RESUMEN
Adaptive nanopore sequencing as a diagnostic method for imprinting disorders and episignature analysis revealed an intragenic duplication of Exon 6 and 7 in UBE3A (NM_000462.5) in a patient with relatively mild Angelman-like syndrome. In an all-in-one nanopore sequencing analysis DNA hypomethylation of the SNURF:TSS-DMR, known contributing deletions on the maternal allele and point mutations in UBE3A could be ruled out as disease drivers. In contrast, breakpoints and orientation of the tandem duplication could clearly be defined. Segregation analysis in the family showed that the duplication derived de novo in the maternal grandfather. Our study shows the benefits of an all-in-one nanopore sequencing approach for the diagnostics of Angelman syndrome and other imprinting disorders.
Asunto(s)
Síndrome de Angelman , Metilación de ADN , Duplicación de Gen , Secuenciación de Nanoporos , Ubiquitina-Proteína Ligasas , Humanos , Síndrome de Angelman/genética , Síndrome de Angelman/diagnóstico , Ubiquitina-Proteína Ligasas/genética , Secuenciación de Nanoporos/métodos , Metilación de ADN/genética , Femenino , Duplicación de Gen/genética , Masculino , Exones/genética , Linaje , Impresión Genómica/genéticaRESUMEN
Despite clinical evidence of drug superiority, therapeutic modalities, like combination immunotherapy, are mostly considered cost-ineffective due to their high costs per life year(s) gained. This paper, taking an ethical stand, reevaluates the standard cost-effectiveness analysis with that of the more recent justice-enhanced methods and concludes by pointing out the shortcomings of the current methodologies.
Asunto(s)
Atención a la Salud , Humanos , Análisis Costo-BeneficioRESUMEN
Background and objective: Obtaining informed consent in neonatal emergency research is challenging. The aim of this study was to assess parental perceptions of informed consent following participation in a clinical trial in neonatal emergency care. Methods: This was a supplementary analysis of a randomised controlled trial comparing video and direct laryngoscopy for neonatal endotracheal intubation in the delivery room and neonatal intensive care unit. After obtaining informed consent for the clinical trial, parents were asked to answer a series of self-administered questions about their perceptions of clinical trial participation and the consent process. Informed consent had been given either before birth, after birth but before inclusion in the trial, or after inclusion in the trial. Results: We received responses from 33 mothers and 27 fathers (n = 60) of the 63 preterm and term infants who participated in the study. Fifty-three (89.8%, n = 59) parents agreed that infants should participate in clinical trials, and 51 (85%, n = 60) parents agreed that parents should be asked for informed consent. Fifty-three (89.8%, n = 59) parents felt that their infant's participation in this particular trial would be beneficial. Fifty-two (86.7%, n = 60) parents felt that the informed consent process was satisfactory. One parent (100%, n = 1) approached before birth, 23 parents (82.1%, n = 28) approached after birth but before enrolment and 26 (83.9%, n = 31) parents approached after enrolment were satisfied with the timing of the consent process. Eight (13.3%, n = 60) parents felt some pressure to provide informed consent. Of these, two (25%) were approached before enrolment and six (75%) were approached after enrolment. Conclusion: Parents valued their infant's participation in an emergency neonatal clinical trial and considered it important to be asked for consent. In this study, it seemed less important whether consent was obtained before or after the intervention. Future studies may need to investigate which form of consent is most acceptable to parents for the individual study in question.
RESUMEN
COVID-19 has put vaccine efficacy under a spotlight. However, the reluctance of people to be vaccinated has postponed the end of the COVID-19 pandemic. Currently, opioid vaccines are being developed, which could help prevent opioid addiction, overdoses, or relapse in combination with medication-assisted therapy. The fear is that the uptake of opioid vaccines could be met by the same reluctance as seen with COVID-19 vaccines.
Asunto(s)
COVID-19 , Vacunas , Humanos , COVID-19/prevención & control , Vacunas contra la COVID-19 , Pandemias/prevención & control , Analgésicos OpioidesRESUMEN
Organ donation after brain death has been practiced in China since 2003 in the absence of brain death legislation. Similar to international standards, China's brain death diagnostic criteria include coma, absence of brainstem reflexes, and the lack of spontaneous respiration. The Chinese criteria require that the lack of spontaneous respiration must be verified with an apnea test by disconnecting the ventilator for 8 min to provoke spontaneous respiration. However, we have found publications in Chinese medical journals, in which the donors were declared to be brain dead, yet without an apnea test. The organ procurement procedures started with initiating "intratracheal intubation for mechanical ventilation after brain death," indicating that a brain death diagnosis was not performed. The purpose of the intubation was not to resuscitate the patient but rather was directly related to facilitating the explantation of organs. Moreover, it was unmistakably stated in two of these publications that the cardiac arrest was induced in these patients without brain death determination by cold St. Thomas cardioplegic solution or other cold myocardial protection solutions. This means that the condition of these donors neither met the criteria of brain death nor that of cardiac death. In other words, the "donor organs" may well have been procured in these cases from living human beings. Thus, brain death definition is abused in China by some individuals for organ harvesting, and a systematic investigation is needed to clarify the situation of organ donation after brain death in China.
