Atrial fibrillation (AF) is the most common arrhythmia requiring medical treatment and has been associated with enhanced atrial fibrosis and heart failure (HF). Relaxin (RLX), an antifibrosis and antiinflammatory peptide hormone, may be used to evaluate atrial fibrosis and is associated with HF occurrence in AF. We aimed to clarify the clinical significance of RLX level in patients with AF.We measured circulating levels of RLX and other fibrosis-related factors in 311 patients with sinus rhythm  or AF (n = 195). All discharged AF patients were followed up for the occurrence of HF for a mean of 6 months.P < 0.001), and in the subgroup analysis of AF. RLX level was correlated with left atrial diameter . Among followed up AF patients, on Kaplan–Meier curve analysis, patients with the third RLX tertile (T3) had a significantly higher HF rate than those with the 1st tertile (T1) (P = 0.002) and the cut-off value was 294.8 ng/L (area under the ROC curve [AUC] = 0.723). On multivariable analysis, HF occurrence with AF was associated with increased tertile of serum RLX level .Circulating levels of RLX were significantly different in patients with AF as compared with SR (RLX is associated with fibrosis-related biomarkers and significantly elevated in AF. RLX was related to the HF occurrence in patients with AF. Among the most consistently described of these structural abnormalities is atrial fibrosis.3Atrial fibrillation (AF), associated with mortality, morbidity, and high health care costs, affects millions of people worldwide and is increasing in prevalence.4 Atrial fibrosis is associated with AF in both animal models5 and humans.8 Most studies have involved in vitro tissue or explanted tissue, with little translation to the clinic. Delayed enhancement magnetic resonance imaging as a semiquantitative method of quantification has shown promise, but quantifying and relieving atrial fibrosis in AF remains limited.9Atrial fibrosis represents collagen and extracellular matrix deposition within the atria, often resulting in heterogenous conduction and impaired contraction.10 Several risk factors common to both include age, hypertension, valve disease, and myocardial infarction as well as various medical conditions and genetic variants,11 but we lack an exact predictor of HF in AF.AF and congestive heart failure (HF) are commonly encountered together, and either condition predisposes the patient to the other condition. Congestive HF and AF share common mechanisms, including myocardial fibrosis and inflammatory response.12 which results in reduced fibrosis. Some animal experiments have demonstrated that RLX could inhibit both the proliferation of cardiac fibroblasts and the synthesis of collagen.13 Furthermore, RLX has been investigated as treatment for HF in clinical trials and found to have good safety and tolerability in recent investigations.14Relaxin (RLX), as a naturally occurring human hormone, can downregulate the deposition of collagen and other extracellular matrix proteins. A number of downstream pathological processes are involved, including reduced expression of transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α), and increased activity of matrix metalloproteinases (MMP),We speculated that RLX might have a key role in reflecting atrial fibrosis in AF and hypothesized that RLX level is related to HF occurrence in AF. Here, we measured levels of RLX and related indicators in patients with sinus rhythm (SR) and AF to understand the changes in levels of these proteins in AF and the clinical significance of RLX in patients with AF.We included totally 311 consecutive patients with SR (n = 116) or AF (n = 195) from the first affiliated hospital of Wenzhou Medical University. Patients were assigned to the “SR group” provided that their basic rhythm was SR without antiarrhythmic therapy and there was no evidence for AF in previous medical documentation or in electrocardiography, dynamic electrocardiography, or cardiac telemetry system results during hospitalization. Patients were assigned to the “AF group” based on previous medical documentation and electrocardiography, dynamic electrocardiography, or cardiac telemetry system results performed during hospitalization. Converting AF to SR in 7 days indicated a diagnosis of paroxysmal AF (PaAF); otherwise, duration >7 days indicated a diagnosis of persistent AF (PeAF). Key exclusion criteria were severe HF needing dialysis or rescue breathing machine, hemodynamic instability and myocardial infarction of Killip 3–4 needing a breathing machine or intraaortic balloon pump support, because these acute exacerbation states may influence the levels of biomarkers. All discharged AF patients were followed up for 5 to 7 months to identify the occurrence of HF. Each AF and HF episode were blindly adjudicated by a validation committee referring to Guidelines for the Management of Atrial Fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC) and ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012.15 Fibrotic, antifibrotic, and inflammatory markers measured included RLX, TGF-β, TNF-α, MMP-2, and procollagen type I C-terminal peptide (PICP), released from the synthetic process of collagen I.At baseline, patients completed a standardized questionnaire to assess risk factors, including age, sex, duration of AF, smoking, alcohol intake, hypertension, diabetes, and myocardial infarction. Physical examination included blood pressure, heart rate, body mass index, and resting electrocardiography. Laboratory measurements included levels of serum creatinine, transaminase, low-density lipoprotein cholesterol, fasting blood glucose, C-reactive protein, and brain natriuretic peptide (BNP), which was measured by a chemiluminescence method, and D-dimer measured by the immunoturbidimetric method. Ultrasonic cardiography measurements included left ventricular ejection fraction, left atrial diameter (LAD), left ventricular end-diastolic diameter, pulmonary arterial pressure, and cardiac output. In our study, we used the M mode to measure the anteroposterior diameter of the left atrium as LAD in the parasternal long-axis view perpendicular to the aortic root long axis by independent team of echocardiography according to the Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.This study was reviewed and approved by the Ethics Review Board of the First Affiliated Hospital of Wenzhou Medical University. We obtained written informed consent from all the participants in this study.Blood was taken from the peripheral vein on the 2nd day morning of hospitalization with patients in a stable state. Serum was extracted and stored at −80 °C. Samples were analyzed when 90 samples were accumulated or storage time reached 1 month. RLX, MMP-2, TGF-β, TNF-α, and PICP levels were measured by enzyme-linked immunosorbent assay kits . The sensitivity (lower detection limit) for assays was for RLX, 10 ng/L; MMP-2, 2 ng/mL; TGF-β, 10 ng/L; TNF-α, 3ng/L; and PICP, 2 ng/mL. All samples were run in duplicate and measured at 450λ. Other biochemical measurements were performed at the laboratory of the hospital.P < 0.05 was considered statistically significant.SPSS20.0  was used for statistical analysis. Continuous variables are presented as mean ± SD, and categorical variables as frequencies and percentages. Continuous variables were compared by 1-way ANOVA; the Student–Newman–Keuls test was used for analyzing intergroup differences and the Chi-square test for categorical variables. Correlations between 2 parameters were assessed by simple linear regression. Receiver operating characteristic (ROC) curves were used to assess the clinical application for RLX. The proportion of patients free of HF in AF was plotted by the Kaplan–Meier method, with statistical significance examined by the log-rank test. Predictors of AF occurrence were examined by univariate and multivariable logistic regression analysis. Two-sided P < 0.001) and duration of AF was longer for PeAF than PaAF patients (P = 0.006). LAD was greater for PeAF than other patients (P < 0.001). There were no significant differences among 3 groups in other characteristics.A total of 311 patients (age 39–91 years) were studied. The included patients had SR (n = 116), PaAF (n = 80), and PeAF (n = 115). The baseline subject characteristics are in Table P < 0.001) (Table P < 0.001), TNF-α (P < 0.001), TGF-β (P < 0.001), PICP (P < 0.001), and reduced MMP-2 activity (P = 0.001). Level of RLX (P < 0.001), TNF-α (P = 0.004), TGF-β (P = 0.001), and PICP (P = 0.047) was higher and MMP-2 (P = 0.001) was lower for PaAF than SR patients. The level of RLX, TNF-α, and PICP in PaAF patients was in the middle of that for SR and PeAF patients.Levels of fibrosis-related biomarkers  significantly differed among the 3 groups P < 0.00 , TGF-β , and PICP . Serum RLX level was not correlated with MMP-2 level . We assessed whether RLX was correlated with the level of BNP, with log base-e transformation for BNP (lnBNP) because it did not exhibit a normal distribution. lnBNP level was correlated with levels of RLX .We investigated a connection between circulating levels of RLX and other fibrosis-related biomarkers in Figure R = 0.358, P < 0.001) in Figure R = 0.083, P = 0.159).We examined whether left atrial dilatation was associated with upregulation of RLX. We established a significant positive linear correlation between RLX level and elevated LAD . On post hoc analysis, the difference in HF rate between T1 and T3 patients was significant .Next, we examined whether serum RLX can be used to early predict HF occurrence in AF. For mean follow-up period was 6 months range 5–7 months). Forty-three cases occurred HF in AF patients. We divided AF patients into 3 groups according to the trisection of AF RLX concentration: 1st tertile , 2nd tertile , and 3rd tertile . In T1, T2, and T3, the HF occurred respectively 6 cases, 13 cases, and 24 cases. The mean RLX level was 177.42 ± 22.92, 266.59 ± 20.53, and 348.37 ± 24.31 ng/mL, respectively. Figure –7 monthsP < 0.001), PeAF , and increased tertile of serum RLX level  (Table P = 0.004) and increased tertile of serum RLX level .On univariate analysis, the occurrence of HF was associated with increased LAD  were related to AF structural processes. Therefore, they considered microRNAs, as an AF biomarkers, may differentiate responders versus nonresponders to an ablative approach. All these studies highlight the association between atrial fibrosis and AF. Thus, attenuating atrial fibrosis may be a plausible approach to treating AF.3 However, detection of atrial fibrosis remains a challenge. In our study, we used PICP, a peptide released with synthetic process of collagen I, which constitutes more than 80% of the myocardial interstitium,25 as a biomarker of atrial fibrosis. In this study the serum PICP level increased, which supported the mechanism of AF. Previous research also supports increased serum PICP levels positively associated with the development of AF.7AF is the most common arrhythmia and recently has been found associated with an increased risk of silent cerebral infarct, stroke, and autonomic dysfunction in type 2 diabetes.26 In rat models of hypertension and diabetic cardiomyopathy, RLX significantly inhibited TGF-β-mediated collagen production and cardiac fibrosis.28 Meanwhile, RLX has been found to promote MMP expression and activity, while inhibiting the actions of tissue inhibitors of MMP to induce collagen breakdown.29 It also decreased the release of TNF-α in response to an adjuvant and endotoxin.31 In this study, we found that in patients with PeAF, the levels of RLX, TNF-α, TGF-β, and PICP were upregulated and the level of MMP-2 was downregulated, and TNF-α, TGF-β, and PICP levels were positive correlative with RLX. These shown that the RLX was closely related with fibrosis. In chronic HF patients, a research confirmed that plasma H2RLX increased even significant correlation with collagen.32 Although the own secretion of RLX might insufficient to modify extracellular matrix deposition and turnover the synthesis and deposition of collagen. Therefore, exogenous application of RLX may relieve fibrosis. In the present study, recombinant human RLX was used to inhibit both the proliferation of cardiac fibroblasts and the synthesis of collagen under the high glucose condition in vitro.33 Moreover, RELAX-AHF study had discovered serelaxin was associated with improvement in several acute HF clinical outcomes and proved its security in acute HF.35RLX as an endogenously reproductive hormone that has extracellular matrix remodeling effects, potent antifibrotic activity, and other cardio-protective actions.36 Various causes result in atrial dilatation finally might raise the secretion of RLX, meanwhile upregulated the serum of BNP. Although atrial remodeling was the most common phenomenon of atrial fibrillation. RLX level was elevated in larger LAD, which may suggest that RLX was associated with the progression of LAD in AF.Whether the elevated level of RLX in patients with AF was associated with dilatation of atria remains unknown. This study revealed that RLX level was proportional to LAD and lnBNP in AF, which similar to the research of Dschietzig et al in congestive HF.10 In addition, the abnormal hemodynamics of AF, including long-term elevated heart rate, increased atrial filling pressure, invalid atrial contraction, and the lack of synchrony in atrioventricular contraction, will impair ventricular function and contribute to symptoms of congestive HF.37 Nevertheless, our ability to early predict HF occurrence in AF remains limited. However, we found an association of increased RLX level and increased rate of occurrence HF in AF. LAD was also an independent risk factor of HF occurrence in AF.From recent findings, AF and HF are interdependently relationship. Patients with one of the disorder will increase the risk of another illness. When the AF and HF occur together rather than either alone will carry an observably worse prognosis.There are some limitations to this study. First, we did not distinguish atrial fibrosis and ventricular fibrosis, so the PICP results should be interpreted with caution. Second, blood specimens were collected only once during hospitalization, so we unable to provide the daily variability and changes in RLX levels after discharge. Still some other confounders of RLX cannot be excluded. Finally, in this study, we discovered the mean heart rate was greater for PeAF than SR patients. However, we need more data to realize the relationship between heart rate variability and HF recurrence. Hence, in our further study, we will observe heart rate variability. Further studies will be needed to fully characterize the panoply of the actions of RLXIn conclusion, RLX is associated with fibrosis-related biomarkers. Serum RLX level differed among 3 groups of patients  and arose with the development of AF. PICP and LAD were positively associated with RLX level. High RLX level, as well as LAD, was correlated with occurrence of HF in AF. Although research into the fundamentals of structural remodeling has not been exhausted, the use of biomarkers involved in atrial fibrosis may be a promising new approach.


N = 106; M(SD)age = 23.9(3.2) years; 68% women) show a stable AB towards multiple categories of threatening information using the emotional visual dot probe task. AB with respect to five categories of threat stimuli  was evaluated. In contrast with current theories, we found that 34% of participants expressed AB towards threat stimuli, 20.8% AB away from threat stimuli, and 34% AB towards some categories of threat stimuli and away from others. The multiple observed expressions of AB were not an artifact of a specific criterion AB score cut-off; not specific to certain categories of threat stimuli; not an artifact of differences in within-subject variability in reaction time; nor accounted for by individual differences in anxiety-related variables. Findings are conceptualized as reflecting the understudied dynamics of AB expression, with implications for AB measurement and quantification, etiology, relations, and intervention research.The aim of the present study was to question untested assumptions about the nature of the expression of Attentional Bias (AB) towards and away from threat stimuli. We tested the idea that high trait anxious individuals ( However, the degree to which AB is indeed a stable phenomenon that is expressed similarly with respect to different classes of threatening stimuli has received limited empirical study. Relatedly, extant study of AB has presumed that a person may exhibit either AB towards or AB away from threatening stimuli, in a mutually exclusive manner It has been theorized that high trait anxious individuals demonstrate a stable tendency to express AB towards threatening stimuli at the early stages of information-processing In the present study, we propose that the expression of AB to threat could be more complex than has been recognized by current theories and AB away from one or multiple other threat categories . To simplify subsequent communication regarding this prediction in the manuscript, we termed the prediction that different individuals could express different patterns of AB the Multiple Expressions of Attentional Bias Hypothesis (MEAB).We therefore sought to examine different possible patterns of AB in high trait anxious individuals where individuals could show: (a) No AB, (b) AB towards one or multiple categories of threat stimuli, (c) AB away from one or multiple categories of threat, and (d) AB towards one or multiple threat categories  towards); and vice-versa when selective attention is allocated away from the motivationally-relevant stimulus . Third, various stimulus durations of threat have been used in this task in past research . To rigorously test the MEAB hypothesis, we measured AB using a 500 ms stimulus duration that has been: (a) most extensively studied Several methodological choices that guided the present study are noteworthy. First, trait anxiety, as a function of the Spielberger Trait-state Anxiety Inventory (STAI) age = 23.9(3.2) years-old, rangeage 18–37; 67.9% female) were recruited from a university community in Israel. The identified STAI cut-off reflecting elevated trait anxiety is based on a local (Israeli) norm reflecting 1SD<STAI mean among a treatment-seeking (mood/anxiety disorders) clinical population (N = 275) and 1SD>STAI mean among healthy control participants (N = 534) One-hundred-six trait anxious (State- Trait- Anxiety Inventory (STAI)-Trait Anxiety scores >42; STAIOverall Anxiety Severity and Impairment ScaleInventory of Depression and Anxiety Symptoms (IDAS) Anxiety Sensitivity Index-3 (ASI-3) Measures were translated from English to Hebrew and then back-translated by a separate party using structured guidelines The visual emotional dot probe task Potential participants completed the trait anxiety section of the STAI. The identified sub-sample of high-anxious participants completed an online battery of self-report measures (see above) and then attended a single laboratory session. Participants were told that task instructions would be delivered via instructions on the computer monitor throughout the experiment. Participants then completed the emotional visual dot probe task to measure levels of AB to threat. This task consisted of 15 practice trials and 160 test trials. Participants were debriefed and compensated via course credit or a small payment.not threatening at all to 5 = extremely threatening) and to what degree  a list of emotions were experienced upon viewing a picture  by subtracting Mean Response Time (RT) of congruent threat trials from Mean RT of incongruent threat trials and BS<25 ms). We identified this initial 25 ms criterion cut-off value for a number of reasons: (1) first and foremost, this