Prospective cohort study of genomic newborn screening: BabyScreen+ pilot study protocol.

INTRODUCTION: Newborn bloodspot screening (NBS) is a highly successful public health programme that uses biochemical and other assays to screen for severe but treatable childhood-onset conditions. Introducing genomic sequencing into NBS programmes increases the range of detectable conditions but raises practical and ethical issues. Evidence from prospectively ascertained cohorts is required to guide policy and future implementation. This study aims to develop, implement and evaluate a genomic NBS (gNBS) pilot programme. METHODS AND ANALYSIS: The BabyScreen+ study will pilot gNBS in three phases. In the preimplementation phase, study materials, including education resources, decision support and data collection tools, will be designed. Focus groups and key informant interviews will also be undertaken to inform delivery of the study and future gNBS programmes. During the implementation phase, we will prospectively recruit birth parents in Victoria, Australia, to screen 1000 newborns for over 600 severe, treatable, childhood-onset conditions. Clinically accredited whole genome sequencing will be performed following standard NBS using the same sample. High chance results will be returned by genetic healthcare professionals, with follow-on genetic and other confirmatory testing and referral to specialist services as required. The postimplementation phase will evaluate the feasibility of gNBS as the primary aim, and assess ethical, implementation, psychosocial and health economic factors to inform future service delivery. ETHICS AND DISSEMINATION: This project received ethics approval from the Royal Children's Hospital Melbourne Research Ethics Committee: HREC/91500/RCHM-2023, HREC/90929/RCHM-2022 and HREC/91392/RCHM-2022. Findings will be disseminated to policy-makers, and through peer-reviewed journals and conferences.

Stem cell-derived embryo models: moral advance or moral obfuscation?

Stem cell-derived embryo models (SCEMs) are model embryos used in scientific research to gain a better understanding of early embryonic development. The way humans develop from a single-cell zygote to a complex multicellular organism remains poorly understood. However, research looking at embryo development is difficult because of restrictions on the use of human embryos in research. Stem cell embryo models could reduce the need for human embryos, allowing us to both understand early development and improve assisted reproductive technologies. There have been several rapid advances in creating SCEMs in recent years. These advances potentially provide a new avenue to study early human development. The benefits of SCEMs are predicated on the claim that they are different from embryos and should, therefore, be exempt from existing regulations that apply to embryos (such as the 14-day rule). SCEMs are proposed as offering a model that can capture the inner workings of the embryo but lack its moral sensitivities. However, the ethical basis for making this distinction has not been clearly explained. In this current controversy, we focus on the ethical justification for treating SCEMs differently to embryos, based on considerations of moral status.

Australian Public Perspectives on Genomic Newborn Screening: Risks, Benefits, and Preferences for Implementation.

Recent dramatic reductions in the timeframe in which genomic sequencing can deliver results means its application in time-sensitive screening programs such as newborn screening (NBS) is becoming a reality. As genomic NBS (gNBS) programs are developed around the world, there is an increasing need to address the ethical and social issues that such initiatives raise. This study therefore aimed to explore the Australian public's perspectives and values regarding key gNBS characteristics and preferences for service delivery. We recruited English-speaking members of the Australian public over 18 years of age via social media; 75 people aged 23-72 participated in 1 of 15 focus groups. Participants were generally supportive of introducing genomic sequencing into newborn screening, with several stating that the adoption of such revolutionary and beneficial technology was a moral obligation. Participants consistently highlighted receiving an early diagnosis as the leading benefit, which was frequently linked to the potential for early treatment and intervention, or access to other forms of assistance, such as peer support. Informing parents about the test during pregnancy was considered important. This study provides insights into the Australian public's views and preferences to inform the delivery of a gNBS program in the Australian context.

Australian parental perceptions of genomic newborn screening for non-communicable diseases.

Background: Newborn bloodspot screening (NBS) programs have improved neonatal healthcare since the 1960s. Genomic sequencing now offers potential to generate polygenic risk score (PRS) that could be incorporated into NBS programs, shifting the focus from treatment to prevention of future noncommunicable disease (NCD). However, Australian parents' knowledge and attitudes regarding PRS for NBS is currently unknown. Methods: Parents with at least one Australian-born child under 18 years were invited via social media platforms to complete an online questionnaire aimed at examining parents' knowledge of NCDs, PRS, and precision medicine, their opinions on receiving PRS for their child, and considerations of early-intervention strategies to prevent the onset of disease. Results: Of 126 participants, 90.5% had heard the term "non-communicable disease or chronic condition," but only 31.8% and 34.4% were aware of the terms "polygenic risk score" and "precision medicine" respectively. A large proportion of participants said they would consider screening their newborn to receive a PRS for allergies (77.9%), asthma (81.0%), cancer (64.8%), cardiovascular disease (65.7%), mental illness (56.7%), obesity (49.5%), and type 2 diabetes (66.7%). Additionally, participants would primarily consider diet and exercise as interventions for specific NCDs. Discussion: The results from this study will inform future policy for genomic NBS, including expected rate of uptake and interventions that parents would consider employing to prevent the onset of disease.

