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We previously reported outcome-associated decreases in muscle energetic status and mitochondrial dysfunction in septic patients with multiorgan failure. We postulate that survivors have a greater ability to maintain or recover normal mitochondrial functionality. To determine whether mitochondrial biogenesis, the process promoting mitochondrial capacity, is affected in critically ill patients. Muscle biopsies were taken from 16 critically ill patients recently admitted to intensive care (average 1-2 d) and from 10 healthy, age-matched patients undergoing elective hip surgery. Survival, mitochondrial morphology, mitochondrial protein content and enzyme activity, mitochondrial biogenesis factor mRNA, microarray analysis, and phosphorylated (energy) metabolites were determined. Ten of 16 critically ill patients survived intensive care. Mitochondrial size increased with worsening outcome, suggestive of swelling. Respiratory protein subunits and transcripts were depleted in critically ill patients and to a greater extent in nonsurvivors. The mRNA content of peroxisome proliferator-activated receptor γ coactivator 1-α (transcriptional coactivator of mitochondrial biogenesis) was only elevated in survivors, as was the mitochondrial oxidative stress protein manganese superoxide dismutase. Eventual survivors demonstrated elevated muscle ATP and a decreased phosphocreatine/ATP ratio. Eventual survivors responded early to critical illness with mitochondrial biogenesis and antioxidant defense responses. These responses may partially counteract mitochondrial protein depletion, helping to maintain functionality and energetic status. Impaired responses, as suggested in nonsurvivors, could increase susceptibility to mitochondrial damage and cellular energetic failure or impede the ability to recover normal function. Clinical trial registered with clinical trials.gov (NCT00187824).

Hepatic dysfunction and jaundice are traditionally viewed as late features of sepsis and portend poor outcomes. We hypothesized that changes in liver function occur early in the onset of sepsis, yet pass undetected by standard laboratory tests. In a long-term rat model of faecal peritonitis, biotransformation and hepatobiliary transport were impaired, depending on subsequent disease severity, as early as 6 h after peritoneal contamination. Phosphatidylinositol-3-kinase (PI3K) signalling was simultaneously induced at this time point. At 15 h there was hepatocellular accumulation of bilirubin, bile acids, and xenobiotics, with disturbed bile acid conjugation and drug metabolism. Cholestasis was preceded by disruption of the bile acid and organic anion transport machinery at the canalicular pole. Inhibitors of PI3K partially prevented cytokine-induced loss of villi in cultured HepG2 cells. Notably, mice lacking the PI3Kγ gene were protected against cholestasis and impaired bile acid conjugation. This was partially confirmed by an increase in plasma bile acids (e.g., chenodeoxycholic acid [CDCA] and taurodeoxycholic acid [TDCA]) observed in 48 patients on the day severe sepsis was diagnosed; unlike bilirubin (area under the receiver-operating curve: 0.59), these bile acids predicted 28-d mortality with high sensitivity and specificity (area under the receiver-operating curve: CDCA: 0.77; TDCA: 0.72; CDCA+TDCA: 0.87). Liver dysfunction is an early and commonplace event in the rat model of sepsis studied here; PI3K signalling seems to play a crucial role. All aspects of hepatic biotransformation are affected, with severity relating to subsequent prognosis. Detected changes significantly precede conventional markers and are reflected by early alterations in plasma bile acids. These observations carry important implications for the diagnosis of liver dysfunction and pharmacotherapy in the critically ill. Further clinical work is necessary to extend these concepts into clinical practice. Please see later in the article for the Editors' Summary.

