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Fasciolosis, caused by the liver flukes Fasciola hepatica and Fasciola gigantica, is a zoonotic parasitic disease associated with substantial economic losses in livestock. The transforming growth factor-beta signalling pathway is implicated in developmental processes and biological functions throughout the animal kingdom, including the Fasciola spp. It may also mediate host–helminth interactions during infection. In this work, we present an exploration of FgSmad4, the sole member of the Co-Smad protein family in F. gigantica. The isolated FgSmad4 cDNA was 4,014 bp in length encoding for a protein comprising 771 amino acids. FgSmad4 exhibited typical Co-Smad protein features, including Mad Homology 1 (MH1) and Mad Homology 2 (MH2) domains, a Nuclear Localisation Signal, a DNA-Binding Motif, and a Nuclear Export Signal. Sequence and phylogenetic analyses of FgSmad4 revealed that its MH1 and MH2 sequences are most similar to those of other trematode species. The MH1 domain, in particular, closely resembles the Co-Smad protein in mammalian hosts more than those in cestodes and nematodes. The expression patterns of FgSmad4 during the liver fluke’s developmental stages showed significant variation. Transcript levels were highest at the newly excysted juvenile stage, followed by unembryonated egg, redia, and metacercaria, with the lowest expression in the adult fluke, embryonated egg, and cercaria stages. Our results underscore the conservation and suggest the potential role of FgSmad4, a key transforming growth factor-beta signalling molecule within the liver fluke F. gigantica. As Co-Smad is typically involved in several biological pathways, the precise functions and mechanisms of this identified FgSmad4 necessitate further exploration.
Metabolic dysfunction has been long associated with severe mental illness (SMI), often viewed as a comorbidity to be managed. However, emerging evidence suggests that metabolic dysfunction, particularly at the mitochondrial level, may be a foundational element in the pathophysiology of neuropsychiatric disorders. This commentary expands on the current understanding by exploring the brain energy theory of mental illness, which posits that mitochondrial dysfunction is central to both metabolic and psychiatric conditions. The roles of insulin resistance, chronic stress and environmental factors are highlighted as shared biopsychosocial determinants that contribute to deterioration in both metabolic and mental health. The therapeutic potential of the ketogenic diet is discussed, particularly its ability to improve mitochondrial function and alleviate psychiatric symptoms. This shift in perspective, from viewing metabolic dysfunction as a secondary concern to recognising it as a root cause of SMI, has significant implications for clinical practice and research. By focusing on bioenergetic deficits and mitochondrial health, psychiatry may advance towards more effective, integrated treatment approaches that target the underlying cellular dysfunctions driving both metabolic and mental illnesses.
Zircon U-Pb geochronology, geochemistry and Hf isotope analysis of supracrustal rocks in the Anshan-Benxi area in the northeastern part of the North China Craton can help constrain their petrogenesis and tectonic background, providing evidence for a further investigation of the late Neoarchaean tectonic environment in the Anshan-Benxi area. The primary rock types observed among the supracrustal rocks in the Anshan-Benxi area comprise amphibolite, metamorphic rhyolite, metamorphic sandstone, chlorite schist, actinolite schist, among others. SHRIMP zircon U-Pb dating indicates that magmatic zircons from the amphibolite (GCN-1) formed at 2553 ± 18Ma. Similarly, LA-ICP-MS zircon U-Pb dating reveals that magmatic zircons from the metamorphic rhyolite (G2304-1) were formed at 2457 ± 35Ma. The peak age of the metamorphic sandstone is determined to be approximately 2500Ma, suggesting that the supracrustal rocks in the Anshan-Benxi area originated in the late Neoarchaean. The protoliths of sericite quartz schist and metamorphic rhyolite are identified as rhyolitic volcanic rocks, displaying a right-leaning distribution pattern of rare earth elements (REEs). On the other hand, actinolite schist, chlorite schist and amphibolite are classified as basaltic volcanic rocks, exhibiting a flat REE pattern with a weak negative Eu anomaly. The εHf(t) value of metamorphic rhyolite ranges between -1.19 and -1.47, with a two- stage depleted mantle model age of tDM2(Ma) = 2922–3132 Ma. The protolith magma of sericite quartz schist and metamorphic rhyolite originates from partial melting of 3.0Ga basaltic crust, while the source of actinolite schist, chlorite schist and amphibolite are mainly derived from the mantle. In summary, the findings suggest that plate already existed in the late Neoarchaean or earlier, with magmatism in the Anshan-Benxi area likely occurring within an arc tectonic environment linked to plate subduction.