is a conservative operational definition of AB as few AB researchers are likely to question whether BS scores greater than that criterion value likely reflect no AB; (2) AB bias scores as small as 10 ms are regularly interpreted as evidence of AB and away from different threat categories artifactually, due to the selected cut-off (see Results below for details); furthermore, as illustrated in We first classified each participant’s BS, per threat category, as reflective of either no AB, AB towards, or AB away. To do so, we operationalized a conservative criterion value to classify attentional responding to threat stimuli as evidence of AB. Specifically, we preliminarily defined BS>25 ms as the criterion for AB towards and BS<−25 ms as the criterion for AB away, per threat category  = 2.9 (3.2) outlier trials/participant,  and error-response trials errors = 0.7(1.1), <1% of trials) were discarded, based on a priori criteria for valid trial selection RT outliers  >3.8, p<.001); violence was perceived as more threatening than weapons (t(19) = 2.2, p = .04); and no other significant differences were found between weapons, attacking snakes, or attacking dogs in terms of perceived threat (t(19) <1.3, n.s). Furthermore, as expected, overall the threatening stimuli were rated as significantly more threatening than emotionally-neutral stimuli (t(19) = 11.5, p<.001). Additionally, threatening stimuli were rated as eliciting significantly elevated levels of anxiety relative to all other negatively-valenced emotions including sadness, anger, disgust, guilt, and embarrassment (t(19) = 8.88, p<.001) and positively-valenced emotions including, interest, joy, amusement, love, and cheerfulness (t(19) = 10.17, p<.001).Prior to testing AB to threat stimuli, it is important to explore differences between threat categories with respect to their perceived level of threat. t(105) = 4.25, p<.001, Cohen’s d = .41). Sample-level bias was then similarly tested by threat category; significant bias towards each threat category, with exception of threatening dogs was observed (MDogs = 2.5(30.3), t(105) = .85, n.s; MFaces = 8.1(33.1), t(105) = 2.5, p = .01, Cohen’s d = .24; MSnakes = 7.1(32.0), t(105) = 2.28, p = .03, Cohen’s d = .22; MWeapon = 6.9(29.2), t(105) = 2.4, p = .02, Cohen’s d = .24; MViolence = 7.9(33.5), t(105) = 2.42, p<.02, Cohen’s d = .24).First, in line with traditional computation of sample-level AB, we tested the direction, magnitude and statistical significance of AB. Sample-level mean(SD) AB = 6.5(15.7) ms towards threat, across all categories of threat stimuli, was significantly larger than 0 . b) 20.8% of participants demonstrated AB away from one or more threat categories (BS<–25 ms), and in all other categories demonstrated BS<25 ms and BS>–25 ms (“AB away from threat only”). c) 34% of participants demonstrated AB towards one or more threat categories (BS>25 ms) and concurrently AB away from one or more other threat categories (BS<–25 ms) (“AB towards and away from threat”). d) 11.2% of participants demonstrated neither AB towards nor away from any category of threat stimuli (BS<25 ms and >–25 vms) (“No AB”). See We then tested the MEAB hypothesis in these data. Based on the AB>25 ms and AB<–25 ms criterion cut-offs, participants expressed the following patterns of AB: a) 34% of participants demonstrated AB towards one or more threat categories (BS>25 ms), and in all other categories demonstrated BS<25 ms and BS>–25 ms  of threat. Third, we rule out that AB towards and away from different categories of threat concurrently was a methodological artifact of greater within-subject variability in RT, relative to participants demonstrating AB towards threat only or AB away from threat only. No significant differences were found between the mean SD of the RTs in categories wherein AB towards was expressed between participants demonstrating AB towards & away (M(SD) = 115(68.2)) and those demonstrating AB towards only (M(SD) = 94.3(67.8) t(57) = 1.2, n.s); nor differences between the mean SD of the RTs in categories wherein AB away was expressed between participants demonstrating AB towards & away (M(SD) = 78.6(32)) and those demonstrating AB away only (M(SD) = 66.8(28.6) t(47) = 1.3, n.s).Three additional analyses were designed to test and thereby rule-out alternative explanations of the observed expressions of AB. First, we rule out that the observed expressions of AB are a by-product of the specific criterion cut-off selected  = 1.16, n.s). Furthermore, the number of participants demonstrating clinical levels of anxiety  relative to participants with AB towards only .See N = 16/36); within the Away only sub-group 31.8% were men (N = 7/22); and within the AB towards and away sub-group 22.2% were men (N = 8/36). These differences did not reach statistical significance  though this analysis was likely underpowered.Recent work has shown gender differences in levels of AB either AB towards or AB away from threatening stimuli The current study tested two central yet untested assumptions of the literature on attentional bias to threat. First, theories of attention to threat propose that high trait anxious individuals should demonstrate AB for multiple categories of threatening information and AB away from other categories of threat stimuli; and 11.2% demonstrated no AB to threat. We then empirically tested and ruled out alternative explanations of the observed multiple expressions of AB phenomenon(a). We found that the observed multiple expressions of AB are not due to a specific criterion BS cut-off operationally defining AB, not specific to certain types of threat stimuli, nor an artifact of differences in within-subject variability in RT. Finally, we observed no significant differences in anxiety-related variables between participants who demonstrated each of the observed expressions of AB; accordingly, those expressing AB towards some and away from other categories of threat stimuli do not appear to exhibit lower risk for problems with anxiety relative to those demonstrating AB towards or away only.We observed an overall AB towards threat in high trait anxious individuals in line with previous studies bi-dimensional ratio scale is a more appropriate scale for a construct for which zero reflects the absolute lack of the phenomenon(a) (true zero = no AB), and for which high positive scores reflect high AB (bias towards) and high negative scores also reflect high AB (bias away). For example, it cannot be argued that +5 ms reflects more AB than −20 ms. Though in studies wherein a uni-dimensional interval scale with an arbitrary value of 0 and single sample-level mean are used to measure and study AB, this is what was done . Finally, because we observed that for each of the 5 studied categories of threat stimuli  some participants demonstrated AB towards and others away  with an arbitrary value of 0 and single sample-level mean estimate of AB  may not provide a valid representation of the nature nor levels of AB within a sample and intended population. Indeed, computing a sample-level mean of AB, by collapsing across sub-groups of individuals who demonstrate conflicting patterns of AB – some towards and others away from threat – forces a single interval scale with an arbitrary zero on a phenomenon(a) with a bi-dimensional ratio scale and a non-arbitrary or true zero. Thus, a ers away –4, the aand away from different threat stimuli may also have implications for the study of AB. The computation of AB which presumes that AB may be expressed as either towards only or away could result in potentially significant mis-estimation of AB. For example, participants exhibiting AB towards one category of threat  and away from another category of threat  may, across categories of threat, be assigned an attenuated or near-zero AB score. Based on the present findings, we may infer that investigations which have operationalized threat by means of multiple types of stimuli  may mis-classify ∼1/3 of the sample with respect to AB and consequently mis-estimate levels for AB for the sample as a whole. Accordingly, we propose that investigations of AB that include multiple threat stimuli compute one AB score per “category” of threat stimuli, each on a bi-dimensional ratio scale of AB  with a true zero. Furthermore, investigations of AB that include only a single category of threat  may need to consider the likelihood that observed AB towards only or away only may be a result of censored observations regarding other categories of threat which were not tested; indeed, were multiple threat categories tested, a substantive proportion of participants exhibiting either AB towards or away from a single category of threat stimuli may in fact demonstrate AB towards certain categories of threat stimuli and away from others. Accordingly, one possible implication of the present findings is that, in contrast to the majority of studies of AB, future investigations may benefit by inclusion of multiple categories of threat stimuli.Second, observing that a significant proportion of trait anxious participants demonstrated AB towards The present findings also highlight the potential significance of future research focused on the mechanisms underlying anxiety-related attentional bias. The observed pattern of variability in AB to threat in high anxious individuals is not in line with an oversensitive threat appraisal system non-discriminantly responding to multiple classes of threat. The current findings suggests that specific learning history  The present study has a number of limitations that qualify interpretation of the findings and may inform future research. First, a large probability-sample would provide more precise estimates of the prevalence of the observed multiple expressions of AB as well as a more representative sample of high-anxious adults, only estimated by the present university sample. Second, it is important that future work test the specificity/generalizability of these findings in non-anxious samples. Third, relatedly, the present findings beg the question regarding the MEAB hypotheses with respect to other forms of attentional bias and stimuli such as negative/positive emotion and away concurrently to different categories of threat stimuli. To permit valid estimation of the observed multiple expressions of AB, we propose the field explore the implications of adopting a conceptual and operational bi-dimensional ratio scale of AB in contrast to the extant uni-dimensional interval scale. We hope that the proposed empirically-grounded model of the expressions of AB to threat will contribute to understanding the nature of AB, and perhaps ultimately, help advance our knowledge of the phenomenon(a), its etiology, correlates, outcomes and interventions.In summary, we found evidence consistent with the proposed Multiple Expressions of Attentional Bias Hypothesis (MEAB) – some trait anxious persons express AB towards threat and not away, others away from threat and not towards, yet others express AB towards