Insulin resistance is a key feature of the metabolic syndrome, a cluster of medical disorders that together increase the chance of developing type 2 diabetes and cardiovascular disease. In turn, type 2 diabetes may cause complications such as diabetic kidney disease (DKD). Obesity is a major risk factor for developing systemic insulin resistance, and skeletal muscle is the first tissue in susceptible individuals to lose its insulin responsiveness. Interestingly, lean individuals are not immune to insulin resistance either. Non-obese, non-diabetic subjects with chronic kidney disease (CKD), for example, exhibit insulin resistance at the very onset of CKD, even before clinical symptoms of renal failure are clear. This uraemic insulin resistance contributes to the muscle weakness and muscle wasting that many CKD patients face, especially during the later stages of the disease. Bioenergetic failure has been associated with the loss of skeletal muscle insulin sensitivity in obesity and uraemia, as well as in the development of kidney disease and its sarcopenic complications. In this mini review, we evaluate how mitochondrial activity of different renal cell types changes during DKD progression, and discuss the controversial role of oxidative stress and mitochondrial reactive oxygen species in DKD. We also compare the involvement of skeletal muscle mitochondria in uraemic and obesity-related muscle insulin resistance.

Correspondence to Dr James H Hull, Respiratory Medicine, Royal Brompton Hospital, London, UK; j.hull@rbht.nhs.uk Introduction This British Thoracic Society (BTS) Clinical Statement addresses the diagnosis, evaluation and management of respiratory problems in athletic individuals. [...]it is estimated that at least one in four individuals report troublesome exercise-related respiratory issues, such as breathlessness, cough and/or wheeze.1 Moreover, in competitive athletes, asthma is the most prevalent medical condition and encountered in approximately a quarter of those partaking in endurance sport.2 3 Although athletic individuals can develop any cardiorespiratory illness and thus general clinical guideline documents are broadly applicable, studies over the past three decades have highlighted issues that are particularly relevant when assessing respiratory problems in athletic individuals or in certain sporting scenarios. Scope The purpose of this document was to provide concise and pragmatic guidance to help clinicians from all aspects of the multidisciplinary team (ie, including doctors, physiotherapists, speech and language therapists, pharmacists, physiologists, psychologists and specialist nurses), in both primary and secondary care settings, in assessing and managing respiratory problems in athletic individuals. A thorough history should characterise the precise nature of exercise-related clinical features (eg, breathlessness and wheeze) and their relationship with exercise intensity and recovery.

BackgroundApproximately 70% of elite swimmers experience exercise-induced-bronchoconstriction (EIB), with the eucapnic-voluntary-hyperpnoea (EVH) challenge recommended to provide objective evidence to support diagnosis. Research on the impact of inhaler therapy in elite swimmers with a positive EVH challenge (EIBpositive) is limited, and the repeatability of the EVH challenge questioned.ObjectiveInvestigate impact of inhaler therapy on hyperpnoea-induced-bronchoconstriction in EIBpositive elite swimmers adherent to therapy. Evaluate long-term test-retest repeatability of EVH challenge in those non-adherent to inhaler therapy.DesignRetrospective data analysis.SettingGreat Britain swimming team.ParticipantsNineteen elite-international swimmers (8 males, 11 females; 20±3 yrs).InterventionsFollowing initial assessment, EIBpositive athletes were prescribed appropriate inhaler therapy in accordance to greatest fall in FEV1 (FEV1max) and asked to maintain therapy throughout the year. Athletes were grouped dependent on adherence to inhaler therapy (Non-adherent = EVH1→EVH2;n=13; adherent = EVHOFF→EVHON;n=6).Main outcome measurementsDifferences in FEV1max between screening visits separated by a calendar year were analysed using paired t-tests and presented as mean ± SD. The test-retest repeatability between EVH1→EVH2 was expressed as mean bias with 95% limits of agreement and Pearson’s correlation coefficient (rp).ResultsFEV1max was significantly lower in EVHON (-9.17±-3.4%) than EVHOFF (-26.7±-13.3%; p=0.02) and a trend for baseline FEV1 to be greater in EVHON than EVHOFF (p=0.06). EVH1→EVH2 FEV1max did not differ significantly between screening visits (p≥0.05). There was acceptable repeatability of FEV1max in EVH1→EVH2 (0.85%; -5.97, 7.67), and significant strong positive correlation (rp=0.72, p=0.01).ConclusionsElite swimmers adherent to inhaler therapy demonstrated significant reduction in FEV1max severity. The EVH challenge result was repeatable in elite swimmers with EIB non-adherent to inhaler therapy. Therefore, the EVH challenge is effective to initially assess elite swimmers for EIB, and use as a follow-up assessment after initiation of inhaler therapy.