Evaluation of Managing Cancer and Living Meaningfully (CALM) in people with advanced non-small cell lung cancer treated with immunotherapies or targeted therapies: protocol for a single-arm, mixed-methods pilot study.

INTRODUCTION: People with advanced non-small cell lung cancer (NSCLC) treated with immunotherapies (IT) or targeted therapies (TT) may have improved outcomes in a subset of people who respond, raising unique psychological concerns requiring specific attention. These include the need for people with prolonged survival to reframe their life plans and tolerate uncertainty related to treatment duration and prognosis. A brief intervention for people with advanced cancer, Managing Cancer and Living Meaningfully (CALM), could help people treated with IT or TT address these concerns. However, CALM has not been specifically evaluated in this population. This study aims to evaluate the acceptability and feasibility of CALM in people with advanced NSCLC treated with IT or TT and obtain preliminary evidence regarding its effectiveness in this population. METHODS AND ANALYSIS: Twenty people with advanced NSCLC treated with IT or TT will be recruited from Peter MacCallum Cancer Centre, Melbourne, Australia. Participants will complete three to six sessions of CALM delivered over 3-6 months. A prospective, single-arm, mixed-methods pilot study will be conducted. Participants will complete outcome measures at baseline, post-intervention, 3 months and 6 months, including Patient Health Questionnaire, Death and Dying Distress Scale, Functional Assessment of Cancer Therapy General and Clinician Evaluation Questionnaire. The acceptability of CALM will be assessed using patient experiences surveys and qualitative interviews. Feasibility will be assessed by analysis of recruitment rates, treatment adherence and intervention delivery time. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Peter MacCallum Cancer Centre Human Research Ethics Committee (HREC/82047/PMCC). Participants with cancer will complete a signed consent form prior to participation, and carers and therapists will complete verbal consent. Results will be made available to funders, broader clinicians and researchers through conference presentations and publications. If CALM is found to be acceptable in this cohort, this will inform a potential phase 3 trial.

Mycobacterium abscessus skin and soft tissue infection following autologous fat grafting in Kurdistan treated with an antibiotic combination including Imipenem-Relebactam and Rifabutin.

Medical tourism is becoming increasingly popular. The most popularly sought operations are cosmetic procedures. With the increase in cosmetic tourism, it is unsurprising that there has also been a rise in skin and soft tissue infections caused by nontuberculous mycobacteria (NTM); in particular by the rapidly growing mycobacteria species. Here we provide a case of a 35 year-old woman who presented after autologous fat grafting with multiple painful, violaceous, and purulent nodules on her arms, legs, and breasts. Infection was found to be due to Mycobacterium abscessus. She was successfully treated with azithromycin, clofazimine, rifabutin, amikacin, imipenem-cilastatin-relebactam (Recarbrio™) and imipenem-cilastatin. This is the first described case of a M. abscessus infection successfully treated using this combination.

Intensive Care Clinicians' Perspectives on Ethical Challenges Raised by Rapid Genomic Testing in Critically Ill Infants.

Rapid genomic testing (rGT) enables genomic information to be available in a matter of hours, allowing it to be used in time-critical settings, such as intensive care units. Although rGT has been shown to improve diagnostic rates in a cost-effective manner, it raises ethical questions around a range of different areas, including obtaining consent and clinical decision-making. While some research has examined the perspectives of parents and genetics health professionals, the attitudes of intensive care clinicians remain under-explored. To address this gap, we administered an online survey to English-speaking neonatal/paediatric intensivists in Europe, Australasia and North America. We posed two ethical scenarios: one relating to obtaining consent from the parents and the second assessing decision-making regarding the provision of life-sustaining treatments. Descriptive statistics were used to analyse the data. We received 40 responses from 12 countries. About 50-75% of intensivists felt that explicit parental consent was necessary for rGT. About 68-95% felt that a diagnosis from rGT should affect the provision of life-sustaining care. Results were mediated by intensivists' level of experience. Our findings show divergent attitudes toward ethical issues generated by rGT among intensivists and suggest the need for guidance regarding ethical decision-making for rGT.