Under well-watered conditions leaf hydraulic conductance increases with transpiration rate. This reduces the water potential gradient in leaves and potentially improves productivity under daily variation in evaporative demand. kleaf) is a central element in the regulation of leaf water balance but the properties of kleaf remain uncertain. Here, the evidence for the following two models for kleaf in well-hydrated plants is evaluated: (i) kleaf is constant or (ii) kleaf increases as transpiration rate (E) increases. The difference between stem and leaf water potential (ΔΨstem–leaf), stomatal conductance (gs), kleaf, and E over a diurnal cycle for three angiosperm and gymnosperm tree species growing in a common garden, and for Helianthus annuus plants grown under sub-ambient, ambient, and elevated atmospheric CO2 concentration were evaluated. Results show that for well-watered plants kleaf is positively dependent on E. Here, this property is termed the dynamic conductance, kleaf(E), which incorporates the inherent kleaf at zero E, which is distinguished as the static conductance, kleaf(0). Growth under different CO2 concentrations maintained the same relationship between kleaf and E, resulting in similar kleaf(0), while operating along different regions of the curve owing to the influence of CO2 on gs. The positive relationship between kleaf and E minimized variation in ΔΨstem–leaf. This enables leaves to minimize variation in Ψleaf and maximize gs and CO2 assimilation rate over the diurnal course of evaporative demand.Leaf hydraulic conductance ( As E increases, kleaf may stay relatively constant, with Ψleaf decreasing until a threshold is reached that results in the formation of xylem emboli, followed by a rapid decline in kleaf with any further decrease in Ψleaf  and E  increases with E which, via the hydraulic feedback loop, tends to reduce gs and CO2 assimilation rate .Although stomata and the leaf hydraulic network control two distinct phases of water transport across the soil–plant–atmosphere continuum (i.e. vapour and liquid flux), coordination between these two regulatory systems must exist if leaves are to maintain physiologically favourable water contents and avoid desiccation while maximizing carbon gain. If the goal is to maximize carbon gain, then leaves need to keep stomata open over a broad diurnal range of evaporative demand. The problem for any leaf with fixed stem–leaf  constant kleaf, versus (ii) increasing kleaf as E increases.Isohydrodynamic behaviour has been shown for whole-plant hydraulic conductance (tem–leaf  suggest Acer macrophyllum Pursh (Aceraceae), Populus fremontii Watson , and Quercus kelloggii Newberry (Fagaceae), and three gymnosperms, Metasequoia glyptosrtoboides Hu and Cheng (Cupressaceae), Pinus ponderosa P. Laws (Pinaceae), and Sequoia sempervirens D. Don (Cupressaceae). Four or five saplings of each species were grown from seed in 40 l pots and transferred to a single site (common garden), in full sun, on a ridge top at the University of California Botanical Garden  between 1–7 March 2007. Individual saplings from each species were randomized spatially throughout the common garden. Saplings ranged from ~1.5–2.5 m in height. Plants were kept well watered using drip irrigation. Data were collected when leaves were fully expanded, ~1 month after the start of leaf emergence, which occurred in late May/early June of 2008 and 2009 for A. macrophyllum, M. glyptostroboides, P. fremontii, and Q. kelloggii and mid to late July for P. ponderosa, and S. sempervirens. Air temperature and relative humidity were measured with a Li-1600 steady-state porometer  in close proximity to the leaves in which gas exchange and water potential were measured. Photosynthetically active radiation intercepted by the adaxial surface of the leaf was measured with a quantum sensor .Four deciduous and two evergreen temperate forest tree species were evaluated; three angiosperms, kleaf; mmol m–2 s–1 MPa–1) for sun-exposed leaves was measured on four to five individuals of each species using the in situ evaporative flux method (in situ EFM), with kleaf calculated as , and ΔΨstem–leaf is the difference between stem xylem water potential  and leaf water potential . This in situ technique required sampling two adjacent leaves, one of which was used to measure Ψstem whereas the adjacent leaf was sampled for E and Ψleaf. Leaves used as an assay for Ψstem were covered in plastic film and aluminium foil on the evening before the measurement period to ensure equilibration between the covered Ψleaf and Ψstem. Transpiration rate (E) was measured with the Li-1600 porometer. Owing to the open crown structure of the saplings, the wide spacing between trees, and the windy ridge top exposure of the common garden, it was assumed that leaf boundary layer conductance (gb) was much greater than gs. Additionally, during each measurement of E, leaf orientation, ambient humidity, and radiation interception was conserved. Therefore, E measured by the Li-1600 was likely to be similar to the actual E immediately before the measurement. While measuring E, the water potential of the adjacent covered leaf was sampled as a proxy for Ψstem. Immediately following determination of E, the uncovered leaf was excised, wrapped in plastic, and placed in a Scholander-type pressure chamber for determination of Ψleaf . Balancing pressure was recorded when xylem sap reached the cut stem surface, as verified by a dissecting scope at ×25 magnification. E, Ψstem, and Ψleaf were measured every ~2.5h over the course of a 14–18h period, beginning at pre-dawn (0400–0500h). Regression analysis was used to evaluate the co-variation between ΔΨstem–leaf, E, gs, and kleaf over a diurnal cycle of evaporative demand. Regression analyses were performed using SigmaPlot .where stem–leaf, E, gs, A, and kleaf were measured at two light levels (509±11.5 and 1310±26.4 µmol m–2 s–1) for Helianthus annuus plants grown under sub-ambient (194±35 ppm), ambient (450±46 ppm), and elevated CO2 (1027±74 ppm). H. annuus plants were grown in growth chambers located in the Controlled Environment Facility at the Center for Carbon, Water, and Food at the University of Sydney. Ten plants were grown under each CO2 concentration at 900±50 µmol m–2 s–1 of photosynthetically active radiation (PAR). Ambient CO2 concentrations were monitored using an isotope ratio infrared spectrometer  that cycled through each room every 10min. Using the method outlined above, gs and E were measured with a portable photosynthesis system fitted with a large leaf cuvette that enclosed the entire leaf . Water potential was measured using a Scholander-style pressure chamber  and kleaf was calculated from Eqn 1. Measurements were taken after the leaves were in the cuvette for ~40min during stable gs, E, A, and Tleaf. After the 40min period leaves were cut from the stem, removed from the cuvette, and covered in plastic for water potential measurements with the Scholander-style pressure chamber as described above. Projected leaf area was measured digitally using the software program Image J . Two leaves were used as an assay for Ψstem using the method outlined above. Leaves directly above and below the leaf in the cuvette were selected and the average of the two water potential measurements was taken as Ψstem. In all cases the distal leaf showed a slightly more negative Ψstem, ~0.02–0.04MPa. Measurements of Ψleaf, E, gs, A, and kleaf were made at 450 ppm CO2 inside the cuvette at two light levels, ~500 and 1300 µmol m–2 s–1 PAR, and a relatively constant leaf temperature of 24.7±0.2 °C by varying air temperature and ambient humidity inside the cuvette. In total, five leaves from each CO2 growth environment were measured at each light level (~500 and 1300 µmol m–2 s–1 PAR), all at 450 ppm CO2. All statistical analyses were performed using SigmaPlot and JMP . ANCOVA was used to test for main and interactive effects of growth CO2 , light , and VPD on gs and A. An ANCOVA was also used to test for main and interactive effects of CO2 , light , and E (covariate) on kleaf. Because measurements within the light treatment were done on the same plant, plants nested within the light treatment were used as a random factor . Assumptions of normality were met.