Asunto(s)
Trasplante de Órganos , Obtención de Tejidos y Órganos , Apnea , Muerte Encefálica/diagnóstico , China , Muerte , Humanos , Donantes de TejidosRESUMEN
The widespread use of opioids to treat chronic pain led to a nation-wide crisis in the United States. Tens of thousands of deaths annually occur mainly due to respiratory depression, the most dangerous side effect of opioids. Non-opioid drugs and non-pharmacological treatments without addictive potential are urgently required. Traditional Chinese medicine (TCM) is based on a completely different medical theory than academic Western medicine. The scientific basis of acupuncture and herbal treatments as main TCM practices has been considerably improved during the past two decades, and large meta-analyses with thousands of patients provide evidence for their efficacy. Furthermore, opinion leaders in the United States favor non-pharmacological techniques including TCM for pain management to fight the opioid crisis. We advocate TCM as therapeutic option without addictive potential and without life-threatening side effects (e.g., respiratory depression) to treat chronic pain patients suffering from opioid misuse. The evidence suggests that: (1) opioid misuse cannot be satisfactorily managed with standard medication; (2) opinion leaders in the United States favor to consider non-opioid and non-pharmacological treatment strategies including those from TCM to treat acute and chronic pain conditions; (3) large meta-analyses provide scientific evidence for the clinical activity of acupuncture and herbal TCM remedies in the treatment of chronic pain. Future clinical trials should demonstrate the safety of TCM treatments if combined with Western medical practices to exclude negative interactions between both modalities.
Asunto(s)
Terapia por Acupuntura , Medicamentos Herbarios Chinos , Epidemias , Analgésicos Opioides/efectos adversos , Humanos , Medicina Tradicional China , Epidemia de Opioides , Estados UnidosRESUMEN
Patients with childhood, adolescent, and young adult cancer who will be treated with gonadotoxic therapies are at increased risk for infertility. Many patients and their families desire biological children but effective communication about treatment-related infertility risk and procedures for fertility preservation does not always happen. The PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the literature and developed a clinical practice guideline that provides recommendations for ongoing communication methods for fertility preservation for patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger and their families. Moreover, the guideline panel formulated considerations of the ethical implications that are associated with these procedures. Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the evidence and recommendations. In this clinical practice guideline, existing evidence and international expertise are combined to develop transparent recommendations that are easy to use to facilitate ongoing communication between health-care providers and patients with childhood, adolescent, and young adult cancer who might be at high risk for fertility impairment and their families.
Asunto(s)
Supervivientes de Cáncer , Preservación de la Fertilidad/ética , Guías como Asunto , Neoplasias/epidemiología , Adolescente , Adulto , Niño , Progresión de la Enfermedad , Femenino , Preservación de la Fertilidad/tendencias , Humanos , Masculino , Neoplasias/complicaciones , Neoplasias/patología , Neoplasias/terapia , Adulto JovenRESUMEN
Opioid abuse and misuse have led to an epidemic which is currently spreading worldwide. Since the number of opioid overdoses is still increasing, it is becoming obvious that current rather unsystematic approaches to tackle this health problem are not effective. This review suggests that fighting the opioid epidemic requires a structured public health approach. Therefore, it is important to consider not only scientific and biomedical perspectives, but societal implications and the lived experience of groups at risk as well. Hence, this review evaluates the risk factors associated with opioid overdoses and investigates the rates of chronic opioid misuse, particularly in the context of chronic pain as well as post-surgery treatments, as the entrance of opioids in people's lives. Linking pharmaceutical biology to narrative analysis is essential to understand the modulations of the usual themes of addiction and abuse present in the opioid crisis. This paper shows that patient narratives can be an important resource in understanding the complexity of opioid abuse and addiction. In particular, the relationship between chronic pain and social inequality must be considered. The main goal of this review is to demonstrate how a deeper transdisciplinary-enriched understanding can lead to more precise strategies of prevention or treatment of opioid abuse.
