A QALY is [still] a QALY is [still] a QALY? : Evaluating proportional shortfall as the answer to the problem of equity in healthcare allocations.

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.

Cases Abusing Brain Death Definition in Organ Procurement in China.

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.

Communication and ethical considerations for fertility preservation for patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group.

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.

Resilience beyond reductionism: ethical and social dimensions of an emerging concept in the neurosciences.

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.

Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor α.

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.

Organophosphate ester tri-o-cresyl phosphate interacts with estrogen receptor α in MCF-7 breast cancer cells promoting cancer growth.

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.

Indeno[1,2,3-cd]pyrene and picene mediate actions via estrogen receptor α signaling pathway in in vitro cell systems, altering gene expression.

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.

[Studies on novel immune therapies: challenges from an ethical point of view]. / Studien zu neuen Immuntherapien: Herausforderungen aus Sicht der Ethik.

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.

Determination of Death in Execution by Lethal Injection in China.

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.

Human rights violations in organ procurement practice in China.

BACKGROUND: Over 90% of the organs transplanted in China before 2010 were procured from prisoners. Although Chinese officials announced in December 2014 that the country would completely cease using organs harvested from prisoners, no regulatory adjustments or changes in China's organ donation laws followed. As a result, the use of prisoner organs remains legal in China if consent is obtained. DISCUSSION: We have collected and analysed available evidence on human rights violations in the organ procurement practice in China. We demonstrate that the practice not only violates international ethics standards, it is also associated with a large scale neglect of fundamental human rights. This includes organ procurement without consent from prisoners or their families as well as procurement of organs from incompletely executed, still-living prisoners. The human rights critique of these practices will also address the specific situatedness of prisoners, often conditioned and traumatized by a cascade of human rights abuses in judicial structures. CONCLUSION: To end the unethical practice and the abuse associated with it, we suggest to inextricably bind the use of human organs procured in the Chinese transplant system to enacting Chinese legislation prohibiting the use of organs from executed prisoners and making explicit rules for law enforcement. Other than that, the international community must cease to abet the continuation of the present system by demanding an authoritative ban on the use of organs from executed Chinese prisoners.

Historical development and current status of organ procurement from death-row prisoners in China.

BACKGROUND: In December 2014, China announced that only voluntarily donated organs from citizens would be used for transplantation after January 1, 2015. Many medical professionals worldwide believe that China has stopped using organs from death-row prisoners. DISCUSSION: In the present article, we briefly review the historical development of organ procurement from death-row prisoners in China and comprehensively analyze the social-political background and the legal basis of the announcement. The announcement was not accompanied by any change in organ sourcing legislations or regulations. As a fact, the use of prisoner organs remains legal in China. Even after January 2015, key Chinese transplant officials have repeatedly stated that death-row prisoners have the same right as regular citizens to "voluntarily donate" organs. This perpetuates an unethical organ procurement system in ongoing violation of international standards. CONCLUSIONS: Organ sourcing from death-row prisoners has not stopped in China. The 2014 announcement refers to the intention to stop the use of organs illegally harvested without the consent of the prisoners. Prisoner organs procured with "consent" are now simply labelled as "voluntarily donations from citizens". The semantic switch may whitewash sourcing from both death-row prisoners and prisoners of conscience. China can gain credibility only by enacting new legislation prohibiting use of prisoner organs and by making its organ sourcing system open to international inspections. Until international ethical standards are transparently met, sanctions should remain.

A case of an Angelman-syndrome caused by an intragenic duplication of UBE3A uncovered by adaptive nanopore sequencing.

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.

Parental perceptions of informed consent in a study of tracheal intubations in neonatal intensive care.

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.

Lessons from COVID-19 to increase opioid vaccine acceptance.

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.

Health(care) in the Crisis: Reflections in Science and Society on Opioid Addiction.

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.

Can eastern wisdom resolve western epidemics? Traditional Chinese medicine therapies and the opioid crisis.

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.

Ethical aspects of genome diversity research: genome research into cultural diversity or cultural diversity in genome research?

The goal of the Human Genome Diversity Project (HGDP) was to reconstruct the history of human evolution and the historical and geographical distribution of populations with the help of scientific research. Through this kind of research, the entire spectrum of genetic diversity to be found in the human species was to be explored with the hope of generating a better understanding of the history of humankind. An important part of this genome diversity research consists in taking blood and tissue samples from indigenous populations. For various reasons, it has not been possible to execute this project in the planned scope and form to date. Nevertheless, genomic diversity research addresses complex issues which prove to be highly relevant from the perspective of research ethics, transcultural medical ethics, and cultural philosophy. In the article at hand, we discuss these ethical issues as illustrated by the HGDP. This investigation focuses on the confrontation of culturally diverse images of humans and their cosmologies within the framework of genome diversity research and the ethical questions it raises. We argue that in addition to complex questions pertaining to research ethics such as informed consent and autonomy of probands, genome diversity research also has a cultural-philosophical, meta-ethical, and phenomenological dimension which must be taken into account in ethical discourses. Acknowledging this fact, we attempt to show the limits of current guidelines used in international genome diversity studies, following this up by a formulation of theses designed to facilitate an appropriate inquiry and ethical evaluation of intercultural dimensions of genome research.