The assessment and appraisal of regenerative medicines and cell therapy products : an exploration of methods for review, economic evaluation and appraisal

BACKGROUND: The National Institute for Health and Care Excellence (NICE) commissioned a 'mock technology appraisal' to assess whether changes to its methods and processes are needed. This report presents the findings of independent research commissioned to inform this appraisal and the deliberations of a panel convened by NICE to evaluate the mock appraisal. METHODS: Our research included reviews to identify issues, analysis methods and conceptual differences and the relevance of alternative decision frameworks, alongside the development of an exemplar case study of chimeric antigen receptor (CAR) T-cell therapy for treating acute lymphoblastic leukaemia. RESULTS: An assessment of previous evaluations of regenerative medicines found that, although there were a number of evidential challenges, none was unique to regenerative medicines or was beyond the scope of existing methods used to conceptualise decision uncertainty. Regarding the clinical evidence for regenerative medicines, the issues were those associated with a limited evidence base but were not unique to regenerative medicines: small non-randomised studies, high variation in response and the intervention subject to continuing development. The relative treatment effects generated from single-arm trials are likely to be optimistic unless it is certain that the historical data have accurately estimated the efficacy of the control agent. Pivotal trials may use surrogate end points, which, on average, overestimate treatment effects. To reduce overall uncertainty, multivariate meta-analysis of all available data should be considered. Incorporating indirectly relevant but more reliable (more mature) data into the analysis can also be considered; such data may become available as a result of the evolving regulatory pathways being developed by the European Medicines Agency. For the exemplar case of CAR T-cell therapy, target product profiles (TPPs) were developed, which considered the 'curative' and 'bridging to stem-cell transplantation' treatment approaches separately. Within each TPP, three 'hypothetical' evidence sets (minimum, intermediate and mature) were generated to simulate the impact of alternative levels of precision and maturity in the clinical evidence. Subsequent assessments of cost-effectiveness were undertaken, employing the existing NICE reference case alongside additional analyses suggested within alternative frameworks. The additional exploratory analyses were undertaken to demonstrate how assessments of cost-effectiveness and uncertainty could be impacted by alternative managed entry agreements (MEAs), including price discounts, performance-related schemes and technology leasing. The panel deliberated on the range of TPPs, evidence sets and MEAs, commenting on the likely recommendations for each scenario. The panel discussed the challenges associated with the exemplar and regenerative medicines more broadly, focusing on the need for a robust quantification of the level of uncertainty in the cost-effective estimates and the potential value of MEAs in limiting the exposure of the NHS to high upfront costs and loss associated with a wrong decision. CONCLUSIONS: It is to be expected that there will be a significant level of uncertainty in determining the clinical effectiveness of regenerative medicines and their long-term costs and benefits, but the existing methods available to estimate the implications of this uncertainty are sufficient. The use of risk sharing and MEAs between the NHS and manufacturers of regenerative medicines should be investigated further. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Mixed CFD-1D wind turbine diffuser design optimization

A method to design a diffuser augmented wind turbine (DAWT) is proposed, using as a guiding point the optimal pressure drop at the turbine. The use of concepts and expressions derived from a 1D analytic model helped to reduce the number of computational fluid dynamics simulations needed to find the optimal configuration. The proposed configuration can extract energy from the flow with the same efficiency as the state-of-the-art shrouded wind turbine (SWT) configurations but generating a significantly smaller wake, which makes this configuration a good candidate for wind farms or tidal applications. Furthermore, as a product of the 1D model, universal curves for the power coefficient have been obtained, as a function of the thrust coefficient, or disk loading, which have been compared with numerical and experimental results, showing a good agreement. Finally, the maximum ideal power coefficient has been found for a given configuration, which helps to estimate the margin for improvement of an actual design

Behandlung komorbider Störungen, Syndrome und Symptome der Posttraumatischen Belastungsstörung nach Missbrauchserfahrungen in der Kindheit mit STAIR-NT. Klinische Empfehlungen und Herausforderungen

