Climate change mitigation policies can have significant co-benefits for air quality, including benefits to disadvantaged communities experiencing substantial air pollution. However, the effects of ...these mitigation policies have rarely been evaluated with respect to their influence on disadvantaged communities. Here we assess the air pollution and environmental justice implications of California’s cap-and-trade mitigation program through analysis of (1) the sources of air pollution in disadvantaged communities, (2) emissions-reduction offset usage under the cap-and-trade program, and (3) the relationship between reductions in greenhouse gas emissions and reductions in co-pollutant emissions. Our analysis suggests that the cap-and-trade program has limited impacts, including limited disproportionate impacts, on air quality in disadvantaged communities. The sources of most air pollution in these communities have not been subject to the cap-and-trade program, and the use of emissions-reduction offsets is only marginally higher in disadvantaged communities than in other communities. Furthermore, reductions in greenhouse gas emissions imply smaller proportional reductions in co-pollutant emissions. While climate policies lead to important air quality co-benefits in some contexts, especially through reduced coal usage, targeted air quality policies and regulations may be more effective for reducing air pollution in disadvantaged communities in California and throughout the state.
Differential interleukin-2 (IL-2) signaling and production are associated with disparate effector and memory fates. Whether the IL-2 signals perceived by CD8 T cells come from autocrine or paracrine ...sources, the timing of IL-2 signaling and their differential impact on CD8 T cell responses remain unclear. Using distinct models of germline and conditional IL-2 ablation in post-thymic CD8 T cells, this study shows that paracrine IL-2 is sufficient to drive optimal primary expansion, effector and memory differentiation, and metabolic function. In contrast, autocrine IL-2 is uniquely required during primary expansion to program robust secondary expansion potential in memory-fated cells. This study further shows that IL-2 production by antigen-specific CD8 T cells is largely independent of CD4 licensing of dendritic cells (DCs) in inflammatory infections with robust DC activation. These findings bear implications for immunizations and adoptive T cell immunotherapies, where effector and memory functions may be commandeered through IL-2 programming.
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•Paracrine IL-2 is sufficient to drive primary CTL expansion and formation of memory pool•Autocrine IL-2 is required by CTL in primary expansion to program secondary expansion•CD4 T cell help is less critical for autocrine IL-2 production in memory CD8 T cells
Using murine models of conditional T-cell-specific IL-2 ablation, Toumi et al. highlight the distinct roles of paracrine and autocrine IL-2 in regulating effector and memory CD8 T cell responses, respectively. CD8 T-cell-derived IL-2 is critical for programming robust secondary expansion potential in memory-fated cells.
The Xpert MTB/RIF (Xpert) assay offers rapid and accurate diagnosis of tuberculosis (TB) but still suffers from imperfect sensitivity. The newer Xpert MTB/RIF Ultra cartridge has shown improved ...sensitivity in recent field trials, but at the expense of reduced specificity. The clinical implications of switching from the existing Xpert cartridge to the Xpert Ultra cartridge in different populations remain uncertain.
We developed a Markov microsimulation model of hypothetical cohorts of 100,000 individuals undergoing diagnostic sputum evaluation with Xpert for suspected pulmonary TB, in each of 3 emblematic settings: an HIV clinic in South Africa, a public TB center in India, and an adult primary care setting in China. In each setting, we used existing data to project likely diagnostic results, treatment decisions, and ultimate clinical outcomes, assuming use of the standard Xpert versus Xpert Ultra cartridge. Our primary outcomes were the projected number of additional unnecessary treatments generated, the projected number of TB deaths averted, and the projected number of unnecessary treatments generated per TB death averted, if standard Xpert were switched to Xpert Ultra. We also simulated alternative approaches to interpreting positive results of the Ultra cartridge's semi-quantitative trace call. Extensive sensitivity and uncertainty analyses were performed to evaluate the drivers and generalizability of projected results. In the Indian TB center setting, replacing the standard Xpert cartridge with the Xpert Ultra cartridge was projected to avert 0.5 TB deaths (95% uncertainty range UR: 0, 1.3) and generate 18 unnecessary treatments (95% UR: 10, 29) per 1,000 individuals evaluated-resulting in a median ratio of 38 incremental unnecessary treatments added by Ultra per incremental death averted by Ultra compared to outcomes using standard Xpert (95% UR: 12, indefinite upper bound). In the South African HIV care setting-where TB mortality rates are higher and Ultra's improved sensitivity has greater absolute benefit-this ratio improved to 7 unnecessary treatments per TB death averted (95% UR: 2, 43). By contrast, in the Chinese primary care setting, this ratio was much less favorable, at 372 unnecessary treatments per TB death averted (95% UR: 75, indefinite upper bound), although the projected number of unnecessary treatments using Xpert Ultra was lower (with a possibility of no increased overtreatment) when using specificity data only from lower-burden settings. Alternative interpretations of the trace call had little effect on these ratios. Limitations include uncertainty in key parameters (including the clinical implications of false-negative results), the exclusion of transmission effects, and restriction of this analysis to adult pulmonary TB.
