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Background Numerous pathologies result in multiple-organ failure, which is thought to be a direct consequence of compromised cellular bioenergetic status. Neither the nature of this phenotype nor its relevance to survival are well understood, limiting the efficacy of modern life-support. Methods To explore the hypothesis that survival from critical illness relates to changes in cellular bioenergetics, we combined assessment of mitochondrial respiration with metabolomic, lipidomic and redox profiling in skeletal muscle and blood, at multiple timepoints, in 21 critically ill patients and 12 reference patients. Results We demonstrate an end-organ cellular phenotype in critical illness, characterized by preserved total energetic capacity, greater coupling efficiency and selectively lower capacity for complex I and fatty acid oxidation (FAO)-supported respiration in skeletal muscle, compared to health. In survivors, complex I capacity at 48 h was 27% lower than in non-survivors (p = 0.01), but tended to increase by day 7, with no such recovery observed in non-survivors. By day 7, survivors’ FAO enzyme activity was double that of non-survivors (p = 0.048), in whom plasma triacylglycerol accumulated. Increases in both cellular oxidative stress and reductive drive were evident in early critical illness compared to health. Initially, non-survivors demonstrated greater plasma total antioxidant capacity but ultimately higher lipid peroxidation compared to survivors. These alterations were mirrored by greater levels of circulating total free thiol and nitrosated species, consistent with greater reductive stress and vascular inflammation, in non-survivors compared to survivors. In contrast, no clear differences in systemic inflammatory markers were observed between the two groups. Conclusion Critical illness is associated with rapid, specific and coordinated alterations in the cellular respiratory machinery, intermediary metabolism and redox response, with different trajectories in survivors and non-survivors. Unravelling the cellular and molecular foundation of human resilience may enable the development of more effective life-support strategies., Graphical abstract Image 1

The syndrome of critical illness is a complex physiological stressor that can be triggered by diverse pathologies. It is widely believed that organ dysfunction and death result from bioenergetic failure caused by inadequate cellular oxygen supply. Teleologically, life has evolved to survive in the face of stressors by undergoing a suite of adaptive changes. Adaptation not only comprises alterations in systemic physiology but also involves molecular reprogramming within cells. The concept of cellular adaptation in critically ill patients is a matter of contention in part because medical interventions mask underlying physiology, creating the artificial construct of “chronic critical illness,” without which death would be imminent. Thus far, the intensive care armamentarium has not targeted cellular metabolism to preserve a temporary equilibrium but instead attempts to normalize global oxygen and substrate delivery. Here, we review adaptations to hypoxia that have been demonstrated in cellular models and in human conditions associated with hypoxia, including the hypobaric hypoxia of high altitude, the intrauterine low-oxygen environment, and adult myocardial hibernation. Common features include upregulation of glycolytic ATP production, enhancement of respiratory efficiency, downregulation of mitochondrial density, and suppression of energy-consuming processes. We argue that these innate cellular adaptations to hypoxia represent potential avenues for intervention that have thus far remained untapped by intensive care medicine.

Delirium is a common and debilitating syndrome in hospitalized patients, and its impact on mortality, morbidity and duration of hospital admission is increasingly apparent. Delirium is a complex phenomenon, for which there is no specific treatment, but research over the last decade has revealed contributing factors, many of which are modifiable, and preventative strategies have demonstrated benefit. This review highlights the importance of reducing the impact of delirium on hospitalized patients, and summarizes the current evidence for strategies to achieve this. Current recommendations focus on the pre-emptive implementation of multi-modal non-pharmacological interventions to reduce the occurrence of delirium in the first place, and routine monitoring using validated tools to identify delirious patients early. Potential therapies for established delirium remain controversial.

