The Human Genome Organisation (HUGO) and a vision for Ecogenomics: the Ecological Genome Project.

BACKGROUND: The following outlines ethical reasons for widening the Human Genome Organisation's (HUGO) mandate to include ecological genomics. MAIN: The environment influences an organism's genome through ambient factors in the biosphere (e.g. climate and UV radiation), as well as the agents it comes into contact with, i.e. the epigenetic and mutagenic effects of inanimate chemicals and pollution, and pathogenic organisms. Emerging scientific consensus is that social determinants of health, environmental conditions and genetic factors work together to influence the risk of many complex illnesses. That paradigm can also explain the environmental and ecological determinants of health as factors that underlie the (un)healthy ecosystems on which communities rely. We suggest that The Ecological Genome Project is an aspirational opportunity to explore connections between the human genome and nature. We propose consolidating a view of Ecogenomics to provide a blueprint to respond to the environmental challenges that societies face. This can only be achieved by interdisciplinary engagement between genomics and the broad field of ecology and related practice of conservation. In this respect, the One Health approach is a model for environmental orientated work. The idea of Ecogenomics-a term that has been used to relate to a scientific field of ecological genomics-becomes the conceptual study of genomes within the social and natural environment. CONCLUSION: The HUGO Committee on Ethics, Law and Society (CELS) recommends that an interdisciplinary One Health approach should be adopted in genomic sciences to promote ethical environmentalism. This perspective has been reviewed and endorsed by the HUGO CELS and the HUGO Executive Board.

Storage trends, usage and disposition outcomes following egg freezing.

RESEARCH QUESTION: What happens to eggs after egg freezing? DESIGN: A retrospective cohort study was performed spanning 2012-2022. Data were obtained from seven assisted reproductive technology clinics in Victoria, Australia. Aggregated, de-identified data were collected on cycles that resulted in egg freezing and the following outcomes, including treatment involving thawed eggs and disposition outcomes of surplus eggs. RESULTS: The number of patients with eggs in storage grew rapidly from 144 in 2012 to 2015 in 2022. In 2022, 73% of patients had stored their eggs for <5 years, 25% for 5-10 years, and 2% for ≥10 years. Most thaw cycles (600/645, 93%) involved eggs that had been frozen for <5 years, of which 47% had been frozen for <6 months. Overall, the live birth rate per initiated thaw cycle was 12%. Across the study period, 2800 eggs from 286 patients were either discarded, donated or exported. Of the 128 patients who discarded their eggs, 32% had stored their eggs for <5 years, 32% for 5-10 years and 36% for >10 years. Of the 23 patients who donated their eggs to someone else, all but four had stored their eggs for <5 years. No eggs were donated to research over the study period. CONCLUSIONS: This study shows that very few patients have made the decision to use or relinquish their eggs. Strategies may be needed to address the prolonged storage of surplus eggs, and ensure that patients are supported to make decisions regarding the fate of their eggs which align with their preferences and values.

Medicine in the marketplace: clinician and patient views on commercial influences on assisted reproductive technology.

RESEARCH QUESTION: What are the views and experiences of patient and expert stakeholders on the positive and negative impacts of commercial influences on the provision of assisted reproductive technology (ART) services, and what are their suggestions for governance reforms? DESIGN: Semi-structured interviews were conducted with 31 ART industry experts from across Australia and New Zealand and 25 patients undergoing ART from metropolitan and regional Australia, between September 2020 and September 2021. Data were analysed using thematic analysis. RESULTS: Expert and patient participants considered that commercial forces influence the provision of ART in a number of positive ways - increasing sustainability, ensuring consistency in standards and providing patients with greater choice. Participants also considered commercial forces to have a number of negative impacts, including increased costs to government and patients; the excessive use of interventions that lack sufficient evidence to be considered part of standard care; inadequately informed consent (particularly with regard to financial information); and threats to patient-provider relationships and patient-centred care. Participants varied in whether they believed that professional self-regulation is sufficient. While recognizing the benefits of commercial investment in healthcare, many considered that regulatory reforms, as well as organizational cultural initiatives, are needed as means to ensure the primacy of patient well-being. CONCLUSIONS: The views expressed in this study should be systematically and critically examined to derive insights into how best to govern ART. These insights may also inform the design and delivery of other types of healthcare that are provided in the private sector.

