCOS; the highest levels were present in cells from patients with NOR. The localization of FSHR was not affected by TOP5300 relative to rh-FSH in any patient group. TOP5300 stimulated greater expression of StAR and CYP19A1 across cells from all patients with NOR, ARA, and PCOS combined, although rh-FSH was unable to stimulate StAR and aromatase (CYP19A1) expression in cells from patients with PCOS. TOP5300-induced expression of StAR and CYP19A1 mRNA among patients with ARA and NOR was consistently lower than that observed in cells from patients with PCOS. TOP5300 appears to stimulate E 2 production and steroidogenic gene expression from GL cells more than rh-FSH in PCOS, relative to patients with ARA and NOR. It does not appear that localization of FSHR at cell membranes is a limiting step for TOP5300 or rh-FSH stimulation of steroidogenic gene expression and E 2 production. [ABSTRACT FROM AUTHOR]

Background There has been some controversy on whether the costs of omalizumab outweigh its benefits for severe persistent allergic asthma. Objectives This study aimed to resolve the uncertainties and limitations of previous analyses and establish the cost-effectiveness of omalizumab under the list price and Patient Access Scheme (PAS) discounted price for the UK National Health Service. Methods A decision-analytic model was developed to evaluate the long-term cost-effectiveness of omalizumab under the perspective of the National Health Service. Outcomes were expressed as quality-adjusted life-years (QALYs). Patient subgroups were defined post hoc on the basis of data collected in clinical trials: previous hospitalization, on maintenance oral corticosteroids, and three or more previous exacerbations. Results The incremental cost-effectiveness ratio varied from £30,109 to £57,557 per QALY gained depending on the population considered using the PAS price; incremental cost-effectiveness ratios were over a third higher using the list price. Omalizumab is likely to be cost-effective at the threshold of £30,000 per QALY gained in the severe subgroups if the improvement in health-related quality of life from omalizumab is mapped from an asthma-specific measure to the EuroQol five-dimensional questionnaire (vs. the EuroQol five-dimensional questionnaire directly collected from patients) or asthma mortality refers to death after hospitalization from asthma (vs. asthma-mortality risk in the community). Conclusions Although the cost-effectiveness of omalizumab is more favorable under the PAS price, it represents good value for money only in severe subgroups and under optimistic assumptions regarding asthma mortality and improvement in health-related quality of life. For these reasons, omalizumab should be carefully targeted to ensure value for money. [ABSTRACT FROM AUTHOR]

MAGNITUDE (NCT03748641) demonstrated favourable outcomes with niraparib plus abiraterone acetate plus prednisone (+AAP) versus placebo+AAP in patients with BRCA1/2 -altered metastatic castration-resistant prostate cancer (mCRPC). Imbalances in prognostic variables were reported between arms, which impacts estimation of both the clinical benefit and cost‑effectiveness of niraparib+AAP for healthcare systems. A pre-specified multivariable analysis (MVA) demonstrated improved overall survival (OS) with niraparib+AAP. Here, we used an inverse probability of treatment weighting (IPTW) model to adjust for covariate imbalances and assess time-to-event outcomes. IPTW analysis of time-to-event outcomes was conducted using data from patients with BRCA1/2 -altered mCRPC (N = 225) in MAGNITUDE. Patients received niraparib+AAP or placebo+AAP. OS, radiographic progression-free survival, time to symptomatic progression, time to initiation of cytotoxic chemotherapy and time to prostate-specific antigen progression were assessed. Weighted Kaplan-Meier curves were generated for each endpoint, and adjusted hazard ratios (HR) were obtained from a weighted Cox model. Improvements in survival outcomes were estimated for niraparib+AAP versus placebo+AAP: unadjusted median OS was 30.4 months versus 28.6 months, respectively (HR: 0.79; 95 % confidence interval [CI]: 0.55, 1.12; p = 0.183). Following IPTW, median OS increased to 34.1 months with niraparib+AAP versus a decrease to 27.4 with placebo (HR: 0.65; 95 % CI: 0.46, 0.93; p = 0.017). Similar improvements were observed for other time-to-event endpoints. IPTW adjustment provided a more precise estimate of the clinical benefit of niraparib+AAP versus placebo+AAP in patients with BRCA1/2 -altered mCRPC. Results were consistent with the pre-specified MVA, and further demonstrated the value of adjusting for baseline imbalances, particularly in smaller studies. NCT03748641 (MAGNITUDE) • Baseline characteristic imbalances can cause reduced estimated treatment efficacy. • Robustness can be shown using multiple adjustment methods for baseline imbalances. • We used novel IPTW to assess time-to-event outcomes in the phase 3 MAGNITUDE trial. • Outcomes were consistent with the pre-specified MVA, with additional value shown. • This confirmed the clinical benefit of niraparib+AAP in BRCA1/2 -altered mCRPC. [ABSTRACT FROM AUTHOR]