Storing paediatric genomic data for sequential interrogation across the lifespan.

Genomic sequencing (GS) is increasingly used in paediatric medicine to aid in screening, research and treatment. Some health systems are trialling GS as a first-line test in newborn screening programmes. Questions about what to do with genomic data after it has been generated are becoming more pertinent. While other research has outlined the ethical reasons for storing deidentified genomic data to be used in research, the ethical case for storing data for future clinical use has not been explicated. In this paper, we examine the ethical case for storing genomic data with the intention of using it as a lifetime health resource. In this model, genomic data would be stored with the intention of reanalysis at certain points through one's life. We argue this could benefit individuals and create an important public resource. However, several ethical challenges must first be met to achieve these benefits. We explore issues related to privacy, consent, justice and equality. We conclude by arguing that health systems should be moving towards futures that allow for the sequential interrogation of genomic data throughout the lifespan.

Two-step offer and return of multiple types of additional genomic findings to families after ultrarapid trio genomic testing in the acute care setting: a study protocol.

INTRODUCTION: As routine genomic testing expands, so too does the opportunity to look for additional health information unrelated to the original reason for testing, termed additional findings (AF). Analysis for many different types of AF may be available, particularly to families undergoing trio genomic testing. The optimal model for service delivery remains to be determined, especially when the original test occurs in the acute care setting. METHODS AND ANALYSIS: Families enrolled in a national study providing ultrarapid genomic testing to critically ill children will be offered analysis for three types of AF on their stored genomic data: paediatric-onset conditions in the child, adult-onset conditions in each parent and reproductive carrier screening for the parents as a couple. The offer will be made 3-6 months after diagnostic testing. Parents will have access to a modified version of the Genetics Adviser web-based decision support tool before attending a genetic counselling appointment to discuss consent for AF. Parental experiences will be evaluated using qualitative and quantitative methods on data collected through surveys, appointment recordings and interviews at multiple time points. Evaluation will focus on parental preferences, uptake, decision support use and understanding of AF. Genetic health professionals' perspectives on acceptability and feasibility of AF will also be captured through surveys and interviews. ETHICS AND DISSEMINATION: This project received ethics approval from the Melbourne Health Human Research Ethics Committee as part of the Australian Genomics Health Alliance protocol: HREC/16/MH/251. Findings will be disseminated through peer-review journal articles and at conferences nationally and internationally.

Australian public perspectives on genomic data governance: responsibility, regulation, and logistical considerations.

Genomic sequencing generates huge volumes of data, which may be collected or donated to form large genomic databases. Such information can be stored for future use, either for the data donor themselves or by researchers to help improve our understanding of the genetic basis of disease. Creating datasets of this magnitude and diversity is only possible if patients, their families, and members of the public worldwide share their data. However, there is no consensus on the best technical approach to data sharing that also minimises risks to individuals and exploration of stakeholders' views on aspects of genomic data governance models-the ways genomic data is stored, managed, shared and used-has been minimal. To address this need, we conducted focus groups with 39 members of the Australian public exploring their views and preferences for different aspects of genomic data governance models. We found that consent and control were essential to participants, as they wanted the option to choose who had access to their data and for what purposes. Critically, participants wanted a trustworthy body to enforce regulation of data storage, sharing and usage. While participants recognised the importance of data accessibility, they also expressed a strong desire for data security. Finally, financial responsibility for data storage raised concerns for inequity as well as organisations and individuals using data in ethically contentious ways to generate profit. Our findings highlight some of the trade-offs that need to be considered in the development of genomic data governance systems.

Evaluation of the validity and screening performance of a revised single-item fear of cancer recurrence screening measure (FCR-1r).