Spatial prioritization for widespread invasive species control: Trade-offs between current impact and future spread.

Spatially explicit prioritization of invasive species control is a complex issue, requiring consideration of trade-offs between immediate and future benefits. This study aimed to prioritize management efforts to account for current and future threats from widespread invasions and examine the strength of the trade-off between these different management goals. As a case study, we identified spatially explicit management priorities for the widespread invasion of introduced willow into riparian and wetland habitats across a 102,145-km2 region in eastern Australia. In addition to targeting places where willow threatens biodiversity now, a second set of management goals was to limit reinfestation and further spread that could occur via two different mechanisms (downstream and by wind). A model of likely willow distribution across the region was combined with spatial data for biodiversity (native vegetation, threatened species and communities), ecological conditions, management costs, and two potential dispersal layers. We used systematic conservation planning software (Zonation) to prioritize where willow management should be focussed across more than 100,000 catchments for a range of different scenarios that reflected different weights between management goals. For willow invasion, we found that we could prioritize willow management to reduce the future threat of dispersal downstream with little reduction in the protection of biodiversity. However, accounting for future threats from wind dispersal resulted in a stronger trade-off with protection of threatened biodiversity. The strongest trade-off was observed when both dispersal mechanisms were considered together. This study shows that considering current and future goals together offers the potential to substantially improve conservation outcomes for invasive species management. Our approach also informs land managers about the relative trade-offs among different management goals under different control scenarios, helping to make management decisions more transparent. This approach can be used for other widespread invasive species to help improve invasive species management decisions.

Disparities in integrating non-invasive prenatal testing into antenatal healthcare in Australia: a survey of healthcare professionals.

BACKGROUND: Non-invasive prenatal testing (NIPT) has been clinically available in Australia on a user-pays basis since 2012. There are numerous providers, with available tests ranging from targeted NIPT (only trisomies 21, 18, and 13 +/- sex chromosome aneuploidy) to genome-wide NIPT. While NIPT is being implemented in the public health care systems of other countries, in Australia, the implementation of NIPT has proceeded without public funding. The aim of this study was to investigate how NIPT has been integrated into antenatal care across Australia and reveal the successes and challenges in its implementation in this context. METHODS: An anonymous online survey was conducted from September to October 2022. Invitations to participate were sent to healthcare professionals (HCPs) involved in the provision of NIPT in Australia through professional society mailing lists and networks. Participants were asked questions on their knowledge of NIPT, delivery of NIPT, and post-test management of results. RESULTS: A total of 475 HCPs responded, comprising 232 (48.8%) obstetricians, 167 (35.2%) general practitioners, 32 (6.7%) midwives, and 44 (9.3%) genetic specialists. NIPT was most commonly offered as a first-tier test, with most HCPs (n = 279; 60.3%) offering it to patients as a choice between NIPT and combined first-trimester screening. Fifty-three percent (n = 245) of respondents always offered patients a choice between NIPT for the common autosomal trisomies and expanded (including genome-wide) NIPT. This choice was understood as supporting patient autonomy and informed consent. Cost was seen as a major barrier to access to NIPT, for both targeted and expanded tests. Equitable access, increasing time demands on HCPs, and staying up to date with advances were frequently reported as major challenges in delivering NIPT. CONCLUSIONS: Our findings demonstrate substantial variation in the clinical implementation of NIPT in Australia, including in the offers of expanded screening options. After a decade of clinical use, Australian clinicians still report ongoing challenges in the clinical and equitable provision of NIPT.

Unconditional access to non-invasive prenatal testing (NIPT) for adult-onset conditions: a defence.