Switching from the standard Xpert cartridge to the Xpert Ultra cartridge for diagnosis of adult pulmonary TB may have different consequences in different clinical settings. In settings with high TB and HIV prevalence, Xpert Ultra is likely to offer considerable mortality benefit, whereas in lower-prevalence settings, Xpert Ultra will likely result in considerable overtreatment unless the possibility of higher specificity of Ultra in lower-prevalence settings in confirmed. The ideal use of the Ultra cartridge may therefore involve a more nuanced, setting-specific approach to implementation, with priority given to populations in which the anticipated prevalence of TB (and HIV) is the highest.
Dry-coated microprojections can deliver vaccine to abundant antigen-presenting cells in the skin and induce efficient immune responses and the dry-coated vaccines are expected to be thermostable at ...elevated temperatures. In this paper, we show that we have dramatically improved our previously reported gas-jet drying coating method and greatly increased the delivery efficiency of coating from patch to skin to from 6.5% to 32.5%, by both varying the coating parameters and removing the patch edge. Combined with our previous dose sparing report of influenza vaccine delivery in a mouse model, the results show that we now achieve equivalent protective immune responses as intramuscular injection (with the needle and syringe), but with only 1/30th of the
actual dose. We also show that influenza vaccine coated microprojection patches are stable for at least 6
months at 23
°C, inducing comparable immunogenicity with freshly coated patches. The dry-coated microprojection patches thus have key and unique attributes in ultimately meeting the medical need in certain low-resource regions with low vaccine affordability and difficulty in maintaining “cold-chain” for vaccine storage and transport.
Influenza vaccine coated microprojection patches are stable for at least 6
months at 23
°C, inducing comparable immunogenicity with freshly coated patches.
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The assessment of creativity as an individual difference has historically focused on divergent thinking, which is increasingly viewed as involving the associative processes that are also understood ...to be a key component of creative potential. Research on associative processes has proliferated in many sub-fields, often using Compound Remote Associates (CRA) tasks with an open response format and relatively small participant samples. In the present work, we introduce a new format that is more amenable to large-scale data collection in survey designs, and present evidence for the reliability and validity of CRA measures in general using multiple large samples. Study 1 uses a large, representative dataset (N = 1,323,480) to demonstrate strong unidimensionality and internal consistency (α = .97; ωt = .87), as well as links to individual differences in temperament, cognitive ability, occupation, and job characteristics. Study 2 uses an undergraduate sample (N = 685) to validate the use of a multiple-choice format relative to the traditional approach. Study 3 uses a crowdsourced sample (N = 357) to demonstrate high test-retest reliability of the items (r =.74). Finally, Study 4 uses a sample that overlaps with Study 1 (N = 1,502,922) to provide item response theory (IRT) parameters for a large set of high-quality CRA items that use a multiple-choice response mode, thus facilitating their use in future research on creativity, insight, and related topics.
Better delivery systems are needed for routinely used vaccines, to improve vaccine uptake. Many vaccines contain alum or alum based adjuvants. Here we investigate a novel dry-coated densely-packed ...micro-projection array skin patch (Nanopatch™) as an alternate delivery system to intramuscular injection for delivering an alum adjuvanted human papillomavirus (HPV) vaccine (Gardasil®) commonly used as a prophylactic vaccine against cervical cancer.
