RESUMEN
Investigating the genomic epidemiology of major bacterial pathogens is integral to understanding transmission, evolution, colonization, disease, antimicrobial resistance and vaccine impact. Furthermore, the recent accumulation of large numbers of whole genome sequences for many bacterial species enhances the development of robust genome-wide typing schemes to define the overall bacterial population structure and lineages within it. Using the previously published data, we developed the Pneumococcal Genome Library (PGL), a curated dataset of 30 976 genomes and contextual data for carriage and disease pneumococci recovered between 1916 and 2018 in 82 countries. We leveraged the size and diversity of the PGL to develop a core genome multilocus sequence typing (cgMLST) scheme comprised of 1222 loci. Finally, using multilevel single-linkage clustering, we stratified pneumococci into hierarchical clusters based on allelic similarity thresholds and defined these with a taxonomic life identification number (LIN) barcoding system. The PGL, cgMLST scheme and LIN barcodes represent a high-quality genomic resource and fine-scale clustering approaches for the analysis of pneumococcal populations, which support the genomic epidemiology and surveillance of this leading global pathogen.
Asunto(s)
Código de Barras del ADN Taxonómico , Genoma Bacteriano , Tipificación de Secuencias Multilocus , Infecciones Neumocócicas , Streptococcus pneumoniae , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/clasificación , Streptococcus pneumoniae/aislamiento & purificación , Tipificación de Secuencias Multilocus/métodos , Humanos , Código de Barras del ADN Taxonómico/métodos , Infecciones Neumocócicas/microbiología , Infecciones Neumocócicas/epidemiología , Filogenia , Biblioteca de Genes , Secuenciación Completa del Genoma/métodosRESUMEN
BACKGROUND: The discourse surrounding medical artificial intelligence (AI) often focuses on narratives that either hype the technology's potential or predict dystopian futures. AI narratives have a significant influence on the direction of research, funding, and public opinion and thus shape the future of medicine. OBJECTIVE: The paper aims to offer critical reflections on AI narratives, with a specific focus on medical AI, and to raise awareness as to how people working with medical AI talk about AI and discharge their "narrative responsibility." METHODS: Qualitative semistructured interviews were conducted with 41 participants from different disciplines who were exposed to medical AI in their profession. The research represents a secondary analysis of data using a thematic narrative approach. The analysis resulted in 2 main themes, each with 2 other subthemes. RESULTS: Stories about the AI-physician interaction depicted either a competitive or collaborative relationship. Some participants argued that AI might replace physicians, as it performs better than physicians. However, others believed that physicians should not be replaced and that AI should rather assist and support physicians. The idea of excessive technological deferral and automation bias was discussed, highlighting the risk of "losing" decisional power. The possibility that AI could relieve physicians from burnout and allow them to spend more time with patients was also considered. Finally, a few participants reported an extremely optimistic account of medical AI, while the majority criticized this type of story. The latter lamented the existence of a "magical theory" of medical AI, identified with techno-solutionist positions. CONCLUSIONS: Most of the participants reported a nuanced view of technology, recognizing both its benefits and challenges and avoiding polarized narratives. However, some participants did contribute to the hype surrounding medical AI, comparing it to human capabilities and depicting it as superior. Overall, the majority agreed that medical AI should assist rather than replace clinicians. The study concludes that a balanced narrative (that focuses on the technology's present capabilities and limitations) is necessary to fully realize the potential of medical AI while avoiding unrealistic expectations and hype.