Asunto(s)
Conducta Adictiva , Dolor Crónico , Trastornos Relacionados con Opioides , Analgésicos Opioides/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/epidemiología , Humanos , Epidemia de Opioides , Trastornos Relacionados con Opioides/tratamiento farmacológico , Trastornos Relacionados con Opioides/epidemiología , Factores SocioeconómicosRESUMEN
Since a number of years, popular and scientific interest in resilience is rapidly increasing. More recently, also neuroscientific research in resilience and the associated neurobiological findings is gaining more attention. Some of these neuroscientific findings might open up new measures to foster personal resilience, ranging from magnetic stimulation to pharmaceutical interventions and awareness-based techniques. Therefore, bioethics should also take a closer look at resilience and resilience research, which are today philosophically under-theorized. In this paper, we analyze different conceptualizations of resilience and argue that especially one-sided understandings of resilience which dismiss social and cultural contexts of personal resilience do pose social and ethical problems. On a social level such unbalanced views on resilience could hide and thereby stabilize structural social injustices, and on an individual level it might even lead to an aggravation of stress-related mental health problems by overexerting the individual. Furthermore, some forms of fostering resilience could be a latent form of human enhancement and trigger similar criticisms.
Asunto(s)
Bioética , Neurociencias , Humanos , Principios MoralesRESUMEN
Novel immune therapies are more and more based on the molecular differentiation of disease patterns and related clinical studies are thus more often characterized by so-called adaptive study designs (umbrella or basket studies including platform studies), which are continuously adjusted based on novel results. This paper analyses new study designs beyond the often-postulated need for regulation in order to identify ethical problems based on typical structural features and to - whenever possible - suggest solutions. Additionally to the relationship between social and scientific values of a study as well as aspects of the scientific validity of new forms of evidence, the inclusion of study subjects under the condition of relative uncertainty, specific challenges in the process of ethical approval, as well as ethical and practical challenges in the process of informing patients and receiving informed consent will be addressed.
Asunto(s)
Consentimiento Informado , Principios Morales , Alemania , Humanos , Proyectos de InvestigaciónRESUMEN
Plasticizers released from microplastic are increasingly viewed with concern. While adverse health effects induced by bisphenol A and its analogues on marine animals are well documented in the literature, the endocrine potential of bisphenolic compounds on human health remains elusive. We applied next generation sequencing (NGS) with the estrogen receptor α (ERα) positive human breast cancer cell line MCF-7 treated with 17-ß-estradiol (E2), bisphenol A (BPA), bisphenol B (BPB), bisphenol Z (BPZ) and tetramethyl bisphenol A (4MeBPA). We used molecular docking, microscale thermophoresis, ERα activation assay, and cell cycle experiments on MCF-7 and ERα overexpressing HEK293 cells to verify the impact of the compounds on ERα. 14 genes were found upregulated (ADORA1, DDIT4, CELSR2, FOSL2, JUN, HSPA13, IER3, IGF1R, PGR, RUNX2, SLC7A11, SLC7A2, SLC7A5, STC2) and 3 genes were downregulated (BCAS3, PHF19, PRKCD) in almost all samples. These genes are associated with cell growth, invasion, migration, apoptosis and cancer development. We further confirmed the binding, activation and proliferative effect of BPA, BPB, BPZ, and 4MeBPA on ERα. We provide evidence for the endocrine potential of bisphenolic compounds and give insights into their molecular effects in MCF-7 cells.
