Conspiracy theories have accrued around recent world events, and many of them have been endorsed by leaders seeking to garner support. Drawing from compensatory control theory, we argue a reduced sense of control will increase support for leaders who use conspiratorial rhetoric. Moreover, we posit that the congruence between one's political identity and a leader's conspiratorial rhetoric is an important consideration with regard to when this effect will emerge. Studies 1a and 1b established causality by directly manipulating sense of control and finding greater support for conspiratorial leaders in the lacking vs. having control condition. Studies 2 and 3 examined the effects of real-world events that are posited to reduce a sense of control, along with the moderating effect of political identity. Study 2 showed, in two waves collected before and during COVID-19 lockdowns, that the lockdowns reduced a sense of control. Congruently, individuals supported leaders espousing a COVID-19 conspiracy theory more during the lockdowns than before. In addition, for leaders espousing conspiratorial rhetoric related to paid protests, Republicans exhibited greater support during than before the lockdown; however, the lockdown did not affect Democrats' support. Study 3 showed, in two waves collected before and after the 2020 U.S. Presidential election, that Biden supporters felt greater control after the election and decreased their support for conspiratorial leaders. Trump supporters' sense of control did not change, and concurrently they did not change their support for conspiratorial leaders. Implications are discussed for leadership during times of crisis and beyond.
The Proterozoic Eon covers 40% of Earth's history, from 2500 to 541 Ma (million years ago), and was home to a series of major events in Earth's history. The tectonic configuration of the early stages of the Proterozoic is not known, but from 1500 Ma onwards there are reconstructions available. They are used here in a dedicated tidal model to simulate how the tides changed during the middle-late part of the Eon. We also revisit the Cryogenian period (715–630 Ma), when it has been proposed that Earth was home to vast near-global glaciations and extend the simulations into the later parts of the Eon. We show that the tides are far less energetic than today (about 40% of present-day tidal dissipation rates) for most of the period we could simulate, with the exception of a tidal maximum around 1250 Ma. The reason is that the period we simulated is home to the supercontinents Rodinia and Pannotia, and the results confirm the existence of a supertidal cycle linked to the supercontinent cycle.
The Phanerozoic Eon spans the past 541 Myr (million years) and includes present day. It was home to the assembly and breakup of the latest supercontinent, Pangea, and the subsequent scattering of the continents into Earth as we know it today. The changing face of the Earth is shown here, using a dedicated numerical tidal model and recent paleo-bathymetries, to have had a profound impact on the tides, with prolonged period of very weak tidal energy levels. These quiescent states were interrupted by tidal maxima lasting 5–20 Myr between the supercontinents; these were found around 430 Ma (million years ago), 150 Ma, and 20 Ma and we propose that Earth is currently on the way out of the most recent tidal maximum. We also present three case studies to highlight the importance of tides in the Earth system. These include the Devonian (~ 400 Ma) when key evolution events took place, the Turonian around 95 Ma when there was a marine extinction event due to anoxia, and the Eocene, 55 Ma, where it has been proposed that enhanced tidal dissipation rates could explain the reduced meridional temperature gradient found in proxies.
Lightweight materials design of friction parts promises aluminum matrix composites to achieve comparable anti-wear properties as steel. However, it is still challenging due to the limited effects of monotonous reinforcement. In this work, (TiB2-TiC)/Al-Cu-Mg composites were fabricated with particle content from 10 to 60 vol% and scaled from nano-sized to nano-/micron-sized. The microstructures, mechanical properties, elevated-temperature tribology behaviors and wear mechanisms of the Al-Cu-Mg composites reinforced by TiB2-TiC particles with tunable size and volume fractions were systematically investigated. Compared to the Al-Cu-Mg composite reinforced by nano-sized particles, the significant micron-/nano-sized effect and thicker mechanical mixture layer in the composites can weaken the influence of load on the composites and thus better protect the matrix. The incorporated particles evolved from single nano-sized to micron-/nano-sized hybridized, and the dominant wear mechanism transformed from severe adhesive and delamination wear (surface fatigue) to slight adhesive wear. 60 vol% micron-/nano-sized (TiB2-TiC)/Al-Cu-Mg composite showed the lowest wear rate (0.047 mm3/m) and coefficient of friction (0.38) at 473 K, 0.32 mm/s sliding velocity and 40 N load, reduced 24% and 20% than composite with 10 vol% nano-sized particles. This work provided a strategy for improving the wear resistance of aluminum matrix composites reinforced by size-tunable particles for their extended applications on structural components.