Dietary inorganic nitrate has been shown to lower blood pressure (BP) and improve endothelial function(1). The main sources of dietary nitrate are vegetables (root and green leafy varieties) as well as drinking water but data available on dietary analysis software on nitrate levels in vegetables and vegetable-based foods is very limited. To date, very few studies have investigated the relationship between the level of consumption of dietary nitrate on BP and other cardiovascular disease (CVD) risk factors in a representative UK population. The aim of the study was to address this knowledge gap using data from the National Diet and Nutrition Survey (NDNS) years 1–8, a cross-sectional study conducted in 3339 men and women aged 19–64 y between 2008/09–2011/12. A comprehensive database was first developed to evaluate the nitrate and nitrite levels in vegetables, cured meats and composite dishes to more accurately estimate the dietary nitrate intakes of the NDNS participants. The population was then classified into quartiles of daily nitrate intake, with quartile 1 (Q1: 26–106 mg/d) and quartile 4 (Q4: 183–559 mg/d) representing diets with the lowest and highest intakes, respectively. ANCOVA analysis was performed to determine the relationship between the level of daily nitrate intake with available data on biomarkers of CVD risk (including BP (systolic, diastolic and pulse pressure), lipid profile, (total, high-density lipoprotein and low-density lipoprotein (LDL-C) cholesterol), C-reactive protein, anthropometric measures (body mass index and waist to hip ratio) and glycaemic control (glucose and glycated haemoglobin). There were significant differences in systolic (P-trend = 0.008) and diastolic (P-trend = 0.025) BP across increasing quartiles of dietary nitrate intake, with BP significantly lower in Q3 than all other quartiles. Pulse pressure (calculated as systolic–diastolic BP) was also found to be significantly different across quartiles (P-trend = 0.001), with diets of participants in Q3 and Q4 being associated with significantly lower pulse pressures than those in Q1 (P-Q1 vs. Q3 = 0.005, P-Q1 vs. Q4 = 0.007). All of the other CVD risk markers were not different between quartile groups. Our preliminary results suggest that the level of dietary nitrate intake may be significantly associated with BP, a key independent CVD risk factor. There is an urgent need to more accurately estimate the dietary nitrate intake in the UK population and to determine whether the source of dietary nitrate (vegetables vs cured meats) impacts on the significant relationship with BP.

The harshest environment that many people will ever face is the critical care unit, where pathology can stress homeostatic mechanisms beyond their limits, leading to multiple organ failure and death. Our understanding of the biology that underlies this catastrophic process remains limited. There is significant variation in survival between individuals with apparently similar severity of organ dysfunction and it is difficult to predict which patients will weather the storm. Survival may be influenced by as yet undiscovered innate adaptive mechanisms that determine an individual's ability to tolerate physiological stress. Identifying favourable phenotypes, and the molecular machinery underlying them, could yield new therapeutic targets to improve outcome in life-threatening illness. Unfortunately, the complexity of critical illness makes it difficult to elucidate subtle adaptive mechanisms that could favour survival during stress. However, comparisons can be drawn between the stress of critical illness and that imposed by austere environments. The Earth is comprised of a wide range of different physical environments, each of which challenges homeostasis. Whilst technological advances have played a significant role in our capacity to survive in austere environments, biological adaptation and evolutionary change have been crucial. Studying human responses to environmental stressors such as heat, cold, hypoxia and microgravity has taught us a great deal about innate human adaptation, from the system to the cellular level, and the field continues to expand. Translating this to the pathophysiological stress of critical illness could offer alternative approaches to the current practice of intensive care medicine.

There has been a clear decline in the volume of oxygen in Earth's atmosphere over the past 20 years. Although the magnitude of this decrease appears small compared to the amount of oxygen in the atmosphere, it is difficult to predict how this process may evolve, due to the brevity of the collected records. A recently proposed model predicts a non-linear decay, which would result in an increasingly rapid fall-off in atmospheric oxygen concentration, with potentially devastating consequences for human health. We discuss the impact that global deoxygenation, over hundreds of generations, might have on human physiology. Exploring the changes between different native high-altitude populations provides a paradigm of how humans might tolerate worsening hypoxia over time. Using this model of atmospheric change, we predict that humans may continue to survive in an unprotected atmosphere for ~3600 years. Accordingly, without dramatic changes to the way in which we interact with our planet, humans may lose their dominance on Earth during the next few millennia.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the benefits and harms of antioxidant use in the perioperative period in adults who undergo non‐cardiac surgery.