Abstract: Seasonal variation in temperature is known to drive annual patterns of tick activity and can influence the dynamics of tick-borne diseases. An age-structured model of the dynamics of Ixodes ricinus populations was developed to explore how changes in average temperature and different levels of temperature variability affect seasonal patterns of tick activity and the transmission of tick-borne diseases. The model produced seasonal patterns of tick emergence that are consistent with those observed throughout Great Britain. Varying average temperature across a continuous spectrum produced a systematic pattern in the times of peak emergence of questing ticks which depends on cumulative temperature over the year. Examination of the effects of between-year stochastic temperature variation on this pattern indicated that peak emergence times are more strongly affected by temperature stochasticity at certain levels of average temperature. Finally the model was extended to give a simple representation of the dynamics of a tick-borne disease. A threshold level of annual cumulative temperature was identified at which disease persistence is sensitive to stochastic temperature variation. In conclusion, the effect of changing patterns of temperature variation on the dynamics of I. ricinus ticks and the diseases they transmit may depend on the cumulative temperature over the year and will therefore vary across different locations. The results also indicate that diapause mechanisms have an important influence on seasonal patterns of tick activity and require further study. [Copyright &y& Elsevier]

Calluna vulgaris-dominated heaths and moorlands are habitats of international conservation importance. Degradation has occurred throughout their range with Calluna typically being replaced by grass species. The cessation of grazing is often impractical and rarely results in the recovery of Calluna abundance when it is initially present at low cover. Thus the development of restoration methods is required; these should be practical at a large-scale, in remote areas and create suitable conditions for Calluna germination and establishment, whilst still allowing grazing to occur. A replicated field experiment was established on Nardus stricta and Molinia caerulea-dominated moorlands to test the efficacy of different grazing regimes and intervention techniques aimed at establishing Calluna. Disturbance (rotavation and trampling by animals) to create bare ground increased Calluna establishment. On the Nardus site, Calluna establishment was equally successful on rotavated and trampled plots, but rotavation was more successful on the Molinia site. Seeding with Calluna increased Calluna establishment irrespective of whether a seed-bank was present. At the Nardus site, 0.5cow/ha for two months in summer led to Calluna establishment and growth similar to that of ungrazed plots and was more successful than a mixed grazing regime (1ewe/ha plus 0.5cow/ha for 2 months) or a sheep only regime (1.5ewes/ha). The creation of small patches of bare ground, seed addition and low intensity grazing enabled the rapid establishment of Calluna on grass-dominated moorlands; such techniques may also be applicable in other habitats where restoration requires the addition of a single/few species and minimal intervention. [Copyright &y& Elsevier]

Summary: Nine databases were searched for studies reporting a range of measures on the effectiveness of screening for oral cancer and precancer in primary care. Of 1114 papers generated in a search of nine databases, full texts of 90 were scrutinised by two reviewers to ensure that they were concerned with oral cancer/precancer, reported an oral cancer screening programme/exercise and included at least one effectiveness outcome. Criteria for considering studies for the review covered types of studies, participants, interventions and outcome measures. The latter included measures of both end point and interim outcome and also process. Of 90 full text articles screened, examiners agreed on the inclusion of 28 (initial agreement—kappa=0.60). The remaining 62 were excluded and the reasons recorded. The studies included showed substantial heterogeneity regarding objectives and study design, location and setting, numbers and characteristics of participants, screening personnel, methods of recruitment and types of data collected. Only one study, from the Indian sub-continent, reported a randomised controlled trial: interim results showed 14.9% of intervention subjects died after 3 years compared with 56.3% of non-intervention controls. The review overall produced no evidence in favour of or against the potential benefits associated with an oral cancer screening programme. It was concluded that there are insufficient available data to make an unequivocal determination as to the effectiveness of oral cancer screening programmes at the present time. However, a recent further report on the Indian study published after completion of the review, provides some evidence that screening for oral cancer may be effective, at least in developing countries with a high incidence of the disease. [Copyright &y& Elsevier]

