Health-Related Quality-of-Life Impacts Associated with Transfusion-Dependent β-Thalassemia in the USA and UK:A Qualitative Assessment

Background: Individuals living with transfusion-dependent β-thalassemia (TDT) experience reduced health-related quality of life (HRQoL) due to fatigue and chronic pain, which cause disruptions to daily life. Currently, limited qualitative data exist that describe these impacts. Objective: This study aimed to examine the ways in which symptoms and current treatments of TDT impact HRQoL, to holistically describe the humanistic burden of TDT, and to identify the unmet needs of individuals living with TDT. Methods: Adults (aged ≥18 years) with TDT and caregivers of adolescents (aged 12‒17 years) with TDT participated in semi-structured one-on-one virtual interviews and focus group discussions. Interviews were conducted in the United States and United Kingdom and lasted approximately 60 minutes. After transcription, the interviews were analyzed thematically using a framework approach. Results: A total of 10 interviews/focus group discussions (six interviews and four focus group discussions) were conducted with 14 adults with TDT and two caregivers of adolescents with TDT. Framework analysis revealed five themes describing HRQoL (negative impacts on daily activities, social life, family life, work and education, and psychological wellbeing) and three themes describing the lived experience of TDT (impact of red blood cell transfusions and iron chelation therapy, treatment, and stigma). Physical, psychological, and treatment-related factors contributed to negative impacts on daily activities, social and family life, and work and education. Concerns about reduced lifespan, relationships and family planning, and financial independence were detrimental to participants’ mental wellbeing. Participants reported having high resilience to the many physical and psychological challenges of living with TDT. A lack of TDT-specific knowledge among healthcare professionals, particularly regarding chronic pain associated with the disease, left some participants feeling ignored or undermined. Additionally, many participants experienced stigma and were reluctant to disclose their disease to others. Conclusions: Individuals living with TDT experience substantial negative impacts on HRQoL that disrupt their daily lives, disruptions which are intensified by inadequate healthcare interactions, demanding treatment schedules, and stigma. Our study highlights the unmet needs of individuals living with TDT, especially for alternative treatments that reduce or eliminate the need for red blood cell transfusions and iron chelation therapy.<br/

Thermally Driven Interfacial Degradation between Li 7 La 3 Zr 2 O 12 Electrolyte and LiNi 0.6 Mn 0.2 Co 0.2 O 2 Cathode

© 2020 American Chemical Society Solid-state batteries offer higher energy density and enhanced safety compared to the present lithium-ion batteries using liquid electrolytes. A challenge to implement them is the high resistances, especially at the solid electrolyte interface with the cathode. Sintering at elevated temperature is needed in order to get good contact between the ceramic solid electrolyte and oxide cathodes and thus to reduce contact resistances. Many solid electrolyte and cathode materials react to form secondary phases. It is necessary to find out which phases arise as a result of interface sintering and evaluate their effect on electrochemical properties. In this work, we assessed the interfacial reactions between LiNi0.6Mn0.2Co0.2O2 (NMC622) and Li7La3Zr2O12 (LLZO) as a function of temperature in air. We prepared model systems by depositing thin-film NMC622 cathode layers on LLZO pellets. The thin-film cathode approach enabled us to use interface-sensitive techniques such as X-ray absorption spectroscopy in the near-edge as well as the extended regimes and identify the onset of detrimental reactions. We found that the Ni and Co chemical environments change already at moderate temperatures, on-setting from 500 °C and becoming especially prominent at 700 °C. By analyzing spectroscopy results along with X-ray diffraction, we identified Li2CO3, La2Zr2O7, and La(Ni,Co)O3 as the secondary phases that formed at 700 °C. The interfacial resistance for Li transfer, measured by electrochemical impedance spectroscopy, increases significantly upon the onset and evolution of the detected interface chemistry. Our findings suggest that limiting the bonding temperature and avoiding CO2 in the sintering environment can help to remedy the interfacial degradation

Selective targeting of brain tumors with gold nanoparticle-induced radiosensitization.

Successful treatment of brain tumors such as glioblastoma multiforme (GBM) is limited in large part by the cumulative dose of Radiation Therapy (RT) that can be safely given and the blood-brain barrier (BBB), which limits the delivery of systemic anticancer agents into tumor tissue. Consequently, the overall prognosis remains grim. Herein, we report our pilot studies in cell culture experiments and in an animal model of GBM in which RT is complemented by PEGylated-gold nanoparticles (GNPs). GNPs significantly increased cellular DNA damage inflicted by ionizing radiation in human GBM-derived cell lines and resulted in reduced clonogenic survival (with dose-enhancement ratio of ~1.3). Intriguingly, combined GNP and RT also resulted in markedly increased DNA damage to brain blood vessels. Follow-up in vitro experiments confirmed that the combination of GNP and RT resulted in considerably increased DNA damage in brain-derived endothelial cells. Finally, the combination of GNP and RT increased survival of mice with orthotopic GBM tumors. Prior treatment of mice with brain tumors resulted in increased extravasation and in-tumor deposition of GNP, suggesting that RT-induced BBB disruption can be leveraged to improve the tumor-tissue targeting of GNP and thus further optimize the radiosensitization of brain tumors by GNP. These exciting results together suggest that GNP may be usefully integrated into the RT treatment of brain tumors, with potential benefits resulting from increased tumor cell radiosensitization to preferential targeting of tumor-associated vasculature

Gold nanoparticle characterization.

