RationaleThe molecular mechanisms underlying the muscle atrophy of intensive care unit-acquired weakness (ICUAW) are poorly understood. We hypothesised that increased circulating and muscle growth and differentiation factor-15 (GDF-15) causes atrophy in ICUAW by changing expression of key microRNAs.ObjectivesTo investigate GDF-15 and microRNA expression in patients with ICUAW and to elucidate possible mechanisms by which they cause muscle atrophy in vivo and in vitro.MethodsIn an observational study, 20 patients with ICUAW and seven elective surgical patients (controls) underwent rectus femoris muscle biopsy and blood sampling. mRNA and microRNA expression of target genes were examined in muscle specimens and GDF-15 protein concentration quantified in plasma. The effects of GDF-15 on C2C12 myotubes in vitro were examined.Measurements and main resultsCompared with controls, GDF-15 protein was elevated in plasma (median 7239 vs 2454 pg/mL, p=0.001) and GDF-15 mRNA in the muscle (median twofold increase p=0.006) of patients with ICUAW. The expression of microRNAs involved in muscle homeostasis was significantly lower in the muscle of patients with ICUAW. GDF-15 treatment of C2C12 myotubes significantly elevated expression of muscle atrophy-related genes and down-regulated the expression of muscle microRNAs. miR-181a suppressed transforming growth factor-β (TGF-β) responses in C2C12 cells, suggesting increased sensitivity to TGF-β in ICUAW muscle. Consistent with this suggestion, nuclear phospho-small mothers against decapentaplegic (SMAD) 2/3 was increased in ICUAW muscle.ConclusionsGDF-15 may increase sensitivity to TGF-β signalling by suppressing the expression of muscle microRNAs, thereby promoting muscle atrophy in ICUAW. This study identifies both GDF-15 and associated microRNA as potential therapeutic targets.

An 86-year-old man underwent pacemaker implantation for symptomatic atrio-ventricular block grade 2 Mobitz II. The patient suffered repeated admissions for iterative sterile wound necrosis, leading to two generator re-implantations. No bacterial infection was detected in the microbiological screening tests. The skin patch testing to titanium was negative. Nevertheless, we decided to remove the pacemaker system and to implant a gold-plated generator with polyurethane leads. Since then, there has been no recurrence of wound complications. Gold-plated generator and polyurethane leads are effective in treating allergic reactions to pacemaker system components in selected cases. Negative skin patch testing to titanium does not exclude allergic reaction to this pacemaker component.

Early aeromedical risk i was based on aeromedical standards designed to eliminate individuals ii from air operations with any identifiable medical risk, and led to frequent medical disqualification. The concept of considering aeromedical risk as part of the spectrum of risks that could lead to aircraft accidents (including mechanical risks and human factors) was first proposed in the 1980s and led to the development of the 1% rule which defines the maximum acceptable risk for an incapacitating medical event as 1% per year (or 1 in 100 person-years) to align with acceptable overall risk in aviation operations. Risk management has subsequently evolved as a formal discipline, incorporating risk assessment as an integral part of the process. Risk assessment is often visualised as a risk matrix, with the level of risk, urgency or action required defined for each cell, and colour-coded as red, amber or green depending on the overall combination of risk and consequence. This manuscript describes an approach to aeromedical risk management which incorporates risk matrices and how they can be used in aeromedical decision-making, while highlighting some of their shortcomings.