The Himalayan Sherpas, a human population of Tibetan descent, are highly adapted to life in the hypobaric hypoxia of high altitude. Mechanisms involving enhanced tissue oxygen delivery in comparison to Lowlander populations have been postulated to play a role in such adaptation. Whether differences in tissue oxygen utilization (i.e., metabolic adaptation) underpin this adaptation is not known, however. We sought to address this issue, applying parallel molecular, biochemical, physiological, and genetic approaches to the study of Sherpas and native Lowlanders, studied before and during exposure to hypobaric hypoxia on a gradual ascent to Mount Everest Base Camp (5,300 m). Compared with Lowlanders, Sherpas demonstrated a lower capacity for fatty acid oxidation in skeletal muscle biopsies, along with enhanced efficiency of oxygen utilization, improved muscle energetics, and protection against oxidative stress. This adaptation appeared to be related, in part, to a putatively advantageous allele for the peroxisome proliferator-activated receptor A (PPARA) gene, which was enriched in the Sherpas compared with the Lowlanders. Our findings suggest that metabolic adaptations underpin human evolution to life at high altitude, and could have an impact upon our understanding of human diseases in which hypoxia is a feature. metabolism | altitude | skeletal muscle | hypoxia | mitochondria

Inorganic nitrate was once considered an oxidation end-product of nitric oxide metabolism with little biological activity. However, recent studies have demonstrated that dietary nitrate can modulate mitochondrial function in man and is effective in reversing features of the metabolic syndrome in mice. Using a combined histological, metabolomics, and transcriptional and protein analysis approach we mechanistically define that nitrate not only increases the expression of thermogenic genes in brown-adipose tissue but also induces the expression of brown adipocyte-specific genes and proteins in white adipose tissue, substantially increasing oxygen consumption and fatty acid β-oxidation in adipocytes. Nitrate induces these phenotypic changes through a mechanism distinct from known physiological small molecule activators of browning, the recently identified nitrate-nitrite-nitric oxide pathway. The nitrate-induced browning effect was enhanced in hypoxia, a serious co-morbidity affecting white adipose tissue in obese individuals, and corrected impaired brown adipocyte-specific gene expression in white adipose tissue in a murine model of obesity. Since resulting beige/brite cells exhibit anti-obesity and anti-diabetic effects, nitrate may be an effective means of inducing the browning response in adipose tissue to treat the metabolic syndrome.

BackgroundInsulin sensitivity in skeletal muscle is associated with metabolic flexibility, including a high capacity to increase fatty acid (FA) oxidation in response to increased lipid supply. Lipid overload, however, can result in incomplete FA oxidation and accumulation of potentially harmful intermediates where mitochondrial tricarboxylic acid cycle capacity cannot keep pace with rates of β-oxidation. Enhancement of muscle FA oxidation in combination with mitochondrial biogenesis is therefore emerging as a strategy to treat metabolic disease. Dietary inorganic nitrate was recently shown to reverse aspects of the metabolic syndrome in rodents by as yet incompletely defined mechanisms.ResultsHerein, we report that nitrate enhances skeletal muscle FA oxidation in rodents in a dose-dependent manner. We show that nitrate induces FA oxidation through a soluble guanylate cyclase (sGC)/cGMP-mediated PPARβ/δ- and PPARα-dependent mechanism. Enhanced PPARβ/δ and PPARα expression and DNA binding induces expression of FA oxidation enzymes, increasing muscle carnitine and lowering tissue malonyl-CoA concentrations, thereby supporting intra-mitochondrial pathways of FA oxidation and enhancing mitochondrial respiration. At higher doses, nitrate induces mitochondrial biogenesis, further increasing FA oxidation and lowering long-chain FA concentrations. Meanwhile, nitrate did not affect mitochondrial FA oxidation in PPARα−/− mice. In C2C12 myotubes, nitrate increased expression of the PPARα targets Cpt1b, Acadl, Hadh and Ucp3, and enhanced oxidative phosphorylation rates with palmitoyl-carnitine; however, these changes in gene expression and respiration were prevented by inhibition of either sGC or protein kinase G. Elevation of cGMP, via the inhibition of phosphodiesterase 5 by sildenafil, also increased expression of Cpt1b, Acadl and Ucp3, as well as CPT1B protein levels, and further enhanced the effect of nitrate supplementation.ConclusionsNitrate may therefore be effective in the treatment of metabolic disease by inducing FA oxidation in muscle.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-015-0221-6) contains supplementary material, which is available to authorized users.