Objectives: State-transition models (STMs) applied in oncology have given limited considerations to modeling postprogression survival data. This study presents an application of an STM focusing on methods to evaluate the postprogression transition and its impact on survival predictions.Methods: Data from the lenalidomide plus dexamethasone arm of the ASPIRE trial was used to estimate transition rates for an STM. The model accounted for the competing risk between the progression and preprogression death events and included an explicit structural link between the time to progression and subsequent death. The modeled transition rates were used to simulate individual disease trajectories in a discrete event simulation framework, based on which progression-free survival and overall survival over a 30-year time horizon were estimated. Survival predictions were compared with the observed trial data, matched external data, and estimates obtained from a more conventional partitioned survival analysis approach.Results: The rates of progression and preprogression death were modeled using piecewise exponential functions. The rate of postprogression mortality was modeled using an exponential function accounting for the nonlinear effect of the time to progression. The STM provided survival estimates that closely fitted the trial data and gave more plausible long-term survival predictions than the best-fitting Weibull model applied in a partitioned survival analysis.Conclusions: The fit of the STM suggested that the modeled transition rates accurately captured the underlying disease process over the modeled time horizon. The considerations of this study may apply to other settings and facilitate a wider use of STMs in oncology. [ABSTRACT FROM AUTHOR]

Nine databases were searched for studies on test performance in screening for oral cancer and precancer in primary care. Of 481 papers, full texts of 47 were scrutinised by two reviewers. Only prospective investigations of population screening involving examination of the oral mucosa, with gold standard verification (examination by an expert of subjects screened positive and at least a proportion of negatives), were selected. Seven papers describing eight studies were finally included (κ=0.83). The weighted pooled value of sensitivity, from random effects meta-analysis, was 0.848 (95% CI 0.730, 0.919). The corresponding value for specificity was 0.965 (95% CI 0.930, 0.982). Main sources of clinical heterogeneity occurred between large house-to-house case finding programmes from SE Asia, utilising primary health workers, and smaller studies from England and Japan. Meta-analysis regression showed no difference (P=0.99) in the generally high level of discriminatory ability of the test between these two groups. [Copyright &y& Elsevier]

The interacting impacts of habitat fragmentation and climate change present a substantial threat for biodiversity, constituting a 'deadly anthropogenic cocktail'. A range of conservation actions has been proposed to allow biodiversity to respond to those environmental changes. However, determining the relative effectiveness of these actions has been hampered by incomplete evidence. Empirical studies have provided important insights to inform conservation, but the challenge of considering multiple actions at large spatial and temporal scales is considerable. We adopt an individual-based modelling approach to qualitatively assess the effectiveness of alternative conservation actions in facilitating range expansion and patch occupancy for eight virtual species. We test actions to: (i) improve the quality of existing habitat patches, (ii) increase the permeability of the surrounding matrix, (iii) restore degraded habitat, (iv) create new habitat patches to form stepping-stones or (v) create new habitat to enlarge existing habitat patches. These actions are systematically applied to six real landscapes of the UK, which differ in their degree of habitat fragmentation and availability. Creating new habitat close to existing patches typically provides the strongest benefits for both range expansion and patch occupancy across species and landscapes. However, some landscapes may be so degraded that even under unrealistically high levels of management action, species' performances cannot be rescued. We identify that it is possible to develop a triage of conservation actions at the landscape, species and investment level, thereby providing timely evidence to inform action on the ground to lessen the hangover from the deadly anthropogenic cocktail. • Conservation actions allow biodiversity to respond to climate change or habitat fragmentation. • Their actual effectiveness is hardly measurable in the field. • Individuals-based models incorporating demography and dispersal help develop a triage of conservation actions. [ABSTRACT FROM AUTHOR]

