Inherited retinal diseases (IRDs) are a broad range of diseases associated with abnormalities/degeneration of retinal cells. We aimed to identify the top 10 Australian research priorities for IRDs to ultimately facilitate more meaningful and potentially cost-effective research.

We conducted a James Lind Alliance priority setting partnership that involved two Australian-wide surveys and online workshops.

Australia-wide.

Individuals aged 16 years or older were eligible to participate if they had an IRD, were caregivers of an individual with an IRD or were health professionals providing care to this community.

In Survey 1, we gathered participants’ unanswered questions about IRDs. We grouped these into summary questions and undertook a literature review to verify if they were truly unanswered (ie, evidence uncertainties). In Survey 2, participants voted for the uncertainties that they considered a priority. Top-ranked uncertainties progressed for discussion and final prioritisation in two workshops.

In Survey 1, we collected 223 questions from 69 participants. We grouped these into 42 summary questions and confirmed 41 as evidence uncertainties. In Survey 2, 151 participants voted, with the 16 uncertainties progressing to final prioritisation. The top 10 priorities, set by the 24 workshop participants, represented (1) treatment/cure; (2) symptoms and disease progression; (3) psychosocial well-being and (4) health service delivery. The #1 priority was for treatment to prevent, slow down or stop vision loss, followed by the #2 priority to address the psychological impact of having an IRD.

The top 10 research priorities highlight the need for IRD research that takes a whole-person, systems approach. Collaborations to progress priorities will accelerate the translation of research into real-world benefits.

Neonatal death and later disability remain common sequelae of hypoxic-ischaemic encephalopathy (HIE) despite the now standard use of therapeutic hypothermia (HT). New therapeutic approaches to brain protection are required. Melatonin is an indolamine hormone with free-radical scavenging, antiapoptotic, anti-inflammatory and gene regulatory neuroprotective properties, which has extensive preclinical evidence of safety and efficacy. Pharmacokinetic (PK) data suggest it is necessary to reach melatonin levels of 15–30 mg/L within 6–8 hours of hypoxia-ischaemia for brain protection. We developed a novel Good Manufacturing Practice (GMP) grade melatonin in ethanol 50 mg/mL solution for intravenous use. In preclinical studies, ethanol is an adjuvant excipient with additional neuroprotective benefit; optimised dosing protocols can achieve therapeutic melatonin levels while limiting blood alcohol concentrations (BACs).

The Acute High Dose Melatonin for Encephalopathy of the Newborn (ACUMEN) Study is a first-in-human, international, multicentre, phase 1 safety study of intravenous melatonin in babies with moderate/severe HIE receiving HT. Sixty babies will be studied over two phases: a dose escalation study including four dose levels to establish the recommended phase 2 dose (RP2D), followed by a 6-month cohort expansion study of RP2D to further characterise PKs and affirm safety. Participants will receive a 2-hour intravenous infusion of melatonin within 6 hours of birth, followed by five maintenance doses every 12 hours to cover the period of HT. Plasma melatonin and BACs will be monitored. The RP2D will be based on the attainment of therapeutic melatonin levels while limiting BACs and the frequency of dose-limiting events (DLEs). A Bayesian Escalation with Overdose Control approach will be used to estimate the risk of DLE per dose level, with a target level of

Approval has been given by the London Central National Health Service Health Research Authority Ethics Committee (25/LO/0170) and UK Clinical Trials Authorisation from the Medicines and Healthcare products Regulatory Agency. Separate approvals have been sought in Ireland and Australia. Dissemination will be via peer-reviewed journals, conference presentations, public registries and plain language summaries for parent/legal guardian(s), in accordance with national requirements.

ISRCTN61218504. EU CT: 2025-520538-49-00.

Publication based on the UK protocol V.3.0, 08 May 2025

SARS-CoV-2 infection provides protection against reinfection and severe COVID-19 disease; however, this protective effect may diminish over time. We assessed waning of natural immunity conferred by previous infection against severe disease and symptomatic reinfection in Brazil and Scotland.

We undertook a test-negative design study and nested case–control analysis to estimate waning of natural immunity against severe COVID-19 outcomes and symptomatic reinfection using national linked datasets. We used logistic regression to estimate ORs with 95% CIs. A stratified analysis assessed immunity during the Omicron dominant period in Brazil.

We included data from the adult populations of Brazil and Scotland from 1 June 2020 to 30 April 2022.

Severe COVID-19 was defined as hospitalisation or death. Reinfection was defined as reverse-transcriptase PCR or rapid antigen test confirmed at least 120 days after primary infection.

From Brazil, we included 30 881 873 tests and 1 301 665 severe COVID-19 outcomes, and from Scotland, we included 1 520 201 tests and 7988 severe COVID-19 outcomes. Against severe outcomes, sustained protection was observed for at least 12 months after primary SARS-CoV-2 infection with little evidence of waning: 12 months postprimary infection: Brazil OR 0.12 (95% CI 0.10 to 0.14), Scotland OR 0.03 (95% CI 0.02 to 0.04). For symptomatic reinfection, Brazilian data demonstrated evidence of waning in the 12 months following primary infection, although some residual protection remained beyond 12 months: 12 months postprimary infection: OR 0.42 (95% CI 0.40 to 0.43). The greatest reduction in risk of SARS-CoV-2 infection was in individuals with hybrid immunity (history of previous infection and vaccination), with sustained protection against severe outcomes at 12 months postprimary infection. During the Omicron dominant period in Brazil, odds of symptomatic reinfection were higher and increased more quickly over time when compared with the overall study period, although protection against severe outcomes was sustained at 12 months postprimary infection (whole study: OR 0.12 (95% CI 0.10 to 0.14); Omicron phase: OR 0.15 (95% CI 0.12 to 0.19)).