ΔΨin situ EFM technique to measure kleaf requires an evaporative flux and a water potential drawdown which in turn prevents direct calculation of kleaf when E=0. However, theory predicts that when E=0, kleaf will have some finite value. By measuring kleaf across a broad range of E a linear model can be used to extrapolate to kleaf at zero E ). Linear regression was used to estimate kleaf(0) for both gymnosperm and angiosperm trees from the common garden and H. annuus plants from the growth chamber experiment.As shown by Eqn 1, using the stem–leaf and E for both the gymnosperm , with angiosperms attaining higher overall ΔΨstem–leaf and E (stem–leaf and E was the result of a strong coupling between kleaf and E (kleaf and E across the gymnosperm and angiosperm species from the common garden (y-intercept of the linear model describing the co-variation between kleaf and E was greater than 0 (E=0 (kleaf(0)), varied greatly between angiosperm and gymnosperm species (kleaf(0) (kleaf(0) was associated with greater maximum daytime gs, kleaf, and lower dkleaf/dE  ; Table 1leaf/dE ; Table 1gs, E, Ψleaf, Ψstem, and kleaf were observed for the angiosperm and gymnosperm species grown in the common garden. In general, from dawn to midday, Ψleaf and Ψstem decreased while gs, E, and kleaf increased . After midday, Ψleaf and Ψstem increased slightly, whereas gs, E, and kleaf decreased . Overall, plants in the common garden were well hydrated, with Ψstem and Ψleaf greater than –0.8 and –1.2MPa, respectively. The diurnal changes in Ψleaf and Ψstem followed a similar pattern such that ΔΨstem-leaf changed very little over the course of a day . On average the angiosperm species showed greater diurnal variation in gs, E, and kleaf compared with the gymnosperm species .Qualitatively similar diurnal trends in 2 treatments a similar range of E, VPD, A, Tleaf, and gs, occurred at each light level  followed by VPD  and CO2  with no significant interaction between PAR, CO2, and VPD. Across CO2 treatments, increases in PAR were associated with greater gs  but were not statistically different from plants grown under ambient CO2 . Although VPD showed a significant main effect on gs, correlations between gs and VPD within each CO2 treatment were not significantly different, which was probably due to the small range of VPD and limited number of measurements at different VPD (n=5) at a given light level. Both PAR  and CO2  significantly influenced variation in A. Across treatments, increasing PAR had a positive effect on A . Similar to gs, when measured at the same atmospheric CO2 concentration (450 ppm), plants from the sub-ambient CO2 treatment showed higher A than plants from the elevated CO2 treatment  but were not statistically different from the ambient CO2 treatment . Using an ANCOVA to test for main and interactive effects of CO2, light, and E on kleaf, it was found that E had the only significant effect on kleaf .Across all three COht level –E. Overa2 treatments an increase in E was associated with a decrease in Ψleaf, although the decreases in Ψleaf were relatively minor despite relatively large variation in E . This was the result of a significant positive relationship between kleaf and E across all three CO2 treatments  was not significantly influenced by growth CO2 , r2=0.23, P=0.009; kleaf/A vs. VPD: y=0.4837×e(0.4634×VPD), r2=0.30, P=0.002).Across all COion in E . Similarowth CO2 . Similarkleaf model, under well-watered conditions, and instead are consistent with a hydraulic mechanism whereby kleaf increases with E. Additionally, here it is shown that a positive dependence of kleaf on E results in a dynamic coupling between kleaf and gs that ultimately minimizes the water potential drawdown across the leaf (i.e. ΔΨstem–leaf) which, via the hydraulic feedback loop, increases the maximum potential gs and A for a given VPD  and boundary layer conductance (gb) to water vapour in series, wi and wa are the mole fractions of water vapour (mol mol–1) inside the leaf and of the ambient atmosphere, ei and ea are the vapour pressures of water inside the leaf and in ambient air, and P is atmospheric pressure. The term (ei–ea)/P is commonly referred to as ‘VPD’. According to this steady-state description, when gs<<gb, up- or down-regulation of E via feedback responses of stomata to VPD can occur via changes in ΔΨstem–leaf, kleaf, or both.where kleaf is static or only decreases as E increases then changes in gs and E, before water-stressed-induced xylem embolism, would require large changes in ΔΨstem–leaf and ultimately a positive linear correlation between ΔΨstem–leaf and g(wi – wa) or E /ΔΨleaf remains constant. Eventually, increases in g(wi–wa) may lower leaf water potential sufficiently to induce cavitation and embolisms, reducing kleaf and resulting in a positive feedback on ΔΨstem–leaf (g(wi–wa)/ΔΨleaf is negatively correlated with E. Because increasing ΔΨstem–leaf reduces maximum potential g and by extension CO2 assimilation rate (kleaf constrains carbon gain to occur within a relatively narrow range of low evaporative demand and high water availability. One way to avoid large drops in Ψleaf and g over a broad range of evaporative demand is to vary kleaf positively with E. This dynamic coupling between E and kleaf is represented here by the term kleaf(E), which is the leaf hydraulic conductance for a given magnitude of E. Here, kleaf(E) represents the dynamic hydraulic conductance.If a) or E . From Eqtem–leaf . In thisg(wi–wa)/ΔΨleaf is constant or decreases with E. In fact the opposite relationship was observed: as E increased g(wi–wa)/ΔΨleaf increased (e.g. kleaf on E can lead to increasing g(wi–wa)/ΔΨleaf as E increases. Therefore, these results provide strong evidence that the relationship between kleaf, gs, and CO2 assimilation rate, in response to short-term changes in evaporative demand (VPD), is the result of a positive dependence of kleaf on E ) or static, it has a finite value when E=0, i.e. kleaf(0) (see Methods). Here it is shown that, for the well-watered gymnosperm and angiosperm tree species in the common garden, this inherent capacity to transport water is greater for the angiosperm species than the gymnosperms /ΔΨleaf increased as E increased. As with plants from the common garden experiment, this trend can be attributed to a positive correlation between kleaf and E which was relatively decoupled from variation in PAR  was relatively conserved between CO2 treatments  across sub-ambient, ambient, and elevated CO2 treatments despite a significant decrease in gs between sub-ambient and elevated CO2 is consistent with previous research. Across species, the sensitivity of maximum stomatal conductance (gs(max)) to variation in atmospheric CO2 (ca) seems to be strongly non-linear whereby the sensitivity of gs(max) to changes in ca increases at low ca  and kleaf(0) when exposed to elevated CO2, as shown here with the H. annuus plants. Similarly, recent research on soybean suggests that kleaf is relatively insensitive to elevated CO2 (700 ppm) despite decreases in gs at elevated CO2 +(dkleafdE×E))for a dynamic kleaf model compared with Ψleaf=Ψstem−(Ekleaf(0))for a static kleaf model. This damping of variation in Ψleaf as E changes is expected to reduce the sensitivity of gs to changes in VPD via the hydraulic feedback loop  is a good index of the sensitivity of leaf water status (i.e. Ψleaf) and gs to a change in E.Previous research has clearly demonstrated a hydromechanical basis for stomatal movement whereby changes in the maximum potential aperture of stomata and by extension eaf e.g.  This canack loop . In othegs, originally developed by stem–leaf/E, as E increases), the impact of a dynamic conductance (kleaf(E)), as compared with a static kleaf, on the sensitivity of gs to changes in VPD was evaluated. The model output suggests that, for well-hydrated plants with a fixed Ψstem, a positive dependence of kleaf on E reduces the sensitivity of gs to variation in VPD when compared with a constant kleaf , with kleaf(0) positively correlated with daytime maximum gs (dkleaf/dE and kleaf(0) observed here provide a mechanistic framework for evaluating empirical correlations between stomatal sensitivity to VPD and daytime operating gs under well-watered conditions at low VPD. Further research is needed to better characterize the coordination between kleaf(0), dkleaf/dE, maximum gs, and stomatal sensitivity to VPD across plants spanning a wide range in maximum potential gs.Using a hydromechanical model of t kleaf . Previouimum gs , C. Takekleaf and leaf gas exchange are strongly influenced by variation in leaf vein traits (e.g. kleaf(0)) it is unlikely that short-term increases in E and kleaf, when leaves are well-hydrated, are driven by up-regulation of xylem hydraulic conductance alone. Changes in the ion concentrations of stem xylem sap have been shown to significantly influence stem hydraulic conductance . For example, recent research suggests that vapour transport through the intercellular air spaces can account for a substantial amount of water transport between mesophyll cells and thus the hydraulic conductance of the extra-xylary component (E may shift the depth of the evaporation front within leaves (Clearly one of the missing pieces of the puzzle is the location of the site(s) of evaporation inside the leaf . It is domponent . Addition leaves  and altekleaf does not remain fixed or decrease as E increases, but rather increases with E. Here, this dynamic kleaf is referred to as kleaf(E), which incorporates the inherent kleaf at zero E, kleaf(0). This positive dependence of kleaf on E tends to minimize or reduce water potential gradients along the soil–plant–atmosphere continuum. Minimizing variation in ΔΨstem–leaf over a broad range of E (i.e. maintaining isohydrodynamic conditions), and therefore maximizing leaf water content (LWC), has many potential implications for whole plant carbon balance. It is well recognized that decreases in Ψleaf and LWC can increase stomatal and biochemical limitations to CO2 assimilation rate (A) and thus decrease potential A for given environmental conditions , stomatal conductance , stem and leaf water potential , leaf hydraulic conductance  and transpiration rate  for three angiosperm species growing in a common garden.Figure S2. Diurnal variation in photosynthetically active radiation , stomatal conducatance , stem and leaf water potential , leaf hydraulic conductance , and transpiration rate  for three gymnosperm species growing in a common garden.


