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Alkaptonuria (AKU, OMIM, No. 203500) is a rare, slow-progressing, irreversible, multisystemic disease resulting from a deficiency of the homogentisate 1,2-dioxygenase enzyme, which leads to the accumulation of homogentisic acid (HGA) and subsequent deposition as pigment in connective tissues called ochronosis. As a result, severe arthropathy of large joints and spondyloarthropathy with frequent fractures, ligament ruptures, and osteoporosis develops in AKU patients. Since 2020, the first-time treatment with nitisinone has become available in the European Union. Nitisinone significantly reduces HGA production and arrests ochronosis in AKU patients. However, blocking of the tyrosine metabolic pathway by the drug leads to tyrosine plasma and tissue concentrations increase. The nitisinone-induced hypertyrosinemia can lead to the development of corneal keratopathy, and once it develops, the treatment needs to be interrupted. A decrease in overall protein intake reduces the risk of the keratopathy during nitisinone-induced hypertyrosinemia in AKU patients. The low-protein diet is not only poorly tolerated by patients, but over longer periods, leads to a severe muscle loss and weight gain due to increased energy intake from carbohydrates and fats. Therefore, the development of novel nutritional approaches is required to prevent the adverse events due to nitisinone-induced hypertyrosinemia and the negative impact on skeletal muscle metabolism in AKU patients.
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Alcaptonuria , Ocronosis , Tirosinemias , Humanos , Alcaptonuria/tratamiento farmacológico , Alcaptonuria/metabolismo , Ocronosis/tratamiento farmacológico , Tirosina/uso terapéutico , Ácido Homogentísico/metabolismoRESUMEN
Conversational artificial intelligence (CAI) presents many opportunities in the psychotherapeutic landscape-such as therapeutic support for people with mental health problems and without access to care. The adoption of CAI poses many risks that need in-depth ethical scrutiny. The objective of this paper is to complement current research on the ethics of AI for mental health by proposing a holistic, ethical, and epistemic analysis of CAI adoption. First, we focus on the question of whether CAI is rather a tool or an agent. This question serves as a framework for the subsequent ethical analysis of CAI focusing on topics of (self-) knowledge, (self-)understanding, and relationships. Second, we propose further conceptual and ethical analysis regarding human-AI interaction and argue that CAI cannot be considered as an equal partner in a conversation as is the case with a human therapist. Instead, CAI's role in a conversation should be restricted to specific functions.
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Inteligencia Artificial , Psicoterapia , Humanos , Comunicación , Análisis Ético , Salud MentalRESUMEN
The article "The Bacterial Population of Neutral Mine Drainage Water of Elizabeth's Shaft (Slovinky, Slovakia)", written by Jana Kisková, Zuzana Perháèová, Ladislav Vlèko, Jana Sedláková, Simona Kvasnová and Peter Pristas, was originally published electronically on the publisher's internet portal on 12 March 2018 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on 9 April 2020 to © The Author(s) 2018 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ ), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The original article has been corrected.
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Although neutral mine drainage is the less frequent subject of the interest than acid mine drainage, it can have adverse environmental effects caused mainly by precipitation of dissolved Fe. The aim of the study was to characterize the composition of bacterial population in environment with high concentration of iron and sulfur compounds represented by neutral mine drainage water of Elizabeth's shaft, Slovinky (Slovakia). Direct microscopic observations, cultivation methods, and 454 pyrosequencing of the 16S rRNA gene amplicons were used to examine the bacterial population. Microscopic observations identified iron-oxidizing Proteobacteria of the genera Gallionella and Leptothrix which occurrence was not changed during the years 2008-2014. Using 454 pyrosequencing, there were identified members of 204 bacterial genera that belonged to 25 phyla. Proteobacteria (69.55%), followed by Chloroflexi (10.31%) and Actinobacteria (4.24%) dominated the bacterial community. Genera Azotobacter (24.52%) and Pseudomonas (14.15%), followed by iron-oxidizing Proteobacteria Dechloromonas (11%) and Methyloversatilis (8.53%) were most abundant within bacterial community. Typical sulfur bacteria were detected with lower frequency, e.g., Desulfobacteraceae (0.25%), Desulfovibrionaceae (0.16%), or Desulfobulbaceae (0.11%). Our data indicate that the composition of bacterial community of the Elizabeth's shaft drainage water reflects observed neutral pH, high level of iron and sulfur ions in this aquatic habitat.