Harry Knights and Nikhil Mayor contributed equally to this work Background This retrospective cohort study aims to define the clinical findings and outcomes of every patient admitted to a district general hospital in Surrey with COVID-19 in March 2020, providing a snapshot of the first wave of infection in the UK. This study is the first detailed insight into the impact of frailty markers on patient outcomes and provides the infection rate among healthcare workers. Methods Data were obtained from medical records. Outcome measures were level of oxygen therapy, discharge and death. Patients were followed up until 21 April 2020. Results 108 patients were included. 34 (31%) died in hospital or were discharged for palliative care. 43% of patients aged over 65 died. The commonest comorbidities were hypertension (49; 45%) and diabetes (25; 23%). Patients who died were older (mean difference ±SEM, 13.76±3.12 years; p<0.0001) with a higher NEWS2 score (median 6, IQR 2.5-7.5 vs median 2, IQR 2-6) and worse renal function (median differences: urea 2.7 mmol/L, p<0.01; creatinine 4 µmol/L, p<0.05; eGFR 14 mL/min, p<0.05) on admission compared with survivors. Frailty markers were identified as risk factors for death. Clinical Frailty Scale (CFS) was higher in patients over 65 who died than in survivors (median 5, IQR 4-6 vs 3.5, IQR 2-5; p<0.01). Troponin and creatine kinase levels were higher in patients who died than in those who recovered (p<0.0001). Lymphopenia was common (median 0.8, IQR 0.6-1.2; p<0.005). Every patient with heart failure died (8). 26 (24%) were treated with continuous positive airway pressure (CPAP; median 3 days, IQR 2-7.3) and 9 (8%) were intubated (median 14 days, IQR 7-21). All patients who died after discharge (4; 6%) were care home residents. 276 of 699 hospital staff tested were positive for COVID-19. Conclusions This study identifies older patients with frailty as being particularly vulnerable and reinforces government policy to protect this group at all costs.

Morash AJ, Kotwica AO, Murray AJ. Tissue-specific changes in fatty acid oxidation in hypoxic heart and skeletal muscle. Am J Physiol Regul Integr Comp Physiol 305: R534 -R541, 2013. First published June 19, 2013 doi:10.1152/ajpregu.00510.2012.-Exposure to hypobaric hypoxia is sufficient to decrease cardiac PCr/ATP and alters skeletal muscle energetics in humans. Cellular mechanisms underlying the different metabolic responses of these tissues and the time-dependent nature of these changes are currently unknown, but altered substrate utilization and mitochondrial function may be a contributory factor. We therefore sought to investigate the effects of acute (1 day) and more sustained (7 days) hypoxia (13% O 2) on the transcription factor peroxisome proliferator-activated receptor ␣ (PPAR␣) and its targets in mouse cardiac and skeletal muscle. In the heart, PPAR␣ expression was 40% higher than in normoxia after 1 and 7 days of hypoxia. Activities of carnitine palmitoyltransferase (CPT) I and ␤-hydroxyacyl-CoA dehydrogenase (HOAD) were 75% and 35% lower, respectively, after 1 day of hypoxia, returning to normoxic levels after 7 days. Oxidative phosphorylation respiration rates using palmitoyl-carnitine followed a similar pattern, while respiration using pyruvate decreased. In skeletal muscle, PPAR␣ expression and CPT I activity were 20% and 65% lower, respectively, after 1 day of hypoxia, remaining at this level after 7 days with no change in HOAD activity. Oxidative phosphorylation respiration rates using palmitoyl-carnitine were lower in skeletal muscle throughout hypoxia, while respiration using pyruvate remained unchanged. The rate of CO2 production from palmitate oxidation was significantly lower in both tissues throughout hypoxia. Thus cardiac muscle may remain reliant on fatty acids during sustained hypoxia, while skeletal muscle decreases fatty acid oxidation and maintains pyruvate oxidation. fatty acids; mitochondrial respiration; hypoxia; metabolism; heart HYPOBARIC HYPOXIA elicits a myriad of physiological responses that aim to increase oxygen availability at the tissues or decrease tissue oxygen demand (42). Central to this response is an acute increase in cardiac output, which in the face of atmospheric hypoxia can lead to an inability to match oxygen demand at the heart tissue itself (17). In a study of humans returning from exposure to hypobaric hypoxia at high altitude, resting energy levels were maintained in the subjects' skeletal muscle (9), whereas their hearts showed impaired energetics as indicated by decreased PCr/ATP (17). The cellular mechanisms underlying the different responses of these two tissues are unknown; however, the process of metabolic remodelling may differ under hypoxic conditions, and it has been suggested that altered substrate selection and mitochondrial respiration may be key factors in this regard (23,38,50).In the healthy heart, 90% of ATP production is generated via mitochondrial oxidative phosphorylation with 60 -70% of that energy being derived from lipid oxidation (3...