The aim of this study was to determine the levels of leptin (Lep) and adiponectin (AdipoQ) in patients with gout and its relationship with joint inflammatory data and/or with metabolic syndrome (MetS) variables, during 1 year follow-up.U test, Fisher test, x2, ANOVA, Cochran Q, Pearson and Spearman correlation tests, as well as linear regression.Forty-one patients  with gout diagnosis, attending for the first time to a rheumatology department, were included. Evaluations were performed baseline, at 6 and 12 months. Variables included the following: demographic, clinical and laboratory data related to gout and associated diseases. Lep and AdipoQ determinations by the ELISA method were performed in frozen serum from each visit. The pharmacological and no-pharmacological treatment for gout and associated diseases was individualized for each patient according to published guidelines. Statistical analysis included Mann–Whitney P = 0.033]. Although not significant, also had higher Lep and lower AdipoQ levels . During follow-up, our patients had significant improvement in serum uric acid (sUA) levels and variables evaluating pain and joint swelling (P ≤ 0.05). Metabolic abnormalities tended to persist or even worsen during the monitoring period: significant increase in total cholesterol (P = 0.004), tendency to higher triglycerides (P = 0.883) and slight improvement in glycaemia (P = 0.052). Lep values increased significantly during follow-up (P = 0.001) while AdipoQ levels diminished slightly (P = 0.317). Neither Lep nor AdipoQ values showed important correlation (r > 0.5) with metabolic variables or joint swelling.In the baseline evaluation, 29.2% had MetS ; patients with MetS had higher C reactive protein (CRP) levels [34.1 ± 28.6 vs. 12.2 ± 11.2 mg/dL, This study suggests that in patients with gout, concentrations of Lep and AdipoQ are more in line with the metabolic state than with clinical disease activity. The sample size was no-probabilistic.This was a prospective cohort study (GRESGO (GRupo de EStudio de GOta) that includes patients with gout diagnosis (according to ACR and CGD criteria),The project was approved by the local ethics and research committees and in the baseline visit all patients signed an informed consent form.They were evaluated clinically by 1 of the participating rheumatologists  and received verbal and written information about gout and associated diseases.38The prescription in the baseline and subsequent visits included the following: lifestyle modifications: diet, exercise, and weight reduction, and pharmacological treatment including allopurinol or other urate-lowering drug (ULD), nonsteroidal antiinflammatory drugs (NSAID), steroids, colchicines, and treatment for associated diseases according to published recommendations for gout treatment.The visits were performed as frequent as the clinical status of each patient required, but all them attended at least to the baseline, 6 and 12 months visits. The evaluation included tender, swollen, and limited to motion joint count; the number of acute flares in the last 6 months, clinimetric evaluation .During the patient regular visit to the laboratory for biochemical determinations, 1 mL of serum was frozen at −70°C until adipocytokine determination. It was performed through indirect ELISA using a human anti-leptin antibody , human recombinant leptin , antiadiponectin antibodies , and human recombinant adiponectin (R&D Systems). All of the determinations were done in triplicate in the 3 evaluations and were reported as means and standard deviations.39 obesity (waist circumference ≥88 cm in women or ≥102 cm in men), dyslipidemia (high density lipoprotein-cholesterol (HDL-C) ≥40 mg/dL in men or ≥50 mg/dL in women, and triglycerides ≥150 mg/dL), hyperglycemia defined as fasting glucose ≥110 mg/dL or type 2 diabetes mellitus (DM2),40 hypertension (≥130/85 mm Hg or if under treatment). Mean arterial pressure (MBP) =  + systolic arterial pressure)/3.The presence of MetS and its associated entities was determined according to the criteria proposed by the Adult Treatment Panel III (ATP III):41 Chronic renal failure (CRF) was assumed when the GFR was ≤60 mL/min/1.73 m2.Glomerular filtration rate (GFR) was determined through a 24-hour creatinine clearance test and using the “modification of diet in renal disease” formula (MDRD) (GFR = 186 × (creatinine) − 1.154 × (age) − 0.203 or (× 0.742 in women)).U test, Fisher test, ANOVA with Bonferroni correction, and the χ2 tests were used to compare continuous and categorical variables in each group; we considered statistical significance level of 0.05 (both sides). The Cochran Q, Pearson and Spearman correlation tests as well as linear regression models were carried out: dependent variables: Lep o AdipoQ serum values adjusted by independent variables (forward process): metabolic variables , and variables related to inflammatory join disease activity . All statistical tests were performed using IBM SPSS Statistics 21.Demographic, clinical, and biochemical variables were reported with descriptive statistics: tendency and dispersion measures for continuous variables and proportions for dichotomous or nominal variables. The Mann–Whitney Forty-one patients with gout, mean age of 48.0 ± 12.9 years were included. Forty of them were males; 32 (78.1%) had tophaceous gout and in 80.5% of the patients we demonstrated monosodium urate crystals upon polarized light microscopy of the synovial fluid or tophi.At baseline, the mean duration of disease was 12.6 ± 10.5 years; however, none of them received adequate treatment and therefore had evidence of disease inflammatory activity (frequent acute flares in the 6 months before baseline visit and swollen and tender joints as well as an increase in acute phase reactants) and also chronicity data . Almost one third of the patients had MetS or its comprising entities, the most common of which was hypertriglyceridemia, followed by hypertension and obesity; a third of the patients had CRF , but only serum creatinine levels had a tendency to be significantly different Table .As expected, when comparing patients with MetS to those without it, the former had a greater frequency of hypertension, obesity, hyperglycemia, and dyslipidemia; however, we did not find significant differences in the related demographic or clinical variables related to gout or in the AdipoQ levels Table .We found significant improvement in the sUA values, MDRD, and in the variables evaluating joint pain and swelling at 6 and 12 months Figure .After 1 year of follow-up, only 10 patients (24.4%) had sUA levels ≤6.0 mg/dL; treatment was individualized but in general terms consisted of starting regular treatment with allopurinol at a low dose followed by a steady increase: (300 ± 189.8 mg/day at the baseline visit to 450 ± 206 mg/day at 12 months). Forty patients received allopurinol and only 1 patient received probenecid ; all patients received prophylaxis with colchicine (1 mg/day).During the follow-up, we did not find significant improvement in the associated metabolic entities, our patients showed increase in total cholesterol and tryglicerides, maintained their waist circumference and MBP, and had slight improvement in HDL-C and glycaemia Table . AlthougThe levels of adipocytokines, especially Lep, tended to increase both in the group of patients with MetS as well as overall, in the same way that metabolic abnormalities tended to persist or even worsen during follow-up Table .r > 0.5) between other metabolic variables and those measuring the activity of gout.After performing a linear correlation of the Leptin and AdipoQ values, there was no important correlation , his baseline Lep and AdipoQ serum levels were similar to the values from other patients.This study evaluated the possible relationship between improvement in clinical gout and/or metabolic data and the serum concentration of adipocytokines in patients in whom regular treatment was initiated.33During follow-up with regular treatment, the patients improved significantly in all the variables directly related to gout as joint inflammatory activity and in the sUA levels; although only one fourth of them achieved sUA ≤6.0 mg/dL. Similar to other studies, we did not find relation among the concentration of adipocytokines and sUA levels.45Lep values had relationship with obesity, MetS, and CRP, but not with gout-related variables and course during 6 and 12 months follow-up. These Lep and AdipoQ  values related to MetS course had been previously reported in patients with MetS, without gout.Interestingly CRP, a marker of systemic inflammatory state and considered a marker for joint “activity” as well as marker for metabolic and cardiovascular risk, tended to lower levels during follow-up in patients with gout associated with MetS, but not in patients without it.46Previous reports evaluating whether adipocytokines are protective or harmful in joint inflammatory diseases had been controversial. However, at the same time, some authors have reported that the presence of high levels of these adipocytokines must always be considered abnormal and may be associated with metabolic or inflammatory abnormalities; in addition, the diversity of cells containing receptors for these adipocytokines makes them scarcely specific and finally, their expression and functions seem to be different in different body tissues.Unfortunately, we were not capable of modifying most metabolic variables during 1 year of follow-up. The data are unsatisfactory because, excepting a tendency to lower glucose levels, the rest of the variables did not improve and there was even a significant increase in the total cholesterol levels; in addition, during follow-up we observed increase in the number of patients with low HDL-C values and MetS.47There are difficulties in compliance and adherence in patients with chronic diseases and especially in gout patients, in 1 study >80% of gout patients had partial and poor adherence to ULD therapy, the adherence to lifestyle modifications in them seems to be lesser, although not known.Probably, the sample size of this study, although adequate to evaluate clinical improvement, was not enough to evaluate minor changes in AdipoQ values. Finally, all the above results suggest that in patients with gout, the concentrations of Lep and AdipoQ are mainly related to the metabolic state and not the articular clinical activity itself.


