Alzheimer’s Disease (AD) provides an excellent case study to investigate emerging conceptions of health, disease, pre-disease, and risk. Two scientific working groups have recently reconceptualized AD and created a new category of asymptomatic biomarker positive persons, who are either said to have preclinical AD, or to be at risk for AD. This article examines how prominent theories of health and disease would classify this condition: healthy or diseased? Next, the notion of being “at risk”—a state somewhere in-between health and (...) disease—is considered from various angles. It is concluded that medical-scientific developments urge us to let go of dichotomous ways of understanding disease, that the notion of “risk,” conceptualized as an increased chance of getting a symptomatic disease, might be a useful addition to our conceptual framework, and that we should pay more attention to the practical usefulness and implications of the ways in which we draw lines and define concepts. (shrink)

Human germline gene editing is often debated in hypothetical terms: if it were safe and efficient, on what further conditions would it then be ethically acceptable? This paper takes another course. The key question is: how can scientists reduce uncertainty about safety and efficiency to a level that may justify initiation of first-time clinical trials? The only way to proceed is by well-designed preclinical studies. However, what kinds of investigation should preclinical studies include and what specific conditions should (...) they satisfy in order to be considered well-designed? It is argued that multispecies and multigenerational animal studies are needed as well as human embryo editing without implantation. In order to be possible to translate to first-time clinical trials, animal studies need to satisfy strict conditions of validity. Moreover, embryo studies intended for translation to first-time clinical trials need to correspond to the animal studies in experimental design. Only in this way can uncertainty about risk for harm and prospect of benefit in first-time clinical trials be reduced to a modest level. If uncertainty is not reduced to such a level, first-time clinical trials in germline gene editing should not be initiated. (shrink)

Human germline gene editing is often debated in hypothetical terms: if it were safe and efficient, on what further conditions would it then be ethically acceptable? This paper takes another course. The key question is: how can scientists reduce uncertainty about safety and efficiency to a level that may justify initiation of first-time clinical trials? The only way to proceed is by well-designed preclinical studies. However, what kinds of investigation should preclinical studies include and what specific conditions should (...) they satisfy in order to be considered well-designed? It is argued that multispecies and multigenerational animal studies are needed as well as human embryo editing without implantation. In order to be possible to translate to first-time clinical trials, animal studies need to satisfy strict conditions of validity. Moreover, embryo studies intended for translation to first-time clinical trials need to correspond to the animal studies in experimental design. Only in this way can uncertainty about risk for harm and prospect of benefit in first-time clinical trials be reduced to a modest level. If uncertainty is not reduced to such a level, first-time clinical trials in germline gene editing should not be initiated. (shrink)

Deep brain stimulation is a clinical intervention for the treatment of movement disorders. It has also been applied to the treatment of psychiatric disorders such as depression, anorexia nervosa, obsessive-compulsive disorder, and schizophrenia. Psychiatric disorders including schizophrenia, bipolar disorder, and major depression can lead to psychosis, which can cause patients to lose touch with reality. The ventral tegmental area, located near the midline of the midbrain, is an important region involved in psychosis. However, the clinical application of electrical stimulation of (...) the VTA to treat psychotic diseases has been limited, and related mechanisms have not been thoroughly studied. In the present study, hyperlocomotion and stereotyped behaviors of the mice were employed to mimic and evaluate the positive-psychotic-like behaviors. We attempted to treat positive psychotic-like behaviors by electrically stimulating the VTA in mice and exploring the neural mechanisms behind behavioral effects. Local field potential recording and in vivo fiber photometry to observe the behavioral effects and changes in neural activities caused by DBS in the VTA of mice. Optogenetic techniques were used to verify the neural mechanisms underlying the behavioral effects induced by DBS. Our results showed that electrical stimulation of the VTA activates local gamma-aminobutyric acid neurons, and dopamine neurons, reduces hyperlocomotion, and relieves stereotyped behaviors induced by MK-801 injection. The results of optogenetic manipulation showed that the activation of the VTA GABA neurons, but not DA neurons, is involved in the alleviation of hyperlocomotion and stereotyped behaviors. We visualized changes in the activity of specific types in specific brain areas induced by DBS, and explored the neural mechanism of DBS in alleviating positive psychotic-like behaviors. This preclinical study not only proposes new technical means of exploring the mechanism of DBS, but also provides experimental justification for the clinical treatment of psychotic diseases by electrical stimulation of the VTA. (shrink)

Background and Aims Progress towards validating amyloid beta as an early indicator of Alzheimer’s disease (AD) heightens the need for evaluation of stakeholders’ perspectives of the benefits and harms of preclinical testing in asymptomatic individuals. Methods Investigators conducted and analyzed 14 semi-structured interviews with family members of patients diagnosed with AD. Results Participants reported benefits, including the potential to seek treatment, make lifestyle changes, and prepare for cognitive impairment. Participants identified harms, including social harms, adverse life decisions, and psychological (...) harms. Nine participants reported either a “positive global perspective” or a “positive global perspective (qualified).” Conclusion Results from this study characterized stakeholders’ perspectives on the potential benefits and harms of clinical use of preclinical testing for AD. Investigators used data from this study to develop a framework that contributes to ongoing discussions that will evaluate widespread adoption of preclinical testing and will inform future research. (shrink)

According to the received view, the transportation view, animal extrapolation consists in inductive prediction of the outcome of a mechanism in a target, based on an analogical mechanism in a model. Through an analysis of the failure of preclinical studies of TGN1412, an innovative drug, to predict the tragic consequences of its first-in-man trial in 2006, the received view is challenged by a proposed view of animal extrapolation, the chimera view. According to this view, animal extrapolation is based on (...) a hypothesis about how human organisms work, supported by the amalgamation of results drawn from various experimental organisms, and only predicting the ‘predictive grid’, that is, a global framework of the effects to be expected. (shrink)

