Patients receiving haemodialysis are at very high risk of fragility fracture, yet there are no proven treatments for fracture prevention. We will advance a pilot study on the feasibility of a large, pragmatic, randomised controlled trial (RCT) of denosumab for fragility fracture prevention in haemodialysis.

PRevEnting FracturEs in REnal Disease-1 is a pragmatic, open-label, pilot study of an RCT of a denosumab care pathway embedded in routine care haemodialysis centres.

We will recruit at least 60 participants at high risk of fracture from at least 6 haemodialysis centres in Ontario, Canada. They must be aged 40 years or older, have access to provincial drug coverage, have appropriate baseline calcium and parathyroid hormone levels and be deemed suitable for denosumab by their kidney care provider. Participants will be randomised 1:1 to denosumab (with supports to mitigate hypocalcaemia) versus usual care using block randomisation by a central statistician (computer-generated sequence). Primary outcomes include recruitment feasibility and adherence. Secondary outcomes include safety (hypocalcaemia) and participant satisfaction with our protocol and processes. Study investigators and data analysts will be blind to treatment allocation.

We will present results descriptively. The trial was approved by Clinical Trials Ontario and local research ethics boards across study sites.

Primary and secondary outcomes will be published on trial completion.

This pilot will inform the feasibility of conducting a large-scale, efficiently run, pragmatic RCT to test whether a denosumab care pathway safely reduces the risk of fragility fracture in patients receiving haemodialysis. Results have the potential to transform fracture care in real-world patients with kidney and metabolic bone disease.

NCT05096195.

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

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.