Decoding the hallmarks of allograft dysfunction with a comprehensive pan-organ transcriptomic atlas.

The pathogenesis of allograft (dys)function has been increasingly studied using 'omics'-based technologies, but the focus on individual organs has created knowledge gaps that neither unify nor distinguish pathological mechanisms across allografts. Here we present a comprehensive study of human pan-organ allograft dysfunction, analyzing 150 datasets with more than 12,000 samples across four commonly transplanted solid organs (heart, lung, liver and kidney, n = 1,160, 1,241, 1,216 and 8,853 samples, respectively) that we leveraged to explore transcriptomic differences among allograft dysfunction (delayed graft function, acute rejection and fibrosis), tolerance and stable graft function. We identified genes that correlated robustly with allograft dysfunction across heart, lung, liver and kidney transplantation. Furthermore, we developed a transfer learning omics prediction framework that, by borrowing information across organs, demonstrated superior classifications compared to models trained on single organs. These findings were validated using a single-center prospective kidney transplant cohort study (a collective 329 samples across two timepoints), providing insights supporting the potential clinical utility of our approach. Our study establishes the capacity for machine learning models to learn across organs and presents a transcriptomic transplant resource that can be employed to develop pan-organ biomarkers of allograft dysfunction.

A Neptune-mass exoplanet in close orbit around a very low-mass star challenges formation models.

Theories of planet formation predict that low-mass stars should rarely host exoplanets with masses exceeding that of Neptune. We used radial velocity observations to detect a Neptune-mass exoplanet orbiting LHS 3154, a star that is nine times less massive than the Sun. The exoplanet's orbital period is 3.7 days, and its minimum mass is 13.2 Earth masses. We used simulations to show that the high planet-to-star mass ratio (>3.5 × 10-4) is not an expected outcome of either the core accretion or gravitational instability theories of planet formation. In the core-accretion simulations, we show that close-in Neptune-mass planets are only formed if the dust mass of the protoplanetary disk is an order of magnitude greater than typically observed around very low-mass stars.

International perspective on integrated care models in child and adult mental health.

The dearth of child and adolescent mental health services (CAMHS) is a global problem. Integrating CAMHS in primary care has been offered as a solution. We sampled integrated care perspectives from colleagues around the world. Our findings include various models of integrated care namely: the stepped care model in Australia; shared care in the United Kingdom (UK) and Spain; school-based collaborative care in Qatar, Singapore and the state of Texas in the US; collaborative care in Canada, Brazil, US, and Uruguay; coordinated care in the US; and, developing collaborative care models in low-resource settings, like Kenya and Micronesia. These findings provide insights into training initiatives necessary to build CAMHS workforce capacity using integrated care models, each with the ultimate goal of improving access to care. Despite variations and progress in implementing integrated care models internationally, common challenges exist: funding within complex healthcare systems, limited training mechanisms, and geopolitical/policy issues. Supportive healthcare policy, robust training initiatives, ongoing quality improvement and measurement of outcomes across programs would provide data-driven support for the expansion of integrated care and ensure its sustainability.

Piloting online training in the Pacific-Ophelia project for child and adolescent mental health.

INTRODUCTION: In June 2020, St Vincent's Mental Health, Fiji National University, and the Royal Australian and New Zealand College of Psychiatrists, Faculty of Child and Adolescent Psychiatry collaborated to deliver online, specialized child and adolescent mental health (CAMH) training to Pacific-based healthcare workers. This accompanying research aimed to understand the telehealth model and structures that would sustain an engaged community of practice and support the development of professional networks across the Pacific. METHOD: Quantitative and qualitative feedback was analyzed to understand participation and self-rated measures of skills, knowledge, and confidence in providing health care for children and young people, as well as experiences of training, including access, engagement, and applicability of the initiative to the Pacific Islands health care organizations. RESULTS: Ophelia Training was able to meet the stated learning objectives. The data from all stakeholders identifies the value of a telehealth initiative incorporating training, technical assistance, knowledge networks, and professional coaching as a capacity building approach. CONCLUSION: This program offers an integration of research and practice. This regional approach to understanding telehealth capacity for Pacific Island mental health services is valuable for informing decision-making with respect to clinical care, management, workforce training and policy. It also provided an opportunity to improve health inequalities, by improving access to CAMH training via telehealth.

The making of child and adolescent psychiatrists in Australia and New Zealand.

Child and adolescent psychiatry has an opportunity to adapt alongside the advancements in medical knowledge, post-graduate training, epidemiological realities and clinical service models. Here, we are guided by the mental health needs of our community's young and their families in our review of child and adolescent psychiatry training in Australia and New Zealand. We recognise that training must respond to clinical demand and service reform while ensuring a range of clinical and educational experiences to deliver expectable competencies in order to produce child and adolescent psychiatrists that meet the communities' needs now and in the future. We argue that training programmes be subject to rigorous evaluation by embedding continuing cycles of improvement including regular review and international bench marking.