Cross-national analyses demonstrate sustained protection against severe COVID-19 disease for at least 12 months following natural SARS-CoV-2 infection, with vaccination further enhancing protection. Protection against symptomatic reinfection was lower with evidence of waning, but there remained a protective effect beyond 12 months from primary infection.

There have been previous initiatives to identify key performance indicators (KPIs) for continuous kidney replacement therapy. However, no formal reviews of the evidence for KPIs of intermittent kidney replacement therapy (IKRT) have been conducted. This systematic review will appraise the evidence for KPIs of IKRT in critically ill patients and is part of the DIALYZING WISELY (NCT05186636) programme which aims to improve the performance of acute renal replacement therapy in intensive care units by aligning local practices with evidence-based best practices.

Ovid MEDLINE, Ovid Embase, CINAHL and Cochrane Library will be searched for studies involving KPIs for IKRT. Grey literature will also be searched and include technical reports, practice guidelines and conference proceedings as well as websites of relevant organisations. We will search the Agency of Healthcare Research and National Quality Measures Clearinghouse for IKRT-related KPIs. Studies will be included if they contain KPIs, occur in critically ill patients and are associated with IKRT. We will evaluate the risk of bias using the modified Cochrane tool and certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations methodology. The analysis will be primarily descriptive. Each KPI will be evaluated for importance, scientific acceptability, usability and feasibility using the four criteria proposed by the United States Strategic Framework Board for a National Quality Measurement and Reporting System. Finally, KPIs will be appraised for potential operational characteristics, potential to be integrated into electronic medical records, adoptability by stakeholders and affordability, if applicable.

Ethics approval is not required as primary data will not be collected. Findings of this review will be disseminated through peer-related publication.

CRD42022074444.

Minority ethnic groups disproportionately experienced adverse COVID-19 outcomes, partly a consequence of disproportionate exposure to socioeconomic disadvantage and high-risk occupations. We examined whether minority ethnic groups were also disproportionately vulnerable to the consequences of socioeconomic disadvantage and high-risk occupations in Scotland.

We investigated effect modification and interaction between area deprivation, education and occupational risk and ethnicity (assessed as both a binary white vs non-white variable and a multi-category variable) in relation to severe COVID-19 (hospitalisation or death). We used electronic health records linked to the 2011 census and Cox proportional hazards models, adjusting for age, sex and health board. We were principally concerned with additive interactions as a measure of vulnerability, estimated as the relative excess risk due to interaction (RERI).

Analyses considered 3 730 837 individuals aged ≥16 years (with narrower age ranges for analyses focused on education and occupation). Severe COVID-19 risk was typically higher for minority ethnic groups and disadvantaged socioeconomic groups, but additive interactions were not consistent. For example, non-white ethnicity and highest deprivation level experienced elevated risk ((HR=2.7, 95% CI: 2.4, 3.2) compared with the white least deprived group. Additive interaction was not present (RERI=–0.1, 95% CI: –0.4, 0.2), this risk being less than the sum of risks of white ethnicity/highest deprivation level (HR=2.4, 95% CI: 2.3, 2.5) and non-white ethnicity/lowest deprivation level (1.4, 95% CI: 1.2, 1.7). Similarly, non-white ethnicity/no degree education (HR=2.5, 95% CI: 2.2, 2.7; RERI=–0.1, 95% CI: –0.4, 0.2) and non-white ethnicity/high-risk occupation (RERI=0.3, 95% CI: –0.2, 0.8) did not experience greater than additive risk. No clear evidence of effect modification was identified when using the multicategory ethnicity variable or on the multiplicative scale either.

We found no definitive evidence that minority ethnic groups were more vulnerable to the effect of social disadvantage on the risk of severe COVID-19.

Myocardial protection against ischaemia–reperfusion injury is a key determinant of heart function and outcome following cardiac surgery in children. However, myocardial injury still occurs routinely following aortic cross-clamping, as demonstrated by the ubiquitous rise in circulating troponin. del Nido cardioplegia was designed to protect the immature myocardium and is widely used in the USA but has not previously been available in the UK, where St. Thomas’ blood cardioplegia is most common. The del Nido versus St. Thomas’ blood cardioplegia in the young (DESTINY) trial will evaluate whether one solution is better than the other at improving myocardial protection by reducing myocardial injury, shortening ischaemic time and improving clinical outcomes.

The DESTINY trial is a multicentre, patient-blinded and assessor-blinded, parallel-group, individually randomised controlled trial recruiting up to 220 children undergoing surgery for congenital heart disease. Participants will be randomised in a 1:1 ratio to either del Nido cardioplegia or St. Thomas’ blood cardioplegia, with follow-up until 30 days following surgery. The primary outcome is area under the time–concentration curve for plasma high-sensitivity troponin I in the first 24 hours after aortic cross-clamp release. Secondary outcome measures include the incidence of low cardiac output syndrome and Vasoactive-Inotropic Score in the first 48 hours, total aortic cross-clamp time, duration of mechanical ventilation and lengths of stay in the paediatric intensive care unit and the hospital.

The trial was approved by the West Midlands—Coventry and Warwickshire National Health Service Research Ethics Committee (21/WM/0149) on 30 June 2021. Findings will be disseminated to the academic community through peer-reviewed publications and presentation at national and international meetings. Parents will be informed of the results through a newsletter in conjunction with a national charity.

ISRCTN13638147; Pre-results.