Introduction A few studies have identified childhood animal exposure as associated with adiposity, but results are inconsistent and differ in timing. Methods We conducted an observational cohort study of children ages 4–8 in the Environmental Influences on Child Health Outcomes [ECHO] study. The main exposure was having a dog in the home and/or regular contact with farm animals during the first year of life. Outcomes of interest were child BMI percentile (adjusted for gender and age) categorized as normal/underweight (<85th percentile), overweight (85th to <95th), and obese (≥95th), and percent fat mass (continuous). Associations were analyzed using multinomial logistic regression and multivariable linear regression, respectively, with and without multiple imputation. Results First-year animal exposure occurred in 245 of 770 (31.8%) children. Children with early animal exposure had 0.53 (95% CI: 0.28, 0.997) times the odds of being in the obese BMI category compared to those exposed to animals after controlling for covariates: maternal pre-pregnancy BMI, race/ethnicity, reported child activity level, receiving food assistance, age child began daycare (<1 year vs 1+), exclusively breastfed x6 months, and NICU admission (n = 721). Children with early animal exposure had, on average, 1.5% (95% CI: −3.0, −0.1) less fat mass than exposed children after adjustment for maternal BMI, race/ethnicity, activity, food assistance, breastfeeding, and maternal education (n = 548). Multiple imputation did not alter either result. Conclusion These results provide evidence that exposure to dogs or farm animals in the first year of life is associated with lower odds of obesity and lower percent fat mass in childhood.
Background: Enediynes are anti-cancer agents that are highly cytotoxic due to their propensity for low thermal activation of radical generation. The diradical intermediate produced from Bergman cyclization of the enediyne moiety may induce DNA damage and cell lethality. The cytotoxicity of enediynes and difficulties in controlling their thermal cyclization has limited their clinical use. We recently showed that enediyne toxicity at 37 °C can be mitigated by metallation, but cytotoxic effects of 'metalloenediynes' on cultured tumor cells are potentiated by hyperthermia. Reduction of cytotoxicity at normothermia suggests metalloenediynes will have a large therapeutic margin, with cell death occurring primarily in the heated tumor. Based on our previous in vitro findings, FeSO4-PyED, an Fe co-factor complex of (Z)-N,N'-bis[1-pyridin-2-yl-meth-(E)-ylidene]oct-4-ene-2,6-diyne-1,8-diamine, was prioritized for further in vitro and in vivo testing in normal human melanocytes and melanoma cells. Methods: Clonogenic survival, apopotosis and DNA binding assays were used to determine mechanisms of enhancement of FeSO4-PyED cytotoxicity by hyperthermia. A murine human melanoma xenograft model was used to assess in vivo efficacy of FeSO4-PyED at 37 or 42.5 °C. Results: FeSO4-PyED is a DNA-binding compound. Enhancement of FeSO4-PyED cytotoxicity by hyperthermia in melanoma cells was due to Bergman cyclization, diradical formation, and increased apoptosis. Thermal enhancement, however, was not observed in melanocytes. FeSO4-PyED inhibited tumor growth when melanomas were heated during drug treatment, without inducing normal tissue damage. Conclusion: By leveraging the unique thermal activation properties of metalloenediynes, we propose that localized moderate hyperthermia can be used to confine the cytotoxicity of these compounds to tumors, while sparing normal tissue.