The relationship between tendency to attend to detail, sensory sensitivity, and affective response to food cues - A registered report.

Understanding the underlying drivers of food choice remains a challenge and has highlighted the need for measures that capture data over and above that offered by self-reporting tools. Consequently, a growing body of research has set out to interpret facial responses to food cues to offer a greater insight into the emotional responses that may drive food acceptance. However, interpreting facial responses is challenging, as there are numerous factors that may influence affective response to foods, including expectation, context, and individual differences. Existing findings suggest there is a link between autistic traits and sensory sensitivities; research highlights further links between sensory sensitivities and eating behaviour, and autistic traits and eating behaviour, with a body of research focusing on the autistic trait attention to detail (ATD). As such, the current study aimed to examine rapid facial activity in response to foods cues while capturing these individual differences present in the general population. This study found no evidence to suggest facial responses to food pictures were linked with attention to detail or hyper-sensitivity. The findings did support a general link between self-reported pleasantness ratings of viewed foods and activity of facial muscles. Post-hoc analyses suggested scoring on the social skills sub-scale of the Autism Quotient (AQ) was associated with levator activity while viewing pictures low in pleasantness. This study offers a greater understanding of variations, at the individual level, which are associated with affective response to foods, and may help to inform the development of tools that set out to predict food acceptance.

Pilot study of a noninvasive real-time optical backscatter probe in liver transplantation.

Transplantation of severely steatotic donor livers is associated with early allograft dysfunction and poorer graft survival. Histology remains the gold standard diagnostic of donor steatosis despite the lack of consensus definition and its subjective nature. In this prospective observational study of liver transplant patients, we demonstrate the feasibility of using a handheld optical backscatter probe to assess the degree of hepatic steatosis and correlate the backscatter readings with clinical outcomes. The probe is placed on the surface of the liver and emits red and near infrared light from the tip of the device and measures the amount of backscatter of light from liver tissue via two photodiodes. Measurement of optical backscatter (Mantel-Cox P < 0.0001) and histopathological scoring of macrovesicular steatosis (Mantel-Cox P = 0.046) were predictive of 5-year graft survival. Recipients with early allograft dysfunction defined according to both Olthoff (P = 0.0067) and MEAF score (P = 0.0097) had significantly higher backscatter levels from the donor organ. Backscatter was predictive of graft loss (AUC 0.75, P = 0.0045). This study demonstrates the feasibility of real-time measurement of optical backscatter in donor livers. Early results indicate readings correlate with steatosis and may give insight to graft outcomes such as early allograft dysfunction and graft loss.

Relative survival and quality of life benefits of pancreas-kidney transplantation, deceased kidney transplantation and dialysis in type 1 diabetes mellitus-a probabilistic simulation model.

For patients with type 1 diabetes mellitus who progress to the point of requiring renal replacement therapy, the relative benefits of simultaneous pancreas and kidney transplantation (SPK) and deceased donor kidney transplantation across different age categories compared to dialysis are uncertain. Using Australian and New Zealand registry data from 2006 to 2016, a probabilistic Markov model (n = 10 000) was built comparing patient survival between SPK and deceased donor kidney transplantation with dialysis. Compared to dialysis, the average life years saved (LYS) and quality-adjusted life years (QALY) for SPK and deceased donor kidney transplantation were 5.48 [95% CI 5.47, 5.49] LYS and 6.48 [6.47, 6.49] QALY, and 3.38 [3.36, 3.40] LYS and 2.46 [2.45, 2.47] QALY, respectively. For recipients aged 50 years or younger, receiving a deceased donor kidney, the average incremental gains compared to dialysis were 4.13 [4.10, 4.16] LYS and 2.99 [2.97, 3.01] QALY, and for recipients older than 50 years, 3.05 [3.02, 3.08] LYS and 2.25 [2.23, 2.27] QALY. Compared to dialysis, SPK transplantation incurs the greatest benefits in LYS and QALY for patients with type 1 diabetes requiring renal replacement therapy. Patients older than 50 years still experience survival benefits from deceased donor kidney transplantation compared to dialysis.

Child and Adolescent Psychiatry International Relations (CAPIR): building bridges for psychiatry workforce capacity with Pacific Island nations.

OBJECTIVE: To describe the span of work of child and adolescent psychiatrists in Australia and New Zealand in recent years aimed at collaborative efforts to build mental health capacity in the Pacific Island nations of Fiji, Samoa, Cook Islands, Tonga, Kiribati, Vanuatu, Solomon Islands and Papua New Guinea. METHOD: Steps taken to coordinate resourcing, networking, delivery of appropriate initiatives, establishing and maintaining key relationships with partners are described. RESULTS: Engagement with Pacific nations mental health professionals, ministries of health, NGOs, universities, multilateral agencies and professional and international organisations has expanded and strengthened since 2013. CONCLUSIONS: Planned and staged implementation of initiatives can harness RANZCP (and its faculties and interest groups) goodwill to effectively contribute to psychiatry and mental health capacity building in partnerships with Pacific Island nations to address mental health needs over the life-span.