Background: Timely implementation of recommended interventions can provide health benefits to patients and cost savings to the health service provider. Effective approaches to increase the implementation of guidance are needed. Since investment in activities that improve implementation competes for funding against other health generating interventions, it should be assessed in term of its costs and benefits.Objective: In 2010, the National Institute for Health and Care Excellence released a clinical guideline recommending natriuretic peptide (NP) testing in patients with suspected heart failure. However, its implementation in practice was variable across the National Health Service in England. This study demonstrates the use of multi-period analysis together with diffusion curves to estimate the value of investing in implementation activities to increase uptake of NP testing.Methods: Diffusion curves were estimated based on historic data to produce predictions of future utilization. The value of an implementation activity (given its expected costs and effectiveness) was estimated. Both a static population and a multi-period analysis were undertaken.Results: The value of implementation interventions encouraging the utilization of NP testing is shown to decrease over time as natural diffusion occurs. Sensitivity analyses indicated that the value of the implementation activity depends on its efficacy and on the population size.Conclusions: Value of implementation can help inform policy decisions of how to invest in implementation activities even in situations in which data are sparse. Multi-period analysis is essential to accurately quantify the time profile of the value of implementation given the natural diffusion of the intervention and the incidence of the disease. [ABSTRACT FROM AUTHOR]

Background: The key principles regarding what assessments lead to different types of guidance about the use of health technologies (Only in Research, Approval with Research, Approve, or Reject) provide an explicit and transparent framework for technology appraisal.Objective: We aim to demonstrate how these principles and assessments can be applied in practice through the use of a seven-point checklist of assessment.Methods: The value of access to a technology and the value of additional evidence are explored through the application of the checklist to the case studies of enhanced external counterpulsation for chronic stable angina and clopidogrel for the management of patients with non-ST-segment elevation acute coronary syndromes.Results: The case studies demonstrate the importance of considering 1) the expected cost-effectiveness and population net health effects; 2) the need for evidence and whether the type of research required can be conducted once a technology is approved for widespread use; 3) whether there are sources of uncertainty that cannot be resolved by research but only over time; and 4) whether there are significant (opportunity) costs that once committed by approval cannot be recovered.Conclusions: The checklist demonstrates that cost-effectiveness is a necessary but not sufficient condition for approval. Only in Research may be appropriate when a technology is expected to be cost-effective due to significant irrecoverable costs. It is only approval that can be ruled out if a technology is not expected to be cost-effective. Lack of cost-effectiveness is not a necessary or sufficient condition for rejection. [ABSTRACT FROM AUTHOR]

Abstract: FSH signalling through its cognate receptor is critical for follicular development and ovulation. An earlier study had documented thiazolidinone derivatives to activate FSH receptor expressed in CHO cells and rat granulosa cells; however development of this compound for clinical use was halted for unobvious reasons. The objective of the current study is to extend the previous investigations in detail on the ability of thiazolidinone derivative (henceforth referred to as Compound 5) to activate FSH signalling and learn the barriers that preclude development of this derivative for clinical purposes. Our results demonstrate that the Compound 5 in a dose-dependent manner stimulated cAMP production, activated AKT and ERK signalling pathways and induced estradiol production in cultured rat granulosa cells. Compound 5 also caused dose-dependent increase in estradiol production from human granulosa cells. In increasingly more complex in vitro systems, Compound 5 was able to induce the expansion of mouse cumulus-oocyte-complex and support in vitro development of mouse preantral follicle to preovulatory stage and release of oocyte from the follicle. In vivo, the compound stimulated preovulatory follicular development and ovulation in immature rats. Pharmacokinetic and safety investigations reveal poor oral availability and genotoxcity. Together, our results document Compound 5 to act as a FSHR allosteric modulator but have poor pharmacological properties for development of an oral FSH receptor modulator. [Copyright &y& Elsevier]

Abstract: Follicle-stimulating hormone (FSH), acting on its receptor (FSHR), plays a pivotal role in the stimulation of follicular development and maturation. Multiple injections of protein formulations are used during clinical protocols for ovulation induction and for in vitro fertilization that are followed by a selection of assisted reproductive technologies. In order to increase patient convenience and compliance several research groups have searched for orally bioavailable FSH mimetics for innovative fertility medicines. We report here the discovery of a series of substituted benzamides as positive allosteric modulators (PAM) targeting FSHR. Optimization of this series has led to enhanced activity in primary rat granulosa cells, as well as remarkable selectivity against the closely related luteinizing hormone receptor (LHR) and thyroid stimulating hormone receptor (TSHR). Two modulators, 9j and 9k, showed promising in vitro and pharmacokinetic profiles. [Copyright &y& Elsevier]