Over the past decade, non-invasive prenatal testing (NIPT) has been adopted into routine obstetric care to screen for fetal sex, trisomies 21, 18 and 13, sex chromosome aneuploidies and fetal sex determination. It is predicted that the scope of NIPT will be expanded in the future, including screening for adult-onset conditions (AOCs). Some ethicists have proposed that using NIPT to detect severe autosomal AOCs that cannot be prevented or treated, such as Huntington's disease, should only be offered to prospective parents who intend to terminate a pregnancy in the case of a positive result. We refer to this as the 'conditional access model' (CAM) for NIPT. We argue against CAM for NIPT to screen for Huntington's disease or any other AOC. Next, we present results from a study we conducted in Australia that explored NIPT users' attitudes regarding CAM in the context of NIPT for AOCs. We found that, despite overall support for NIPT for AOCs, most participants were not in favour of CAM for both preventable and non-preventable AOCs. Our findings are discussed in relation to our initial theoretical ethical theory and with other comparable empirical studies. We conclude that an 'unconditional access model' (UAM), which provides unrestricted access to NIPT for AOCs, is a morally preferable alternative that avoids both CAM's fundamental practical limitations and the limitations it places on parents' reproductive autonomy.

Against epigenetic responsibility: The problem of causality in 'foetal programming' science.

Emerging evidence that intrauterine exposures to environmental stressors can 'programme' epigenetic modifications in offspring, leading to long-lasting health risks, has generated debate about whether prospective mothers have a specific 'epigenetic' moral responsibility. However, to date, proposals for maternal epigenetic responsibility have failed to grapple adequately with the uncertainty of scientific evidence, and specifically, whether the causal basis for intrauterine epigenetic effects is sufficiently established to ground claims of moral responsibility. Causality is widely considered a necessary condition for the attribution of moral responsibility. In this paper, we show that much foetal programming science in humans has yet to establish a causal epigenetic connection between intrauterine exposures and subsequent offspring health impacts. This research struggles to establish that the relationship between such exposures and offspring health risks is in fact causal, neither has it been able to evince the causal significance of exposures during pregnancy to such outcomes. We argue that these two challenges to establishing causality in foetal programming research seriously undercut the idea that prospective mothers may have a moral responsibility to ensure the epigenetics of their offspring.

NIPT for adult-onset conditions: Australian NIPT users' views.

Noninvasive prenatal testing (NIPT) has become widely available in recent years. While initially used to screen for trisomies 21, 18, and 13, the test has expanded to include a range of other conditions and will likely expand further. This paper addresses the ethical issues that arise from one particularly controversial potential use of NIPT: screening for adult-onset conditions (AOCs). We report data from our quantitative survey of Australian NIPT users' views on the ethical issues raised by NIPT for AOCs. The survey ascertained support for NIPT for several traits and conditions including AOCs. Participants were then asked about their level of concern around implications of screening for AOCs for the future child and parent(s). Descriptive and comparative data analyses were conducted. In total, 109 respondents were included in data analysis. The majority of respondents expressed support for NIPT screening for preventable (70.9%) and nonpreventable AOCs (80.8%). Most respondents indicated concern around potential harmful impacts associated with NIPT for AOCs, including the psychological impact on the future child and on the parent(s). Despite this, the majority of participants thought that continuation of a pregnancy known to be predisposed to an AOC is ethically acceptable. The implications of these data are critically discussed and used to inform the normative claim that prospective parents should be given access to NIPT for AOCs. The study contributes to a body of research debating the ethical acceptability and regulation of various applications of NIPT as screening panels expand.

Ethical issues associated with prenatal screening using non-invasive prenatal testing for sex chromosome aneuploidy.

Prenatal screening for sex chromosome aneuploidies (SCAs) is increasingly available through expanded non-invasive prenatal testing (NIPT). NIPT for SCAs raises complex ethical issues for clinical providers, prospective parents and future children. This paper discusses the ethical issues that arise around NIPT for SCAs and current guidelines and protocols for management. The first section outlines current practice and the limitations of NIPT for SCAs. It then outlines key guidelines before discussing the ethical issues raised by this use of NIPT. We conclude that while screening for SCAs should be made available for people seeking to use NIPT, its implementation requires careful consideration of what, when and how information is provided to users.

Protecting the future child: Foetal alcohol spectrum disorder, easy rescue and the regulation of maternal behaviour.