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Actinobacteria/aislamiento & purificación , Chloroflexi/aislamiento & purificación , Hierro/análisis , Proteobacteria/aislamiento & purificación , Azufre/análisis , Aguas Residuales/química , Aguas Residuales/microbiología , Actinobacteria/clasificación , Actinobacteria/genética , Chloroflexi/clasificación , Chloroflexi/genética , ADN Bacteriano/genética , Minería , Técnicas de Amplificación de Ácido Nucleico , Proteobacteria/clasificación , Proteobacteria/genética , ARN Ribosómico 16S/genética , Eslovaquia , Calidad del AguaRESUMEN
Unlabelled: Large language model (LLM)-powered services are gaining popularity in various applications due to their exceptional performance in many tasks, such as sentiment analysis and answering questions. Recently, research has been exploring their potential use in digital health contexts, particularly in the mental health domain. However, implementing LLM-enhanced conversational artificial intelligence (CAI) presents significant ethical, technical, and clinical challenges. In this viewpoint paper, we discuss 2 challenges that affect the use of LLM-enhanced CAI for individuals with mental health issues, focusing on the use case of patients with depression: the tendency to humanize LLM-enhanced CAI and their lack of contextualized robustness. Our approach is interdisciplinary, relying on considerations from philosophy, psychology, and computer science. We argue that the humanization of LLM-enhanced CAI hinges on the reflection of what it means to simulate "human-like" features with LLMs and what role these systems should play in interactions with humans. Further, ensuring the contextualization of the robustness of LLMs requires considering the specificities of language production in individuals with depression, as well as its evolution over time. Finally, we provide a series of recommendations to foster the responsible design and deployment of LLM-enhanced CAI for the therapeutic support of individuals with depression.
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Inteligencia Artificial , Depresión , Humanos , Depresión/psicología , Depresión/terapia , Lenguaje , Comunicación , HumanismoRESUMEN
Introduction: Patient decision aids (PDAs) are important tools to empower patients and integrate their preferences and values in the decision-making process. Even though patients with mental health problems have a strong interest in being more involved in decision making about their treatment, research has mainly focused on PDAs for somatic conditions. In this scoping review, we focus on patients suffering from depression and the role of PDAs for this patient group. The review offers an overview of digital and analog PDAs, their advantages and disadvantages as well as recommendations for further research and development. Methods: A systematic search of the existing literature guided by the Cochrane Handbook for Systematic Reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses - extension for scoping reviews (PRISMA-ScR) was conducted. Three electronic literature databases with the appropriate thematic focus were searched (PubMed, PsycInfo, and Web of Science). The search strategy used controlled and natural language to search for the key concepts decision aids and depression. The articles were selected in a two-step process guided by predefined inclusion and exclusion criteria. We narratively synthetized information extracted from 40 research articles. Results: We included 40 articles in our review. Our review revealed that there is more focus on digital PDAs in research than in clinical practice. Digitalization can enhance the benefits of PDAs by developing tools that are more efficient, interactive, and personalized. The main disadvantages of both types of PDAs for the treatment of depression are related to time, dissemination, and capacity building for the health care providers. Digital PDAs need to be regularly updated, effective strategies for their dissemination and acceptance need to be identified, and clinicians need sufficient training on how to use digital PDAs. There is more research needed to study which forms of PDAs are most appropriate for various patient groups (e.g., older adults, or patients with comorbidities), and to identify the most effective ways of PDAs' integration in the clinical workflow. The findings from our review could be well aligned with the International Patient Decision Aids Standards. Discussion: More research is needed regarding effective strategies for the implementation of digital PDAs into the clinical workflow, ethical issues raised by the digital format, and opportunities of tailoring PDAs for diverse patient groups.
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Digital data play an increasingly important role in advancing health research and care. However, most digital data in healthcare are in an unstructured and often not readily accessible format for research. Unstructured data are often found in a format that lacks standardization and needs significant preprocessing and feature extraction efforts. This poses challenges when combining such data with other data sources to enhance the existing knowledge base, which we refer to as digital unstructured data enrichment. Overcoming these methodological challenges requires significant resources and may limit the ability to fully leverage their potential for advancing health research and, ultimately, prevention, and patient care delivery. While prevalent challenges associated with unstructured data use in health research are widely reported across literature, a comprehensive interdisciplinary summary of such challenges and possible solutions to facilitate their use in combination with structured data sources is missing. In this study, we report findings from a systematic narrative review on the seven most prevalent challenge areas connected with the digital unstructured data enrichment in the fields of cardiology, neurology and mental health, along with possible solutions to address these challenges. Based on these findings, we developed a checklist that follows the standard data flow in health research studies. This checklist aims to provide initial systematic guidance to inform early planning and feasibility assessments for health research studies aiming combining unstructured data with existing data sources. Overall, the generality of reported unstructured data enrichment methods in the studies included in this review call for more systematic reporting of such methods to achieve greater reproducibility in future studies.
