Search Results (8)

Background: Marfan syndrome (MFS) is a connective tissue disorder caused by FBN1 mutations, leading to elastic fiber disarray and early thoracic aortic aneurysm (TAA) formation. Currently, pharmacological treatments lack specificity and only delay progression. We previously reported a specific TGFβ-driven miR-632 upregulation in MFS TAA tissues and blood causing smooth muscle cell dedifferentiation and aortic wall degeneration. This study evaluated the effects of three conventional antihypertensive drugs (β-blocker, ACE inhibitor, and sartan) on parietal remodeling, comparing them with a miR-632 inhibitor in an ex vivo TGFβ1-induced model of MFS TAA. Methods and Results: Using an ex vivo paired experimental framework based on independent biological pools of human TAA tissue, gene expression and Western blot analyses demonstrated that only losartan significantly reduced miR-632 and vascular degeneration markers. Notably, combined treatment with ramipril and carvedilol compromised losartan’s efficacy, highlighting the need for careful therapeutic selection. In this ex vivo setting, miR-632 inhibition demonstrated a promising capacity to counteract aortic remodeling, serving as a mechanistic proof-of-concept that warrants further preclinical in vivo validation. Conclusions: Our data emphasize that choosing the right treatment in MFS aortopathy requires understanding its specific impact on cellular pathways. Our findings identify losartan as the most effective standard drug in this model, while suggesting miR-632 as a potential future target to stabilize the aortic wall and, prospectively, delay surgery. Full article

The 2025 approval of the selective NaV1.8 blocker suzetrigine for acute pain marked a pivotal advance in analgesic drug development. Yet the subsequent failure of Vertex’s next-generation NaV1.8 inhibitor VX993 to demonstrate clinical analgesia underscores enduring challenges in translating mechanistic promise into patient benefit. This review examines why promising targets and compounds, spanning NaV and TRP channels, often falter and outlines a path toward more reliable target selection and validation. I first summarize the pain pathway, from nociceptor transduction through spinal processing to cortical perception, emphasizing how inflammation and peripheral sensitization reshape excitability. Historically serendipitous, pain drug discovery now prioritizes molecular precision. Most approved chronic pain therapies act in the CNS and are limited by modest efficacy and adverse effects. Nociceptor-enriched targets (NaV1.7/1.8/1.9; TRP channels) remain attractive, yet redundancy among NaV subtypes and the necessity of blocking targets at the correct anatomical sites complicate translation. Human genetics and multi-omics provide a powerful, unbiased engine for target discovery. Rare high-impact variants offer strong causal hypotheses, while common polygenic contributions illuminate broader susceptibility. Large biobanks increasingly reveal a mismatch between legacy pain targets and genetically supported candidates across neuronal and non-neuronal cells. Human DRG transcriptomics highlight NaV channel redundancy. Human in vitro electrophysiology and PK/PD analyses show suzetrigine achieves ~90–95% NaV1.8 engagement, yet neurons can still fire unless additional channels are blocked. Species differences and drug distribution (including BBB/PNS penetration and P-gp efflux) critically influence efficacy; centrally accessible blockade (e.g., for NaV1.7 or TRPA1) may be necessary to achieve robust analgesia, challenging peripherally restricted strategies. Osteoarthritis illustrates how obesity-driven metabolic inflammation, synovial immune activation, subchondral bone remodeling, and specific nociceptor subtypes converge to drive mechanical pain. Multi-omic integration across diseased human tissues can pinpoint causal processes and cell types, enabling more selective and safer target choices. I propose a practical framework for target validation that integrates: (i) rigorous human genetic support; (ii) cell-type and site-of-action mapping; (iii) human-relevant electrophysiology and PK/PD with verified target engagement; (iv) species-appropriate models; (v) consideration of modality (small molecule, biologic, RNA, targeted protein degradation). Advancing genetically and anatomically aligned targets, tested at the right sites and exposures, offers the best path to genuinely effective, better-tolerated pain therapeutics. Full article