Many physiological and cellular processes cycle with time, with the period between one peak and the next being roughly equal to 24 h. These circadian rhythms underlie ‘permissive homeostasis’, whereby anticipation of periods of increased energy demand or stress may enhance the function of individual cells, organ systems or whole organisms. Many physiological variables related to survival during critical illness have a circadian rhythm, including the sleep/wake cycle, haemodynamic and respiratory indices, immunity and coagulation, but their clinical significance remains underappreciated. Critically ill patients suffer from circadian dysrhythmia, manifesting overtly as sleep disturbance and delirium, but with widespread covert effects on cellular and organ function. Environmental and pharmacological strategies that ameliorate or prevent circadian dysrhythmia have demonstrated clinical benefit. Harnessing these important biological phenomena to match metabolic supply to demand and bolster cell defenses at the apposite time may be a future therapeutic strategy in the intensive care unit.

What you need to know ### Sources and selection criteria We selected published guidance on sleep and shift work from the National Institute for Health and Care Excellence (NICE) and the Royal Colleges of Physicians and Anaesthetists. We then searched PubMed and Cochrane databases (to May 2017) for observational studies, randomised controlled studies, meta-analyses, and systematic and narrative reviews relating to the health consequences of shift work and for each proposed sleep intervention given in table 1. Priority was given to randomised controlled trials and meta-analyses, but given the interdisciplinary nature of sleep and shift work, and the overall quality of evidence, we also considered observational studies and grey literature from aviation and heavy industries, as well as published expert opinion. Night shift work occurs during the period of the sleep-wake cycle (“circadian phase”) programmed for sleep. Alertness, cognitive function, psychomotor coordination, and mood all reach their lowest point between 3 and 5 am1 After the shift, workers must rest during the circadian phase least conducive to sleeping,2 which compounds fatigue and can lead to chronic sleep disturbance.3 A recent systematic review linked night shift work with an increased risk of sleep loss, occupational accidents, obesity and weight gain, type 2 diabetes, coronary heart disease, and breast, prostate, and colorectal cancers.4 In a 2017 survey of 2231 UK trainee anaesthetists, more than 70% reported that fatigue affected their physical and psychological wellbeing. Fifty seven per cent described an accident or near-miss travelling home from night shifts.5 Performance on night shift declines with …

Background: Self-management strategies have been reported to be effective for people with thumb base osteoarthritis (OA) in spite of claims that thumb splinting can restore function there is limited evidence to support the effectiveness of these splints. Hand splints are currently recommended for hand OA by NICE and EULAR. Methods: A three-arm randomised controlled pilot trial was conducted across five UK NHS outpatient therapy departments. Patients with symptoms of thumb base OA and with an AUSCAN score for thumb base pain > 5 and of hand function > 9 were recruited and randomised to receive optimal NHS Occupational therapy care, optimal NHS Occupational therapy care plus a biomechanically active splint or optimal NHS Occupational therapy care plus a biomechanically inactive (placebo) splint. Patients were assessed at baseline and at 4 weeks. The primary outcome was the AUSCAN Osteoarthritis Hand Index (Pain). Secondary outcomes included: AUSCAN (Function and Stiffness), Michigan Hand Outcomes Questionnaire, Global Rating of Change Scale. Mixed between-within subjects ANOVAs were conducted to compare the impact of the three interventions Results: Eighteen participants (27 OA thumbs) were recruited. Eleven females (78%) and 3 males (22%) completed the study with a mean age of 61.24 (SD=9.40); 13 (92.86%) were right-hand dominant. Seven patients were treated for bilateral thumb base OA, 4 patients were treated for right thumb base OA and 3 for left thumb base OA. Statistically significant differences were reported between the 3 intervention groups over 4 weeks for AUSCAN Pain (F(2,18)=5.892, p=0.011), AUSCAN Stiffness (F(2,18)=22.629, p