OBJECTIVE: Fear of cancer recurrence (FCR) is highly prevalent among cancer survivors, but irregularly identified in practice. Single-item FCR measures suitable for integration into broader psychosocial screening are needed. This study evaluated the validity of a revised version of the original FCR-1 (FCR-1r) and screening performance alongside the Edmonton Symptom Assessment System - Revised (ESAS-r) anxiety item. METHODS: The FCR-1r was adapted from the FCR-1 and modelled on the ESAS-r. Associations between FCR-1r and FCR Inventory-Short Form (FCRI-SF) scores determined concurrent validity. Relationships of FCR-1r scores with variables related (e.g., anxiety, intrusive thoughts) and unrelated (e.g., employment/marital status) to FCR determined convergent and divergent validity respectively. A Receiver-Operating Characteristic analysis examined screening performance and cut-offs for the FCR-1r and ESAS-r anxiety item. RESULTS: 107 participants were recruited in two studies (Study 1, July-October 2021, n = 54; Study 2: November 2021-May 2022, n = 53). The FCR-1r demonstrated concurrent validity against the FCRI-SF (r = 0.83, p < 0.0001) and convergent validity versus the Generalised Anxiety Disorder-7 (r = 0.63, p < 0.0001) and Impact of Event Scale-Revised Intrusion subscale (r = 0.55, p < 0.0001). It did not correlate with unrelated variables (e.g., employment/marital status), indicating divergent validity. An FCR-1r cut-off ≥5/10 had 95% sensitivity and 77% specificity for detecting clinical FCR (area under the curve (AUC) = 0.91, 95% CI 0.85-0.97, p < 0.0001); ESAS-r anxiety cut-off ≥4 had 91% sensitivity and 82% specificity (AUC = 0.87, 95% CI 0.77-0.98, p < 0.0001). CONCLUSIONS: The FCR-1r is a valid and accurate tool for FCR screening. Further evaluation of the screening performance of the FCR-1r versus the ESAS-r anxiety item in routine care is needed.

Australian public perspectives on genomic data storage and sharing: Benefits, concerns and access preferences.

Diagnostic genomic sequencing generates unprecedented amounts of data. In addition to its primary use, this data could be used for a wide range of secondary purposes, including research and informing future healthcare for the data donor. These opportunities may require data to be shared with third parties. Although effective data sharing relies on public support, there are barriers which may prevent people from choosing to donate their genomic data and surprisingly few studies explore these barriers in depth. To address this need, this study aimed to qualitatively explore the Australian public's views and preferences for storing and sharing genomic data. Online focus groups were recorded, transcribed, and analysed using inductive content analysis. A total of 7 focus groups were conducted with 39 members of the Australian public ranging from 18 to 67 years of age. Participants were mostly supportive of genomic data being stored and shared for secondary purposes, recognising the potential benefits for individual health and wider medical research. However, some concerns were identified. Participants felt genomic data was particularly sensitive information, and raised the potential for discrimination, stigma, and other malicious uses of such data. Concerns for privacy and security of the data were also prevalent. Trustworthiness of data users was important when considering who genomic data should be shared with. Although participants were supportive of data being freely available to health professionals and researchers, they were opposed to insurance companies and employers accessing the data. There was greater controversy around sharing data with law enforcement and pharmaceutical companies. Participants recognised both benefits and harms to sharing with law enforcement. They were also cognizant of the dual purpose of pharmaceutical companies as both research and profit-driven organisations. Finally, participants expressed varying perspectives about sharing genomic data with family members, yet most agreed that explicit consent from the data donor should be required to share their information with relatives. This study highlighted several of the Australian public's perceived barriers and motivators for the storage and sharing of genomic data. Participants recognised both the benefits of collecting, storing and sharing such data widely but also the potential for harm from data misuse. While public acceptance of such endeavours is required to maximise the volume of data made available, the concerns around data access and security need to be addressed before this can occur. These findings also highlight the nuance and ethical complexity of decisions about who we should allow to access donated genomic data. These perspectives will be essential in helping to shape the way large-scale genomic data storage and sharing is developed and implemented in Australia, and internationally.

Rapid Genome Sequencing: Consent for New Technologies in the Neonatal Intensive Care Context.

The clinical utility of rapid genome sequencing (rGS) in critically unwell infants has been consistently demonstrated, and there are calls for rGS to be implemented as a first-line test in the NICU. A diagnosis from rGS can enable rapid initiation of precision treatment, making it potentially lifesaving. However, in many patients rGS leads to the diagnosis of severe and life-limiting conditions, prompting discussion with families about withdrawal of life-sustaining treatment. The complexity of information about rGS, together with the heightened emotions of parents in the NICU, poses significant challenges for informed decision making in this context. We present a case where both parents are unable to provide informed consent, and the treating team must decide whether to proceed with rGS. Our discussion highlights the important differences between genome sequencing and other types of genetic testing, and the crucial role played by pre-test counseling in facilitating informed consent and preparing parents for a range of possible outcomes. We then discuss the consent paradigms at play in NICUs; whereas admission generally comes with an understanding that the treating team will perform interventions thought to be in the best interest of the child, rGS is substantially different because of its long-term implications for patients and family members. Finally, we look at the ethical interplay between parental consent and the interests of the child. We conclude by showing how cases like this are resolved at our tertiary center and how they may be resolved differently in future.