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Human factors and a safe operating theatre environment are of paramount importance, wherever surgery is undertaken. The majority of patients in sub-Saharan Africa do not yet have access to safe surgery. The Paediatric ENT Skills and Airway Course introduced and evaluated here was designed to improve outcomes and safety in a typical East African environment. The lectures, tutorials and practicals covered technical and non-technical skills. Responses from pre- and post-course questionnaires were evaluated as an initial surrogate for effectiveness of this course. The latter showed improvement in all taught skills and found universal recommendation. The course had been established to try to minimise morbidity and mortality after paediatric surgery at our institution, KCMC. We encouraged team co-operation in the care of patients, and recommend other centres consider similar courses building on human factors for safer operating theatre working practices.

Background The pathophysiology of COVID-19 remains poorly understood. We aimed to estimate the contribution of intrapulmonary shunting and ventilation-to-perfusion (VA/Q) mismatch using a mathematical model to construct oxygen-haemoglobin dissociation curves (ODCs). Methods ODCs were constructed using transcutaneous pulse oximetry at two different fractions of inspired oxygen (FiO2). 199 patients were included from two large district general hospitals in the South East of England from 1st to 14th January 2021. The study was supported by the National Institute of Health Research (NIHR) Clinical Research Network. Results Overall mortality was 29%. Mean age was 68.2 years (SEM 1·2) with 46% female. Median shunt on admission was 17% (IQR 8–24.5); VA/Q was 0.61 (IQR 0.52–0.73). Shunt was 37.5% higher in deaths (median 22%, IQR 9–29) compared to survivors (16%, 8–21; p = 0.0088) and was a predictor of mortality (OR 1.04; 95% CI 1.01–1.07). Admission oxygen saturations were more strongly predictive of mortality (OR 0.91, 95% CI 0.87–0.96). There was no difference in VA/Q mismatch between deaths (0.60; IQR 0.50–0.73) and survivors (0.61; IQR 0.52–0.73; p = 0.63) and it was not predictive of mortality (OR 0.68; 95% CI 0.18–2.52; p = 0.55). Shunt negatively correlated with admission oxygen saturation (R -0.533; p<0.0001) whereas VA/Q was not (R 0.1137; p = 0.12). Interpretation Shunt, not VA/Q mismatch, was associated with worsening hypoxia, though calculating shunt was not of prognostic value. This study adds to our understanding of the pathophysiology of hypoxaemia in COVID-19. Our inexpensive and reliable technique may provide further insights into the pathophysiology of hypoxia in other respiratory diseases.