Background: Overweight and obesity are major risk factors for noncommunicable diseases. This presents a major burden to health systems and to society in South Africa. Collectively, these conditions are overwhelming public healthcare. This is happening when the country has embarked on a journey to universal health coverage, hence the need to estimate the cost of overweight and obesity. Objective: Our objective was to estimate the healthcare cost associated with treatment of weight-related conditions from the perspective of the South African public sector payer. Methods: Using a bottom-up gross costing approach, this study draws data from multiple sources to estimate the direct healthcare cost of overweight and obesity in South Africa. Population Attributable Fractions (PAF) were calculated and multiplied by each disease’s total treatment cost to apportion costs to overweight and obesity. Annual costs were estimated for 2020. Results: The total cost of overweight and obesity is estimated to be ZAR33,194 million in 2020. This represents 15.38% of government health expenditure and is equivalent to 0.67% of GDP. Annual per person cost of overweight and obesity is ZAR2,769. The overweight and obesity cost is disaggregated as follows: cancers (ZAR352 million), cardiovascular diseases (ZAR8,874 million), diabetes (ZAR19,861 million), musculoskeletal disorders (ZAR3,353 million), respiratory diseases (ZAR360 million) and digestive diseases (ZAR395 million). Sensitivity analyses show that the total overweight and obesity cost is between ZAR30,369 million and ZAR36,207 million. Conclusion: This analysis has demonstrated that overweight and obesity impose a huge financial burden on the public health care system in South Africa. It suggests an urgent need for preventive, population-level interventions to reduce overweight and obesity rates. The reduction will lower the incidence, prevalence, and healthcare spending on noncommunicable diseases. © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Osteopontin (OPN) is produced by tumor cells as well as by myeloid cells and is enriched in the tumor microenvironment (TME) of many cancers. Given the roles of OPN in tumor progression and immune suppression, we hypothesized that targeting OPN with aptamers that have high affinity and specificity could be a promising therapeutic strategy. Bi-specific aptamers targeting ligands for cellular internalization were conjugated to siRNAs to suppress OPN were created, and therapeutic leads were selected based on target engagement and in vivo activity. Aptamers as carriers for siRNA approaches were created including a cancer targeting nucleolin aptamer Ncl-OPN siRNA and a myeloid targeting CpG oligodeoxynucleotide (ODN)-OPN siRNA conjugate. These aptamers were selected as therapeutic leads based on 70-90% OPN inhibition in cancer (GL261, 344SQ, 4T1B2b) and myeloid (DC2.4) cells relative to scramble controls. In established immune competent 344SQ lung cancer and 4T1B2b breast cancer models, these aptamers, including in combination, demonstrate therapeutic activity by inhibiting tumor growth. The Ncl-OPN siRNA aptamer demonstrated efficacy in an immune competent orthotopic glioma model administered systemically secondary to the ability of the aptamer to access the glioma TME. Therapeutic activity was demonstrated using both aptamers in a breast cancer brain metastasis model. Targeted inhibition of OPN in tumor cells and myeloid cells using bifunctional aptamers that are internalized by specific cell types and suppress OPN expression once internalized may have clinical potential in cancer treatment.
The majority of patients with metastatic colorectal cancer (CRC) to the liver are not amenable to curative-intent surgery or thermal ablation; there is a need for alternative locoregional therapies to control oligometastatic liver disease. Sequential lobar Yttrium-90 (Y90) radioembolization has demonstrated favorable results in the salvage setting for CRC patients with liver only or liver-dominant metastatic disease, but the role of Y90 in earlier-stage disease has not shown to be as promising. Recently, radiation segmentectomy, the super selective delivery of high (ablative) dose Y90 microspheres, has been introduced as a novel approach for patients with unresectable hepatocellular carcinoma. This review provides an overview of the current role of Y90 radioembolization for CRC patients with metastasis to the liver, with specific focus on the evolving application of radiation segmentectomy for patients with limited hepatic metastases from colorectal cancer.