Communication can be defined as the process of sharing ideas, experiences, attitudes and knowledge by transmission of symbolic messages. Dental medicine is an area where technical skills are not the only prerequisites for being a good health care provider. Soft skills, such as active listening to the patient, appropriate verbal and non-verbal communication, empathy, and respecting ethical rules are significant in the dentist–patient communication process. Consequently, they influence patients’ attitudes, satisfaction, and ongoing health-related behaviour. Therefore, a training course on communication (...) skills has been introduced at the Faculty of Dental Medicine of the Medical University in Sofia. The aim is to improve students’ soft skills, and to form a behavioural design pattern concerning dentist–patient interactions. (shrink)

Authorship transgressions, duplicate data reporting and reporting/data errors compromise the integrity of biomedical publications. Using a standardized template, we raised concerns with journals about each of these characteristics in 33 pairs of publications originating from 15 preclinical trials reported by a group of researchers. The outcomes of interest were journal responses, including time to acknowledgement of concerns, time to decision, content of decision letter, and disposition of publications at 1 year. Authorship transgressions affected 27/36 publications. The median proportion of (...) duplicate data within pairs of publications was 45%. Data/reporting discrepancies [median 3 ] were present in 28/33 pairs. Journals acknowledged receipt of concerns for 53% and 94% of publications by 1 month and 9 months, respectively. After 1 year, journals had communicated decisions for 16/36 publications. None of the decision letters specifically addressed each of the concerns raised. Decisions were no action, correction and retraction for 9, 3 and 4 publications, respectively: the amounts of duplicate data reporting and data/reporting discrepancies were similar irrespective of journal decision. Authorship transgressions affected 6/9 publications for which no action was decided. Journal responses to concerns about duplicate publication, authorship transgressions, and data/reporting discrepancies were slow, opaque and inconsistent. (shrink)

It's not unusual to hear someone say, ‘I'd rather be dead than have Alzheimer's’. In ‘Alzheimer Disease and Preemptive Suicide’,1 Dena Davis explains why this is a reasonable position. People taking this position will welcome the discovery of biomarkers permitting very early AD diagnosis, Davis suggests, for this will enable more of them to end their lives while they remain motivated and able to do so. At the same time, Davis observes, people would have less reason to resort to the (...) drastic remedy of pre-emptive suicide if they had absolute authority over the medical treatment they received as patients with dementia; but the threat of pre-emptive suicide is not, in my view, a sufficient reason to grant competent individuals that authority.If preclinical diagnosis of AD becomes possible, some pre-emptive suicides will probably occur. There would be no ethical or practical way to ban such suicides, and it would be silly to try. Clinicians will undoubtedly try to discourage people seeking biomarker information in furtherance of a suicide plan, but savvy individuals will simply conceal their true motivation for having the tests. The real problem for people intent on self-destruction is that biomarkers are unlikely to deliver a clear suicide signal.First, as Davis notes, work on biomarkers remains in the research stage. No one yet knows whether biomarker tests will prove accurate enough to warrant clinical use. Second, even clinically accepted biomarker tests will generate imperfect information about future disease. Biomarkers may produce more accurate estimates of a person's risk of developing AD, but like all predictive tests, they will also yield false positive and negative results. The …. (shrink)

In the field of medically assisted reproduction (MAR), there is a growing emphasis on the importance of introducing new assisted reproductive technologies (ARTs) only after thorough preclinical safety research, including the use of animal models. At the same time, there is international support for the three R’s (replace, reduce, refine), and the European Union even aims at the full replacement of animals for research. The apparent tension between these two trends underlines the urgency of an explicit justification of the (...) use of animals for the development and preclinical testing of new ARTs. Considering that the use of animals remains necessary for specific forms of ART research and taking account of different views on the moral importance of helping people to have a genetically related child, we argue that, in principle, the importance of safety research as part of responsible innovation outweighs the limited infringement of animal wellbeing involved in ART research. (shrink)

Moodle is applied as an online learning management system in the Faculty of Medicine, Thammasat University (TU), where the curriculum has been based on problem-based learning (PBL) since 2015. Little research on the effectiveness of Moodle and students’ attitudes during their studies at the pre-clinical medical level within a PBL curriculum has been conducted. Hence, this cross-sectional study focuses on second- and the third-year (MD-2 and MD-3) preclinical medical students’ attitudes towards Moodle and its effectiveness in the PBL curriculum (...) by using a 27-itemed self-constructed online questionnaire. Additionally, students’ preferences as regards the materials managed by the Moodle platform were also evaluated as students’ preferred behaving style (SPBS). After obtaining ethical approval from the Human Ethics Committee of TU No. 1 (Faculty of Medicine), the data was collected and analyzed by medians and inter-quartile ranges, Mann-Whitney U test, and Spearman correlation (ρ). After analyzing the data, the results indicated the following: (1) the top four attitudes scores, (2) the two lowest-attitude scores, (3) the top five effectiveness scores (Ef), (4) the three lowest effectiveness scores, and (5) the top three SPBS scores. Interestingly, a stronger positive Spearman’s correlation (ρ) between ‘Prefer doing quizzes in Moodle to in classroom’ and ‘Moodle enhances learning capability’ was found for MD-3 compared with MD-2. This study reports that Moodle is preferable as a platform supporting students’ self-learning within a PBL curriculum. However, to use the Moodle platform to the highest benefit, instructors need to upgrade its capabilities, especially in the area of student-teacher interaction and the enhancement of students’ critical thinking and creativity, as demonstrated by the lowest scores obtained in this study. (shrink)

