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The Ediacaran rangeomorph Fractofusus misrai is the most common and best-preserved of the E Surface fossil assemblage in the Mistaken Point Ecological Reserve of southeastern Newfoundland, Canada. Fractofusus has been interpreted as a fusiform epifaunal soft-sediment recliner, and like other rangeomorphs it has a self-similar, fractal-like branching morphology. The rangeomorph branching of Fractofusus has been considered to be identical on the upper and lower surfaces; however, study of specimens with complex biostratinomic histories suggests clear differences between the upper and lower surfaces. The first-order branches grew downwards into the sediment from a high point near the midline but grew above the sediment–water interface at their lateral and distal margins. Our new three-dimensional appreciation of rangeomorph branching in Fractofusus explains many of the taphomorphs of Fractofusus including straight, curved, kinked and tousled forms. The three-dimensional morphology, mode of life, taphonomy and palaeoenvironmental interactions of F. misrai are discussed along with a new three-dimensional reconstruction.
Many male prisoners have significant mental health problems, including anxiety and depression. High proportions struggle with homelessness and substance misuse.
This study aims to evaluate whether the Engager intervention improves mental health outcomes following release.
The design is a parallel randomised superiority trial that was conducted in the North West and South West of England (ISRCTN11707331). Men serving a prison sentence of 2 years or less were individually allocated 1:1 to either the intervention (Engager plus usual care) or usual care alone. Engager included psychological and practical support in prison, on release and for 3–5 months in the community. The primary outcome was the Clinical Outcomes in Routine Evaluation Outcome Measure (CORE-OM), 6 months after release. Primary analysis compared groups based on intention-to-treat (ITT).
In total, 280 men were randomised out of the 396 who were potentially eligible and agreed to participate; 105 did not meet the mental health inclusion criteria. There was no mean difference in the ITT complete case analysis between groups (92 in each arm) for change in the CORE-OM score (1.1, 95% CI –1.1 to 3.2, P = 0.325) or secondary analyses. There were no consistent clinically significant between-group differences for secondary outcomes. Full delivery was not achieved, with 77% (108/140) receiving community-based contact.
Engager is the first trial of a collaborative care intervention adapted for prison leavers. The intervention was not shown to be effective using standard outcome measures. Further testing of different support strategies for prison with mental health problems is needed.
Schimperella acanthocercus, a new species of lophogastrid crustacean, is described from the Triassic of southwest China. This species is very similar to modern forms as well as the rare fossil Lophogastrida, known to date only from the Jurassic and Triassic. The sister “mysidacean” group to the Lophogastrida, the Mysida, are also rare in the fossil record; they too demonstrate remarkable similarities to living forms, suggesting that the extant “mysidaceans” had achieved “stable body plans” relatively early in their history, certainly by the Jurassic and Triassic. The third “mysidacean” group, the Pygocephalomorpha, have a considerably more extensive fossil record and are thus better understood. While “mysidaceans” are relatively rare in the fossil record, enough is known to suggest some possible biogeographic and evolutionary relationships.
Objectives: The aim of this study was to review and compare current health technology assessment (HTA) activities for medical devices across non-European Union HTA agencies.
Methods: HTA activities for medical devices were evaluated from three perspectives: organizational structure, processes, and methods. Agencies were primarily selected upon membership of existing HTA networks. The data collection was performed in two stages: stage 1–agency Web-site assessment using a standardized questionnaire, followed by review and validation of the collected data by a representative of the agency; and stage 2–semi-structured telephone interviews with key informants of a sub-sample of agencies.
Results: In total, thirty-six HTA agencies across twenty non-EU countries assessing medical devices were included. Twenty-seven of thirty-six (75 percent) agencies were judged at stage 1 to have adopted HTA-specific approaches for medical devices (MD-specific agencies) that were largely organizational or procedural. There appeared to be few differences in the organization, process and methods between MD-specific and non–MD-specific agencies. Although the majority (69 percent) of both categories of agency had specific methods guidance or policy for evidence submission, only one MD-specific agency had developed methodological guidelines specific to medical devices. In stage 2, many MD-specific agencies cited insufficient resources (budget, skilled employees), lack of coordination (between regulator and reimbursement bodies), and the inability to generalize findings from evidence synthesis to be key challenges in the HTA of medical devices.
Conclusions: The lack of evidence for differentiation in scientific methods for HTA of devices raises the question of whether HTA needs to develop new methods for medical devices but rather adapt existing methodological approaches. In contrast, organizational and/or procedural adaptation of existing HTA agency frameworks to accommodate medical devices appear relatively commonplace.