Supplemental Digital Content is available in the text N-acetylgalactosaminyltransferase 14 (GALNT14)-rs9679162 genotype is a prognostic predictor for chemotherapy response in advanced hepatocellular carcinoma. Here, we investigated whether this genotype was related to the therapeutic outcome of stage III CRC.Adjuvant oxaliplatin-based chemotherapy is widely used for stage III colorectal cancer (CRC) after curative surgery. CRC is a molecularly heterogeneous disease, and our current knowledge of therapeutic response-related genetic factors remains limited. GALNT14 genotypes and the clinicopathological factors were correlated with posttherapeutic prognosis.A cohort of 300 stage III CRC patients receiving curative resection followed by oxaliplatin-based chemotherapy was retrospectively recruited. GALNT14-rs9679162 “TT” and 82% had the “GT” + “GG” genotypes. The analysis showed that the “TT” genotype was associated with unfavorable overall survival  but not with recurrence-free survival . The subgroup analysis showed that the “TT” genotype was associated with unfavorable OS in the following subgroups: age ≤65 years, men, left side CRC, N2 stage, carcinoembryonic antigen >5 ng/mL, and mucinous histology . Within the latter 2 subgroups, the “TT” genotype was the only independent predictor for OS. Finally, the “TT” genotype was associated with the T4 tumor stage (P = 0.017) and in patients with T4 tumors, the “TT” genotype was the only independent predictor for unfavorable RFS (P = 0.007).Of these patients, 18% patients had GALNT14 “TT” genotype was associated with unfavorable OS in stage III CRC patients receiving curative surgery and adjuvant oxaliplatin-based chemotherapy. It has been found that patients with stage III CRC are not a single aggregate with homogeneous risk but rather consisted of variable subsets of patients with different outcomes. The 5-year survival rate varies from 73% in stage IIIA (T1–2N1) to only 28% in stage IIIC CRC (N2).6 Moreover, CRC is a molecularly heterogeneous disease, and genetic analysis of the cancerous tissues revealed candidate prognostic markers such as 18q loss of heterozygosity, microsatellite instability, and large deletions in heat shock protein 110.10 Despite the success of these elegant studies, clinical applications of these markers are greatly limited by the accessibility to well-established molecular laboratories and the availability of standardized clinical assays. Therefore, there remain unmet needs for easily accessible genetic makers that can predict prognosis of CRC.Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide. Among all newly diagnosed CRCs, stage III CRC constitutes the greatest proportion.N-acetylgalactosaminyltransferase 14 (GALNT14) could be used as a prognostic predictor for chemotherapy for hepatocellular carcinoma.11 A leading single nucleotide polymorphism (SNP) marker, rs9679162, was capable of predicting the time-to-tumor progression, overall survival (OS), and responses to chemotherapy. In patients with advanced hepatocellular carcinoma receiving palliative chemotherapy, the “TT” genotype predicted a favorable treatment outcome.13 The product of GALNT14 gene was a catalytic enzyme that catalyzed O-glycosylation of many proteins including the death receptor (DR)-4 and -5. Because the O-glycosylation of DR 4 of 5 increased their sensitivity to apoptotic signals, this genotype association of chemotherapy sensitivities might not be restricted to hepatocellular carcinoma. In CRC cells, it has been demonstrated that the increase of DR-5 enhances cytotoxic effects of 5-fluorouracil and oxaliplatin.14 Here, we hypothesized that the GALNT14 genotype might also affect the outcome of stage III CRC patients and examined the clinicopathological parameters in relationship to GALNT14 genotype and the prognosis predictive values of these factors.By the use of genome-wide association method followed by prospective validation, it was found that the genotype of polypeptide This study was conducted under the approval of the institutional review board of Chang Gung Memorial Hospital, Taiwan. Surgical samples of 300 stage III CRC patients resected between years 2003 and 2013 were retrieved from the hospital's tissue bank without other particular selection criteria. The stage was based on tumor-node-metastasis classification. CRCs with regional lymph nodes involvement , and tumor invasion  but without distant metastasis (M0) were classified as stage III. All the patients received oxaliplatin-based adjuvant chemotherapies after curative resection. The clinicopathological data were collected including age, sex, carcinoembryonic antigen (CEA), tumor location, tumor size, tumor surface area, tumor-free margin, tumor invasion, regional lymph node involvement, tumor differentiation, histology type, and chemotherapy regimen used.2) and leucovorin (400 mg/m2) were administered continuously over 2 hours via intravenous route on day 1. The 5-fluorouracil was given intravenous bolus at the dose of 400 mg/m2 on day 1, followed by 1200 mg/m2/day for 2 days  with continuous intravenous infusion. The mFOLFOX6 regimen was repeated every 2 weeks for 12 cycles. The XELOX protocol was given as the following: oxaliplatin (130 mg/m2) was continuously administered via intravenous route for 2 hours on day 1. Capecitabine (1700–2000 mg/m2) was given via oral route on day 1 to day 14. The XELOX regimen was repeated every 3 weeks for 8 cycles.Two oxaliplatin-based regimens, modified Folinic acid, Fluorouracil, Oxaliplatin 6 (mFOLFOX6) and capecitabine plus oxaliplatin (XELOX), were given to patients after curative resection. The mFOLFOX6 was given as the following: oxaliplatin  patients were “TT” type and 246 (82%) were “non-TT” type (“GG” + “GT”). The proportion of “TT” type was significantly lower than those in the HapMap Chinese Han Beijing (30.15%) and Metropolitan Denver (28.44%) cohorts (χ2 test P = 0.0044 and 0.0214) respectively.15 Most clinicopathological factors showed no significant association to GALNT14 genotype  and OS. The median posttherapeutic follow-up period was 47 (5–133) months. Cox proportional hazard method and Kaplan–Meier plot with log-rank analysis showed there was no significance between the “TT” genotype and RFS . However, the patients with “TT” genotype had a significantly shorter OS compared with patients with “non-TT” genotype .To study whether GALNT14 “TT” genotype in various clinical subgroups using Cox proportional hazard method , men , CEA >5 ng/mL , left CRC , N2 stage , and mucinous histology .Subsequently, we examined the predictive role of P = 0.030), tumor size (P = 0.012), surface area (P = 0.022), and N stage (P = 0.014) were associated with RFS by univariate analysis. After adjusting for the confounding factors, multivariate analysis showed that CEA level (P = 0.027) and N stage (P = 0.004) were independent predictors for RFS.To identify other clinicopathological predictors for RFS and OS, univariate followed by multivariate Cox proportional hazard analysis was performed Table . The CEAGALNT14 “TT” genotype (P = 0.019), the T4 stage (P = 0.003), and the mucinous histology (P = 0.028) were associated with poor prognosis by univariate Cox proportional models. Multivariate analysis revealed that only T4 stage (P = 0.021) was the independent predictor for OS.For OS, the GALNT14 genotypes were associated with both T4 stage . For OS, the mucinous histology was the only unfavorable predictor .Because ge Table , we subsGALNT14 genotype in other clinical subgroups associated with poor OS . In patients with mucinous histology , the “TT” genotype was the only unfavorable predictor for OS (Cox P = 0.037). Other analysis for the predictive value of GALNT14 genotype in clinical subgroups was given in supplementary Tables 3–6.In addition to T4 stage subgroup, we also analyzed the prognosis predictive value of GALNT14 “TT” genotype was positively associated with T4 stage, a well-known poor prognostic predictor. Further analysis showed that the “TT” genotype was associated with poor OS in all included patients and several clinical subgroups, including age ≤65 years, men, CEA >5 ng/mL, left-side CRC, N2 stage, and mucinous histology.At this time, routine adjuvant chemotherapeutic treatment is recommended for patients with high-risk stage II and stage III CRC. It has been documented that oxaliplatin-based adjuvant chemotherapy confers survival advantage in stage III CRC patients. However, no pretreatment prognostic molecular biomarkers for stage III CRC receiving oxaliplatin-based adjuvant chemotherapy regimen has been established until now. The present study demonstrated that the GALNT14 “TT” genotype, several poor prognostic subgroups were identified including CEA >5 ng/mL, N2 stage, T4 stage, and mucinous histology. This is consistent with previous studies from other groups.17 To identify useful prognostic predictors within these subgroups, we further analyzed the RFS and OS with respect to the clinicopathological parameters and GALNT14 genotype. Intriguingly, GALNT14 was again identified as a valuable prognostic predictor in these subgroups. For patients in T4 stage, the “TT” genotype was significantly associated with poor RFS. For patients with CEA >5 ng/mL or mucinous histology, the “TT” genotype was the only predictor associated with poor OS.In addition to KRAS expression, levels of DNA mismatch repair, 18q deletion, and p53 expression).19 However, personal genetic background might contribute greatly to this disease. Our study showed that patients with GALNT14 “TT” genotype had a higher rate to develop tumor invasion (T4 stage) and thus have an unfavorable OS. Furthermore, the “TT” genotype was associated with poor RFS in T4 stage patients. Thus, GALNT14 “TT” genotype has 2 major clinicopathological implications. First, tumors with GALNT14 “TT” genotype have more aggressive cancer invasion property during oncogenesis. Second, tumors with “TT” genotype may have decreased drug sensitivity to oxaliplatin, which is reflected from its association with poor RFS in T4 stage patients. Therefore, other more potent cytotoxic agents should be considered in patients with GALNT14 “TT” genotype.Like many other cancers, development and progression of CRC are affected by multiple factors. Most research efforts have been focused on the underlying molecular mechanisms of CRC carcinogenesis, and a variety of candidate genetic markers with predictive value of outcome have been discovered by studying the cancerous tissues  codon 118C/T or T/T genotype was associated with worse survival,23 whereas other groups showed that metastatic CRC patients with the same genotype had better response or survival compared with C/C patients.25 Although the results on the predictive value of ERCC1 codon 118 polymorphism have been inconsistent, these studies raise the possibility that genetic SNP might play a role in therapeutic response. Our current study of GALNT14 genotype supported this view. Moreover, the gene product of GALNT14 is an enzyme that catalyzes O-glycosylation of many proteins including the DR-4 and -5. It has been reported that the cytotoxic effects of oxaliplatin in CRC can be enhanced by tenovin-6 through upregulating DR-5,14 suggesting that modulation of DR-mediated signaling may affect the effects of oxaliplatin-based chemotherapy. In this study, 1 convenient explanation for the GALNT14 genotypes–associated therapeutic outcomes is the differential intensities of DR-mediated apoptosis signaling between the “TT” and “non-TT” genotypes. However, because O-glycosylation is a body-wise process, it is unclear whether there are other unrecognized important glycoproteins involved. Moreover, several genetic alternations in colorectal cancerous tissues, such as 18q loss of heterozygosity, microsatellite instability, and large deletions in heat shock protein 110, have been proposed as candidate prognostic markers, but the association between GALNT14 genotypes and these genetic makers is unclear. Further studies to clarify these issues are needed.Oxaliplatin is a platin analogue that has been widely used in treating a variety of solid tumors, especially in CRCs. It induces apoptosis and cell death through the inhibition of DNA replication by forming intrastrand cross-link DNA adducts.This study had several limitations, including its retrospective nature, limited case number, and restriction of the sample to a Chinese population from a single medical center. Our eligibility criteria confined the treatment to oxaliplatin-based chemotherapies (mFOLFOX6 and XELOX) for interpretative clarity. Therefore, it may not pertain to other regimens not containing oxaliplatin. The decision of which oxaliplatin-based regimens to be used was not only dependent on clinical criteria but also on nonclinical considerations such as doctors’ decision and patients’ willingness. The age of patients in this cohort study was relatively young compared with other CRC cohort studies. This was because elderly CRC patients were more often willing to have chemotherapy via oral route than intravenous route. Despite all these drawbacks, our study results are considered useful in routine clinical practice.GALNT14 “TT” genotype was correlated with T4 stage and associated with poor OS in stage III CRC patients receiving curative resection and adjuvant oxaliplatin-based chemotherapy. It was further associated with poor treatment outcome in subgroups of T4 stage, CEA >5 ng/mL, or mucinous histology. Taken together, GALNT14 genotype is a valuable prognostic predictor in advanced CRC.In conclusion,