Purpose Moral orientation can affect ethical decision-making. Very few studies have focused on whether medical education can change the moral orientation of the students. The purpose of the present study was to document the types of moral orientation exhibited by medical students, and to study if their moral orientation was changed after preclinical education. Methods From 2007 to 2009, the Mojac scale was used to measure the moral orientation of Taiwan medical students. The students included 271 first-year and 109 (...) third-year students. They were rated as a communitarian, dual, or libertarian group and followed for 2 years to monitor the changes in their Mojac scores. Results In both first and third-year students, the dual group after 2 years of preclinical medical education did not show any significant change. In the libertarian group, first and third-year students showed a statistically significant increase from a score of 99.4 and 101.3 to 103.0 and 105.7, respectively. In the communitarian group, first and third-year students showed a significant decline from 122.8 and 126.1 to 116.0 and 121.5, respectively. Conclusion During the preclinical medical education years, students with communitarian orientation and libertarian orientation had changed in their moral orientation to become closer to dual orientation. These findings provide valuable hints to medical educators regarding bioethics education and the selection criteria of medical students for admission. (shrink)

BackgroundSubjective cognitive decline, non-amnestic mild cognitive impairment, and amnestic mild cognitive impairment are regarded to be at high risk of converting to Alzheimer’s disease. Amplitude of low-frequency fluctuations can reflect functional deterioration while diffusion tensor imaging is capable of detecting white matter integrity. Our study aimed to investigate the structural and functional alterations to further reveal convergence and divergence among SCD, naMCI, and aMCI and how these contribute to cognitive deterioration.MethodsWe analyzed ALFF under slow-4 and slow-5 bands and white matter (...) fiber integrity among normal controls, SCD, naMCI, and aMCI groups. Correlation analyses were further utilized among paired DTI alteration, ALFF deterioration, and cognitive decline.ResultsFor ALFF calculation, ascended ALFF values were detected in the lingual gyrus and superior frontal gyrus within SCD and naMCI patients, respectively. Descended ALFF values were presented mainly in the LING, SFG, middle frontal gyrus, and precuneus in aMCI patients compared to CN, SCD, and naMCI groups. For DTI analyses, white matter alterations were detected within the uncinate fasciculus in aMCI patients and within the superior longitudinal fasciculus in naMCI patients. SCD patients presented alterations in both fasciculi. Correlation analyses revealed that the majority of these structural and functional alterations were associated with complicated cognitive decline. Besides, UF alterations were correlated with ALFF deterioration in the SFG within aMCI patients.ConclusionsSCD shares structurally and functionally deteriorative characteristics with aMCI and naMCI, and tends to convert to either of them. Furthermore, abnormalities in white matter fibers may be the structural basis of abnormal brain activation in preclinical AD stages. Combined together, it suggests that structural and functional integration may characterize the preclinical AD progression. (shrink)

Background This study used a scenario- and discussion-based approach to teach preclinical medical students the socio-philosophical aspects of psychiatry and qualitatively evaluated the learning outcomes in a medical humanities course in Taiwan. Methods The seminar session focused on three hypothetical psychiatry cases. Students discussed the cases in groups and were guided by facilitators from multiple disciplines and professions. At the end of the semester, students submitted a narrative report comprising their reflections on the cases and discussions. The authors utilized (...) content analysis to categorize students’ narratives into three facets, namely, the philosophical, social and individual. Results In total 163 preclinical medical students participated in the class; 150 of them mentioned the scenario-based lesson in their reports; 33.3% of these reports discussed the case at the philosophical dimension (n = 50), 45.3% at the social dimension (n = 68), and 26.6% at the individual dimension (n = 40). Four major themes emerged: (1) a psychiatric diagnosis has far-reaching consequences for an individual’s life, (2) the social structure affects how patients experience psychiatric disorders, (3) students related personal experience or those of friends and family to understand psychiatric disorders, and (4) medical humanities are of particular importance in psychiatric education. Conclusions This study demonstrated that the scenario-based discussions led by a multidisciplinary team of facilitators can benefit medical students with limited clinical experience to contemplate the socio-philosophical aspects of psychiatry. The authors suggest that this pedagogical model during preclinical education should be encouraged. (shrink)

BackgroundThe public and healthcare workers have a high expectation of animal research which they perceive as necessary to predict the safety and efficacy of drugs before testing in clinical trials. However, the expectation is not always realised and there is evidence that the research often fails to stand up to scientific scrutiny and its 'predictive value' is either weak or absent.DiscussionProblems with the use of animals as models of humans arise from a variety of biases and systemic failures including: 1) (...) bias and poor practice in research methodology and data analysis ; 2) lack of transparency in scientific assessment and regulation of the research; 3) long-term denial of weaknesses in cross-species translation; 4) profit-driven motives overriding patient interests; 5) lack of accountability of expenditure on animal research; 6) reductionist-materialism in science which tends to dictate scientific inquiry and control the direction of funding in biomedical research.SummaryBias in animal research needs to be addressed before medical research and healthcare decision-making can be more evidence-based. Research funding may be misdirected on studying 'disease mechanisms' in animals that cannot be replicated outside tightly controlled laboratory conditions, and without sufficient critical evaluation animal research may divert attention away from avenues of research that hold promise for human health. The potential for harm to patients and trial volunteers from reliance on biased animal data1 requires measures to improve its conduct, regulation and analysis. This article draws attention to a few of the many forms of bias in animal research that have come to light in the last decade and offers a strategy incorporating ten recommendations stated at the end of each section on bias. The proposals need development through open debate and subsequent rigorous implementation so that reviewers may determine the value of animal research to human health. The 10Rs + are protected by a Creative Commons Attribution 3.0 Unported License and therefore may be 'shared, remixed or built on, even commercially, so long as attributed by giving appropriate credit with a link to the license, and indicate if changes were made.’. (shrink)

