Impact of Th1 CD4 Follicular Helper T Cell Skewing on Antibody Responses to an HIV-1 Vaccine in Rhesus Macaques.

Generating durable humoral immunity through vaccination depends upon effective interactions of follicular helper T (Tfh) cells with germinal center (GC) B cells. Th1 polarization of Tfh cells is an important process shaping the success of Tfh-GC B cell interactions by influencing costimulatory and cytokine-dependent Tfh help to B cells. However, the question remains as to whether adjuvant-dependent modulation of Tfh cells enhances HIV-1 vaccine-induced antienvelope (anti-Env) antibody responses. We investigated whether an HIV-1 vaccine platform designed to increase the number of Th1-polarized Tfh cells enhances the magnitude and quality of anti-Env antibodies. Utilizing a novel interferon-induced protein 10 (IP-10)-adjuvanted HIV-1 DNA prime followed by a monophosphoryl lipid A and QS-21 (MPLA+QS-21)-adjuvanted Env protein boost (DIP-10 PALFQ) in macaques, we observed higher anti-Env serum IgG titers with greater cross-clade reactivity, specificity for V1V2, and effector functions than in macaques primed with DNA lacking IP-10 and boosted with MPLA-plus-alum-adjuvanted Env protein (DPALFA) The DIP-10 PALFQ vaccine regimen elicited higher anti-Env IgG1 and lower IgG4 antibody levels in serum, showing for the first time that adjuvants can dramatically impact the IgG subclass profile in macaques. The DIP-10 PALFQ regimen also increased vaginal and rectal IgA antibodies to a greater extent. Within lymph nodes, we observed augmented GC B cell responses and the promotion of Th1 gene expression profiles in GC Tfh cells. The frequency of GC Tfh cells correlated with both the magnitude and avidity of anti-Env serum IgG. Together, these data suggest that adjuvant-induced stimulation of Th1-Tfh cells is an effective strategy for enhancing the magnitude and quality of anti-Env antibody responses.IMPORTANCE The results of the RV144 trial demonstrated that vaccination could prevent HIV transmission in humans and that longevity of anti-Env antibodies may be key to this protection. Efforts to improve upon the prime-boost vaccine regimen used in RV144 have indicated that booster immunizations can increase serum anti-Env antibody titers but only transiently. Poor antibody durability hampers efforts to develop an effective HIV-1 vaccine. This study was designed to identify the specific elements involved in the immunological mechanism necessary to produce robust HIV-1-specific antibodies in rhesus macaques. By clearly defining immune-mediated pathways that improve the magnitude and functionality of the anti-HIV-1 antibody response, we will have the foundation necessary for the rational development of an HIV-1 vaccine

Alternative Waste Forms for Electro-Chemical Salt Waste

This study was undertaken to examine alternate crystalline (ceramic/mineral) and glass waste forms for immobilizing spent salt from the Advanced Fuel Cycle Initiative (AFCI) electrochemical separations process. The AFCI is a program sponsored by U.S. Department of Energy (DOE) to develop and demonstrate a process for recycling spent nuclear fuel (SNF). The electrochemical process is a molten salt process for the reprocessing of spent nuclear fuel in an electrorefiner and generates spent salt that is contaminated with alkali, alkaline earths, and lanthanide fission products (FP) that must either be cleaned of fission products or eventually replaced with new salt to maintain separations efficiency. Currently, these spent salts are mixed with zeolite to form sodalite in a glass-bonded waste form. The focus of this study was to investigate alternate waste forms to immobilize spent salt. On a mole basis, the spent salt is dominated by alkali and Cl with minor amounts of alkaline earth and lanthanides. In the study reported here, we made an effort to explore glass systems that are more compatible with Cl and have not been previously considered for use as waste forms. In addition, alternate methods were explored with the hope of finding a way to produce a sodalite that is more accepting of as many FP present in the spent salt as possible. This study was done to investigate two different options: (1) alternate glass families that incorporate increased concentrations of Cl; and (2) alternate methods to produce a mineral waste form