Micro-projection arrays dry-coated with vaccine material (Gardasil®) delivered to C57BL/6 mouse ear skin released vaccine within 5 minutes. To assess vaccine immunogenicity, doses of corresponding to HPV-16 component of the vaccine between 0.43 ± 0.084 ng and 300 ± 120 ng (mean ± SD) were administered to mice at day 0 and day 14. A dose of 55 ± 6.0 ng delivered intracutaneously by micro-projection array was sufficient to produce a maximal virus neutralizing serum antibody response at day 28 post vaccination. Neutralizing antibody titres were sustained out to 16 weeks post vaccination, and, for comparable doses of vaccine, somewhat higher titres were observed with intracutaneous patch delivery than with intramuscular delivery with the needle and syringe at this time point.
Use of dry micro-projection arrays (Nanopatch™) has the potential to overcome the need for a vaccine cold chain for common vaccines currently delivered by needle and syringe, and to reduce risk of needle-stick injury and vaccine avoidance due to the fear of the needle especially among children.
Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection
. Here we examine the underlying basis for this synergy. We show that ...PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1
TCF1
stem-like CD8
T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8
T cells that resemble highly functional effector CD8
T cells seen after an acute viral infection. The generation of these qualitatively superior CD8
T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1
TCF1
stem-like CD8
T cells, also referred to as precursors of exhausted CD8
T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8
T cells emerging from the stem-like CD8
T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25-CD122-CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1 + IL-2 combination therapy. There is considerable interest in PD-1 + IL-2 combination therapy for patients with cancer
, and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.
Vaccine-mediated immunity often relies on the generation of protective antibodies and memory B cells, which commonly stem from germinal center (GC) reactions. An in-depth comparison of the GC ...responses elicited by SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals has not yet been performed due to the challenge of directly probing human lymph nodes. Herein, through a fine-needle aspiration-based approach, we profiled the immune responses to SARS-CoV-2 mRNA vaccines in lymph nodes of healthy individuals and kidney transplant recipients (KTXs). We found that, unlike healthy subjects, KTXs presented deeply blunted SARS-CoV-2-specific GC B cell responses coupled with severely hindered T follicular helper cell, SARS-CoV-2 receptor binding domain-specific memory B cell, and neutralizing antibody responses. KTXs also displayed reduced SARS-CoV-2-specific CD4 and CD8 T cell frequencies. Broadly, these data indicate impaired GC-derived immunity in immunocompromised individuals and suggest a GC origin for certain humoral and memory B cell responses following mRNA vaccination.
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•Human GC responses to SARS-CoV-2 vaccines are restricted to draining lymph nodes•Vaccine-induced GC responses are associated with SARS-CoV-2 neutralizing antibodies•Kidney transplant recipients lack GC responses to SARS-CoV-2 vaccines•Vaccines expand S+RBD− memory B cells in healthy donors and transplant recipients
Fine-needle aspiration of lymph nodes in humans reveals that SARS-CoV-2 vaccination induces neutralizing antibody-producing germinal centers, enhanced by repeated vaccination. Conversely, in patients receiving immunosuppressant medication, this process is disrupted, resulting in stunted protective immune responses, highlighting issues about vaccine and booster efficacy in patients with compromised immune systems.
Family language policy (FLP) links studies of child language acquisition and early second language learning and bilingualism with the field of language policy. A timeline focusing on empirical ...research into FLP is presented.
There is increasing evidence that musculoskeletal tissues are differentiallys regulated by sex hormones in males and females. The influence of sex hormones, in addition to other sex-based differences ...such as in anatomical alignment and immune-system function, impact the prevalence and severity of disease as well as the types of injuries that affect the musculoskeletal system and the outcomes of prevention measures and treatment. Literature specifically addressing sex differences related to the musculoskeletal system is limited, underscoring the imperative for both basic and clinical research on this topic. This review highlights areas of research that have implications for bone and cartilage health, including growth and development, sports injuries, osteoarthritis, osteoporosis, and bone frailty. It is clear that important aspects of the musculoskeletal system have been understudied. Consideration of how sex hormone therapy will affect musculoskeletal tissues in prepuberty, during puberty, and in adults is vital, yet little is known. The purpose of this article is to foster awareness and interest in advancing our understanding of how sex differences influence orthopaedic practice.
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