The rapid development of generative artificial intelligence (AI) systems, particularly those fuelled by increasingly advanced large language models, has raised concerns of their potential risks among policymakers globally. In July 2023, Chinese regulators enacted the Interim Measures for the Management of Generative AI Services (“the Measures”). The Measures aim to mitigate various risks associated with public-facing generative AI services, particularly those concerning information content safety and security. China’s approach to regulating AI to date has sought to address the risks associated with rapidly advancing AI technologies while fostering innovation and development. Tensions between these policy objectives are reflected in the provisions of the Measures. As Beijing moves towards establishing a comprehensive legal framework for AI governance, there will be growing interest in how China’s approach may influence AI governance and regulation at a global level.
Large or “foundation” models are now being widely used to generate not just text and images but also video, music and code from prompts. Although this “generative AI” revolution is clearly driving new opportunities for innovation and creativity, it is also enabling easy and rapid dissemination of harmful speech and potentially infringing existing laws. Much attention has been paid recently to how we can draft bespoke legislation to control these risks and harms; however, private ordering by generative AI providers, via user contracts, licenses and privacy policies, has so far attracted less attention. Drawing on the extensive history of study of the terms and conditions (T&C) and privacy policies of social media companies, this paper reports the results of pilot empirical work conducted in January–March 2023, in which T&C were mapped across a representative sample of generative AI. With the focus on copyright and data protection, our early findings indicate the emergence of a “platformisation paradigm,” in which providers of generative AI attempt to position themselves as neutral intermediaries. This study concludes that new laws targeting “big tech” must be carefully reconsidered to avoid repeating past power imbalances between users and platforms.
This project was initiated in a large pediatric intensive care unit to reduce catheter-associated urinary tract infections (CAUTIs). Implementing removal of diapers and a urine collection device that prevented urine backflow in March 2021 decreased the rate from 3.3 to 0.9 CAUTIs/1000 catheter-days. These interventions could augment CAUTI prevention strategies.
Studying the effect of interleukin-17 (IL-17) on the mechanism of CD4+ T-cell immune regulation and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway may offer new ideas and methods for the therapy of dilated cardiomyopathy.
Methods:
Naive CD4+ T cells were isolated from mice using a magnetic bead sorting reagent and manipulated by overexpression or knockdown of IL-17. Protein levels of Janus kinase 2 (JAK2), phosphorylated JAK2 (p-JAK2), signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3 (p-STAT3), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) were determined by Western blotting. Quantitative polymerase chain reaction was used to assess the levels of JAK2, STAT3, MMP-2, and MMP-9. Expression of tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-4 (IL-4), and interferon-gamma (IFNγ) was determined by enzyme-linked immunosorbent assay test kits. TNF-α, IL-1β, IL-4, and IFNγ secretion was measured by flow cytometry.
Results:
In CD4+ T cells, IL-17 overexpression increased TNF-α, IL-1β, IL-4, IFNγ, p-JAK2, p-STAT3, MMP-2, MMP-9 levels, and apoptosis. Knockdown of IL-17 reduced the levels of TNF-α, IL-1β, IL-4, IFNγ, p-JAK2, p-STAT3, MMP-2, and MMP-9, as well as the level of apoptosis.
Conclusion:
Through regulation of IL-17 expression in CD4+ T cells, this study reveals its crucial role in regulating the secretion of inflammatory factors, activation of the JAK/STAT signaling pathway, expression of matrix metalloproteinases, and apoptosis of CD4+ T cells.