Objectives: Licensing of, and coverage decisions on, new therapies should rely on evidence from patient-relevant endpoints such as overall survival (OS). Nevertheless, evidence from surrogate endpoints may also be useful, as it may not only expedite the regulatory approval of new therapies but also inform coverage decisions. It is, therefore, essential that candidate surrogate endpoints be properly validated. However, there is no consensus on statistical methods for such validation and on how the evidence thus derived should be applied by policy makers.
Methods: We review current statistical approaches to surrogate-endpoint validation based on meta-analysis in various advanced-tumor settings. We assessed the suitability of two surrogates (progression-free survival [PFS] and time-to-progression [TTP]) using three current validation frameworks: Elston and Taylor's framework, the German Institute of Quality and Efficiency in Health Care's (IQWiG) framework and the Biomarker-Surrogacy Evaluation Schema (BSES3).
Results: A wide variety of statistical methods have been used to assess surrogacy. The strength of the association between the two surrogates and OS was generally low. The level of evidence (observation-level versus treatment-level) available varied considerably by cancer type, by evaluation tools and was not always consistent even within one specific cancer type.
Conclusions: Not in all solid tumors the treatment-level association between PFS or TTP and OS has been investigated. According to IQWiG's framework, only PFS achieved acceptable evidence of surrogacy in metastatic colorectal and ovarian cancer treated with cytotoxic agents. Our study emphasizes the challenges of surrogate-endpoint validation and the importance of building consensus on the development of evaluation frameworks.
Objectives: The aim of this study was to explore the use of surrogate outcomes—a substitute outcome that predicts final patient-related outcomes—in cost-effectiveness models (CEM) within health technology assessment (HTA) reports and provide guidance for their future use.
Methods: Our sampling frame was all UK HTA Program monograph series reports published in 2005 and 2006. Reports were included if they addressed a treatment effectiveness/efficacy question and included a CEM based on a surrogate outcome. The two authors independently applied inclusion and exclusion criteria, and the following data was extracted from included reports: source of surrogate outcome, level of evidence for validation of the surrogate outcomes, methods used in report to quantify link between surrogate outcome and final outcome, and consideration of the uncertainty associated with using surrogate outcomes in the results or conclusions of report.
Results: Of 100 HTA reports, 35 complied with the inclusion criteria. Of these, four (11 percent) reports included a CEM based on a surrogate outcome. All four reports sourced treatment-related changes in surrogate outcome through a systematic review of the literature. One provided Level 1 surrogate evidence (randomized controlled trial data showing a strong association between the change in surrogate outcome and change final outcome); two reported Level 2 evidence (observational study data); and one provided Level 3 evidence (disease natural/ history data). The transparency of quantification and exploration of uncertainty of the surrogate and final outcome relationship varied considerably across all four reports.
Conclusions: Recommendations are made for the use of surrogate outcomes in future HTA reports.
Objectives: The aim of this study was to develop a decision-analytic model to assess the cost-effectiveness of spinal cord stimulation (SCS), relative to nonsurgical conventional medical management (CMM), for patients with failed back surgery syndrome (FBSS).
Methods: A decision tree and Markov model were developed to synthesize evidence on both health-care costs and outcomes for patients with FBSS. Outcome data of SCS and CMM were sourced from 2-year follow-up data of two randomized controlled trials (RCTs). Treatment effects were measured as levels of pain relief. Short- and long-term health-care costs were obtained from a detailed Canadian costing study in FBSS patients. Results are presented as incremental cost per quality adjusted life year (QALY) and expressed in 2003 Euros. Costs were discounted at 6 percent and outcomes at 1.5 percent.
Results: Over the lifetime of the patient, SCS was dominant (i.e., SCS is cost-saving and gives more health gain relative to CMM); a finding that was robust across sensitivity analyses. At a 2-year time horizon, SCS gave more health gain but at an increased cost relative to CMM. Given the uncertainty in effectiveness and cost parameters, the 2-year cost-effectiveness of SCS ranged from €30,370 in the base case to €63,511 in the worst-case scenario.
Conclusions: SCS was found to be both more effective and less costly than CMM, over the lifetime of a patient. In the short-term, although SCS is potentially cost-effective, the model results are highly sensitive to the choice of input parameters. Further empirical data are required to improve the precision in the estimation of short-term cost-effectiveness.