BACKGROUND: One of the challenges of the 21st century is the high turnover rate in the nursing profession due to burnout and mental illness. From a biopsychosocial perspective, an individual's personality is an important vulnerability-resilience factor that comprises four temperament traits (i.e., a person's emotional reactions) and three character traits (i.e., self-regulation systems). Indeed, different personality profiles are associated to different coping strategies and health outcomes. OBJECTIVE: We investigated and mapped the temperament and character of Swedish newly graduated and employed nurses’ in relation to the Swedish general population and an age-matched sub-sample. DESIGN: In this cross-sectional study, nurses self-reported their personality (Temperament and Character Inventory) at the beginning of their employment. SETTING: The data collection was conducted at a hospital in the South of Sweden. PARTICIPANTS: A total of 118 newly graduated and employed nurses (Mage = 25.95±5.58) and 1,564 individuals from the Swedish general population participated in the study. METHODS: We calculated T-scores and percentiles for all seven personality dimensions using the Swedish norms (N = 1,564). The profiles were calculated by combining high/low percentiles scores in three temperament dimensions (Novelty Seeking: N/n, Harm Avoidance: H/h, and Reward Dependence: R/r) and in the three character dimensions (Self-Directedness: S/s, Cooperativeness: C/c and Self-Transcendence: T/t). RESULTS: Regarding T-scores, the nurses reported moderately lower Novelty Seeking (> 0.5 SD), slightly higher Harm-Avoidance (about 0.5 SD), moderately higher Persistence (> 0.5 SD) and Reward Dependence (> 0.5 SD), and extremely lower Self-Directedness (> 1 SD). The prevalence of the most common temperament profiles among the nurses (Swedish general population in brackets) were: 39.80% [10.90%] Cautious (nHR), 21.20% [10.90] Reliable (nhR), and 15.30% [16.50%] Methodical (nHr). The prevalence of the most common character profiles among the nurses were: 31.40% [4.90%] Dependent (sCt), 25.40% [14.40%] Apathetic (sct), and 19.50% [8.80%] Moody (sCT). CONCLUSIONS: The analyses of the personality profiles showed that low Novelty Seeking (79%), high Harm Avoidance (65%) high Reward Dependence (80%), low Self-Directedness (95%), and low Self-Transcendence (60%) were more prevalent among the newly graduated and employed nurses. This may partially explain newly graduated nurses’ difficulties at work and high turnover rate. After all, a well-developed character is of special importance when working with patients with serious and terminal illness or under large global crises, such as the current pandemic. Hence, both education at universities and development at work need to be person-centered to reduce stress levels and promote positive self-regulation strategies.
In this conceptual paper, we describe the approach in storylines that builds on principles of project-based learning and focuses on supports for making science learning coherent from the students’ perspective. In storylines, students see their science work as addressing questions and problems their class has identified. We present design principles that guide the teaching and enactment of storyline units and explore the connections of these principles to ideas of project-based science. We illustrate how these design strategies are reflected in a high school biology unit co-developed by teachers and researchers. We present student artifacts that document the agency students take on in this work. We then summarize results from earlier studies examining students’ learning and perceptions of coherence of their learning experiences.
Recent advances in technology and expanding therapeutic opportunities in neuromuscular disorders has resulted in greater interest in and development of remote assessments. Over the past year, the rapid and abrupt COVID-19 shutdowns and stay-at-home orders imposed challenges to routine clinical management and clinical trials. As in-person services were severely limited, clinicians turned to remote assessments through telehealth to allow for continued care. Typically, disease-specific clinical outcome assessments (COAs) for neuromuscular disorders (NMD) are developed over many years through rigorous and iterative processes to fully understand their psychometric properties. While efforts were underway towards developing remote assessments for NMD before the pandemic, few if any were fully developed or validated. These included assessments of strength, respiratory function and patient-reported outcomes, as well as wearable technology and other devices to quantify physical activity and function. Without many choices, clinicians modified COAs for a virtual environment recognizing it was not yet known how they compared to standard in-person administration. Despite being able to quickly adapt to the demands of the COVID-19 pandemic, these experiences with remote assessments uncovered limitations and opportunities. It became clear that existing COAs required modifications for use in a virtual environment limiting the interpretation of the information gathered. Still, the opportunity for real-world evaluation and reduced patient burden were clear benefits to remote assessment and may provide a more robust understanding and characterization of disease impact in NMD. Hence, we propose a roadmap navigating an informed post-pandemic path toward development and implementation of safe and successful use of remote assessments for patients with NMD.