This article explores Vietnam’s distinctive approach to data privacy regulation and its implications for the established understandings of privacy law. While global data privacy regulations are premised on individual freedom and integrity of information flows, the recent Vietnamese Decree 13/2023/NĐ-CP on Personal Data Protection (herein PDPD) prioritise state oversight and centralised control over information flows to safeguard collective interests and cyberspace security. The fresh regulatory logic puts data privacy under the regulation of government agencies and moves the privacy law arena even further away from the already distant judicial power. This prompts an exploration of the nuances underlying the ways regulators and the regulated communities understand data privacy regulation. The article draws on social constructionist accounts of regulation and discourse analysis to explore the epistemic interaction between regulators and those subject to regulation during the PDPD’s drafting period. The process is highlighted by the dynamics between actors within a complex semantic network established by the state’s policy initiatives, where tacit assumptions and normative beliefs direct the way actors in various communities favour one type of thinking about data privacy regulation over another. The findings suggest that reforms to privacy laws may not result in “more privacy” to individuals and that divergences in global privacy regulation may not be easily explained by drawing merely from cultural and institutional variances.
This paper explores the regulatory awakening regarding generative AI (GenAI) in the United States and European Union (EU) institutions with the release of ChatGPT. Based on a thematic analysis of regulatory documents, it investigates how governments have approached the deployment and use of this emerging technology within their classic government activities. The analysis shows several layers of regulatory approaches, ranging from command-and-control to an experimental approach, combined with risk- and management-based approaches. It also reveals different perspectives. The EU institutions have notably adopted more restrictive guidelines on the use of publicly available Large Language Models (LLMs) - a type o GenAI that is trained on vast amounts of text data to understand, generate, and respond in human-like language. This approach reflects greater caution about data security and confidentiality and the risks of foreign interference. However, the American and EU documents share a common concern about the risk of reinforcing discrimination and the protection of human rights. Interestingly, considering the administrative environment, neither the administrative activities in which GenAI may be used nor the key legal principles embedded by the rule of law are explicitly used for guiding administration in their development and use of GenAI. In this context, the paper calls for future research that could help contribute to the renewal of administrative law theory in the context of the digital transformation of public administration.
Antidepressants are commonly prescribed for mood disorders. Epidemiological studies suggest antidepressant use may be associated with cataracts and glaucoma. We aim to investigate the association between antidepressants and cataracts and glaucoma.
Methods
Data was collected from the United States Food and Drug Administration Adverse Event Reporting System. Reporting odds ratio (ROR) and Bayesian information components (IC025) were calculated for antidepressants (ie, selective serotonin reuptake inhibitors [SSRIs], selective norepinephrine reuptake inhibitors [SNRIs], serotonin-norepinephrine-dopamine reuptake inhibitors, serotonin modulators and stimulators, serotonin antagonists and reuptake inhibitors [SARIs], norepinephrine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, tricyclic antidepressants [TCAs], tetracyclic antidepressants [TeCAs], and monoamine oxidase inhibitors [MAOIs]). The reference agent was acetaminophen.
Results
TeCAs and MAOIs were significantly associated with a decreased risk of cataracts (ROR = 0.11-0.65 and 0.16-0.69, respectively). TCAs, brexanolone, esketamine, and opipramol reported an increased cataract risk (ROR = 1.31-12.81). For glaucoma, SSRIs, SNRIs, SARIs, TCAs, MAOIs, and other investigated antidepressants reported significant RORs ranging from 1.034 to 21.17. There was a nonsignificant association of angle closure glaucoma (ACG) and open angle glaucoma (OAG) with the investigated antidepressants.
Limitations
For adverse event cases, multiple suspected product names are listed, and as cases are not routinely verified, there may be a possibility of duplicate reports and causality cannot be established.
Conclusion
Most of the investigated antidepressants were associated with a lower risk of cataract reporting. TCAs, brexanolone, esketamine, and opipramol were associated with greater odds of cataract. For most antidepressants, there was an insignificant increase in reports of ACG and OAG.