Abstract: Objective: To assess the cost-effectiveness of eplerenone versus spironolactone as an adjunctive therapy to standard care in patients with heart failure (HF) following a myocardial infarction (post-MI) from the perspective of the National Health Service in the United Kingdom. Methods: A systematic review was conducted, and a Bayesian meta-regression approach was used to establish the relative effectiveness of eplerenone and spironolactone by using evidence from randomized controlled trials. A decision analytic model was developed to assess the costs and consequences associated with the primary outcome of the trials over a lifetime time horizon. Results: The incremental cost-effectiveness ratio of eplerenone compared with that of standard care alone was £4457 and £7893 for each additional quality-adjusted life-year when 2-year and lifetime treatment duration was assumed, respectively. In both scenarios, spironolactone did not appear cost-effective compared with eplerenone. The results were sensitive to the higher relative effectiveness estimated for eplerenone compared with spironolactone from the meta-regression. When a class effect was assumed for the effect on mortality and hospitalizations, spironolactone emerged as the most cost-effective treatment. Conclusions: Eplerenone appears more cost-effective than spironolactone for the treatment of post-MI HF. These findings, however, remain subject to important uncertainties regarding the effects of treatment on major clinical events. An adequately powered, well-conducted randomized controlled trial that directly compares spironolactone and eplerenone may be required to provide more robust evidence on the optimal management of post-MI HF. Despite these uncertainties, the use of an aldosterone antagonist was consistently demonstrated to be a highly cost-effective strategy for the management of post-MI HF in the National Health Service. [Copyright &y& Elsevier]

Abstract: Objectives: To compare four UK models evaluating the cost-effectiveness of interventions in coronary heart disease (CHD), exploring the relative importance of structure and inputs in accounting for differences, and the scope for consensus on structure and data. Methods: We compared published cost-effectiveness results (incremental cost, quality-adjusted life year, and cost-effectiveness ratio) of three models conforming to the National Institute for Health and Clinical Excellence guidelines dealing with three interventions (statins, percutaneous coronary intervention, and clopidogrel) with a model developed in Southampton. Comparisons were made using three separate stages: 1) comparison of published results; 2) comparison of the results using the same data inputs wherever possible; and 3) an in-depth exploration of reasons for differences and the potential for consensus. Results: Although published results differed by up to 73% (for statins), standardization of inputs (stage 2) narrowed these gaps. Greater understanding of the reasons for differences was achieved, but a consensus on preferred values for all data inputs was not reached. Conclusions: We found that published guidance on methods was important to reduce variation in important model inputs. Although the comparison of models did not lead to consensus for all model inputs, it provided a better understanding of the reasons for these differences, and enhanced the transparency and credibility of all models. Similar comparisons would be aided by fuller publication of models, perhaps through detailed web appendices. [Copyright &y& Elsevier]

Background: Elicitation can be used to characterize structural uncertainty within a decision analytic model. This allows the value of acquiring further evidence to resolve these uncertainties to be established. Aim: This article demonstrated the use of expert elicitation for this purpose and also compared the elicited results with the results from alternative assumptions previously used to characterize the uncertainties. Materials and Methods: Distributions for two unknown parameters were elicited. These were used within a model developed to assess the cost-effectiveness of infliximab and etanercept for the treatment of active psoriatic arthritis (PsA), compared with palliative care. The experts’ distributions were synthesized using two approaches: linear pooling and random effects meta-analysis. Weighting of experts is also explored. Results: The four methods produce broadly similar results, and in each, the choice of optimum strategy is between etanercept and palliative care (incremental cost-effective ratio for etanercept is between £29,021 and £39,259 per costs and quality adjusted life years). Decision uncertainty, at a £30,000 threshold, is high in all of the synthesis models thus generating high values of further research at between £141 and £634 million. In each model, the greatest value of further research was for the short-term effectiveness of treatment (£47–£406 million). Discussion: Although the cost-effectiveness results do not differ substantially between the models using the elicited values and the original scenarios, there are some stark contrasts in terms of the values of further research generated. Conclusion: Elicitation offers a feasible method to generate evidence for the missing information but there are a number of key issues for which further research is required. [ABSTRACT FROM AUTHOR]

