Core data set on safety, efficacy, and durability of hemophilia gene therapy for a global registry: Communication from the SSC of the ISTH

BackgroundGene therapy for people with hemophilia (PWH) will soon become available outside current clinical trials. The World Federation of Hemophilia (WFH), in collaboration with International Society of Thrombosis and Hemostasis Scientific and Standardization Committee (ISTH SSC), the European Haemophilia Consortium (EHC), the US National Hemophilia Foundation (NHF), the American Thrombosis and Hemostasis Network (ATHN), industry gene therapy development partners and Regulatory liaisons have developed the Gene Therapy Registry (GTR), designed to collect long- term data on all PWH who receive hemophilia gene therapy.ObjectiveThe objectives of the GTR are to record the long- term safety and efficacy data post gene therapy infusion and to assess the changes in quality of life and burden of disease post- gene- therapy infusion.MethodsThe GTR is a prospective, observational, and longitudinal registry developed under the guidance of a multi- stakeholder GTR Steering Committee (GTR SC), composed of health care professionals, patient advocates, industry representatives, and regulatory agency liaisons. All PWH who receive gene therapy by clinical trial or commercial product will be invited to enrol in the registry through their hemophilia treatment centers (HTCs). The registry aims to recruit 100% of eligible post gene therapy PWH globally. Through an iterative process, and following the guidance of the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), the GTR SC has developed a core set of data to be collected on all patients post gene therapy.ResultsThe core data set includes demographic information, vector infusion details, safety, efficacy, quality of life and burden of disease.ConclusionsThe GTR is a global effort to ensure that long term safety and efficacy outcomes are recorded and analysed and rare adverse events, in a small patient population, are identified. Many unknowns on the long- term safety and efficacy of gene therapy for hemophilia may also be addressed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163440/2/jth15023.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163440/1/jth15023_am.pd

Markedly enhanced absorption and direct radiative forcing of black carbon under polluted urban environments

Black carbon (BC) exerts profound impacts on air quality and climate because of its high absorption cross-section over a broad range of electromagnetic spectra, but the current results on absorption enhancement of BC particles during atmospheric aging remain conflicting. Here, we quantified the aging and variation in the optical properties of BC particles under ambient conditions in Beijing, China, and Houston, United States, using a novel environmental chamber approach. BC aging exhibits two distinct stages, i.e., initial transformation from a fractal to spherical morphology with little absorption variation and subsequent growth of fully compact particles with a large absorption enhancement. The timescales to achieve complete morphology modification and an absorption amplification factor of 2.4 for BC particles are estimated to be 2.3 h and 4.6 h, respectively, in Beijing, compared with 9 h and 18 h, respectively, in Houston. Our findings indicate that BC under polluted urban environments could play an essential role in pollution development and contribute importantly to large positive radiative forcing. The variation in direct radiative forcing is dependent on the rate and timescale of BC aging, with a clear distinction between urban cities in developed and developing countries, i.e., a higher climatic impact in more polluted environments. We suggest that mediation in BC emissions achieves a cobenefit in simultaneously controlling air pollution and protecting climate, especially for developing countries

Multi-level strategies to improve equitable timely person-centred osteoarthritis care for diverse women: qualitative interviews with women and healthcare professionals