AI has the potential to revolutionize mental health services by providing personalized support and improving accessibility. However, it is crucial to address ethical concerns to ensure responsible and beneficial outcomes for individuals. This systematic review examines the ethical considerations surrounding the implementation and impact of artificial intelligence (AI) interventions in the field of mental health and well-being. To ensure a comprehensive analysis, we employed a structured search strategy across top academic databases, including PubMed, PsycINFO, Web of Science, and Scopus. The search scope encompassed articles published from 2014 to 2024, resulting in a review of 51 relevant articles. The review identifies 18 key ethical considerations, including 6 ethical considerations associated with using AI interventions in mental health and wellbeing (privacy and confidentiality, informed consent, bias and fairness, transparency and accountability, autonomy and human agency, and safety and efficacy); 5 ethical principles associated with the development and implementation of AI technologies in mental health settings to ensure responsible practice and positive outcomes (ethical framework, stakeholder engagement, ethical review, bias mitigation, and continuous evaluation and improvement); and 7 practices, guidelines, and recommendations for promoting the ethical use of AI in mental health interventions (adhere to ethical guidelines, ensure transparency, prioritize data privacy and security, mitigate bias and ensure fairness, involve stakeholders, conduct regular ethical reviews, and monitor and evaluate outcomes). This systematic review highlights the importance of ethical considerations in the responsible implementation and impact of AI interventions for mental health and well-being. By addressing privacy, bias, consent, transparency, human oversight, and continuous evaluation, we can ensure that AI interventions like chatbots and AI-enabled medical devices are developed and deployed in an ethically sound manner, respecting individual rights, promoting fairness, and maximizing benefits while minimizing potential harm. Full article

In autonomous vehicles (AVs), ensuring pedestrian safety within intricate and dynamic settings, particularly at crosswalks, has gained substantial attention. While AVs perform admirably in standard road conditions, their integration into unique environments like shared spaces devoid of traditional traffic infrastructure control presents complex challenges. These challenges involve issues of right-of-way negotiation and accessibility, particularly in “naked streets”. This research delves into an innovative smart pole interaction unit (SPIU) with an external human–machine interface (eHMI). Utilizing virtual reality (VR) technology to evaluate the SPIU efficacy, this study investigates its capacity to enhance interactions between vehicles and pedestrians at crosswalks. The SPIU is designed to communicate the vehicles’ real-time intentions well before arriving at the crosswalk. The study findings demonstrate that the SPIU significantly improves secure decision making for pedestrian passing and stops in shared spaces. Integrating an SPIU with an eHMI in vehicles leads to a substantial 21% reduction in response time, greatly enhancing the efficiency of pedestrian stops. Notable enhancements are observed in unidirectional (one-way) and bidirectional (two-way) scenarios, highlighting the positive impact of the SPIU on interaction dynamics. This work contributes to AV–pedestrian interaction and underscores the potential of fuzzy-logic-driven solutions in addressing complex and ambiguous pedestrian behaviors. Full article

The occurrence of antimicrobial resistance due to the use of antimicrobials is considered to be a main cause for treatment failure of bacterial infections in humans and animals. The right of German veterinarians to use and prescribe medications such as antimicrobials is regulated by the Regulation of Veterinary Pharmacies (TÄHAV). The aim of this study was to investigate the impact of the second amendment to the TÄHAV in 2018 on the occurrence of antimicrobial resistance in selected bacterial pathogens isolated from dogs and cats in Germany. For this purpose, we analyzed antimicrobial susceptibility data from 38 German small animal practices gathered between 2015 and 2021 in cooperation with Laboklin (Labor für klinische Diagnostik GmbH & Co.KG, Bad Kissingen, Germany). Annual cumulative susceptibility data of eight bacterial species were analyzed and compared. The mean value of resistant isolates was determined for each year and supplemented by 95% confidence intervals. Encouraged by the amendment, an increase in sample submissions was observed in Germany. The highest resistance rates to the analyzed substances penicillin G, ampicillin, amoxicillin-clavulanic acid, cefovecin, and enrofloxacin were found for Staphylococcus pseudintermedius (S. pseudintermedius), S. aureus, and Escherichia coli (E. coli). In contrast, resistance rates were low for Pasteurella multocida (P. multocida) and β-hemolytic streptococci. Significant resistance trends (p < 0.05) assumed as influenced by the TÄHAV amendment could be the significant decreases in resistance rates of S. pseudintermedius against penicillin G to 67% (n = 322/479), and ampicillin to 63% (n = 286/453), as well as S. felis against amoxicillin-clavulanic acid and cefovecin to 2% (n = 2/109), furthermore, the reduction in the occurrence of resistance of S. aureus against enrofloxacin to 4% (n = 3/76) in 2021. Moreover, for all species, the efficacy against the analyzed substances was maintained over the study period. Full article