Collinearity refers to the non independence of predictor variables, usually in a regression-type analysis. It is a common feature of any descriptive ecological data set and can be a problem for parameter estimation because it inflates the variance of regression parameters and hence potentially leads to the wrong identification of relevant predictors in a statistical model. Collinearity is a severe problem when a model is trained on data from one region or time, and predicted to another with a different or unknown structure of collinearity. To demonstrate the reach of the problem of collinearity in ecology, we show how relationships among predictors differ between biomes, change over spatial scales and through time. Across disciplines, different approaches to addressing collinearity problems have been developed, ranging from clustering of predictors, threshold-based pre-selection, through latent variable methods, to shrinkage and regularisation. Using simulated data with five predictor-response relationships of increasing complexity and eight levels of collinearity we compared ways to address collinearity with standard multiple regression and machine-learning approaches. We assessed the performance of each approach by testing its impact on prediction to new data. In the extreme, we tested whether the methods were able to identify the true underlying relationship in a training dataset with strong collinearity by evaluating its performance on a test dataset without any collinearity. We found that methods specifically designed for collinearity, such as latent variable methods and tree based models, did not outperform the traditional GLM and threshold-based pre-selection. Our results highlight the value of GLM in combination with penalised methods (particularly ridge) and threshold-based pre-selection when omitted variables are considered in the final interpretation. However, all approaches tested yielded degraded predictions under change in collinearity structure and the ‘ folk lore ’ -thresholds of correlation coefficients between predictor variables of |r| > 0.7 was an appropriate indicator for when collinearity begins to severely distort model estimation and subsequent prediction. The use of ecological understanding of the system in pre-analysis variable selection and the choice of the least sensitive statistical approaches reduce the problems of collinearity, but cannot ultimately solve them.

The origin of modern disjunct plant distributions in the Brazilian Highlands with strong floristic affinities to distant montane rainforests of isolated mountaintops in the northeast and northern Amazonia and the Guyana Shield remains unknown. We tested the hypothesis that these unexplained biogeographical patterns reflect former ecosystem rearrangements sustained by widespread plant migrations possibly due to climatic patterns that are very dissimilar from present-day conditions. To address this issue, we mapped the presence of the montane arboreal taxa Araucaria, Podocarpus, Drimys, Hedyosmum, Ilex, Myrsine, Symplocos, and Weinmannia, and cool-adapted plants in the families Myrtaceae, Ericaceae, and Arecaceae (palms) in 29 palynological records during Heinrich Stadial 1 Event, encompassing a latitudinal range of 30°S to 0°S. In addition, Principal Component Analysis and Species Distribution Modelling were used to represent past and modern habitat suitability for Podocarpus and Araucaria. The data reveals two long-distance patterns of plant migration connecting south/southeast to northeastern Brazil and Amazonia with a third short route extending from one of them. Their paleofloristic compositions suggest a climatic scenario of abundant rainfall and relative lower continental surface temperatures, possibly intensified by the effects of polar air incursions forming cold fronts into the Brazilian Highlands. Although these taxa are sensitive to changes in temperature, the combined pollen and speleothems proxy data indicate that this montane rainforest expansion during Heinrich Stadial 1 Event was triggered mainly by a less seasonal rainfall regime from the subtropics to the equatorial region.

Pritchard reviews several fiction books, including William Trevor's \"The Hill Bachelors,\" John Updike's \"Licks of Love: Short Stories and a Sequel,\" and Gore Vidal's \"The Golden Age.\"