Abstract Background Women are more likely to develop osteoarthritis (OA), and have greater OA pain and disability compared with men, but are less likely to receive guideline-recommended management, particularly racialized women. OA care of diverse women, and strategies to improve the quality of their OA care is understudied. The purpose of this study was to explore strategies to overcome barriers of access to OA care for diverse women. Methods We conducted qualitative interviews with key informants and used content analysis to identify themes regarding what constitutes person-centred OA care, barriers of OA care, and strategies to support equitable timely access to person-centred OA care. Results We interviewed 27 women who varied by ethno-cultural group (e.g. African or Caribbean Black, Chinese, Filipino, Indian, Pakistani, Caucasian), age, region of Canada, level of education, location of OA and years with OA; and 31 healthcare professionals who varied by profession (e.g. family physician, nurse practitioner, community pharmacist, physio- and occupational therapists, chiropractors, healthcare executives, policy-makers), career stage, region of Canada and type of organization. Participants within and across groups largely agreed on approaches for person-centred OA care across six domains: foster a healing relationship, exchange information, address emotions, manage uncertainty, share decisions and enable self-management. Participants identified 22 barriers of access and 18 strategies to overcome barriers at the patient- (e.g. educational sessions and materials that accommodate cultural norms offered in different languages and formats for persons affected by OA), healthcare professional- (e.g. medical and continuing education on OA and on providing OA care tailored to intersectional factors) and system- (e.g. public health campaigns to raise awareness of OA, and how to prevent and manage it; self-referral to and public funding for therapy, greater number and ethno-cultural diversity of healthcare professionals, healthcare policies that address the needs of diverse women, dedicated inter-professional OA clinics, and a national strategy to coordinate OA care) levels. Conclusions This research contributes to a gap in knowledge of how to optimize OA care for disadvantaged groups including diverse women. Ongoing efforts are needed to examine how best to implement these strategies, which will require multi-sector collaboration and must engage diverse women

Shattered pellet injection experiments at JET in support of the ITER disruption mitigation system design

A series of experiments have been executed at JET to assess the efficacy of the newly installed shattered pellet injection (SPI) system in mitigating the effects of disruptions. Issues, important for the ITER disruption mitigation system, such as thermal load mitigation, avoidance of runaway electron (RE) formation, radiation asymmetries during thermal quench mitigation, electromagnetic load control and RE energy dissipation have been addressed over a large parameter range. The efficiency of the mitigation has been examined for the various SPI injection strategies. The paper summarises the results from these JET SPI experiments and discusses their implications for the ITER disruption mitigation scheme

Testing a prediction model for the H-mode density pedestal against JET-ILW pedestals

The neutral ionisation model proposed by Groebner et al (2002 Phys. Plasmas 9 2134) to determine the plasma density profile in the H-mode pedestal, is extended to include charge exchange processes in the pedestal stimulated by the ideas of Mahdavi et al (2003 Phys. Plasmas 10 3984). The model is then tested against JET H-mode pedestal data, both in a 'standalone' version using experimental temperature profiles and also by incorporating it in the Europed version of EPED. The model is able to predict the density pedestal over a wide range of conditions with good accuracy. It is also able to predict the experimentally observed isotope effect on the density pedestal that eludes simpler neutral ionization models

The role of ETG modes in JET-ILW pedestals with varying levels of power and fuelling

We present the results of GENE gyrokinetic calculations based on a series of JET-ITER-like-wall (ILW) type I ELMy H-mode discharges operating with similar experimental inputs but at different levels of power and gas fuelling. We show that turbulence due to electron-temperature-gradient (ETGs) modes produces a significant amount of heat flux in four JET-ILW discharges, and, when combined with neoclassical simulations, is able to reproduce the experimental heat flux for the two low gas pulses. The simulations plausibly reproduce the high-gas heat fluxes as well, although power balance analysis is complicated by short ELM cycles. By independently varying the normalised temperature gradients (omega(T)(e)) and normalised density gradients (omega(ne )) around their experimental values, we demonstrate that it is the ratio of these two quantities eta(e) = omega(Te)/omega(ne) that determines the location of the peak in the ETG growth rate and heat flux spectra. The heat flux increases rapidly as eta(e) increases above the experimental point, suggesting that ETGs limit the temperature gradient in these pulses. When quantities are normalised using the minor radius, only increases in omega(Te) produce appreciable increases in the ETG growth rates, as well as the largest increases in turbulent heat flux which follow scalings similar to that of critical balance theory. However, when the heat flux is normalised to the electron gyro-Bohm heat flux using the temperature gradient scale length L-Te, it follows a linear trend in correspondence with previous work by different authors

A control oriented strategy of disruption prediction to avoid the configuration collapse of tokamak reactors