RESUMEN
Sacrificial dilemmas such as the trolley problem play an important role in experimental philosophy (x-phi). But it is increasingly argued that, since we are not likely to encounter runaway trolleys in our daily life, the usefulness of such thought experiments for understanding moral judgments in more ecologically valid contexts may be limited. However, similar sacrificial dilemmas are experienced in real life by animal research decision makers. As part of their job, they must make decisions about the suffering, and often the death, of many non-human animals. For this reason, a context-specific investigation of so-called "3R dilemmas" (i.e., dilemmas where there is a conflict between the principles of replacement, reduction, and refinement of the use of animals in research) is essential to improve the situation of both non-human animals and human stakeholders. An approach well suited for such investigation is experimental philosophical bioethics ("bioxphi"), which draws on methods similar to x-phi to probe more realistic, practical scenarios with an eye to informing normative debates and ethical policy. In this article, we argue for a need to investigate 3R dilemmas among professional decision-makers using the tools of bioxphi. In a first step, we define 3R dilemmas and discuss previous investigations of professionals' attitudes in such cases. In a second step, we show how bioxphi is a promising method to investigate the whys and hows of professional decision-making in 3R dilemmas. In a last step, we provide a bioxphi template for 3R dilemmas, give recommendations on its use, explore the normative relevance of data collected by such means, and discuss important limitations.
RESUMEN
In Switzerland, the importance of transparency in animal experimentation is emphasized by the Swiss Federal Council, recognizing the public's great interest in this matter. Federal reporting on animal experimentation indicates a total of 585,991 animals used in experiments in Switzerland in 2022. By Swiss law, the report enables the public to learn about many aspects such as the species and degree of suffering experienced by the animals, but some information of interest to the public is missing, such as the fate of the animals at the end of the experiment (e.g., euthanized, rehomed in a private home, reused in another experiment). When it comes to animals bred in facilities but not used in experiments, further information of interest is not required to be made public according to Swiss law, for example, the number and fate of "surplus" animals (i.e., animals bred but not used in experiments for a variety of reasons such as not carrying the phenotypical properties needed). Considering that the Swiss government has a duty to provide a full accounting of animal experimentation conducted on the public's behalf, further relevant information should be disclosed. While efforts toward transparency, such as the STAAR Agreement, have been made in the scientific community, these mostly reflect the legal requirements already in force. If Switzerland is to move toward more transparency in public information on animal experimentation, an update of the legal requirements is needed. In this article, we give recommendations for Swiss law to move toward more transparency in public information on seven aspects: (1) the fate of the animals at the end of the experiment; (2) the sources of funding for animal experimentation; (3) the harm-benefit analysis performed by researchers and ethics committees to justify an experiment using animals; (4) the number of breeding/surplus animals; (5) the fate of breeding/surplus animals; (6) the harms experienced by animals in facilities; and (7) the funding of animal facilities.
RESUMEN
Plasmid DNA (pDNA) is an essential tool in genetic engineering that has gained prevalence in cell and gene therapies. Plasmids exist as supercoiled (SC), open circular (OC), and linear forms. Plasmid multimerization can also occur during the manufacturing process. Even though the SC forms are thought to provide optimal knock-in (KI) efficiency, there is no strong consensus on the effect of the topological forms and multimers on the functional activity. In addition, the results obtained for conventional pDNAs (>5 kbp) do not necessarily translate to smaller pDNAs (â¼3 kbp). In this study, a workflow was developed for the analytical and functional characterization of pDNA topological forms and multimers. An anion exchange chromatography (AEC) method was first developed to quantify the topological forms and multimers. Four AEC columns were initially compared, one of which was found to provide superior chromatographic performance. The effect of mobile phase pH, various salts, column temperature, and acetonitrile content on the separation performance was systematically studied. The method performance, including precision and accuracy, was evaluated. The final AEC method was compared to capillary gel electrophoresis (CGE) by analyzing several pDNA sequences and lots. A forced degradation study revealed unexpectedly high degradation of the SC forms. Finally, the KI efficiency was compared for the SC and OC forms, and the multimers.
Asunto(s)
Plásmidos , Plásmidos/genética , Cromatografía por Intercambio Iónico , Electroforesis Capilar , ADN/química , Concentración de Iones de HidrógenoRESUMEN
While the technologies that enable Artificial Intelligence (AI) continue to advance rapidly, there are increasing promises regarding AI's beneficial outputs and concerns about the challenges of human-computer interaction in healthcare. To address these concerns, institutions have increasingly resorted to publishing AI guidelines for healthcare, aiming to align AI with ethical practices. However, guidelines as a form of written language can be analyzed to recognize the reciprocal links between its textual communication and underlying societal ideas. From this perspective, we conducted a discourse analysis to understand how these guidelines construct, articulate, and frame ethics for AI in healthcare. We included eight guidelines and identified three prevalent and interwoven discourses: (1) AI is unavoidable and desirable; (2) AI needs to be guided with (some forms of) principles (3) trust in AI is instrumental and primary. These discourses signal an over-spillage of technical ideals to AI ethics, such as over-optimism and resulting hyper-criticism. This research provides insights into the underlying ideas present in AI guidelines and how guidelines influence the practice and alignment of AI with ethical, legal, and societal values expected to shape AI in healthcare.