Concerns about the possibility of a sharp rise in the prevalence of Alzheimer’s disease in Western nations have led to both the significant deployment of resources and the development of national research and healthcare plans. Although often focused on treatment, substantial efforts have also been dedicated toward preventing or delaying AD onset. As a result, recent technological and biomedical advances have greatly improved the understanding of AD pathophysiology. While some new tests can assess only risk ), some tests for certain (...) biomarkers (e.g., amyloid beta accumulation in the brain detected via positron... (shrink)

A central principle of bioethics is “subject autonomy,” the acknowledgement of the primacy of the informed consent of the subject of research. Autonomy requires informed consent — the assurance that the research participant is informed about the possible risks and benefits of the research. In fact, informed consent is difficult when a single drug is being tested, although subjects have a baseline understanding of the testing of a pharmacological agent and the understanding that they can stop taking the drug if (...) there were an adverse event. However, informed consent is even less easily achieved in the modern arena of complex new molecular and cellular therapies. In this article, we argue that as science confronts new issues such as transplantation of stem cell products, which may live within the participant for the rest of their lives, researchers must carefully consider and constantly re-examine how they properly inform subjects considering participation trials of these novel therapeutic strategies.For example, the manufacture of a vial of a cell product that consists of a collection of growing cells is very different than the production of a vial of identical pills, which can be presumed to be identical. The scientific concepts on which these cellular approaches are based may seem alien and incomprehensible to a research subject, who thinks of a clinical trial as simply the selection and testing of the most efficacious pharmaceutical agent already proven to work in preclinical animal studies. The research subject would be wrong. (shrink)

Seemingly distant practices of molecular biology and indigenous Xhosa healing have commonalities that I would like to bring into conversation in this article. The preclinical trial of an indigenous medicine brings them together in a research consortium. In this instance, both sets of experts are meant to collaborate in preparing a wild bush for it to pass the tests of the randomized clinical trial (RCT) and to potentially become a biopharmaceutical to counter the tuberculosis pandemic. I aim to tease (...) out how the two sets of actors and their respective practices converge and diverge in their healing hopes and ways of managing uncertainty. Ultimately, I am interested in understanding how the preferred process of making medicine “work” by each set of actors relies upon particular ways of knowing and not knowing life, bringing some ontologies into being, letting others wither away. The shared ways of knowing life as a movement of opening at the edges of the RCT are proposed as paths of recognition between one and the other practice. (shrink)

In this review, we discuss the application of mouse models to the identification and pre‐clinical validation of novel therapeutic targets in colorectal cancer, and to the search for early disease biomarkers. Large‐scale genomic, transcriptomic and epigenomic profiling of colorectal carcinomas has led to the identification of many candidate genes whose direct contribution to tumourigenesis is yet to be defined; we discuss the utility of cross‐species comparative ‘omics‐based approaches to this problem. We highlight recent progress in modelling late‐stage disease using mice, (...) and discuss ways in which mouse models could better recapitulate the complexity of human cancers to tackle the problem of therapeutic resistance and recurrence after surgical resection. (shrink)

Problems in peer review, the backbone of maintaining high standards in scientific publishing, have led to wide spread discontent within the scientific community. Training in the peer review process and a simpler format to assist in decision making are possible courses to improve and expedite the process of peer review and scientific publishing. The authors discuss problems in the peer review process focusing on challenges related to major revisions and reviewer's wish list of experiments; this leads to the loss of (...) time and money. Major revisions rarely lead to significant improvements, while simultaneously delay the dissemination of knowledge. The authors propose simple solutions including training peer reviewers to improve the peer review system. (shrink)

Graphical AbstractThis commentary discusses the novelty of the preclinical opioid choice model published in Heinsbroek et al., Nat Commun, 2021, and the potential influence of altitude on the reported findings. The studies were performed in the Mile High City of Denver, Colorado, where a unique subpopulation of heroin-choosing rats were noted.

Recent preclinical studies have shown the feasibility of specific variants of nuclear transfer to prevent mitochondrial DNA disorders. Nuclear transfer could be a valuable reproductive option for carriers of mitochondrial mutations. A clinical application of nuclear transfer, however, would entail germ-line modification, more specifically a germ-line modification of the mitochondrial genome. One of the most prominent objections against germ-line modification is the fear that it would become possible to alter ‘essential characteristics’ of a future person, thereby possibly violating the (...) child's right to an open future. As only the nuclear DNA would contain the ingredients for individual characteristics, modification of the mtDNA is often considered less controversial than modification of the nuclear DNA. This paper discusses the tenability of this dichotomy. After having clarified the concept of germ-line modification, it argues that modification of the mtDNA is not substantively different from modification of the nuclear DNA in terms of its effects on the identity of the future person. Subsequently the paper assesses how this conclusion affects the moral evaluation of nuclear transfer to prevent mtDNA disorders. It concludes that the moral acceptability of germ-line modification does not depend on whether it alters the identity of the future child—all germ-line modifications do—but on whether it safeguards the child's right to an open future. If nuclear transfer to prevent mtDNA disorders becomes safe and effective, then dismissing it because it involves germ-line modification is unjustified. (shrink)