This paper argues that social contexts of inequality are crucial to understanding the ethics of gestational harm and responsibility. Recent debates on gestational harm have largely ignored the social context of gestators, including contexts of inequality and injustice. This can reinforce existing social injustices arising from colonialism, socio-economic inequality and racism, for example, through increased regulation of maternal behaviour. To demonstrate this, I focus on the related notions of the 'future child' and an obligation of easy rescue, which have been used to discuss the ethics of gestational harm in the context of alcohol consumption during gestation and foetal alcohol spectrum disorder (FASD). I use a feminist perspective to evaluate these ideas and conclude that anyone concerned with remediation of social injustice has good reason to be suspicious of the notion of the future child in the context of gestational harm.

Reproductive deliberation: Supporting autonomous decision making in prenatal genetic counseling.

As both the scope and popularity of non-invasive prenatal testing (NIPT) have expanded, debate has emerged about the extent to which this test enhances or undermines reproductive autonomy. Genetic counseling is crucial to support autonomy in the context of making complex and value-laden decisions about reproductive care following high-chance results from NIPT. Two models of post-test prenatal genetic counseling have been proposed; the first of these, non-directive counseling, is the predominant model, while shared decision making is an alternative model deriving from patient care for chronic conditions. In this paper, we argue that neither of these approaches is adequate for counseling after NIPT to support reproductive autonomy. Instead, then, we propose an alternative approach that we call reproductive deliberation. This approach to prenatal genetic counseling simultaneously recognizes the relationality of the counseling encounter and supports the decision making capacity and decisional responsibility of the pregnant person.

New Transmission-Selective Antimalarial Agents through Hit-to-Lead Optimization of 2-([1,1'-Biphenyl]-4-carboxamido)benzoic Acid Derivatives.

Malaria elimination requires multipronged approaches, including the application of antimalarial drugs able to block human-to-mosquito transmission of malaria parasites. The transmissible gametocytes of Plasmodium falciparum seem to be highly sensitive towards epidrugs, particularly those targeting demethylation of histone post-translational marks. Here, we report exploration of compounds from a chemical library generated during hit-to-lead optimization of inhibitors of the human histone lysine demethylase, KDM4B. Derivatives of 2-([1,1'-biphenyl]-4-carboxamido) benzoic acid, around either the amide or a sulfonamide linker backbone (2-(arylcarboxamido)benzoic acid, 2-carboxamide (arylsulfonamido)benzoic acid and N-(2-(1H-tetrazol-5-yl)phenyl)-arylcarboxamide), showed potent activity towards late-stage gametocytes (stage IV/V) of P. falciparum, with the most potent compound reaching single digit nanomolar activity. Structure-activity relationship trends were evident and frontrunner compounds also displayed microsomal stability and favourable solubility profiles. Simplified synthetic routes support further derivatization of these compounds for further development of these series as malaria transmission-blocking agents.

Ethical implementation of mitochondrial donation in Australia.

Australia has recently legalised mitochondrial donation. However, key ethical and legal issues still need to be addressed. This paper maps the relevant issues and offers some suggestions for how they ought to be resolved.

Application of Pharmacokinetic Prediction Platforms in the Design of Optimized Anti-Cancer Drugs.

Cancer is the second most common cause of death in the United States, accounting for 602,350 deaths in 2020. Cancer-related death rates have declined by 27% over the past two decades, partially due to the identification of novel anti-cancer drugs. Despite improvements in cancer treatment, newly approved oncology drugs are associated with increased toxicity risk. These toxicities may be mitigated by pharmacokinetic optimization and reductions in off-target interactions. As such, there is a need for early-stage implementation of pharmacokinetic (PK) prediction tools. Several PK prediction platforms exist, including pkCSM, SuperCypsPred, Pred-hERG, Similarity Ensemble Approach (SEA), and SwissADME. These tools can be used in screening hits, allowing for the selection of compounds were reduced toxicity and/or risk of attrition. In this short commentary, we used PK prediction tools in the optimization of mitogen activated extracellular signal-related kinase kinase 1 (MEK1) inhibitors. In doing so, we identified MEK1 inhibitors with retained activity and optimized predictive PK properties, devoid of hERG inhibition. These data support the use of publicly available PK prediction platforms in early-stage drug discovery to design safer drugs.

