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.

The management of cardiovascular disease (CVD) has evolved significantly in the last 20 years; however, the last major publication to address a consensus on the management of CVD in aircrew was published in 1999, following the second European Society of Cardiology conference of aviation cardiology experts. This article outlines an introduction to aviation cardiology and focuses on the broad aviation medicine considerations that are required to manage aircrew appropriately and optimally (both pilots and non-pilot aviation professionals). This and the other articles in this series are born out of a 3 year collaborative working group between international military aviation cardiologists and aviation medicine specialists, many of whom also work with and advise civil aviation authorities, as part of a North Atlantic Treaty Organization (NATO) led initiative to address the occupational ramifications of CVD in aircrew (HFM-251). This article describes the types of aircrew employed in the civil and military aviation profession in the 21st century; the types of aircraft and aviation environment that must be understood when managing aircrew with CVD; the regulatory bodies involved in aircrew licensing and the risk assessment processes that are used in aviation medicine to determine the suitability of aircrew to fly with medical (and specifically cardiovascular) disease; and the ethical, occupational and clinical tensions that exist when managing patients with CVD who are also professional aircrew.

This manuscript focuses on the broad aviation medicine considerations that are required to optimally manage aircrew with established coronary artery disease (CAD) without myocardial infarction (MI) or revascularisation (both pilots and non-pilot aviation professionals). It presents expert consensus opinion and associated recommendations and is part of a series of expert consensus documents covering all aspects of aviation cardiology.Aircrew may present with MI (both ST elevation MI (STEMI) and non-ST elevation MI (NSTEMI)) as the initial presenting symptom of obstructive CAD requiring revascularisation. Management of these individuals should be conducted according to published guidelines, ideally with consultation between the cardiologist, surgeon and aviation medical examiner. Return to restricted flight duties is possible in the majority of aircrew; however, they must have normal cardiac function, acceptable residual disease burden and no residual ischaemia. They must also be treated with aggressive cardiac risk factor modification. Aircrew should be restricted to dual pilot operations in non-high-performance aircraft, with return to flying no sooner than 6 months after the event. At minimum, annual follow-up with routine non-invasive cardiac evaluation is recommended.

Coronary events remain a major cause of sudden incapacitation, including death, in both the general population and among aviation personnel, and are an ongoing threat to flight safety and operations. The presentation is often unheralded, especially in younger adults, and is often due to rupture of a previously non-obstructive coronary atheromatous plaque. The challenge for aeromedical practitioners is to identify individuals at increased risk for such events. This paper presents the NATO Cardiology Working Group (HFM 251) consensus approach for screening and investigation of aircrew for asymptomatic coronary disease.A three-phased approach to coronary artery disease (CAD) risk assessment is recommended, beginning with initial risk-stratification using a population-appropriate risk calculator and resting ECG. For aircrew identified as being at increased risk, enhanced screening is recommended by means of Coronary Artery Calcium Score alone or combined with a CT coronary angiography investigation. Additional screening may include exercise testing, and vascular ultrasound imaging. Aircrew identified as being at high risk based on enhanced screening require secondary investigations, which may include functional ischaemia, and potentially invasive coronary angiography. Functional stress testing as a stand-alone investigation for significant CAD is not recommended in aircrew. Aircrew identified with coronary disease require further clinical and aeromedical evaluation before being reconsidered for flying status.

Cardiovascular diseases i are the most common cause of loss of flying licence globally, and cardiac arrhythmia is the main disqualifier in a substantial proportion of aircrew. Aircrew ii often operate within a demanding physiological environment, that potentially includes exposure to sustained acceleration (usually resulting in a positive gravitational force, from head to feet (+Gz)) in high performance aircraft. Aeromedical assessment is complicated further when trying to discriminate between benign and potentially significant rhythm abnormalities in aircrew, many of whom are young and fit, have a resultant high vagal tone, and among whom underlying cardiac disease has a low prevalence. In cases where a significant underlying aetiology is plausible, extensive investigation is often required and where appropriate should include review by an electrophysiologist. The decision regarding restriction of flying activity will be dependent on several factors including the underlying arrhythmia, associated pathology, risk of incapacitation and/or distraction, the type of aircraft operated, and the specific flight or mission criticality of the role performed by the individual aircrew.

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