Preclinical xenotransplantation research using genetically engineered pigs has begun to show some promising results and could one day offer a scalable means of addressing organ shortage. While it is a fundamental tenet of ethical human subject research that participants have a right to withdraw from research once enrolled, several scholars have argued that the right to withdraw from xenotransplant research should be suspended because of the public health risks posed by xenozoonotic transmission. Here, we present a comprehensive critical evaluation (...) of the claim that xenotransplant recipients should be required to waive their right to withdraw from lifelong biosurveillance. We conclude that if xenotransplantation requires participants to waive their right to withdraw, then clinical trials may not be justifiable, given the ethical and legal obstacles involved with doing so. Consequently, if clinical trials are permitted with a right to withdraw, then they may pose a significant public health risk. (shrink)

In the hope of future treatments to prevent or slow down the disease, there is a strong movement towards an ever-earlier detection of Alzheimer's disease. In conjunction with scientific developments, this has prompted a reconceptualization of AD, as a slowly progressive pathological process with a long asymptomatic phase. New concepts such as "preclinical" and "prodromal" AD have been introduced, raising a number of conceptual and ethical questions. We evaluate whether these new concepts are theoretically defensible, in light of theories (...) of health and disease, and whether they should be understood as disease or as an at-risk state. We introduce a pragmatic view on disease concepts and argue that an evaluation of the reconceptualization of AD should also take its aims and effects into account, and assess their ethical acceptability. The reconceptualization of AD is useful to coordinate research into preventive strategies, and may potentially benefit future patients. However, in the short term, early detection and labelling of "preclinical AD" can potentially harm people. Since there is no treatment available and the predictive value is unclear, it may only create a group of "patients in waiting" who may suffer from anxiety, uncertainty and stigmatization, but will never actually develop dementia. We conclude that only if the promise of preventive medication materializes, will the reconceptualization of AD turn out unequivocally to be for the better. Otherwise, the reconceptualization may do more harm than good. (shrink)

The theory stating that oxidative stress is at the root of several diseases is extremely popular. However, so far, no antioxidant is recommended or offered by healthcare systems neither approved as therapy by regulatory agencies that base their decisions on evidence-based medicine. This is simply because, so far, despite many preclinical and clinical studies indicating a beneficial effect of antioxidants in many disease conditions, randomised clinical trials have failed to provide the evidence of efficacy required for drug approval. In (...) this review, we discuss the levels of evidence required to claim causality in preclinical research on OS, the weakness of the oversimplification associated with OS theory of disease and the importance of the narrative in its popularity. Finally, from a more translational perspective, we discuss the reasons why antioxidants acting by scavenging reactive oxygen species might not only prevent their detrimental effects but also interfere with essential signalling roles. We propose that ROS have a complex metabolism and are generated by different enzymes at diverse sites and with different timing. Aggregating this plurality of systems in a single theory of disease may not be the best way to develop new drugs, and future research may need to focus on specific oxygen-toxifying pathways rather than on non-specific ROS scavengers. Finally, similarly to what is nowadays required for clinical trials, we recommend making unpublished data available in repositories, as this will allow big data approaches or meta-analyses without the blinders of the publication bias. (shrink)

First-in-human clinical trials represent a critical juncture in the translation of laboratory discoveries. However, because they involve the greatest degree of uncertainty at any point in the drug development process, their initiation is beset by a series of nettlesome ethical questions [1]: has clinical promise been sufficiently demonstrated in animals? Should trial access be restricted to patients with refractory disease? Should trials be viewed as therapeutic? Have researchers adequately minimized risks? The resolution of such ethical questions inevitably turns on claims (...) about future events like harms, therapeutic response, and clinical translation. Recurrent failures in clinical translation, like Eli Lilly's Alzheimer candidate semagacestat, highlight the severe limitations of current methods of prediction. In this case, patients in the active arm of the placebo-controlled trial had earlier onset of dementia and elevated rates of skin cancer [2]. Various authoritative accounts of human research ethics state that decision-making about risk and benefit should be careful, systematic, and non-arbitrary [3]–[5]. Yet, these sources provide little guidance about what kinds of evidence stakeholders should use to ensure their estimates of such events ground responsible ethical decisions. In this article, we suggest that investigators, oversight bodies, and sponsors often base their predictions on a flawed and inappropriately narrow preclinical evidence base. (shrink)

Deep brain stimulation (DBS) has been proposed as a potential treatment of drug addiction on the basis of its effects on drug self-administration in animals and on addictive behaviours in some humans treated with DBS for other psychiatric or neurological conditions. DBS is seen as a more reversible intervention than ablative neurosurgery but it is nonetheless a treatment that carries significant risks. A review of preclinical and clinical evidence for the use of DBS to treat addiction suggests that more (...) animal research is required to establish the safety and efficacy of the technology and to identify optimal treatment parameters before investigating its use in addicted persons. Severely addicted persons who try and fail to achieve abstinence may, however, be desperate enough to undergo such an invasive treatment if they believe that it will cure their addiction. History shows that the desperation for a cure of addiction can lead to the use of risky medical procedures before they have been rigorously tested. In the event that DBS is used in the treatment of addiction, we provide minimum ethical requirements for clinical trials of its use in the treatment of addiction. These include: restrictions of trials to severely intractable cases of addiction; independent oversight to ensure that patients have the capacity to consent and give that consent on the basis of a realistic appreciation of the potential benefits and risks of DBS; and rigorous assessments of the effectiveness and safety of this treatment compared to the best available treatments for addiction. (shrink)