Background: Early interpersonal traumatic events, such as childhood maltreatment, increase the risk of developing complex posttraumatic stress symptoms. The biphasic treatment program STAIR-NT (Skills Training for Affective and Interpersonal Regulation with Narrative Therapy), developed specifically for this patient group, combines interventions to improve emotion regulation and interpersonal skills with narrative therapy. Objective: Many affected patients with PTSD after childhood maltreatment also suffer from various comorbid mental disorders and symptoms that can affect and impede the course and outcome of treatment with STAIR-NT. Method: Based on experience from a current treatment study, we provide recommendations for integrating treatment of comorbid mental symptoms into STAIR-NT. Results / Conclusion: Training affective and interpersonal regulation skills in the first treatment phase offers various interventions to efficiently adapt transdiagnostic mechanisms such as emotion dysregulation. In cases of severe comorbid mental disorders or symptoms, adding disorder-specific interventions to STAIR-NT may be indicated.Hintergrund: Frühe interpersonelle traumatische Erfahrungen, wie Misshandlung und Missbrauch in Kindheit und Jugend, erhöhen das Risiko eine komplexe posttraumatische Belastungssymptomatik zu entwickeln. Das zwei-phasische Therapieprogramm STAIR-NT (Skillstraining zur affektiven und interpersonellen Regulation mit narrativer Therapie), das speziell für diese Gruppe von Patient_innen entwickelte wurde, kombiniert Interventionen zur Verbesserung der Emotionsregulation und der interpersonellen Fähigkeiten mit einer narrativen Therapie. Fragestellung: Viele der Betroffenen mit einer PTBS nach Misshandlung und Missbrauch in der Kindheit leiden unter einer Vielzahl komorbider psychischer Symptome, die den Verlauf und das Ergebnis der Behandlung mit STAIR-NT beeinflussen und behindern können. Methode: Basierend auf den Erfahrungen aus einer aktuellen Therapiestudie werden hier Empfehlungen für die Integration der Behandlung komorbider psychischer Symptomatik in STAIR-NT gegeben. Ergebnis / Schlussfolgerung: Vor allem das Training affektiver und interpersoneller Regulationsfähigkeiten in der ersten Therapiephase bietet vielfältige Interventionen zur Veränderung störungsübergreifender Mechanismen wie Emotionsdysregulation. Bei besonders schwerwiegender komorbider Symptomatik kann die zusätzliche Anwendung von störungsspezifischen Interventionen zur STAIR-NT indiziert sein

Airfoil catalogue for wind turbine blades with OpenFOAM

A methodology to efficiently simulate wind tunnel tests of several airfoils with OpenFOAM has been developed in this work. This methodology bridges OpenFOAM capabilities with Matlab postprocessing to analyse efficiently the performance of wind turbine airfoils at any angle of attack. This technique has been developed to reduce the cost, in terms of time and resources, of wind tunnel campaigns on wind turbine blade airfoils. Different turbulence models were used to study the behaviour of the airfoils near stall. Wind turbine airfoils need to be characterized for all possible angles of attack, in order to reproduce the real aerodynamic patterns during operation. Unfortunately, this situation is translated into a huge demand of wind tunnel testing resources, airfoil manufacturing and data post-processing. The high costs in terms of experimental measurements have encouraged many researches to elaborate airfoil catalogues by performing CFD simulations.Results are compared with a testing campaign on wind turbine airfoils aerodynamics run at AB6 wind tunnel of IDR/UPM located at the campus Universidad Politécnica de Madrid (Madrid, Spain), this tunnel being particularly suited for bi-dimensional applications. It is an open wind tunnel with a test section of 2.5 x 0.5 m, the turbulence intensity is under 3% at a Reynolds number of Re ∼= 5×105. The central part of the airfoil mock-ups were built with a 3D printer Additive Fused Deposition Modelling technology (FDM). Simulation results show a fair agreement with experiments, and helped to improve the performance of the wind tunnel

Origin of basalts by hybridisation in andesite-dominated arcs

This is the accepted manuscript. The final version is available from OUP at http://dx.doi.org/10.1093/petrology/egv002Mafic magmas are common in subduction zone settings, yet their high density restricts their ascent to the surface. Once stalled in the crust, these magmas may differentiate, assimilate crust and other melts and mushes to produce hybridised intermediate magmas. The Soufriere Hills Volcano on Montserrat is a ?type locality? for these hybridisation processes and yet, just 3 km south of the crater, voluminous basalts have erupted from the South Soufriere Hills volcano within the same time period as the Soufriere Hills Volcano was erupting hybrid andesites (131 - 128 ka). Basaltic South Soufriere Hills magmas have 48 - 53 32 wt% SiO2 and 4 - 6 wt% MgO. They were hot (970 - 1160 ?C), volatile-rich (melt inclusions contain up to 6.2 wt% H2O) and were stored at 8 ? 13 km prior to eruption (based on olivine and pyroxene-hosted melt inclusion volatile geochemistry). Melt inclusions do not preserve basaltic liquids: they are andesitic to rhyolitic in composition, related to one another by a line of descent controlled by simple closed-system fractionation. Whole rock compositions, however, are best described by a hybridisation model involving ?back?-mixing of andesitic to rhyolitic melts with mafic crystal phases such as magnetite, olivine, orthopyroxene and clinopyroxene. Phenocryst zoning illustrates repeated mixing events between evolved melts and mafic phenocrysts, which, when coupled with the heterogeneity of crystal compositions, strongly suggests that although the bulk composition is basalt (containing Fo80 olivine), they were assembled from disparate ingredients, likely derived from mafic crystal mushes and more evolved melt lenses of variable composition. The mixing events occur days to weeks prior to eruption. We propose that the South Soufriere Hills basaltic magmas, with their higher bulk density over andesites from neighbouring volcanoes, ultimately may have been eruptible owing to both the transtensional tectonics imposed by offshore grabens (related to the oblique subduction of the Lesser Antilles) and to surface unloading caused by large scale edifice collapse. Our observations support the idea that compositional changes in arcs might \ud reflect not only changes in source compositions, but also effects caused by patterns in crustal strain and tectonics.MC and SFLW thank NERC for financial support via grant NE/K000403/1

High-speed, low drive-voltage silicon-organic hybrid modulator based on a binary-chromophore electro-optic material