Extraintestinal pathogenic Escherichia coli (ExPEC) causes invasive E. coli disease (IED), including bacteraemia and (uro)sepsis, resulting in a high disease burden, especially among older adults. This study describes the epidemiology of IED in England (2013–2017) by combining laboratory surveillance and clinical data. A total of 191 612 IED cases were identified. IED incidence increased annually by 4.4–8.2% across all ages and 2.8–7.6% among adults ≥60 years of age. When laboratory-confirmed urosepsis cases without a positive blood culture were included, IED incidence in 2017 reached 149.4/100 000 person-years among all adults and 368.4/100 000 person-years among adults ≥60 years of age. Laboratory-confirmed IED cases were identified through E. coli-positive blood samples (55.3%), other sterile site samples (26.3%), and urine samples (16.6%), with similar proportions observed among adults ≥60 years of age. IED-associated case fatality rates ranged between 11.8–13.2% among all adults and 13.1–14.7% among adults ≥60 years of age. This study reflects the findings of other published studies and demonstrates IED constitutes a major and growing global health concern disproportionately affecting the older adult population. The high case fatality rates observed despite available antibiotic treatments emphasize the growing urgency for effective intervention strategies. The burden of urosepsis due to E. coli is likely underestimated and requires additional investigation.
Health technology assessment (HTA) guidelines are intended to support the successful implementation of HTA by enhancing consistency and transparency in concepts, methods, processes, and use, thereby enhancing the legitimacy of the decision-making process. This report lays out good practices and practical recommendations for developing or updating HTA guidelines to ensure successful implementation.
Methods
The task force was established in 2022 and comprised experts and academics from various geographical regions, each with substantial experience in developing HTA guidelines for national health policy making. Literature reviews and key informant interviews were conducted to inform these good practices. Stakeholder consultations, open peer reviews, and expert opinions validated the recommendations. A series of teleconferences among task force members was held to iteratively refine the report.
Results
The recommendations cover six key aspects throughout the guideline development cycle: (1) setting objectives, scope, and principles of the guideline, (2) building a team for a quality guideline, (3) defining a stakeholder engagement plan, (4) developing content and utilizing available resources, (5) putting in place appropriate institutional arrangements, and (6) monitoring and evaluating guideline success.
Conclusion
This report presents a set of resources and context-appropriate practices for developing or updating HTA guidelines. Across all contexts, the recommendations emphasize transparency, building trust among stakeholders, and fostering a culture of ongoing learning and improvement. The report recommends timing development and revision of guidelines according to the HTA landscape and pace of HTA institutionalization. Because HTA is increasingly used to inform different kinds of decision making in a variety of country contexts, it will be important to continue to monitor lessons learned to ensure the recommendations remain relevant and effective.
We are showing a significant enhancement in the temporal contrast by reducing the coherent noise of the 10 PW laser system at the Extreme Light Infrastructure - Nuclear Physics facility. The temporal contrast was improved by four orders of magnitude at 10 picoseconds and by more than one order of magnitude at 50 picoseconds before the main peak. This improvement of the picosecond contrast is critical for the experiments using thin solid targets.
Successfully educating urgent care patients on appropriate use and risks of antibiotics can be challenging. We assessed the conscious and subconscious impact various educational materials (informational handout, priming poster, and commitment poster) had on urgent care patients’ knowledge and expectations regarding antibiotics.
Design:
Stratified Block Randomized Control Trial.
Setting:
Urgent care centers (UCCs) in Colorado, Florida, Georgia, and New Jersey.
Participants:
Urgent care patients.
Methods:
We randomized 29 UCCs across six study arms to display specific educational materials (informational handout, priming poster, and commitment poster). The primary intention-to-treat (ITT) analysis evaluated whether the materials impacted patient knowledge or expectations of antibiotic prescribing by assigned study arm. The secondary as-treated analysis evaluated the same outcome comparing patients who recalled seeing the assigned educational material and patients who either did not recall seeing an assigned material or were in the control arm.
Results:
Twenty-seven centers returned 2,919 questionnaires across six study arms. Only 27.2% of participants in the intervention arms recalled seeing any educational materials. In our primary ITT analysis, no difference in knowledge or expectations of antibiotic prescribing was noted between groups. However, in the as-treated analysis, the handout and commitment poster were associated with higher antibiotic knowledge scores.
Conclusions:
Educational materials in UCCs are associated with increased antibiotic-related knowledge among patients when they are seen and recalled; however, most patients do not recall passively displayed materials. More emphasis should be placed on creating and drawing attention to memorable patient educational materials.