The Coronavirus Disease 2019 (COVID-19) pandemic impacted peoples’ livelihoods and mental wellbeing. Aboriginal and Torres Strait Islander peoples in Australia continue to experience intergenerational trauma associated with colonization and may experience trauma-related distress in response to government responses to public health emergencies. We aimed to develop a culturally responsive trauma-informed public health emergency response framework for Aboriginal and Torres Strait Islander peoples. This Aboriginal and Torres Strait Islander-led study involved: (i) a review of trauma-informed public health emergency responses to develop a draft framework (ii) interviews with 110 Aboriginal and Torres Strait Islander parents about how COVID-19 impacted their lives, and (iii) a workshop with 36 stakeholders about pandemic experiences using framework analysis to refine a culturally responsive trauma-informed framework. The framework included: an overarching philosophy (cultural humility, safety and responsiveness); key enablers (local leadership and Eldership); supporting strategies (provision of basic needs and resources, well-functioning social systems, human rights, dignity, choice, justice and ethics, mutuality and collective responsibility, and strengthening of existing systems); interdependent core concepts (safety, transparency, and empowerment, holistic support, connectedness and collaboration, and compassion, protection and caring); and central goals (a sense of security, resilience, wellbeing, self- and collective-efficacy, hope, trust, resilience, and healing from grief and loss). Full article

Recognition of the right to water in Indian courts has had little impact on the ground. This paper explores the seeming disjuncture between what happens in the court and the everyday reality of living with a less-than-perfect claim on city water services in India’s urban slums. The paper seeks to understand and contextualise a court ruling which looks like it declares a right to water for people in urban slums, but in effect gives them little beyond what they already had. The paper also looks at the ‘everyday reality’ of municipal administration and the provision of drinking water in slums through in-house connections and community taps. In both case studies, the author looks to understand how the practice relates to frameworks of law and policy that shape the rationality and scope of action of the actors concerned, both judges and municipal officials. She found that the issue of land was the main stumbling block in both places, but it was conceptualized a little differently in each situation. These case studies underscore the critical importance of making the local interface between poor people and the state more empowering in order for rights to become local and meaningful. Full article

Antimicrobial resistance (AMR) is one of the greatest challenges facing humanity in the 21st century. Controlled dispensation of antimicrobial drugs is the most echoed solution among many that have been postulated to counter this problem. However, the life-impacting significance of antimicrobials makes this approach a very complex one, which must be considered under the lens of health and planetary ethics. As the problem of AMR is not peculiar to only a few people, the right to know the risk, as well as decisions as to when and how antimicrobials are used should, not be granted to only a few decision makers, but be used as drivers to advance planetary health knowledge in a way that benefits individuals, society, and future generations. Within an ethical framework, implementing policies that extend the efficacy period of antimicrobials should be considered in a way that balances range, choice, and quality of drugs against stewardship activities. The challenge of AMR cannot be eliminated completely by reduced use of antimicrobials only; understanding how, where and when reduction is necessary, and social structures and patterns (as well as existing health and government systems) are required if any global/national intervention would be successful and equitable. We may well have gone past the stage of adopting precautionary principles as the danger we face presents no iota of uncertainty. The measures to control AMR’s emergence and its spread are well presented. Nevertheless, we must not ere from the path of justice and equity even in the face of certain danger. Full article