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OBJECTIVES: Ochronotic spondyloarthropathy represents one of the main clinical manifestations of alkaptonuria (AKU); however, prospective data and description of the effect of nitisinone treatment are lacking. METHODS: Patients with AKU aged 25 years or older were randomly assigned to receive either oral nitisinone 10 mg/day (N=69) or no treatment (N=69). Spine radiographs were recorded yearly at baseline, 12, 24, 36 and 48 months, and the images were scored for the presence of intervertebral space narrowing, soft tissue calcifications, vacuum phenomena, osteophytes/hyperostosis and spinal fusion in the cervical, thoracic and lumbosacral segment at each of the time points. RESULTS: At baseline, narrowing of the intervertebral spaces, the presence of osteophytes/hyperostosis and calcifications were the three most frequent radiographic features in AKU. The rate of progression of the five main features during the 4 years, ranked from the highest to lowest was as follows: intervertebral spaces narrowing, calcifications, vacuum phenomena, osteophytes/hyperostosis and fusions. The rate of progression did not differ between the treated and untreated groups in any of the five radiographic parameters except for a slower rate of progression (sum of all five features) in the treatment group compared with the control group (0.45 (1.11) nitisinone vs 0.74 (1.11) controls, p=0.049) in the thoracic segment. CONCLUSION: The present study shows a relatively slow but significant worsening of radiographic features in patients with AKU over 4 years. Our results demonstrate a modest beneficial effect of 10 mg/day of nitisinone on the slowly progressing spondylosis in AKU during the relatively limited follow-up time. TRIAL REGISTRATION NUMBER: NCT01916382.
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Alcaptonuria , Osteofito , Enfermedades de la Columna Vertebral , Humanos , Alcaptonuria/complicaciones , Alcaptonuria/diagnóstico , Alcaptonuria/tratamiento farmacológico , Estudios ProspectivosRESUMEN
BACKGROUND: Alkaptonuria is a rare, genetic, multisystem disease characterised by the accumulation of homogentisic acid (HGA). No HGA-lowering therapy has been approved to date. The aim of SONIA 2 was to investigate the efficacy and safety of once-daily nitisinone for reducing HGA excretion in patients with alkaptonuria and to evaluate whether nitisinone has a clinical benefit. METHODS: SONIA 2 was a 4-year, open-label, evaluator-blind, randomised, no treatment controlled, parallel-group study done at three sites in the UK, France, and Slovakia. Patients aged 25 years or older with confirmed alkaptonuria and any clinical disease manifestations were randomly assigned (1:1) to receive either oral nitisinone 10 mg daily or no treatment. Patients could not be masked to treatment due to colour changes in the urine, but the study was evaluator-blinded as far as possible. The primary endpoint was daily urinary HGA excretion (u-HGA24) after 12 months. Clinical evaluation Alkaptonuria Severity Score Index (cAKUSSI) score was assessed at 12, 24, 36, and 48 months. Efficacy variables were analysed in all randomly assigned patients with a valid u-HGA24 measurement at baseline. Safety variables were analysed in all randomly assigned patients. The study was registered at ClinicalTrials.gov (NCT01916382). FINDINGS: Between May 7, 2014, and Feb 16, 2015, 139 patients were screened, of whom 138 were included in the study, with 69 patients randomly assigned to each group. 55 patients in the nitisinone group and 53 in the control group completed the study. u-HGA24 at 12 months was significantly decreased by 99·7% in the nitisinone group compared with the control group (adjusted geometric mean ratio of nitisinone/control 0·003 [95% CI 0·003 to 0·004], p<0·0001). At 48 months, the increase in cAKUSSI score from baseline was significantly lower in the nitisinone group compared with the control group (adjusted mean difference -8·6 points [-16·0 to -1·2], p=0·023). 400 adverse events occurred in 59 (86%) patients in the nitisinone group and 284 events occurred in 57 (83%) patients in the control group. No treatment-related deaths occurred. INTERPRETATION: Nitisinone 10 mg daily was well tolerated and effective in reducing urinary excretion of HGA. Nitisinone decreased ochronosis and improved clinical signs, indicating a slower disease progression. FUNDING: European Commission Seventh Framework Programme.