Background Although prior reports have evaluated the clinical and cost impacts of cardiovascular magnetic resonance (CMR) for low-to-intermediate-risk patients with suspected significant coronary artery disease (CAD), the cost-effectiveness of CMR compared to relevant comparators remains poorly understood. We aimed to summarize the cost-effectiveness literature on CMR for CAD and create a cost-effectiveness calculator, useable worldwide, to approximate the cost-per-quality-adjusted-life-year (QALY) of CMR and relevant comparators with context-specific patient-level and system-level inputs. Methods We searched the Tufts Cost-Effectiveness Analysis Registry and PubMed for cost-per-QALY or cost-per-life-year-saved studies of CMR to detect significant CAD. We also developed a linear regression meta-model (CMR Cost-Effectiveness Calculator) based on a larger CMR cost-effectiveness simulation model that can approximate CMR lifetime discount cost, QALY, and cost effectiveness compared to relevant comparators [such as single-photon emission computed tomography (SPECT), coronary computed tomography angiography (CCTA)] or invasive coronary angiography. Results CMR was cost-effective for evaluation of significant CAD (either health-improving and cost saving or having a cost-per-QALY or cost-per-life-year result lower than the cost-effectiveness threshold) versus its relevant comparator in 10 out of 15 studies, with 3 studies reporting uncertain cost effectiveness, and 2 studies showing CCTA was optimal. Our cost-effectiveness calculator showed that CCTA was not cost-effective in the US compared to CMR when the most recent publications on imaging performance were included in the model. Conclusions Based on current world-wide evidence in the literature, CMR usually represents a cost-effective option compared to relevant comparators to assess for significant CAD.
Background Leucine rich repeat kinase 2 ( LRRK2 ) and SNCA are genetically linked to late-onset Parkinson’s disease (PD). Aggregated α-synuclein pathologically defines PD. Recent studies identified elevated LRRK2 expression in pro-inflammatory CD16+ monocytes in idiopathic PD, as well as increased phosphorylation of the LRRK2 kinase substrate Rab10 in monocytes in some LRRK2 mutation carriers. Brain-engrafting pro-inflammatory monocytes have been implicated in dopaminergic neurodegeneration in PD models. Here we examine how α-synuclein and LRRK2 interact in monocytes and subsequent neuroinflammatory responses. Methods Human and mouse monocytes were differentiated to distinct transcriptional states resembling macrophages, dendritic cells, or microglia, and exposed to well-characterized human or mouse α-synuclein fibrils. LRRK2 expression and LRRK2-dependent Rab10 phosphorylation were measured with monoclonal antibodies, and myeloid cell responses to α-synuclein fibrils in R1441C-Lrrk2 knock-in mice or G2019S-Lrrk2 BAC mice were evaluated by flow cytometry. Chemotaxis assays were performed with monocyte-derived macrophages stimulated with α-synuclein fibrils and microglia in Boyden chambers. Results α-synuclein fibrils robustly stimulate LRRK2 and Rab10 phosphorylation in human and mouse macrophages and dendritic-like cells. In these cells, α-synuclein fibrils stimulate LRRK2 through JAK-STAT activation and intrinsic LRRK2 kinase activity in a feed-forward pathway that upregulates phosphorylated Rab10. In contrast, LRRK2 expression and Rab10 phosphorylation are both suppressed in microglia-like cells that are otherwise highly responsive to α-synuclein fibrils. Corroborating these results, LRRK2 expression in the brain parenchyma occurs in pro-inflammatory monocytes infiltrating from the periphery, distinct from brain-resident microglia. Mice expressing pathogenic LRRK2 mutations G2019S or R1441C have increased numbers of infiltrating pro-inflammatory monocytes in acute response to α-synuclein fibrils. In primary cultured macrophages, LRRK2 kinase inhibition dampens α-synuclein fibril and microglia-stimulated chemotaxis. Conclusions Pathologic α-synuclein activates LRRK2 expression and kinase activity in monocytes and induces their recruitment to the brain. These results predict that LRRK2 kinase inhibition may attenuate damaging pro-inflammatory monocyte responses in the brain.