CAMH in Primary Care Fiji: developing child and adolescent mental health in primary care.

OBJECTIVE: To describe the CAMH in Primary Care Fiji Project. METHODS: The context; process of development and planning; aims and goals; delivery and outcome are described. RESULTS: Two CAMH in Primary Care Fiji training workshops were delivered in 2017 and 2018 with positive structured and unstructured feedback. CONCLUSION: A successful, collaboratively developed, culturally appropriate and replicable training for primary care in CAMH is possible.

Pasifika Study Group: a child and adolescent mental health capacity building and leadership workshop with Pacific nations doctors and psychiatrists.

OBJECTIVE: To describe the Pasifika Study Group (PSG), a biennial workshop for Pacific nations psychiatrists and doctors working in psychiatry under the auspices of the Royal Australian and New Zealand College of Psychiatry Faculty of Child and Adolescent Psychiatry. METHOD: Since 2013 the PSG has brought together doctors and other health professionals from eight Pacific nations for a two-day study group. RESULTS: On evaluation the PSG is considered informative and relevant and participants were generally confident of adapting the material to their own context. CONCLUSION: The PSG demonstrates a successful approach to regional engagement in mental health in the Pacific region.

Brief Normothermic Machine Perfusion Rejuvenates Discarded Human Kidneys.

Normothermic machine perfusion (NMP) may allow resuscitation and improved assessment of kidneys before transplantation. Using discarded human kidneys, we investigated the mechanistic basis and translational potential of NMP compared with cold static storage (CS). METHODS: Discarded deceased donor kidneys (n = 15) underwent 1-hour NMP following CS. Renal perfusion, biochemical, and histologic parameters were recorded. NMP was directly compared with CS in paired donor kidneys using simulated transplantation with allogeneic whole blood, followed by assessment of the aforementioned parameters, in addition to RNA sequencing. RESULTS: Kidneys were successfully perfused, with improved renal blood flows and resistance over the course of perfusion, and evidence of urine output (median 21 mL), in all but one kidney. NMP completely resolved nonperfused regions in discarded donation after circulatory death kidneys. In paired kidneys (n = 4 pairs), transcriptomic analyses showed induction of stress and inflammatory pathways in NMP kidneys, with upregulation of pathways promoting cell survival and proliferation. Furthermore, the NMP pairs had significantly better renal perfusion (1.5-2 fold improvement) and functional parameters, and amelioration of cell death, oxidative stress, and complement activation. CONCLUSIONS: In this pilot preclinical study using simulated transplantation of paired kidneys, NMP of discarded marginal kidneys demonstrated some significant mechanistic benefits in comparison to CS alone. NMP may have potential to reduce organ discards and enhance early graft function in such kidneys.

First-in-human trial of rhIL-15 and haploidentical natural killer cell therapy for advanced acute myeloid leukemia.

In vivo expansion of haploidentical natural killer (NK) cell infusions with interleukin-2 (IL-2) can induce remission of refractory acute myeloid leukemia, but efficacy may be hampered by concurrent stimulation of host regulatory T cells. To overcome this limitation, we substituted the NK homeostatic factor IL-15 in 2 phase 1/2 trials. Forty-two patients received either intravenous (IV) (NCT01385423) or subcutaneous (SC) (NCT02395822) recombinant human IL-15 (rhIL-15) after lymphodepleting chemotherapy and haploidentical NK cells. Escalating doses of rhIL-15 (0.3-1.0 µg/kg) were given on 12 consecutive days in a phase 1 trial. Of 26 patients, 36% had robust in vivo NK-cell expansion at day 14, and 32% achieved complete remission. Hypothesizing that SC dosing of rhIL-15 would be safer and better tolerated, 16 patients received 10 once per day doses of SC rhIL-15 at 2.0 µg/kg on a phase 2 trial. NK-cell expansion at day 14 was seen in 27% of the patients, and 40% achieved remission. rhIL-15 induced better rates of in vivo NK-cell expansion and remission compared with previous trials with IL-2, but it was associated with previously unreported cytokine release syndrome (CRS) after SC but not IV dosing. CRS was observed in 56% of patients given SC rhIL-15 (with concurrent neurologic toxicity in 5 of 9 patients) and was responsive to steroids and tocilizumab. SC administration was associated with slower pharmacokinetic clearance and higher levels of IL-6 than IV dosing. These novel trials testing the use of IL-15 to potentiate cell therapy suggest that dosing schedules based on pharmacokinetics and pharmacodynamics will preserve the therapeutic benefits of IL-15 and minimize CRS. These trials were registered at www.clinicaltrials.gov as #NCT01385423 and #NCT02395822.