State Transition Algorithm

In terms of the concepts of state and state transition, a new heuristic random search algorithm named state transition algorithm is proposed. For continuous function optimization problems, four special transformation operators called rotation, translation, expansion and axesion are designed. Adjusting measures of the transformations are mainly studied to keep the balance of exploration and exploitation. Convergence analysis is also discussed about the algorithm based on random search theory. In the meanwhile, to strengthen the search ability in high dimensional space, communication strategy is introduced into the basic algorithm and intermittent exchange is presented to prevent premature convergence. Finally, experiments are carried out for the algorithms. With 10 common benchmark unconstrained continuous functions used to test the performance, the results show that state transition algorithms are promising algorithms due to their good global search capability and convergence property when compared with some popular algorithms.Comment: 18 pages, 28 figure

Summary Report for the Development of Materials for Volatile Radionuclides

The materials development summarized here is in support of the Waste Forms campaign, Volatile Radionuclide task. Specifically, materials are being developed for the removal and immobilization of iodine and krypton, specifically 129I and 85Kr. During FY 2010, aerogel materials were investigated for removal and immobilization of 129I. Two aerogel formulations were investigated, one based on silica aerogels and the second on chalcogenides. For 85Kr, metal organic framework (MOF) structures were investigated

Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial

BACKGROUND: Rituximab is often used as rescue therapy in interstitial lung disease (ILD) associated with connective tissue disease (CTD), but has not been studied in clinical trials. This study aimed to assess whether rituximab is superior to cyclophosphamide as a treatment for severe or progressive CTD associated ILD. METHODS: We conducted a randomised, double-blind, double-dummy, phase 2b trial to assess the superiority of rituximab compared with cyclophosphamide. Patients aged 18-80 years with severe or progressive ILD related to scleroderma, idiopathic inflammatory myositis, or mixed CTD, recruited across 11 specialist ILD or rheumatology centres in the UK, were randomly assigned (1:1) to receive rituximab (1000 mg at weeks 0 and 2 intravenously) or cyclophosphamide (600 mg/m2 body surface area every 4 weeks intravenously for six doses). The primary endpoint was rate of change in forced vital capacity (FVC) at 24 weeks compared with baseline, analysed using a mixed-effects model with random intercepts, adjusted for baseline FVC and CTD type. Prespecified secondary endpoints reported in this Article were change in FVC at 48 weeks versus baseline; changes from baseline in 6 min walk distance, diffusing capacity of the lung for carbon monoxide (DLCO), physician-assessed global disease activity (GDA) score, and quality-of-life scores on the St George's Respiratory Questionnaire (SGRQ), King's Brief Interstitial Lung Disease (KBILD) questionnaire, and European Quality of Life Five-Dimension (EQ-5D) questionnaire at 24 and 48 weeks; overall survival, progression-free survival, and time to treatment failure; and corticosteroid use. All endpoints were analysed in the modified intention-to-treat population, which comprised all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT01862926). FINDINGS: Between Dec 1, 2014, and March 31, 2020, we screened 145 participants, of whom 101 participants were randomly allocated: 50 (50%) to receive cyclophosphamide and 51 (50%) to receive rituximab. 48 (96%) participants in the cyclophosphamide group and 49 (96%) in the rituximab group received at least one dose of treatment and were included in analyses; 43 (86%) participants in the cyclophosphamide group and 42 (82%) participants in the rituximab group completed 24 weeks of treatment and follow-up. At 24 weeks, FVC was improved from baseline in both the cyclophosphamide group (unadjusted mean increase 99 mL [SD 329]) and the rituximab group (97 mL [234]); in the adjusted mixed-effects model, the difference in the primary endpoint at 24 weeks was -40 mL (95% CI -153 to 74; p=0·49) between the rituximab group and the cyclophosphamide group. KBILD quality-of-life scores were improved at 24 weeks by a mean 9·4 points (SD 20·8) in the cyclophosphamide group and 8·8 points (17·0) in the rituximab group. No significant differences in secondary endpoints were identified between the treatment groups, with the exception of change in GDA score at week 48, which favoured cyclophosphamide (difference 0·90 [95% CI 0·11 to 1·68]). Improvements in lung function and respiratory-related quality-of-life measures were observed in both treatment groups. Lower corticosteroid exposure over 48 weeks of follow-up was recorded in the rituximab group. Two (4%) of 48 participants who received cyclophosphamide and three (6%) of 49 who received rituximab died during the study, all due to complications of CTD or ILD. Overall survival, progression-free survival, and time to treatment failure did not significantly differ between the two groups. All participants reported at least one adverse event during the study. Numerically fewer adverse events were reported by participants receiving rituximab (445 events) than those receiving cyclophosphamide (646 events). Gastrointestinal and respiratory disorders were the most commonly reported adverse events in both groups. There were 62 serious adverse events of which 33 occurred in the cyclophosphamide group and 29 in the rituximab group. INTERPRETATION: Rituximab was not superior to cyclophosphamide to treat patients with CTD-ILD, although participants in both treatment groups had increased FVC at 24 weeks, in addition to clinically important improvements in patient-reported quality of life. Rituximab was associated with fewer adverse events. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with CTD-ILD requiring intravenous therapy. FUNDING: Efficacy and Mechanism Evaluation Programme (Medical Research Council and National Institute for Health Research, UK)