Asunto(s)
Inteligencia Artificial , Atención a la Salud , Guías como Asunto , Confianza , Inteligencia Artificial/ética , Humanos , Atención a la Salud/ética , Principios MoralesRESUMEN
BACKGROUND: Data on the health-related quality of life (HRQoL) for invasive meningococcal disease (IMD) survivors, particularly among adolescents and young adults (AYAs), are limited. This study aimed to investigate the in-depth experiences and impacts of IMD on AYAs. METHODS: Participants were recruited from two Australian states, Victoria and South Australia. We conducted qualitative, semi-structured interviews with 30 patients diagnosed with IMD between 2016 and 2021. The interview transcripts were analyzed thematically. RESULTS: Of the participants, 53% were aged 15-19 years old, and 47% were aged 20-24. The majority (70%) were female. Seven themes relating to the participants' experience of IMD were identified: (1) underestimation of the initial symptoms and then rapid escalation of symptoms; (2) reliance on social support for emergency care access; (3) the symptoms prompting seeking medical care varied, with some key symptoms missed; (4) challenges in early medical diagnosis; (5) traumatic and life-changing experience; (6) a lingering impact on HRQoL; and (7) gaps in the continuity of care post-discharge. CONCLUSION: The themes raised by AYA IMD survivors identify multiple areas that can be addressed during their acute illness and recovery. Increasing awareness of meningococcal symptoms for AYAs may help reduce the time between the first symptoms and the first antibiotic dose, although this remains a challenging area for improvement. After the acute illness, conducting HRQoL assessments and providing multidisciplinary support will assist those who require more intensive and ongoing assistance during their recovery.
RESUMEN
Understanding the genetic basis of how plants defend against pathogens is important to monitor and maintain resilient tree populations. Swiss needle cast (SNC) and Rhabdocline needle cast (RNC) epidemics are responsible for major damage of forest ecosystems in North America. Here we investigate the genetic architecture of tolerance and resistance to needle cast diseases in Douglas-fir (Pseudotsuga menziesii) caused by two fungal pathogens: SNC caused by Nothophaeocryptopus gaeumannii, and RNC caused by Rhabdocline pseudotsugae. We performed case-control genome-wide association analyses and found disease resistance and tolerance in Douglas-fir to be polygenic and under strong selection. We show that stomatal regulation as well as ethylene and jasmonic acid pathways are important for resisting SNC infection, and secondary metabolite pathways play a role in tolerating SNC once the plant is infected. We identify a major transcriptional regulator of plant defense, ERF1, as the top candidate for RNC resistance. Our findings shed light on the highly polygenic architectures underlying fungal disease resistance and tolerance and have important implications for forestry and conservation as the climate changes.