<p><b>A.</b> Transmission electron micrograph of GNPs having approximately 12 nm cores. <b>B.</b> Representative dynamic light scattering measurement of GNPs. Data was fit to a Gaussian function to determine the peak ± s.d. of nanoparticle hydrodynamic diameter (d_H). <b>C.</b> UV-vis absorption spectrum of GNPs showing characteristic surface plasmon resonance at λ ≈ 522 nm. <b>D.</b> MTT viability assay of U251 cells treated with increasing concentrations of GNPs for 24 hours. Error bars, mean viability ± s.d. of three replicates.</p

GNP administration in combination with RT improves survival in mice with advanced GBM tumors.

<p><b>A.</b> BLI of a representative mouse with advanced orthotopic GBM xenografts (radiance ∼10⁸ p/sec/cm²/sr) used for the survival study. <b>B.</b> Photograph of a brain and resected tumor 48 hours after intravenous injection of GNPs. Tumor shows darkened appearance due to extravasation due to EPR into the tumor. <b>C.</b> Survival data in mice with advanced orthotopic GBM treated with or without GNPs followed by mock-irradiation or given stereotactic RT (20 Gy). The right cerebral hemispheres of nude mice were initially implanted with 350,000 U251 cells, and tumors were allowed to grow until the measured radiance reached ∼10⁸p/sec/cm²/sr (approximately 3–5 weeks post-implantation), at which point the mice were given their respective treatments (<i>n</i> = 5 for GNP+RT and <i>n</i> = 4 for control, GNP, and RT groups). Median and mean survival analysis were obtained with Kaplan-Meier analysis, and comparison between RT versus GNP+RT survival curves showed <i>p</i> = 0.011. Mean survival times are shown with 95% confidence intervals. N.S. in the figure indicates lack of statistical significance, while the asterisk (*) denotes that significance was reached (α = 0.05).</p

Assessing GNP enhancement with <i>in vitro</i> assays of radiosensitivity.

<p><b>A.</b> Deconvolution imaging of γh2ax foci in U251 cells that were mock-irradiated (upper) or irradiated with 4 Gy (lower). Cells irradiated with 1 mM GNPs display a 1.7-fold higher density of persistent γh2ax foci 24 hours after RT. <b>B.</b> Quantitative analysis of γh2ax foci for N >100 viable nuclei. Error bars, 95% confidence interval. Statistical significance was determined using a two-tailed <i>t</i>-test (α = 0.05), with <i>p</i><0.05 being considered significant. <b>C.</b> Clonogenic assay of U251 cells treated with (red circles) and without (hollow squares) 1 mM GNPs and given radiation doses of 0, 2, 4 and 6 Gy. Error bars represent the mean survival ± s.d. of at least four replicates.</p

Radiation-induced modulation of the blood-brain barrier leads to increased uptake of GNPs in orthotopic GBM xenografts.

<p><b>A.</b> Schematic of BBB-disruption with targeted RT, which leads to endothelial cell death and loosening of tight junctions. <b>B.</b> Representative BLI image of a smaller, less disruptive GBM tumor (max BLI ∼10⁶) used in this experiment. <b>C.</b> T2-weighted MRI image of a stereotactically implanted intracranial GBM tumor (approximated by dashed orange line). <b>D.</b> ICP-MS analysis of gold uptake in the right hemispheres of healthy brains and those with orthotopic GBM excised from mice 48 hours after i.v. injection of saline or 0.4 g Au/kg GNPs administered 7–14 days after 20 Gy RT or mock-irradiation. The right cerebral hemispheres of mice were orthotopically inoculated with 350,000 U251 cells. Tumors were allowed to grow until the measured BLI irradiance reached ∼10⁶ p/sec/cm²/sr (approximately 2 weeks post-implantation), at which point the mice were given their respective treatments. Brains with tumors receiving RT (<i>n</i> = 4) prior to GNP administration show significant increase in EPR-driven gold accumulation compared to mock-irradiated controls (<i>n</i> = 4). Mock-irradiated (<i>n</i> = 3) and irradiated (<i>n</i> = 3) healthy brains, however, show no significant difference in gold uptake, suggesting that normal tissue may recover more quickly than tumor. <b>E.</b> Representative H/E staining of sections from orthotopic tumors with (+) and without (−) GNP injection.</p

Visualization of vascular dose painting effects via immunofluorescent labeling of DNA DSBs and vascular endothelial markers.

<p><b>A.</b> Mouse brain endothelial cells co-cultured with human GBM cells (1∶7, respectively) <i>in vitro</i> show enhanced RT damage when irradiated (4 Gy) with 1 mM GNPs. Upper : Immunofluorescence imaging of γh2ax foci and DAPI in normal mouse brain endothelial cells with the indicated treatments. Lower: Quantitative analysis of γh2ax foci (yellow) for N >10 viable nuclei (blue) of normal murine brain endothelial cells co-cultured with human GBM cells <i>in vitro</i>. Error bars, 95% confidence interval. Statistical significance was determined using a one-tailed <i>t</i>-test (α = 0.05), with <i>p</i><0.05 considered significant. <b>B.</b> Brains irradiated immediately following GNP injection leads to considerable colocalization of DNA DSB and blood vessels compared to those receiving RT alone. Healthy brains were mock-irradiated or irradiated with 20 Gy (whole-brain) immediately (<5 min) after i.v. administration of 1.25 g Au/kg GNPs or saline. Mice were sacrificed 24 hours later, and their brains were fixed/stained for γh2ax, CD31, and DAPI. C. γh2ax colocalization with CD31-positive cells was performed by calculating Mander’s coefficient (M2) in binary projections of CD31 and γh2ax channels.</p