Supporting Aboriginal and Torres Strait Islander Families to Stay Together from the Start (SAFeST Start): Urgent call to action to address crisis in infant removals.

Reducing the rate of over-representation of Aboriginal and Torres Strait Islander children in out-of-home care (OOHC) is a key Closing the Gap target committed to by all Australian governments. Current strategies are failing. The "gap" is widening, with the rate of Aboriginal and Torres Strait Islander children in OOHC at 30 June 2020 being 11 times that of non-Indigenous children. Approximately, one in five Aboriginal and Torres Strait Islander children entering OOHC each year are younger than one year. These figures represent compounding intergenerational trauma and institutional harm to Aboriginal and Torres Strait Islander families and communities. This article outlines systemic failures to address the needs of Aboriginal and Torres Strait Islander parents during pregnancy and following birth, causing cumulative harm and trauma to families, communities and cultures. Major reform to child and family notification and service systems, and significant investment to address this crisis, is urgently needed. The Family Matters Building Blocks and five elements of the Aboriginal and Torres Strait Islander Child Placement Principle (Prevention, Participation, Partnership, Placement and Connection) provide a transformative foundation to address historical, institutional, well-being and socioeconomic drivers of current catastrophic trajectories. The time for action is now.

Gendering the seed: Mitochondrial replacement techniques and the erasure of the maternal.

In order to avoid the implication that 'mitochondrial replacement techniques' (MRT) would produce 'three parent babies', discourses around these techniques typically dismiss the contribution of the mitochondria to genetic parenthood and personal identity. According to many participants in debates about MRT, 'real parenthood' is a matter of contributing nuclear DNA, which in turn implies that men and women make the same contribution to the embryo. Even when the importance of the mitochondria is acknowledged, an emphasis on mitochondrial DNA still has the effect of valorizing the role of DNA (and thus the paternal contribution to conception) at the expense of the role played by the cytoplasm of the oocyte in the development of the embryo and placenta, and that of the mother's body in gestation. In this way, discourses around MRT falsely imply that what men and women contribute to reproduction and parenthood is the same-nuclear DNA-and thus erase the distinctive contribution that women make to conception. The potential of MRT to reconfigure relationships between the sexes in the service of patriarchal norms is perhaps one of the most significant things about it and should, we argue, be counted in the discussion of the ethical and policy implications of legitimating these procedures.

Statement on bioinformatics and capturing the benefits of genome sequencing for society.

The HUGO Committee on Ethics, Law and Society (CELS) undertook a Working Group exploration of the key ethical issues arising from genome sequencing in 2013. The Imagined Futures paper the group subsequently published proposed points to consider when applying genomic bioinformatics to data repositories used in genomic medicine and research ( http://www.hugo-international.org/Resources/Documents/CELS_Article-ImaginedFutures_2014.pdf ). Given the ever-increasing power to sequence the human genome rapidly and inexpensively-as well as trends toward "Big Data" and "Open Science"-we take this opportunity to update and refine the key findings of that paper.

Identification of Optimal Measures of Human Abuse Potential: A Post Hoc Assessment of 19 Studies.

BACKGROUND: Human abuse potential studies include multiple measures to assess the subjective effects of central nervous system-active drugs. In this retrospective analysis, measurement properties of commonly used measures were assessed, and factor analysis was conducted to identify a core battery of measures. METHODS: Measures of positive, negative and other effects, for example, bipolar "at-the-moment" Drug Liking visual analog scale (VAS), were derived for active controls and placebo from 19 studies in recreational drug users (N = 570). Distribution, placebo response, variability, convergent/discriminant validity, parameter effect sizes (eg, maximum effect [Emax], time-averaged area under the effect curve), and predictive validity were evaluated. A factor analysis was conducted with 9 studies. RESULTS: Most parameters were not normally distributed. Bipolar VAS exhibited the lowest variability. Drug Liking VAS Emax was very sensitive, showed large effect sizes (>1.0), and was moderately to strongly correlated with Emax of other positive effects measures (r > 0.5), but weaker with less specific scales (eg, high, Any Effects VAS); time-averaged area under the effect curve showed higher variability and lower effect sizes. Maximum effect at any dose (EmaxD) was significantly correlated with Emax across all selected measures and showed higher effect sizes. In the overall factor analysis, factors could be categorized into positive effects/euphoria (77% of variance), negative effects (17.9%), and pharmacologic effects (5%). For predictive validity, effect sizes for Drug Liking VAS Emax/EmaxD were moderately correlated with postmarket adverse events related to abuse (R = 0.52). CONCLUSIONS: A core battery of 7 subjective measures was proposed, with additional measures added based on pharmacologic effects.