Summary: In publicly funded health systems with finite resources, management decisions are based on assessments of clinical effectiveness and cost-effectiveness. The UK National Institute for Health and Clinical Excellence commissioned a systematic review to inform their 2009 update to guidance on the use of antiviral drugs for the treatment of influenza. We searched databases for studies of the use of neuraminidase inhibitors for the treatment of seasonal influenza. We present the results for healthy adults (ie, adults without known comorbidities) and people at-risk of influenza-related complications. There was an overall reduction in the median time to symptom alleviation in healthy adults by 0·57 days (95% CI −1·07 to −0·08; p=0·02; 2701 individuals) with zanamivir, and 0·55 days (95% CI −0·96 to −0·14; p=0·008; 1410 individuals) with oseltamivir. In those at risk, the median time to symptom alleviation was reduced by 0·98 days (95% CI −1·84 to −0·11; p=0·03; 1252 individuals) with zanamivir, and 0·74 days (95% CI −1·51 to 0·02; p=0·06; 1472 individuals) with oseltamivir. Little information was available on the incidence of complications. In view of the advantages and disadvantages of different management strategies for controlling seasonal influenza in healthy adults recommending the use of antiviral drugs for the treatment of people presenting with symptoms is unlikely to be the most appropriate course of action. [Copyright &y& Elsevier]

Background: The characterization of uncertainty is critical in cost-effectiveness analysis, particularly when considering whether additional evidence is needed. In addition to parameter and methodological uncertainty, there are other sources of uncertainty which include simplifications and scientific judgments that have to be made when constructing and interpreting a model of any sort. These have been classified in a number of different ways but can be referred to collectively as structural uncertainties. Materials and Methods: Separate reviews were undertaken to identify what forms these other sources of uncertainty take and what other forms of potential methods to explicitly characterize these types of uncertainties in decision analytic models. These methods were demonstrated through application to four decision models each representing one of the four types of uncertainty. Results: These sources of uncertainty fall into four general themes: 1) inclusion of relevant comparators; 2) inclusion of relevant events; 3) alternative statistical estimation methods; and 4) clinical uncertainty. Two methods to explicitly characterize such uncertainties were identified: model selection and model averaging. In addition, an alternative approach, adding uncertain parameters to represent the source of uncertainty was also considered. The applications demonstrate that cost-effectiveness may be sensitive to these uncertainties and the methods used to characterize them. The value of research was particularly sensitive to these uncertainties and the methods used to characterize it. It is therefore important, for decision-making purposes, to incorporate such uncertainties into the modeling process. Conclusion: Only parameterizing the uncertainty directly in the model can inform the decision to conduct further research to resolve this source of uncertainty. [ABSTRACT FROM AUTHOR]

Objective: To examine the role of leukemia inhibitory factor (LIF) during in vitro maturation (IVM) on human and mice cumulus expansion and mice oocyte competence by in vitro fertilization (IVF), culture, and embryo transfer (ET). Design: Prospective animal and human study. Setting: Serono laboratories and IVF clinic. Patient(s): Healthy women volunteers and 8-week-old female mice. Intervention(s): Cumulus compacted human and mice oocytes were matured in IVM media with and without recombinant follicle-stimulating hormone (FSH) and with and without LIF. Mice IVM oocytes with and without 0.2 IU/mL of recombinant FSH; or with and without recombinant FSH + LIF (0.1, 1.0, 1000.0 ng/mL) and ovulated oocytes were in vitro fertilized and cultured. We transferred 395 blastocysts to the uterine horn of 2.5-day pseudopregnant female mice. Main Outcome Measure(s): Cumulus expansion in human and mice oocytes, and two-cell rate, blastocyst rate, and delivered rate of live pups in mice. Result(s): In human and mouse oocytes, LIF induced cumulus expansion. When 1000 ng/mL of LIF was added in combination with recombinant FSH, a statistically significant increase in cleavage rate, embryo development rate, and birth rate was observed when compared with oocytes matured with FSH alone. Conclusion(s): Leukemia inhibitory factor induced cumulus expansion similarly in human and mouse cumulus–oocyte complexes, and recombinant FSH plus LIF supplementation during mouse IVM significantly improved oocyte competence as measured by cleavage rate, blastocyst development, and birth rate. [Copyright &y& Elsevier]