Co-design, implementation, and evaluation of plain language genomic test reports.

Understanding and communicating genomic results can be challenging for families and health professionals without genetic specialty training. Unlike modifying existing laboratory reports, plain language genomic test reports provide an opportunity for patient/family-centered approaches. However, emerging examples generally lack co-design and/or evaluation in real-world settings. Through co-design involving patient groups, plain language experts, educators, and genetic health professionals, plain language genomic test report templates were produced for common test outcomes in rare diseases. Eight plain language genomic test report templates were developed. These reports were piloted and evaluated as part of a national pediatric ultra-rapid genomic testing program. Family and genetic health professional experiences with report layout, content, and use were explored using surveys. Of 154 families and 107 genetic health professionals issued with reports, 51 families and 57 clinicians responded (RR = 33% and 53%, respectively). Most families (82%) found their report helpful in understanding the result. Reports were shared by 63% of families, predominantly with family members (72%), or health professionals (68%). Clinicians (15%) adapted the reports for other settings. Through co-design, plain language genomic test reports implemented in a real-world setting can facilitate patient/family and caregiver understanding and communication of genomic test purpose, outcome, and potential clinical implications.

Study protocol for the evaluation of Fear-Less: a stepped-care program for fear of cancer recurrence in survivors with early-stage disease.

BACKGROUND: Fear of cancer recurrence (FCR) is a significant unmet need amongst cancer survivors and is consistently associated with psychological distress and impaired quality of life. Psychological interventions for FCR, such as ConquerFear, have demonstrated efficacy in reducing FCR and improving emotional wellbeing. Unfortunately, there are barriers to the uptake of evidence-based FCR treatments in clinical practice. A stepped-care FCR treatment model may overcome these barriers and has demonstrated potential in people with advanced melanoma. This study aims to evaluate the acceptability, feasibility, and impact of a stepped-care FCR treatment model (Fear-Less) in people with other cancer types, who have completed treatment with curative intent. METHODS: Sixty people with early-stage cancer (defined as individuals who have received treatment with curative intent and with no metastatic disease) will be screened for FCR using the Fear of Cancer Recurrence Inventory-Short Form (FCRI-SF). Individuals reporting moderate FCR (FCRI-SF between 13 and 21) will be offered a clinician-guided self-management resource; those reporting high FCR (FCRI-SF ≥ 22) will be offered individual therapy according to the ConquerFear protocol. Participants will complete purpose-built evaluation surveys assessing their FCR screening and intervention experiences. Clinicians will also complete a survey regarding their experiences of the treatment model. Fear-Less will be evaluated in terms of (1) acceptability (i.e., patient and clinician experience), (2) feasibility (i.e., referral uptake, treatment adherence, and time taken to screen and deliver interventions), and (3) impact (i.e., pre- to post-intervention FCR changes). DISCUSSION: The Fear-Less stepped-care model is a novel framework for screening FCR and stratifying survivors to the appropriate level of treatment. Our study will provide an indication of whether Fear-Less is a feasible and acceptable FCR model of care amongst survivors with early-stage disease and inform further investigations of this model. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR); ACTRN12622000818730 .

Genetics follow up after rapid genomic sequencing in intensive care: current practices and recommendations for service delivery.

The delivery of rapid genomic sequencing (rGS) to critically unwell children in intensive care occurs at a time of immense pressure and stress for parents. Contact with families after result disclosure, particularly after hospital discharge, presents an opportunity to meet their psychological, medical and information needs as they evolve. This study explores the preferences and perspectives of health professionals and parents of genetics follow up after rGS. Semi-structured interviews were conducted with 30 parents, seven genetic counsellors (GCs) and four intensive care physicians with experience in rGS. Transcripts were analysed using reflexive thematic analysis. Current practices surrounding genetics follow up after rGS were highly variable, resulting in some families not receiving the ongoing care they needed. Reasons identified by families for wanting follow-up care represented only a subset of those identified by health professionals. While GCs routinely provided their details to allow parents to initiate further contact, this was not always sufficient for follow-up care. Health professionals identified both organisational and psychosocial barriers to conducting follow up. As rGS transforms the diagnostic pathway in rare disease, there is a need for a co-designed, standardised but flexible model for follow-up care with genetics professionals so that families' evolving needs are met.