Asunto(s)
Ascomicetos , Resistencia a la Enfermedad , Estudio de Asociación del Genoma Completo , Enfermedades de las Plantas , Pseudotsuga , Resistencia a la Enfermedad/genética , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/inmunología , Pseudotsuga/genética , Pseudotsuga/microbiología , Pseudotsuga/fisiología , Ascomicetos/fisiología , Ascomicetos/patogenicidad , Árboles/genética , Adaptación Fisiológica/genética , Herencia Multifactorial , Regulación de la Expresión Génica de las Plantas , Genes de PlantasRESUMEN
Background: Hepatitis C virus (HCV) infection can now be cured with well-tolerated direct-acting antiviral (DAA) therapy. However, a potential barrier to HCV elimination is the emergence of resistance-associated substitutions (RASs) that reduce the efficacy of antiviral drugs, but real-world studies assessing the clinical impact of RASs are limited. Here, an analysis of the impact of RASs on retreatment outcomes for different salvage regimens in patients nationally who failed first-line DAA therapy is reported. Methods: We collected data from 363 Australian patients who failed first-line DAA therapy, including: age, sex, fibrosis stage, HCV genotype, NS3/NS5A/NS5B RASs, details of failed first-line regimen, subsequent salvage regimens, and treatment outcome. Results: Of 240 patients who were initially retreated as per protocol, 210 (87.5%) achieved sustained virologic response (SVR) and 30 (12.5%) relapsed or did not respond. The SVR rate for salvage regimens that included sofosbuvir/velpatasvir/voxilaprevir was 94.3% (n = 140), sofosbuvir/velpatasvir 75.0% (n = 52), elbasvir/grazoprevir 81.6% (n = 38), and glecaprevir/pibrentasvir 84.6% (n = 13). NS5A RASs were present in 71.0% (n = 210) of patients who achieved SVR and in 66.7% (n = 30) of patients who subsequently relapsed. NS3 RASs were detected in 20 patients (20%) in the SVR group and 1 patient in the relapse group. NS5B RASs were observed in only 3 patients. Cirrhosis was a predictor of relapse after retreatment, as was previous treatment with sofosbuvir/velpatasvir. Conclusions: In our cohort, the SVR rate for sofosbuvir/velpatasvir/voxilaprevir was higher than with other salvage regimens. The presence of NS5A, NS5B, or NS3 RASs did not appear to negatively influence retreatment outcomes.
RESUMEN
Euthanasia in psychiatric patients presents unique challenges, especially when combined with organ donation. In this article, the hurdles psychiatric patients might encounter after expressing their wish for organ donation after euthanasia, are discussed and illustrated by the case of Martijn, a 45-year-old psychiatric patient who altruistically donated his organs after euthanasia. Hospital and physician-related factors, including caution in determination of mental capacity, consideration of conflicting interests, and healthcare staff stress are discussed as impediments to organ donation after euthanasia (ODE) in psychiatric patients. The primary objective of this article is to raise awareness among psychiatrists regarding the fact that although the combination of euthanasia and organ donation is an uncommonly performed procedure, it is frequently requested by psychiatric patients. In conclusion, the article advocates for a nuanced approach, respecting patients' altruistic wishes while at the same time addressing challenges associated with ODE in psychiatric suffering. Where possible, and within the current medical, ethical and legal boundaries, the importance of facilitating organ donation without unnecessarily prolonging the suffering of competent psychiatric patients seeking euthanasia is emphasized. The topic calls, for example, for further qualitative research to understand the stakeholders' perspectives to determine the perceived possibilities on the one hand and boundaries on the other.
RESUMEN
BACKGROUND: A barrier to hepatitis C virus (HCV) cure is conventional testing. The aim of this study was to evaluate the effect of HCV antibody and RNA point-of-care-testing (POCT) on testing rates, linkage to care, treatment and acceptability of testing in three priority settings in Australia. METHODS: Participants were enrolled in an interventional cohort study at a reception prison, inpatient mental health service (MHS), and inpatient alcohol and other drug (AOD) unit-between October 2020 and December 2021. HCV POCT was performed using SD Bioline HCV antibody fingerstick test and a reflexive Xpert® HCV Viral Load Fingerstick test using capillary blood samples. A retrospective audit of HCV testing and treatment data was performed at each site for the preceding 12-month period to generate a historical control. RESULTS: 1,549 participants received a HCV antibody test with 17% (264/1,549) receiving a positive result, of which 21% (55/264) tested HCV RNA positive. Across all settings the rate of testing per year significantly increased between the historical controls and the study intervention period by three-fold (RR:2.57 95% CI: 2.32, 2.85) for HCV antibody testing and four-fold (RR:1.62; 95% CI:1.31, 2.01) for RNA testing. Treatment uptake was higher during the POCT intervention (86%, 47/55; P=0.010) compared to the historical controls (61%, 27/44). CONCLUSIONS: This study demonstrated across three settings that the use of HCV antibody and RNA POCT increased testing rates, treatment uptake linkage to care. The testing model was highly acceptable for most participants. CLINICAL TRIAL REGISTRATION: ACTRN-12621001578897.