Development of Crystal-Tolerant High-Level Waste Glasses

Twenty five glasses were formulated. They were batched from HLW AZ-101 simulant or raw chemicals and melted and tested with a series of tests to elucidate the effect of spinel-forming components (Ni, Fe, Cr, Mn, and Zn), Al, and noble metals (Rh2O3 and RuO2) on the accumulation rate of spinel crystals in the glass discharge riser of the high-level waste (HLW) melter. In addition, the processing properties of glasses, such as the viscosity and TL, were measured as a function of temperature and composition. Furthermore, the settling of spinel crystals in transparent low-viscosity fluids was studied at room temperature to access the shape factor and hindered settling coefficient of spinel crystals in the Stokes equation. The experimental results suggest that Ni is the most troublesome component of all the studied spinel-forming components producing settling layers of up to 10.5 mm in just 20 days in Ni-rich glasses if noble metals or a higher concentration of Fe was not introduced in the glass. The layer of this thickness can potentially plug the bottom of the riser, preventing glass from being discharged from the melter. The noble metals, Fe, and Al were the components that significantly slowed down or stopped the accumulation of spinel at the bottom. Particles of Rh2O3 and RuO2, hematite and nepheline, acted as nucleation sites significantly increasing the number of crystals and therefore decreasing the average crystal size. The settling rate of ≤10-μm crystal size around the settling velocity of crystals was too low to produce thick layers. The experimental data for the thickness of settled layers in the glasses prepared from AZ-101 simulant were used to build a linear empirical model that can predict crystal accumulation in the riser of the melter as a function of concentration of spinel-forming components in glass. The developed model predicts the thicknesses of accumulated layers quite well, R2 = 0.985, and can be become an efficient tool for the formulation of the crystal-tolerant HLW glasses for higher waste loading. A physical modeling effort revealed that the Stokes and Richardson-Zaki equations can be used to adequately predict the accumulation rate of spinel crystals of different sizes and concentrations in the glass discharge riser of HLW melters. The determined shape factor for the glass beads was only 0.73% lower than the theoretical shape factor for a perfect sphere. The shape factor for the spinel crystals matched the theoretically predicted value to within 10% and was smaller than that of the beads, given the larger drag force caused by the larger surface area-to-volume ratio of the octahedral crystals. In the hindered settling experiments, both the glass bead and spinel suspensions were found to follow the predictions of the Richardson-Zaki equation with the exponent n = 3.6 and 2.9 for glass beads and spinel crystals, respectively

Perspectives of healthcare providers, service users, and family members about mental illness stigma in primary care settings: A multi-site qualitative study of seven countries in Africa, Asia, and Europe