We report on the hybrid integration of silicon-on-insulator slot waveguides with organic electro-optic materials. We investigate and compare a polymer composite, a dendron-based material, and a binary-chromophore organic glass (BCOG). A record-high in-device electro-optic coefficient of 230 pm/V is found for the BCOG approach resulting in silicon-organic hybrid Mach-Zehnder modulators that feature low UpL-products of down to 0.52 Vmm and support data rates of up to 40 Gbit/

The elusive source of HIV-1 rebound after treatment interruption

Identifying the source of viral rebound during a monitored analytical treatment interruption (ATI) would reveal potential targets for cure strategies. Therefore, we examined the genetic composition of proviral DNA in different subsets from participants on antiretroviral therapy and compared this to rebounding virus after an ATI. Eleven participants underwent a monitored ATI and were sampled from different anatomical sites prior to and after the ATI. From the peripheral blood, Naïve (TNA), central (TCM), transitional (TTM) and effector (TEM) memory CD4+ T cells were sorted as were CD45 cells from gut-associated lymphoid tissue (GALT). Using single-genome sequencing (SGS) the env region of HIV DNA and plasma-derived RNA was sequenced. In an ongoing study, Full-Length Individual Proviral Sequencing (FLIPS) and Integration Site Loop Amplification (ISLA) assays were performed on the T cell subsets from 2 participants. For participant STAR10, 87 integration sites (IS) and 113 proviral genomes were sequenced while only 3 unique intact proviruses (3%) were identified. A cluster of 17 identical defective proviruses were linked to an IS (9% of all IS) in STAT5B located in TCM, TNA, TEM and TTM. When comparing the FLIPS to SGS env sequences a 100% match was found between one defective provirus and one plasma HIV RNA sequence after rebound. For participant STAR11, 37 IS and 105 proviral genomes were sequenced yielding 14 intact proviruses (13%) with the highest proportion found predominantly in the TEM subset (n=13, 45%). Four different clusters of identical sequences could be identified of which 2 (n=3 and n=9) consisted of intact TEM sequences with the smaller cluster linked to an IS in ZNF274. A 99% match between 2 env from rebounding plasma RNA and this smaller cluster of intact proviral genomes was identified. Comparing proviral sequences and their IS to plasma-derived RNA sequences after an ATI reveals additional information in terms of the source of viral rebound. However, this comparison is complicated by multiple factors. For example, we found a plasma-derived RNA sequence obtained during viral rebound matched a defective proviral sequence which highlights the problem of using one HIV RNA subgenomic region for identifying replication-competent virus. In addition, ongoing viral replication during rebound may prevent a 100% match with genetically intact proviral sequences making it challenging to determine the absolute source of rebound

The Nature of Starbursts : II. The Duration of Starbursts in Dwarf Galaxies

The starburst phenomenon can shape the evolution of the host galaxy and the surrounding intergalactic medium. The extent of the evolutionary impact is partly determined by the duration of the starburst, which has a direct correlation with both the amount of stellar feedback and the development of galactic winds, particularly for smaller mass dwarf systems. We measure the duration of starbursts in twenty nearby, ongoing, and "fossil" starbursts in dwarf galaxies based on the recent star formation histories derived from resolved stellar population data obtained with the Hubble Space Telescope. Contrary to the shorter times of 3-10 Myr often cited, the starburst durations we measure range from 450 - 650 Myr in fifteen of the dwarf galaxies and up to 1.3 Gyr in four galaxies; these longer durations are comparable to or longer than the dynamical timescales for each system. The same feedback from massive stars that may quench the flickering SF does not disrupt the overall burst event in our sample of galaxies. While five galaxies present fossil bursts, fifteen galaxies show ongoing bursts and thus the final durations may be longer than we report here for these systems. One galaxy shows a burst that has been ongoing for only 20 Myr; we are likely seeing the beginning of a burst event in this system. Using the duration of the starbursts, we calculate that the bursts deposited 10^(53.9)-10^(57.2) ergs of energy into the interstellar medium through stellar winds and supernovae and produced 3%-26% of the host galaxy's mass.Comment: 28 pages, 4 figure

Estimated sweat loss, fluid and CHO intake, and sodium balance of male major junior, AHL, and NHL players during on-ice practices

Several previous studies have reported performance decrements in team sport athletes who dehydrated approximately 1.5–2% of their body mass (BM) through sweating. This study measured on-ice sweat loss, fluid intake, sodium balance, and carbohydrate (CHO) intake of 77 major junior (JR; 19 ± 1 years), 60 American Hockey League (AHL; 24 ± 4 years), and 77 National Hockey League (NHL; 27 ± 5 years) players. Sweat loss was calculated from pre- to post-exercise BM plus fluid intake minus urine loss. AHL (2.03 ± 0.62 L/hr) and NHL (2.02 ± 0.74 L/hr) players had higher sweat rates (p  .05). Sodium deficits (sodium loss − intake) were greater (p 2% BM) during 60 min of practice. However, ∼15%, 41%, and 48% of the JR, AHL, and NHL players, respectively, may have reached mild dehydration and increased risk of performance decrements in a 90-min practice