Research Ethics Committees (RECs) play a critical gatekeeping role in clinical trials. This role is meant to ensure that only those trials that meet certain ethical thresholds proceed through their gate. Two of these thresholds are that the potential benefits of trials are reasonable in relation to risks and that trials are capable of producing a requisite amount of social value. While one ought not expect perfect execution by RECs of their gatekeeping role, one should expect routine success in it. (...) This article reviews a range of evidence showing that substantial numbers of ethically tainted trials are receiving REC approvals. Many of the trials are early phase trials that evidence shows have benefits that may not be reasonable compared with their risks and many others are later trials that evidence shows may lack sufficient social value. The evidence pertains to such matters as methodologically inadequate preclinical studies incapable of supporting the inferences that REC members must make about the prospects for potential benefit needed to offset the risks in early phase trials and sponsorship bias that can cause improperly designed, conducted, analysed and reported later phase trials. The analysis of the evidence makes clear that REC practices need to be strengthened if they are to adequately fulfil their gatekeeping role. The article also explores options that RECs could use in order to improve their gatekeeping function. (shrink)

Translational science is a 21st century mission. Government officials and industry leaders are making huge investments in an attempt to transform more basic science discoveries into therapeutic applications. Scientists and policymakers express great excitement about the medical advances that could come with the current bench-to-bedside campaign.A key step in translational science is the move from animal and other preclinical studies to initial human testing. Researchers ability to predict human effects is limited, and first-in-human tests present significant uncertainty. Participants in (...) this form of research face risks and can experience serious, even lethal, harm. Well-known incidents involving Jolee Mohr and Jesse Gelsinger, as well as subjects in the 2006 study of the investigational agent TGN1412, show the dangers that can arise in early human research.The bench-to-bedside campaign will need many volunteers to participate in early human testing. Investigators and regulators must not allow the policy enthusiasm for translational science to overshadow the commitment to protect human subjects. Participants in exploratory research are diverse and as a group lack characteristics usually associated with vulnerable populations, such as impaired decisional ability or economic or educational disadvantage. (shrink)

As the world held its breath for news surrounding COVID-19 and hunkered down amidst stay-at-home orders, medical students across the U.S. wondered if they would be called to serve on the front lines of the pandemic. Medical school administrators faced the challenge of protecting learners while also minimizing harm to their medical education. This balancing act raised critical questions in medical education as institutions reacted to changing guidelines. COVID-19 has punctuated already contentious areas of medical education and has forced institutions (...) and organizations to take quick action. From the perspectives of a recent medical school graduate and current resident and a practicing clinician-educator, we examine the pandemic’s impact on undergraduate medical education through an ethical lens. First, we explore the value of medical education, what drives this value, and how COVID-19 may alter it. We next consider student choice and how shifts toward utilitarianism in healthcare during a pandemic may affect learning and career exploration. Then, we inquire how access to technology may impact the experience of medical students from diverse backgrounds and varied institutions during a rapid shift to socially distanced learning. We identify vulnerabilities for students at several phases of the journey: premedical, preclinical, clinical, and preparation for residency. Finally, we address the hidden curriculum of COVID-19, its potential erosion of empathy among current medical students, and possible long-term consequences for future physicians and patients. (shrink)

The 21st-century translational science campaign could lead to an increase in first-in-human trials. As tests of investigational interventions move from the laboratory to human research, scientists, officials, and review committees should address ongoing concerns about the ethics of FIH trials. In this article, I describe three ethical considerations relevant to all FIH trials: the requirement for adequate preclinical research; study design safeguards; and choice of subject population. I also examine specific ethical considerations relevant to the three subject populations involved (...) in FIH research. I recommend a variety of actions that could increase subject protection and the value of the information generated in FIH trials. (shrink)

Background Compulsory treatments represent a legal means of imposing treatment on an individual, usually with a mental illness, who refuses therapeutic intervention and poses a risk of self-harm or harm to others. Compulsory outpatient treatment in psychiatry, also known as community treatment order, is a modality of involuntary treatment that broadens the therapeutic imposition beyond hospitalization and into the community. Despite its existence in over 75 jurisdictions worldwide, COT is currently one of the most controversial topics in psychiatry, and it (...) presents significant ethical challenges. Nonetheless, the ethical debate regarding compulsory treatment almost always stops at a preclinical level, with the different ethical positions arguing for or against its use, and there is little guidance to support for the individual clinicians to act ethically when making the decision to implement COT. Main body The current body of evidence is not clear about the efficacy of COT. Therefore, despite its application in several countries, evidence favouring the use of COT is controversial and mixed at best. In these unclear circumstances, ethical guidance becomes paramount. This paper provides an ethical analysis of use of COT, considering the principlist framework established by Ross Upshur in 2002 to justify public health interventions during the 2002–2004 severe acute respiratory syndrome outbreak. This paper thoroughly examines the pertinence of using the principles of harm, proportionality, reciprocity, and transparency when considering the initiation of COT. Conclusion Ross Upshur’s principlist model provides a useful reflection tool for justifying the application of COT. This framework may help to inform sounder ethical decisions in clinical psychiatric practice. (shrink)

Patient-derived xenografts are currently promoted as new translational models in precision oncology. PDXs are immunodeficient mice with human tumors that are used as surrogate models to represent specific types of cancer. By accounting for the genetic heterogeneity of cancer tumors, PDXs are hoped to provide more clinically relevant results in preclinical research. Further, in the function of so-called “mouse avatars”, PDXs are hoped to allow for patient-specific drug testing in real-time. This paper examines the circulation of knowledge and bodily (...) material across the species boundary of human and personalized mouse model, historically as well as in contemporary practices. PDXs raise interesting questions about the relation between animal model and human patient, and about the capacity of hybrid or interspecies models to close existing translational gaps. We highlight that the translational potential of PDXs not only depends on representational matching of model and target, but also on temporal alignment between model development and practical uses. Aside from the importance of ensuring temporal stability of human tumors in a murine body, the mouse avatar concept rests on the possibility of aligning the temporal horizons of the clinic and the lab. We examine strategies to address temporal challenges, including cryopreservation and biobanking, as well as attempts to speed up translation through modification and use of faster developing organisms. We discuss how featured model virtues change with precision oncology, and contend that temporality is a model feature that deserves more philosophical attention. (shrink)