Background: Stigma among healthcare providers is a barrier to the effective delivery of mental health services in primary care. Few studies have been conducted in primary care settings comparing the attitudes of healthcare providers and experiences of people with mental illness who are service users in those facilities. Such research is necessary across diverse global settings to characterize stigma and inform effective stigma reduction. Methods: Qualitative research was conducted on mental illness stigma in primary care settings in one low-income country (Nepal), two lower-middle income countries (India, Tunisia), one upper-middle-income country (Lebanon), and three high-income countries (Czech Republic, Hungary, Italy). Qualitative interviews were conducted with 248 participants: 64 primary care providers, 11 primary care facility managers, 111 people with mental illness, and 60 family members of people with mental illness. Data were analyzed using framework analysis. Results: Primary care providers endorsed some willingness to help persons with mental illness but reported not having appropriate training and supervision to deliver mental healthcare. They expressed that people with mental illness are aggressive and unpredictable. Some reported that mental illness is incurable, and mental healthcare is burdensome and leads to burnout. They preferred mental healthcare to be delivered by specialists. Service users did not report high levels of discrimination from primary care providers; however, they had limited expectations of support from primary care providers. Service users reported internalized stigma and discrimination from family and community members. Providers and service users reported unreliable psychiatric medication supply and lack of facilities for confidential consultations. Limitations of the study include conducting qualitative interviews in clinical settings and reliance on clinician-researchers in some sites to conduct interviews, which potentially biases respondents to present attitudes and experiences about primary care services in a positive manner. Conclusions: Primary care providers' willingness to interact with people with mental illness and receive more training presents an opportunity to address stigmatizing beliefs and stereotypes. This study also raises important methodological questions about the most appropriate strategies to accurately understand attitudes and experiences of people with mental illness. Recommendations are provided for future qualitative research about stigma, such as qualitative interviewing by non-clinical personnel, involving non-clinical staff for recruitment of participants, conducting interviews in non-clinical settings, and partnering with people with mental illness to facilitate qualitative data collection and analysis

Alternative Electrochemical Salt Waste Forms, Summary of FY/CY2011 Results

This report summarizes the 2011 fiscal+calendar year efforts for developing waste forms for a spent salt generated in reprocessing nuclear fuel with an electrochemical separations process. The two waste forms are tellurite (TeO2-based) glasses and sol-gel-derived high-halide mineral analogs to stable minerals found in nature

Informing UK governance of resilience to climate risks: improving the local evidence-base

International assessments of evidence on climate change (e.g. Intergovernmental Panel on Climate Change, IPCC) or national climate change risk assessments (e.g. UK Climate Change Risk Assessment, CCRA) do not offer a sufficiently granular perspective on climate impacts to adequately inform governance of resilience to climate risks at the local level. Using an analysis of UK decision-makers managing and responding to heatwaves and flood risks, this paper argues how more robust local evidence is needed to inform decision-making regarding adaptation options for enhancing local resilience. We identify evidence gaps and issues relating to local climate change impacts, including sources and quality of evidence used, adequacy and accessibility of evidence available, ill-communicated evidence and conflicting or misused evidence. A lack of appreciation regarding how scientific evidence and personal judgement can mutually enhance the quality of decision-making underpins all of these gaps. Additionally, we find that the majority of evidence currently used is reductively based upon socio-economic and physical characteristics of climate risks. We argue that a step change is needed in local climate resilience that moves beyond current physical and socio-economic risk characterisation to a more inclusive co-constitution of social and politically defined climate risks at the local scale that are better aligned with the local impacts felt and needs of stakeholders

Investigation of Tc Migration Mechanism During Bulk Vitrification Process Using Re Surrogate

As a part of Bulk vitrification (BV) performance enhancement tasks, Laboratory scoping tests were performed in FY 2004-2005 to explore possible ways to reduce the amount of soluble Tc in the BV waste package. Theses scoping tests helped identify which mechanisms play an important role in the migration of Tc in the BV process (Hrma et al. 2005 and Kim et al. 2005). Based on the results from these scoping tests, additional tests were identified that will improve the understanding of Tc migration and to clearly identify the dominant mechanisms. The additional activities identified from previous studies were evaluated and prioritized for planning for Tasks 29 and 30 conducted in FY2006. Task 29 focused on the improved understanding of Tc migration mechanisms, and Task 30 focused on identifying the potential process changes that might reduce Tc/Re migration into the castable refractory block (CRB). This report summarizes the results from the laboratory- and crucible-scale tests in the lab for improved Tc migration mechanism understanding utilizing Re as a surrogate performed in Task 29