Ectogestation ethics: The implications of artificially extending gestation for viability, newborn resuscitation and abortion.

Recent animal research suggests that it may soon be possible to support the human fetus in an artificial uterine environment for part of a pregnancy. A technique of extending gestation in this way ("ectogestation") could be offered to parents of extremely premature infants (EPIs) to improve outcomes for their child. The use of artificial uteruses for ectogestation could generate ethical questions because of the technology's potential impact on the point of "viability"-loosely defined as the stage of pregnancy beyond which the fetus may survive external to the womb. Several medical decisions during the perinatal period are based on the gestation at which infants are considered viable, for example decisions about newborn resuscitation and abortion, and ectogestation has the potential to impact on these. Despite these possible implications, there is little existing evidence or analysis of how this technology would affect medical practice. In this paper, we combine empirical data with ethical analysis. We report a survey of 91 practicing Australian obstetricians and neonatologists; we aimed to assess their conceptual understanding of "viability," and what ethical consequences they envisage arising from improved survival of EPIs. We also assess what the ethical implications of extending gestation should be for newborn and obstetric care. We analyze the concept of viability and argue that while ectogestation might have implications for the permissibility of neonatal life-prolonging treatment at extremely early gestation, it should not necessarily have implications for abortion policy. We compare our ethical findings with the results of the survey.

Characterization of the Safety and Pharmacokinetic Profile of D-Methadone, a Novel N-Methyl-D-Aspartate Receptor Antagonist in Healthy, Opioid-Naive Subjects: Results of Two Phase 1 Studies.

PURPOSE/BACKGROUND: N-methyl-D-aspartate (NMDA) receptor (NMDAR) antagonists are potential agents for the treatment of several central nervous system disorders including major depressive disorder. Racemic methadone, L-methadone, and D-methadone all bind the NMDAR with an affinity similar to that of established NMDAR antagonists, whereas only L-methadone and racemic methadone bind to opioid receptors with high affinity. Therefore, D-methadone is expected to have no clinically significant opioid effects at therapeutic doses mediated by its NMDAR antagonism. METHODS: We conducted 2 phase 1, double-blind, randomized, placebo-controlled, single- and multiple-ascending-dose studies to investigate the safety and tolerability of oral D-methadone and to characterize its pharmacokinetic profile in healthy opioid-naive volunteers. RESULTS: D-Methadone exhibits linear pharmacokinetics with dose proportionality for most single-dose and multiple-dose parameters. Single doses up to 150 mg and daily doses up to 75 mg for 10 days were well tolerated with mostly mild treatment-emergent adverse events and no severe or serious adverse events. Dose-related somnolence and nausea occurred and were mostly present at the higher dose level. There was no evidence of respiratory depression, dissociative and psychotomimetic effects, or withdrawal signs and symptoms upon abrupt discontinuation. An overall dose-response effect was observed, with higher doses resulting in larger QTcF (QT interval corrected using Fridericia formula) changes from baseline, but none of the changes were considered clinically significant by the investigators. Mild, dose-dependent pupillary constriction of brief duration occurred particularly at the 60-mg dose or above in the single-ascending-dose study and at the dose of 75 mg in the multiple-ascending-dose study. No detectable conversion of D-methadone to L-methadone occurred in vivo. CONCLUSIONS: These results support the safety and continued clinical development of D-methadone as an NMDAR antagonist for the treatment of depression and other central nervous system disorders.