Development of biopharmaceuticals is a challenging issue in bioethics. Unlike conventional, small molecular weight drugs, biopharmaceuticals are proteins derived from DNA technology and hybrid techniques with complex three dimensional structures. Immunogenicity of biopharmaceuticals should always be tested in clinical settings due to low predictive value of preclinical animal models. However, non-human primates and transgenic mice could be used to address certain aspects of immunogenicity. Substantial efforts have been made to reduce NHP use in biopharmaceutical drug development, e.g. study design (...) improvements and changes in regulatory policy. In addition, several expert groups are active in this field. Despite that, there is an increasing trend of use of NHP in preclinical safety testing of biopharmaceuticals, especially regarding monoclonal antibodies. Other potential bioethical issues related biopharmaceutical drug development are their cost/effectiveness ratio, clinical safety assessment, production of biosimilars, and comparison of their efficacy with placebo in countries without intention to market. Identification of the human genome has opened many new bioethical issues. Development of biopharmaceuticals is an important bioethical issue for several reasons. It connects all aspects of contemporary bioethics: bio?medicine, animal welfare and the most recent ad?vances in biotechnology. In particular, biopharmaceutical drug development is a challenging issue regarding treatment of rare diseases. Razvoj biofarmaceutika predstavlja izazov u bioetici. Za razliku od uobicajenih lekova male molekulske mase, biofarmaceutici su proteini kompleksne trodimenzionalne strukture koji se dobijaju tehnologijom rekombinantne DNK i tehnikom hibridoma. Imunogenost biofarmaceutika treba uvek proveriti u klinickim studijama zbog male prediktivne prednosti pretklinickih animalnih modela. Medjutim, primati i transgeni sojevi miseva mogu se upotrebiti da bi se naznacili neki aspekti imunogenosti. Znacajni napori su ucinjeni u cilju smanjenja upotrebe primata u razvoju biofarmaceutika, npr. poboljsanja dizajna istrazivanja i promene u zakonskoj regulativi. Osim toga, u ovoj oblasti su aktivne i pojedine ekspertske grupe. Uprkos tome, postoji rastuci trend upotrebe primata izuzev coveka u pretklinickom ispitivanju bezbednosti biofarmaceutika, posebno kada su u pitanju monoklonska antitela. Druga bioeticka pitanja koja se mogu dovesti u vezu sa razvojem biofarmaceutika su odnos njihove cene i efikasnosti, procena bezbednosti u klinickim uslovima, proizvodnja bioloski slicnih lekova i uporedjivanje njihove efikasnosti sa placebom u zemljama u kojima ne postoji namera o plasmanu. Upoznavanje humanog genoma otvorilo je mnoga bioeticka pitanja. Razvoj biofarmaceutika je vazno bioeticko pitanje iz vise razloga. Ono povezuje sve aspekte savremene bioetike: biomedicinu, dobrobit zivotinja i najnovija dostignuca u biotehnologiji. Posebno, razvoj biofarmaceutika je izazov kada je u pitanju lecenje retkih bolesti. (shrink)

Stem cells are likely to be used as an alternate source of biological material for neural transplantation to treat Parkinson’s disease in the not too distant future. Among the several ethical criteria that must be fulfilled before proceeding with clinical research, a favourable benefit to risk ratio must be obtained. The potential benefits to the participant and to society are evaluated relative to the risks in an attempt to offer the participants a reasonable choice. Through examination of preclinical studies (...) transplanting stem cells in animals and the transplantation of fetal tissue in patients with Parkinson’s disease, a current set of potential benefits and risks for neural transplantation of stem cells in clinical research of Parkinson’s disease are derived. The potential benefits to research participants undergoing stem cell transplantation are relief of parkinsonian symptoms and decreasing doses of parkinsonian drugs. Transplantation of stem cells as a treatment for Parkinson’s disease may benefit society by providing knowledge that can be used to help determine better treatments in the future. The risks to research participants undergoing stem cell transplantation include tumour formation, inappropriate stem cell migration, immune rejection of transplanted stem cells, haemorrhage during neurosurgery and postoperative infection. Although some of these risks are general to neurosurgical transplantation and may not be reduced for participants, the potential risk of tumour formation and inappropriate stem cell migration must be minimised before obtaining a favourable potential benefit to risk calculus and to provide participants with a reasonable choice before they enrol in clinical studies. (shrink)

Following the Second Summit on Human Gene Editing in Hong Kong in 2018, where the birth of two girls with germline genome editing was revealed, the need for a responsible pathway to the clinical application of human germline genome editing has been repeatedly emphasised. This paper aims to contribute to the ongoing discussion on research ethics issues in germline genome editing by exploring key issues related to the initial applications of CRISPR in reproductive medicine. Following an overview of the current (...) discussion on bringing germline genome editing into clinical practice, we outline the specific challenges associated with such interventions and the features that distinguish them from conventional clinical testing of new medical treatments. We then review proposed ethical requirements for initial heritable genome editing, such as the absence of reasonable alternatives, the existence of sufficient and reliable preclinical data, appropriate informed consent, requirements related to safety, and long-term follow-up. (shrink)