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Alcaptonuria/tratamiento farmacológico , Alcaptonuria/metabolismo , Ciclohexanonas/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Internacionalidad , Nitrobenzoatos/administración & dosificación , Adulto , Anciano , Alcaptonuria/diagnóstico , Esquema de Medicación , Femenino , Ácido Homogentísico/metabolismo , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Método Simple Ciego , Resultado del TratamientoRESUMEN
ProTides comprise an important class of prodrugs currently marketed and developed as antiviral and anticancer therapies. The ProTide technology employs phosphate masking groups capable of providing more favorable druglike properties and an intracellular activation mechanism for enzyme-mediated release of a nucleoside monophosphate. Herein, we describe the application of phosphoramidate chemistry to 1,3,4-O-acetylated N-acetylmannosamine (Ac3ManNAc) to deliver ManNAc-6-phosphate (ManNAc-6-P), a critical intermediate in sialic acid biosynthesis. Sialic acid deficiency is a hallmark of GNE myopathy, a rare congenital disorder of glycosylation (CDG) caused by mutations in GNE that limit the production of ManNAc-6-P. Synthetic methods were developed to provide a library of Ac3ManNAc-6-phosphoramidates that were evaluated in a series of studies for their potential as a treatment for GNE myopathy. Prodrug 12b showed rapid activation in a carboxylesterase (CPY) enzymatic assay and favorable ADME properties, while also being more effective than ManNAc at increasing sialic acid levels in GNE-deficient cell lines. These results provide a potential platform to address substrate deficiencies in GNE myopathy and other CDGs.
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Miopatías Distales/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Hexosaminas/farmacología , Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Profármacos/farmacología , Fosfatos de Azúcar/farmacología , Animales , Células CHO , Células CACO-2 , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cricetulus , Miopatías Distales/metabolismo , Miopatías Distales/patología , Relación Dosis-Respuesta a Droga , Hexosaminas/síntesis química , Hexosaminas/química , Humanos , Estructura Molecular , Ácido N-Acetilneuramínico/análisis , Fosfotransferasas (Aceptor de Grupo Alcohol)/deficiencia , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Profármacos/síntesis química , Profármacos/química , Relación Estructura-Actividad , Fosfatos de Azúcar/síntesis química , Fosfatos de Azúcar/químicaRESUMEN
BACKGROUND: Electric left ventricular lead position, assessed by the electric delay from the beginning of the QRS complex to the local LV electrogram (QLV), was found in previous studies to be a strong predictor of short-term response to cardiac resynchronization therapy. We hypothesized that suboptimum electric position of the left ventricular lead is associated with an excess of heart failure events and mortality. METHODS AND RESULTS: We analyzed the clinical outcome of patients with left bundle branch block or intraventricular conduction delay treated with cardiac resynchronization therapy at our institution during 9 years. Baseline clinical characteristics, QLV/QRS duration (QLV ratio) at cardiac resynchronization therapy implant, and data about heart failure hospitalization and mode of death were collected in 329 patients who were followed for a period of 3.3±1.9 years. Of them, 83 were hospitalized for heart failure and 83 died. Event rates for all-cause mortality, cardiac mortality, noncardiac mortality, heart failure mortality, and sudden death were 25.2%, 14.9%, 10.3%, 12.2%, and 2.1%, respectively. Patients with a QLV ratio ≤0.70 had significantly worse event-free survival for all study end points--hazard ratio, 1.6; 95% confidence interval, 1.0 to 2.4; P=0.05 for heart failure hospitalization; hazard ratio, 2.9; 95% confidence interval, 1.6 to 5.5; P=0.001 for heart failure mortality; hazard ratio, 1.8; 95% confidence interval, 1.1 to 2.7; P=0.01 for cardiac mortality; and hazard ratio, 2.1; 95% confidence interval, 1.2 to 3.7; P=0.01 for all-cause mortality. In multivariable analysis, QLV ratio ≤0.70 remained associated with all study end points. CONCLUSIONS: Electric left ventricular lead position in cardiac resynchronization therapy patients was a significant predictor of heart failure hospitalization and mortality.