Objective: To design a high-throughput cell assay to identify molecules modulating adhesion induced by tumor necrosis factor alpha (TNF-α) of endometrial cells to mesothelium. Design: Prospective study. Setting: Biotech company. Patient(s): Bovine endometrial (BEND) and human mesothelial cells. Intervention(s): Endometrial cells were treated with TNF-α and different proteins. Main Outcome Measure(s): TNF-α increased binding of fibronectin-coated fluorescein isothiocyanate (FITC) beads. The ability of various proteins to inhibit TNF-α–induced fibronectin-bead binding was measured. Result(s): Treatment of BEND cells with TNF-α increased binding of fibronectin-coated beads. Addition of TNF-α–binding protein abrogated the effect of TNF-α in a dose-dependent manner. The initial screen of 1014 proteins identified interferon-α2 (IFN-α2), inteleukin-17 (IL-17), transforming growth factor beta (TGF-β), and platelet-derived growth factor (PDGF) as inhibiting TNF–α-induced bead binding. Interferon-α2, IL-17, and TGF-β inhibited bead-binding with an IC50 (ng/mL, mean ± SD) of 0.15 ± 0.11, 0.098 ± 0.008, and 5.91 ± 0.72, respectively. All three isoforms of PDGF (AA, AB, and BB) were also found to inhibit TNF-α–induced bead-binding, with IC50s (ng/mL) of 1.8 ± 0.45, 10.0 ± 1.49, and 1.72 ± 0.73, respectively. Conclusion(s): We describe a novel high-throughput cell-based assay for endometrial cell binding to fibronectin. We show that IFN-α, IL-17, TGF-β, and PDGF have inhibitory actions on adhesion of endometrial cells to fibronectin. [Copyright &y& Elsevier]

Summary: By misdirecting the activity of Activation-Induced Deaminase (AID) to a conditional MYC transgene, we have achieved sporadic, AID-dependent MYC activation in germinal center B cells of Vk∗MYC mice. Whereas control C57BL/6 mice develop benign monoclonal gammopathy with age, all Vk∗MYC mice progress to an indolent multiple myeloma associated with the biological and clinical features highly characteristic of the human disease. Furthermore, antigen-dependent myeloma could be induced by immunization with a T-dependent antigen. Consistent with these findings in mice, more frequent MYC rearrangements, elevated levels of MYC mRNA, and MYC target genes distinguish human patients with multiple myeloma from individuals with monoclonal gammopathy, implicating a causal role for MYC in the progression of monoclonal gammopathy to multiple myeloma. [Copyright &y& Elsevier]

Abstract: This paper investigates multilevel associations between the common mental disorders of anxiety, depression and economic inactivity measured at the level of the individual and the UK 2001 census ward. The data set comes from the Caerphilly Health & Social Needs study, in which a representative survey of adults aged 18–74 years was carried out to collect a wide range of information which included mental health status (using the Mental Health Inventory (MHI-5) scale of the Short Form-36 health status questionnaire), and socio-economic status (including employment status, social class, household income, housing tenure and property value). Ward level economic inactivity was measured using non-means tested benefits data from the Department of Work and Pensions (DWP) on long-term Incapacity Benefit and Severe Disablement Allowance. Estimates from multilevel linear regression models of 10,653 individuals nested within 36 census wards showed that individual mental health status was significantly associated with ward-level economic inactivity, after adjusting for individual-level variables, with a moderate effect size of −0.668 (standard error=0.258). There was a significant cross-level interaction between ward-level and individual economic inactivity from permanent sickness or disability, such that the effect of permanent sickness or disability on mental health was significantly greater for people living in wards with high levels of economic inactivity. This supports the hypothesis that living in a deprived neighbourhood has the most negative health effects on poorer individuals and is further evidence for a substantive effect of the place where you live on mental health. [Copyright &y& Elsevier]