RESUMEN
The use of nonhuman animals in biomedical research is regulated under stringent conditions, not only in response to societal attitudes towards animal experimentation but also because ethical responsibility in scientific research requires researchers and veterinarians to be more invested and aim to improve the welfare of animals used for experiments. Analyses of animal research oversight reveal the frequent approval of experiments, and the approval of some experiments has raised and continues to raise public concerns. Societal compliance is required for a consensus-based approach to animal research policy, prompting the need to have transparent discussions about oversight and the frequency of approvals. We discuss how frequent approval may be perceived and why it seems problematic from a societal perspective: the regulatory process exists to approve only legitimate experiments. Although some experiments remain unacceptable irrespective of their harm-benefit ratios, almost all experiments are approved. We explain some possible legitimate reasons for frequent approval and how the review process could be leading to the approval of illegitimate studies. To ensure transparency and improve public trust and understanding of oversight, we propose the adoption of a platform to inform society about how unethical experiments are screened out.
RESUMEN
OBJECTIVES: The purpose of this systematic review was to examine how the scientific community in Europe that is involved with research with animals perceives and experiences the implementation of 3R (Replace, Reduce, Refine). METHODS: A systematic search of the literature published in the past ten years was performed in PubMed, Web of Science and Scopus. Publications were screened for eligibility using a priori inclusion criteria, and only empirical evidence (quantitative, qualitative, or mixed methodologies) was retained. Quantitative survey items were investigated by conducting a meta-analysis, and the qualitative data was summarized using an inductive meta-synthetic approach. Included publications were assessed using the Quality Assessment for Diverse Studies tool. RESULTS: 17 publications were included (eight quantitative, seven qualitative, two mixed-methods). The meta-analysis revealed that scientists are skeptical about achieving replacement, even if they believe that 3R improve the quality of experimental results. They are optimistic concerning the impact of 3R on research costs and innovation, and see education as highly valuable for the implementation of 3R. The meta-synthesis revealed four barriers (systemic dynamics, reification process, practical issues, insufficient knowledge) and four facilitators (efficient use of animals, caring for animals, regulatory uptake, supportive workplace environment). CONCLUSION: These findings show actionable levers at the local and systemic levels, and may inform regulators and institutions in their 3R policies. TRIAL REGISTRATION: The protocol was registered into the PROSPERO database under the number CRD42023395769.
Asunto(s)
Experimentación Animal , Animales , Europa (Continente) , Experimentación Animal/ética , HumanosRESUMEN
Indoor sources of air pollution, such as from cooking and cleaning, play a key role in indoor gas-phase chemistry. The focus of the impact of these activities on air quality tends to be indoors, with less attention given to the impact on air quality outside buildings. This study uses the INdoor CHEmical Model in Python (INCHEM-Py) and the Advanced Dispersion Modelling System (ADMS) to quantify the impact cooking and cleaning have on indoor and outdoor air quality for an idealised street of houses. INCHEM-Py has been developed to determine the concentrations of 106 indoor volatile organic compounds at the point they leave a building (defined as near-field concentrations). For a simulated 140 m long street with 10 equi-distant houses undertaking cooking and cleaning activities, the maximum downwind concentration of acetaldehyde increases from a background value of 0.1 ppb to 0.9 ppb post-cooking, whilst the maximum downwind chloroform concentrations increase from 1.2 to 6.2 ppt after cleaning. Although emissions to outdoors are higher when cooking and cleaning happen indoors, the contribution of these activities to total UK emissions of volatile organic compounds is low (less than 1%), and comprise about a quarter of those emitted from traffic across the UK. It is important to quantify these emissions, particularly as continued vehicle technology improvements lead to lower direct emissions outdoors, making indoor emissions relatively more important. Understanding how indoor pollution can affect outdoor environments, will allow better mitigation measures to be designed in the future that can take into account all sources of pollution that contribute to human exposure.
Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire Interior , Culinaria , Monitoreo del Ambiente , Compuestos Orgánicos Volátiles , Contaminación del Aire Interior/análisis , Contaminación del Aire Interior/estadística & datos numéricos , Contaminantes Atmosféricos/análisis , Compuestos Orgánicos Volátiles/análisis , Ciudades , Contaminación del Aire/estadística & datos numéricos , Contaminación del Aire/análisisRESUMEN
In this article, we describe and analyse the Swiss legislation relating to animal dignity. We conclude that previous criticisms of the law do not go far enough: far from protecting animal dignity, the Swiss law not only undermines such dignity but itself serves as a means to ensure that animals can be used merely as a means, and not treated with respect. As such, the Swiss Animal Welfare Act is deeply unethical and undermines the constitutional requirement to treat animals with dignity.
RESUMEN
The question of the use of expired medication is a constant debate of many years most especially in a difficult environment. In this research, a literature review and reported practice of some countries are used. Findings show that some medications, if properly stored, remain safe to use after the expiry date and this sometimes could be extended by many years. However, the pharmaceutical manufacturers have an interest in producing products with short shelf life. To dispose of expired ones is to generate a sale and therefore put the profit into the improvement and development of new products for the benefit of medicine. This paper emphasizes the benefit of use of some drugs after expiration and the interest for the pharmaceutical industry to dispose of expired drugs and to shorten their shelf life.
RESUMEN
Fibroblast growth factor receptor (FGFR) kinase inhibitors have been shown to be effective in the treatment of intrahepatic cholangiocarcinoma and other advanced solid tumors harboring FGFR2 alterations, but the toxicity of these drugs frequently leads to dose reduction or interruption of treatment such that maximum efficacy cannot be achieved. The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition and diarrhea due to FGFR4 inhibition, as current therapies are not selective among the FGFRs. Designing selective inhibitors has proved difficult with conventional approaches because the orthosteric sites of FGFR family members are observed to be highly similar in X-ray structures. In this study, aided by analysis of protein dynamics, we designed a selective, covalent FGFR2 inhibitor. In a key initial step, analysis of long-timescale molecular dynamics simulations of the FGFR1 and FGFR2 kinase domains allowed us to identify differential motion in their P-loops, which are located adjacent to the orthosteric site. Using this insight, we were able to design orthosteric binders that selectively and covalently engage the P-loop of FGFR2. Our drug discovery efforts culminated in the development of lirafugratinib (RLY-4008), a covalent inhibitor of FGFR2 that shows substantial selectivity over FGFR1 (~250-fold) and FGFR4 (~5,000-fold) in vitro, causes tumor regression in multiple FGFR2-altered human xenograft models, and was recently demonstrated to be efficacious in the clinic at doses that do not induce clinically significant hyperphosphatemia or diarrhea.
Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Hiperfosfatemia , Humanos , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/química , Conductos Biliares Intrahepáticos/metabolismo , Diarrea , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/químicaRESUMEN
Cleaning products emit a range of volatile organic compounds (VOCs), including some which are hazardous or can undergo chemical transformations to generate harmful secondary pollutants. In recent years, "green" cleaners have become increasingly popular, with an implicit assumption that these are better for our health and/or the environment. However, there is no strong evidence to suggest that they are better for indoor air quality compared to regular products. In this study, the VOC composition of 10 regular and 13 green cleaners was examined by headspace analysis. Monoterpenes were the most prevalent VOCs, with average total monoterpene concentrations of 8.6 and 25.0 mg L-1 for regular and green cleaners, respectively. Speciated monoterpene emissions were applied to a detailed chemical model to investigate the indoor air chemistry following a typical cleaning event. Green cleaners generally emitted more monoterpenes than regular cleaners, resulting in larger increases in harmful secondary pollutant concentrations following use, such as formaldehyde (up to 7%) and PAN species (up to 6%). However, emissions of the most reactive monoterpenes (α-terpinene, terpinolene and α-phellandrene), were observed more frequently from regular cleaners, resulting in a disproportionately large impact on the concentrations of radical species and secondary pollutants that were formed after cleaning occurred.