Asunto(s)
Compuestos de Bencidrilo/farmacología , Receptor alfa de Estrógeno/genética , Expresión Génica/efectos de los fármacos , Fenoles/farmacología , Neoplasias de la Mama/genética , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Disruptores Endocrinos/farmacología , Estradiol/genética , Estrógenos/genética , Femenino , Células HEK293 , Humanos , Células MCF-7 , Plastificantes/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
Currently, the environmental impact of ubiquitous plastic debris triggered quite some public attention. However, the global impact of microplastic on human health is by and large either unknown or neglected. By looking at the underlying biochemical mechanisms leading to the global health threat microplastic was discovered to carry persistent organic pollutants, such as polycyclic aromatic hydrocarbons (PAH), to marine life. The effect of microplastic-ingestion in the human body remains unfortunately somewhat elusive as of yet. For this reason, we screened for compounds binding to the human estrogen receptor α (ERα) and identified the PAH compounds indeno[1,2,3-cd]pyrene (Indpy) and picene (Pice) with a high binding affinity. We applied next generation sequencing to analyze the differentially expressed genes in MCF-7 cells after treatment with Indpy and Pice. We found 8 upregulated genes: ABCC5, CCNG2, CYP1A1, DDIT4, IER3, RUNX2, STC2, and SLC7A5 and 14 downregulated genes: ADORA1, CEBPB, CELSR2, CTSD, CXCL12, KRT19, PGR, PKIB, RARA, RET, SEMA3B, SIAH2, TFAP2C, and XBP1 induced by both ligands and associated with ESR1-regulation. The altered gene expression may influence cell proliferation and metastasis, favoring cancer development with a poor response to therapy. In addition, we confirmed the binding of Indpy and Pice to ERα using molecular docking and microscale thermophoresis. ERα activation was measured with ESR1-overexpressing HEK293 (HEK-ESR1) cells and confirmed for Indpy. In conclusion, we showed an ESR1-mediated influence of the PAH compounds Indpy and Pice on the gene expression pattern of MCF-7 cells, possibly also promoting breast cancer development in patients.
Asunto(s)
Crisenos/farmacología , Receptor alfa de Estrógeno/metabolismo , Expresión Génica/efectos de los fármacos , Pirenos/farmacología , Transducción de Señal/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7/efectos de los fármacos , Simulación del Acoplamiento Molecular , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Plastic in the ocean degrades to microplastic, thereby enhancing the leaching of incorporated plasticizers due to the increased particle surface. The uptake of microplastic-derived plasticizers by marine animals and the subsequent entry in the food chain raises concerns for adverse health effects in human beings. Frequently used plasticizers as the organophosphate ester tri-o-cresyl phosphate (TOCP) are known to affect the male reproductive system. However, the overall endocrine potential of TOCP and the underlying molecular mechanisms remain elusive as yet. In this study, we investigated the molecular effects of TOCP on estrogen receptor α (ERα)-transfected HEK-ESR1 cells and the human breast cancer cell line MCF-7. Applying virtual screening and molecular docking, we identified TOCP as potent ligand of ERα in silico. Microscale thermophoresis confirmed the binding in vitro with similar intensity as the natural ligand 17-ß-estradiol. To identify the molecular mechanisms of TOCP-mediated effects, we used next-generation sequencing to analyze the gene expression pattern of TOCP-treated MCF-7 cells. RNA-sequencing revealed 22 differently expressed genes associated with ESR1 as upstream regulator: CYP1A1, SLC7A11, RUNX2, DDIT4, STC2, KLHL24, CCNG2, CEACAM5, SLC7A2, MAP1B, SLC7A5, IGF1R, CD55, FOSL2, VEGFA, and HSPA13 were upregulated and PRKCD, CCNE1, CEBPA, SFPQ, TNFAIP2, KRT19 were downregulated. The affected genes promote tumor growth by increasing angiogenesis and nutritional supply, favor invasion and metastasis, and interfere with the cell cycle. Based on the gene expression pattern, we conclude TOCP to mediate endocrine effects on MCF-7 cells by interacting with ERα.
Asunto(s)
Neoplasias de la Mama/patología , Receptor alfa de Estrógeno/efectos de los fármacos , Plastificantes/toxicidad , Tritolilfosfatos/toxicidad , Neoplasias de la Mama/genética , Ciclo Celular/genética , Disruptores Endocrinos , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HEK293 , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Células MCF-7 , Masculino , Modelos Moleculares , Simulación del Acoplamiento Molecular , Invasividad Neoplásica/genética , Metástasis de la Neoplasia/genética , Neovascularización Patológica/genética , ARN/química , Transfección , Tritolilfosfatos/metabolismoRESUMEN
BACKGROUND: Practices of biopiracy to use genetic resources and indigenous knowledge by Western companies without benefit-sharing of those, who generated the traditional knowledge, can be understood as form of neocolonialism. HYPOTHESIS: The One-World Medicine concept attempts to merge the best of traditional medicine from developing countries and conventional Western medicine for the sake of patients around the globe. STUDY DESIGN: Based on literature searches in several databases, a concept paper has been written. Legislative initiatives of the United Nations culminated in the Nagoya protocol aim to protect traditional knowledge and regulate benefit-sharing with indigenous communities. The European community adopted the Nagoya protocol, and the corresponding regulations will be implemented into national legislation among the member states. Despite pleasing progress, infrastructural problems of the health care systems in developing countries still remain. Current approaches to secure primary health care offer only fragmentary solutions at best. Conventional medicine from industrialized countries cannot be afforded by the impoverished population in the Third World. Confronted with exploding costs, even health systems in Western countries are endangered to burst. Complementary and alternative medicine (CAM) is popular among the general public in industrialized countries, although the efficacy is not sufficiently proven according to the standards of evidence-based medicine. CAM is often available without prescription as over-the-counter products with non-calculated risks concerning erroneous self-medication and safety/toxicity issues. The concept of integrative medicine attempts to combine holistic CAM approaches with evidence-based principles of conventional medicine. CONCLUSION: To realize the concept of One-World Medicine, a number of standards have to be set to assure safety, efficacy and applicability of traditional medicine, e.g. sustainable production and quality control of herbal products, performance of placebo-controlled, double-blind, randomized clinical trials, phytovigilance, as well as education of health professionals and patients.