The Alzheimer field is in desperate need for an effective treatment. After decades of research, the available drugs treat only symptoms, and even their effectiveness is disputed. Because brain changes precede the clinical symptoms by years to decades, disease-modifying treatments should probably be started early, when the first symptoms occur—or even before. But how to determine who to treat? In this issue, Erik Gustavsson c.s. approach this question by addressing the benefits, harms and ethical issues encountered when using different modes (...) of screening for ‘preclinical’ or early symptomatic Alzheimer disease.1 Their overall conclusion is clear—screening for high risk of developing AD dementia to select those who are eligible for treatment is ethically problematic, unless extremely effective treatment becomes available. An additional major challenge is that diagnostic test accuracy is generally poor, with a particularly high risk of false-positive results, that is, biological evidence of Alzheimer pathology in persons who will never develop dementia. The risk of overmedicalisation is serious, and the potential harms of screening for AD should not be ignored, as Le Couteur c.s. previously argued.2 In short, there is no evidence base for any form of screening for AD whether in a preclinical stage (an …. (shrink)

The potential for genetic engineering of enhancements to complex human traits has been the subject of vigorous debate for a number of years. Most of the discussion has centered on the possible moral consequences of pursuing enhancements, especially those that might affect complex behaviours and components of personality. Little has been written on the actual process of implementing this technology. This paper presents a ‘thought experiment’ about the likely form of final preclinical testing for a technology to enhance intelligence (...) as a prototypical multiplex trait. The significance and the potential dangers of implementing enhancements in humans, especially to highly valued traits such as intelligence, would mandate a thorough programme of testing in animals, including non-human primates such as chimpanzees. The implications this would have for researchers, society and, most importantly, the animals themselves are discussed, and the paper concludes with a suggestion for a morally justifiable approach to resolve the tragic question of what to do with research animals who have a cognitive capacity that is close to that of humans. (shrink)

There is increasing attention given to academic integrity across university education and dental schools are not immune to this problem (Andrews et al. J Dent Educ 71; 1027–1039, 2007; Ford & Hughes Eur J Dent Educ 16(1):e180–e186, 2012). While there has been an increasing concern about academic dishonesty in written exams and assignments, there appears to be a false sense of security in the integrity of practical assessments, involving dental procedures on simulated patients.This paper will present a situational analysis of (...) two unusual cases of academic dishonesty in preclinical dental practical assessments. The first case involved a student bringing a previously prepared plastic tooth into the examination room and substituting it for the assessment tooth. The second case involved a student removing key teeth during the exam to enable them to have better access and advantage over others to complete the assessment task. These two cases resulted in a complete review of practical assessment procedures and the application of new processes to maintain academic integrity. (shrink)

The success of deep brain stimulation (DBS) for movement disorders and the improved understanding of the neurobiologic and neuroanatomic bases of psychiatric diseases have led to proposals to expand current DBS applications. Recent preclinical and clinical work with Alzheimer's disease and obsessive-compulsive disorder, for example, supports the safety of stimulating regions in the hypothalamus and nucleus accumbens in humans. These regions are known to be involved in addiction and overeating associated with obesity. However, the use of DBS targeting these (...) areas as a treatment modality raises common ethical considerations, which include informed consent, coercion, enhancement, threat to personhood, and manipulation of the reward center. Pilot studies for both of these conditions are currently investigational. If these studies show promise, then there is a need to address the ethical concerns related to the initiation of clinical trials including the reliability of preclinical evidence, patient selection, study design, compensation for participation and injury, cost-effectiveness, and the need for long-term follow-up. Multidisciplinary teams are necessary for the ethical execution of such studies. In addition to establishing safety and efficacy, the consideration of these ethical issues is vital to the adoption of DBS as a treatment for these conditions. We offer suggestions about the pursuit of future clinical trials of DBS for the treatment of addiction and overeating associated with obesity and provide a framework for addressing ethical concerns related to treatment. (shrink)

Unregulated patient treatments and approved clinical trials have been conducted with haematopoietic stem cells and mesenchymal stem cells for children with autism spectrum disorder. While the former direct-to-consumer practice is usually considered rogue and should be legally constrained, regulated clinical trials could also be ethically questionable. Here, we outline principal objections against these trials as they are currently conducted. Notably, these often lack a clear rationale for how transplanted cells may confer a therapeutic benefit in ASD, and thus, have ill-defined (...) therapeutic outcomes. We posit that ambiguous and unsubstantiated descriptions of outcome from such clinical trials may nonetheless appeal to the lay public as being based on authentic scientific findings. These may further fuel caregivers of patients with ASD to pursue unregulated direct-to-consumer treatments, thus exposing them to unnecessary risks. There is, therefore, a moral obligation on the part of those regulating and conducting clinical trials of stem cell-based therapeutic for ASD minors to incorporate clear therapeutic targets, scientific rigour and reporting accuracy in their work. Any further stem cell-based trials for ASD unsupported by significant preclinical advances and particularly sound scientific hypothesis and aims would be ethically indefensible. (shrink)

The Medical Faculty of the University of Otago, New Zealand is experimenting with a new approach to the teaching of medical ethics, making it an integral part of several courses in all years of the medical curriculum. During the author's twelve-month period as a visiting professor in the faculty, trial runs in ethics have been introduced in the preclinical sciences, in behavioural science and medical-decision analysis and in every clinical attachment. Proposals for permanent course requirements will be considered by (...) the faculty after a full evaluation of these experiments by both students and teaching staff. If such courses are to be implemented and maintained, medical facilities will need to appoint specialists in ethics, at least on a part-time basis. (shrink)