The use of digital tools to measure physiological and behavioural variables of potential relevance to mental health is a growing field sitting at the intersection between computer science, engineering, and clinical science. We summarised the literature on remote measuring technologies, mapping methodological challenges and threats to reproducibility, and identified leading digital signals for depression. Medical and computer science databases were searched between January 2007 and November 2019. Published studies linking depression and objective behavioural data obtained from smartphone and wearable device sensors in adults with unipolar depression and healthy subjects were included. A descriptive approach was taken to synthesise study methodologies. We included 51 studies and found threats to reproducibility and transparency arising from failure to provide comprehensive descriptions of recruitment strategies, sample information, feature construction and the determination and handling of missing data. The literature is characterised by small sample sizes, short follow-up duration and great variability in the quality of reporting, limiting the interpretability of pooled results. Bivariate analyses show consistency in statistically significant associations between depression and digital features from sleep, physical activity, location, and phone use data. Machine learning models found the predictive value of aggregated features. Given the pitfalls in the combined literature, these results should be taken purely as a starting point for hypothesis generation. Since this research is ultimately aimed at informing clinical practice, we recommend improvements in reporting standards including consideration of generalisability and reproducibility, such as wider diversity of samples, thorough reporting methodology and the reporting of potential bias in studies with numerous features.
Face memory, including the ability to recall a person’s name, is of major importance in social contexts. Like many other memory functions, it may rely on sleep. We investigated whether targeted memory reactivation during sleep could improve associative and perceptual aspects of face memory. Participants studied 80 face-name pairs, and then a subset of spoken names with associated background music was presented unobtrusively during a daytime nap. This manipulation preferentially improved name recall and face recognition for those reactivated face-name pairs, as modulated by two factors related to sleep quality; memory benefits were positively correlated with the duration of stage N3 sleep (slow-wave sleep) and negatively correlated with measures of sleep disruption. We conclude that (a) reactivation of specific face-name memories during sleep can strengthen these associations and the constituent memories, and that (b) the effectiveness of this reactivation depends on uninterrupted N3 sleep.
Inflammatory breast cancer (IBC) is an aggressive disease for which the spectrum of preclinical models was rather limited in the past. More recently, novel cell lines and xenografts have been developed. This study evaluates the transcriptome of an extended series of IBC preclinical models and performed a comparative analysis with patient samples to determine the extent to which the current models recapitulate the molecular characteristics of IBC observed clinically. We demonstrate that the IBC preclinical models are exclusively estrogen receptor (ER)-negative and of the basal-like subtype, which reflects to some extent the predominance of these subtypes in patient samples. The IBC-specific 79-signature we previously reported was retrained and discriminated between IBC and non-IBC preclinical models, but with a relatively high rate of false positive predictions. Further analyses of gene expression profiles revealed important roles for cell proliferation, MYC transcriptional activity, and TNFɑ/NFκB in the biology of IBC. Patterns of MYC expression and transcriptional activity were further explored in patient samples, which revealed interactions with ESR1 expression that are contrasting in IBC and nIBC and notable given the comparatively poor outcomes of ER+ IBC. Our analyses also suggest important roles for NMYC, MXD3, MAX, and MLX in shaping MYC signaling in IBC. Overall, we demonstrate that the IBC preclinical models can be used to unravel cancer cell intrinsic molecular features, and thus constitute valuable research tools. Nevertheless, the current lack of ER-positive IBC models remains a major hurdle, particularly since interactions with the ER pathway appear to be relevant for IBC.
Despite recent advances in the treatment of acute myeloid leukemia (AML), relapses remain high, and long-term survival is poor, emphasizing the need for better treatment options. Development of targeted antibody-based immunotherapeutic agents has been an area of growing research in AML. Target antigens of interest include CD33, CD123, CD47, CD70, FLT3, and CLL-1 because of their high expression on AML blasts and leukemic stem cells. Gemtuzumab ozogamicin, a CD33-directed antibody-drug conjugate, is the only Food and Drug Administration-approved monoclonal antibody (mAb) in AML providing evidence for the potential future role of mAb-based therapies in AML. This article provides an overview of the progress made in targeted immunotherapy in AML, particularly focusing on unconjugated and conjugated mAbs.
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