Asunto(s)
Cooperación Internacional , Medicina Tradicional , Plantas Medicinales , Robo , Biodiversidad , Colonialismo , Terapias Complementarias , Países en Desarrollo , Método Doble Ciego , Unión Europea , Medicina Basada en la Evidencia , Humanos , Medicina Tradicional/normas , Naturopatía , Patentes como Asunto , Control de Calidad , AutomedicaciónRESUMEN
AIMS: Survival after cancer diagnosed during childhood or adolescence continues to improve with new treatments and supportive therapies. Optimal long-term care requires that risks to vulnerable organs are clearly defined and translated into guidelines that are implemented into practice. PanCareLIFE is a pan-European consortium that addresses survivorship issues comprising fertility, hearing impairment and quality of life. This article describes the scientific basis of PanCareLIFE's studies. METHODS: PanCareLIFE involves 17 partner institutions from eight European countries, with additional 11 data providers from five other countries. Study designs and methods include molecular genetic, cohort and case-control studies, a longitudinal study and an intervention study. Ethics and data protection issues have been taken into account from the beginning. RESULTS: PanCareLIFE will investigate the way that treatment impairs female fertility, by evaluating anti-Müllerian hormone levels and the underlying genetic susceptibility to loss of fertility. For our fertility studies, more than 6000 survivors have completed questionnaires, more than 1500 provided serum samples and more than 400 case-control triads have been identified. Fertility preservation guidelines for boys and girls will be developed. More than 2000 survivors have contributed audiograms for the ototoxicity study. Almost 1000 samples were sent for genetic analysis related to ototoxicity and gonadal reserve. The SF-36 questionnaire will measure quality of life in more than 10,000 survivors. CONCLUSIONS: The large number of subjects enrolled in PanCareLIFE and the detailed information accumulated will allow in-depth evaluation of important outcomes. Fertility preservation guidelines will help patients and their families make informed decisions and contribute to their long-term well-being.
Asunto(s)
Calidad de Vida/psicología , Adolescente , Adulto , Niño , Preescolar , Europa (Continente) , Estudios de Factibilidad , Femenino , Preservación de la Fertilidad , Humanos , Lactante , Recién Nacido , Cuidados a Largo Plazo , Masculino , Neoplasias , Proyectos Piloto , Sobrevivientes , Adulto JovenRESUMEN
Since 1997, execution in China has been increasingly performed by lethal injection. The current criteria for determination of death for execution by lethal injection (cessation of heartbeat, cessation of respiration, and dilated pupils) neither conform to current medical science nor to any standard of medical ethics. In practice, death is pronounced in China within tens of seconds after starting the lethal injection. At this stage, however, neither the common criteria for cardiopulmonary death (irreversible cessation of heartbeat and breathing) nor that of brain death (irreversible cessation of brain functions) have been met. To declare a still-living person dead is incompatible with human dignity, regardless of the processes following death pronouncement. This ethical concern is further aggravated if organs are procured from the prisoners. Analysis of postmortem blood thiopental level data from the United States indicates that thiopental, as used, may not provide sufficient surgical anesthesia. The dose of thiopental used in China is kept secret. It cannot be excluded that some of the organ explantation surgeries on prisoners subjected to lethal injection are performed under insufficient anesthesia in China. In such cases, the inmate may potentially experience asphyxiation and pain. Yet this can be easily overlooked by the medical professionals performing the explantation surgery because pancuronium prevents muscle responses to pain, resulting in an extremely inhumane situation. We call for an immediate revision of the death determination criteria in execution by lethal injection in China. Biological death must be ensured before death pronouncement, regardless of whether organ procurement is involved or not.