The objective of thermonuclear fusion consists of producing electricity from the coalescence of light nuclei in high temperature plasmas. The most promising route to fusion envisages the confinement of such plasmas with magnetic fields, whose most studied configuration is the tokamak. Disruptions are catastrophic collapses affecting all tokamak devices and one of the main potential showstoppers on the route to a commercial reactor. In this work we report how, deploying innovative analysis methods on thousands of JET experiments covering the isotopic compositions from hydrogen to full tritium and including the major D-T campaign, the nature of the various forms of collapse is investigated in all phases of the discharges. An original approach to proximity detection has been developed, which allows determining both the probability of and the time interval remaining before an incoming disruption, with adaptive, from scratch, real time compatible techniques. The results indicate that physics based prediction and control tools can be developed, to deploy realistic strategies of disruption avoidance and prevention, meeting the requirements of the next generation of devices

Comparing pedestal structure in JET-ILW H-mode plasmas with a model for stiff ETG turbulent heat transport

A predictive model for the electron temperature profile of the H-mode pedestal is described, and its results are compared with the pedestal structure of JET-ILW plasmas. The model is based on a scaling for the gyro-Bohm normalized, turbulent electron heat flux qe/qe,gB resulting from electron temperature gradient (ETG) turbulence, derived from results of nonlinear gyrokinetic (GK) calculations for the steep gradient region. By using the local temperature gradient scale length L-Te in the normalization, the dependence of q(e)/q(e,g)B on the normalized gradients R/L-Te and R/(Lne) can be represented by a unified scaling with the parameter eta(e) = L-ne/L-Te, to which the linear stability of ETG turbulence is sensitive when the density gradient is sufficiently steep. For a prescribed density profile, the value of R/L-Te determined from this scaling, required to maintain a constant electron heat flux qe across the pedestal, is used to calculate the temperature profile. Reasonable agreement with measurements is found for different cases, the model providing an explanation of the relative widths and shifts of the T-e and n(e) profiles, as well as highlighting the importance of the separatrix boundary conditions. Other cases showing disagreement indicate conditions where other branches of turbulence might dominate.This article is part of a discussion meeting issue "H-mode transition and pedestal studies in fusion plasmas'

New H-mode regimes with small ELMs and high thermal confinement in the Joint European Torus

New H-mode regimes with high confinement, low core impurity accumulation, and small edge-localized mode perturbations have been obtained in magnetically confined plasmas at the Joint European Torus tokamak. Such regimes are achieved by means of optimized particle fueling conditions at high input power, current, and magnetic field, which lead to a self-organized state with a strong increase in rotation and ion temperature and a decrease in the edge density. An interplay between core and edge plasma regions leads to reduced turbulence levels and outward impurity convection. These results pave the way to an attractive alternative to the standard plasmas considered for fusion energy generation in a tokamak with a metallic wall environment such as the ones expected in ITER.& nbsp;Published under an exclusive license by AIP Publishing

A control oriented strategy of disruption prediction to avoid the configuration collapse of tokamak reactors

The objective of thermonuclear fusion consists of producing electricity from the coalescence of light nuclei in high temperature plasmas. The most promising route to fusion envisages the confinement of such plasmas with magnetic fields, whose most studied configuration is the tokamak. Disruptions are catastrophic collapses affecting all tokamak devices and one of the main potential showstoppers on the route to a commercial reactor. In this work we report how, deploying innovative analysis methods on thousands of JET experiments covering the isotopic compositions from hydrogen to full tritium and including the major D-T campaign, the nature of the various forms of collapse is investigated in all phases of the discharges. An original approach to proximity detection has been developed, which allows determining both the probability of and the time interval remaining before an incoming disruption, with adaptive, from scratch, real time compatible techniques. The results indicate that physics based prediction and control tools can be developed, to deploy realistic strategies of disruption avoidance and prevention, meeting the requirements of the next generation of devices.Confining plasma and managing disruptions in tokamak devices is a challenge. Here the authors demonstrate a method predicting and possibly preventing disruptions and macroscopic instabilities in tokamak plasma using data from JET