N-butyl-N-methylpyrrolidinium bis(trifluoromethanesulfonyl)imide (Pyr14TFSI) are reported, by investigating the behavior of Li metal electrodes in symmetrical Li/electrolyte/Li cells. Electrochemical impedance spectroscopy measurements and galvanostatic cycling at different temperatures are performed to analyze the influence of temperature on the stabilization of the solid electrolyte interphase (SEI), showing that TFSI-based ionic liquids (ILs) rank among the best candidates for long-lasting Li–air cells.In this work, the electrochemical stability and lithium plating/stripping performance of  Energy densities as high as 3154 Wh·kg−1 can be achieved assuming a practical discharge voltage of 2.7 V [Electric and hybrid cars have successfully entered the market in the last few years, while renewable energy sources, like wind turbines and solar panels, are being deployed at a fast pace. However, the intermittency of these energy sources hinders the possibility to provide a stabilized current baseline for electric grid operation, and batteries with improved performances are actively investigated to meet this shortcoming, as well as for powering electric vehicles. The secondary Li–air battery, first proposed by Abraham et al. , is seenet al. ,3, given−1, a value that is above any other existing secondary battery technology. While problems, like O2 diffusion [2. Since lithium metal is present in the system, cell drying poses a risk that should definitely be avoided. Moreover, most reported tests involve either alkyl carbonate- or ether-based electrolytes, which are not stable enough in oxidation [et al. using 1-ethyl-3-methylimidazolium paired with bis(trifluoromethanesulfonyl)imide (TFSI−) [vs. lithium metal. Among other ionic liquids, it is worth mentioning the use of diethylmethylmethoxyethylammoniumTFSI, N-methoxyethyl-N-methylpiperidiniumTFSI [N-ethyl-N-methylpiperidiniumTFSI [N-butyl-N-methylpyrrolidinium (Pyr14+)-based ILs, such as Pyr14TFSI [14FSI [14FSI allows high voltage Li–ion cathode use [vs. the very reactive superoxide anion, O2−, as evidenced by the lack of an O2− oxidation peak  [2 cell operation [For practical capacities of around 3 Ah per gram of carbon (a reasonable candidate as a cathode substrate/current collector) , this coiffusion , pore cliffusion  and low xidation –13, or sxidation ,14 and dxidation , whose sxidation . There i (TFSI−)  that was (TFSI−) ,18, althniumTFSI ,20 and NniumTFSI –21. N-buyr14TFSI  and Pyr1I [14FSI –25, meethode use , but is ion peak , thus ruvs. O2−) ,28, as s2−, another issue to be addressed is the viability of Li metal as the negative electrode, its theoretical capacity being more than ten times that of graphite (3861 vs. 372 mAh·g−1), even though its lower Coulombic efficiency imposes the use of over-stoichiometric Li metal electrodes for secondary battery applications. So far, only polyethylene oxide (PEO)-based solid polymer electrolytes (SPEs) have allowed Li metal to be commercially used in secondary batteries and electric cars, but ionic liquids [14FSI-based electrolyte [et al. [14TFSI-based electrolytes in combination with a Li metal electrode in 2004 and reported high efficiencies for the Li plating/stripping process. The average faradaic efficiency determination usually consists of plating a given amount of Li onto a substrate, such as Cu [Qp, and then cycling a fraction of it (defined as Qc), until a certain voltage is reached after n cycles, which indicates full lithium consumption. Then, either In addition to their stability in the presence of O liquids ,29 and i liquids –32 have ctrolyte ,29. In pctrolyte . Combinactrolyte ,34. Howl [et al.  proposedch as Cu  or Ni [2ch as Cu , equal t14TFSI-based electrolyte on both Pt and Cu [Qp and Qc, the Qp/Qc ratio is also of paramount importance to correctly interpret the results obtained. For example, if a 330 μm-thick Li foil (corresponding to Qp ≈ 68 mAh·cm−2) is used to run plating/stripping tests in symmetrical Li/electrolyte/Li cells and only a small fraction of it (Qc = 0.025 mAh·cm−2) is actually cycled [Qp/Qc ratio of ≈2700 will yield a mere 45% efficiency, even after 5000 cycles . As calculated above, this requires long-term cycling (if Qp/Qc = 100) for efficiency determination.In general, the low temperature performance of liquid electrolytes based on Pyrnto SPEs ,31. Moreectrodes . Attemptratories , due to i.e., as soon as the fresh surface gets in contact with the dry atmosphere in the production step. This interphase further evolves once it gets in contact with most electrolytes [Another aspect considered is the solid electrolyte interphase (SEI) , the protrolytes –43. As itrolytes ,44–46, t2.2.1.14TFSI-0.1 LiTFSI/Li cells is represented in Rint).A sample impedance spectrum for symmetrical Li/0.9 PyrRint compared  reaches a maximum after 3–4 days (probably due to faster kinetics) and then decreases; finally, at 60 °C, a steady drop is observed for the whole investigated timespan, indicating that the maximum resistance is reached even before the first measurement is performed . Under these conditions, a stable SEI forms within only three days. This behavior can be interpreted as the result of a progressive accumulation of decomposition products at the Li/electrolyte interface, which goes on until the entire lithium surface is completely covered with a mixed inorganic/organic SEI; our tests show that the higher the temperature, the faster this step will reach completion. The decrease, on the other hand, reflects either the dissolution of SEI components or the swelling of the organic external SEI layer, which leads to its gelation/plasticization [+ ion conductive  layer is present close to the Li metal surface, while further away (where the reducing conditions are less stringent), a more organic/polymeric layer forms [+ conducting layer cannot be accounted.A set of Li/electrolyte/Li cells were thermally stabilized for one week (168 h) under OCV conditions and their evolution of compared . A diffecization . This aser forms , as poster forms . Moreove2.2.−2, which was reversed every hour. The resulting voltage vs. time curve can be analyzed by splitting the component related to the ohmic drop (ΔV1) from the one linked to the establishment of a diffusion gradient (ΔV2), as indicated for a sample half-cycle in + diffusion coefficient and that no full Li depletion is reached at the plated electrode. To follow the evolution of the system during cycling, in addition to the equivalent series resistance (ESR = ΔV1/2i), it is possible to define a diffusion-related resistance, corresponding to the additional polarization at the end of each step (Rpol = ΔV2/2i), to account for the additional Li mass transport resistance after one hour. The same quantities can be obtained during the reverse plating.The cells subjected to a one-week stabilization, as well as the freshly assembled ones, were galvanostatically cycled at a current density of 0.1 mA·cm2.3.14TFSI-0.1 LiTFSI/Li cells assembled using a Whatman GF-F separator at different temperatures. As can be seen in i.e., less fluctuations of cell overvoltage over time) and cycling stability at any temperature. While this beneficial influence is more marked at 40 °C than 20 °C, thanks to the faster interface stabilization, the same cannot be said for cells running at 60 °C, where one week of stabilization only brings in 400 more cycles, corresponding only to a small increase in efficiency (+0.5%). The reason for this lies in the fact that “fresh” cells are also thermally equilibrated for 12 h prior to cycling. At 60 °C, this is long enough to create a stable SEI  increases over a critical value, a concentration gradient can establish within this interphase and show up in the voltage vs. time chart  is breached, an increased clogging of the electrodes takes place, slowing down Li+ transport and leading to the end of cycling, as evidenced by the fast final increase of ESR and Rpol. It must be stressed once again that this does not correspond to full Li consumption, but is related to the reactivity of the electrolyte at the Li interface. As stated previously, the native SEI formed in contact with the atmosphere is mainly composed of inorganic compounds  that form microcrystalline or microphase domains [+ ion transport at grain boundaries. Electrolyte components can infiltrate along the grain boundaries and reach the close vicinity of the Li metal, especially through domains where the SEI is less resistive and less protected. With time, the accumulation of these products blocks all the diffusion channels and leads to the final increase in the plating overvoltage.During Li plating, the polarization appears like a single, diffusion-controlled electrochemical process, as shown in  domains . This su2.5.Damage to the lithium surface can also arise after contact with the fibers that make up the separator. These can break the SEI surface similarly to what is believed to occur for polymer electrolytes . To confvs. 0.7 μm for GF-F). In addition, its lower thickness leads to an overall lower resistance and improved Li+ mass transport. The structure of the two separators are similar, as both are non-woven mats imide (Pyr14TFSI) was synthesized according to a well-established procedure [−7 mbar). This procedure leads to ILs exhibiting water content below 2 ppm, measured via coulometric Karl Fischer titration . Lithium bis(trifluoromethanesulfonyl)imide (LiTFSI)  was dried at 120 °C under vacuum for at least 24 h before use. Pyr14TFSI and LiTFSI were mixed in a 9:1 molar ratio and further dried under turbomolecular vacuum at 70 °C for 24 h. Glass fiber separators  were dried at 120 °C for at least 24 h prior to usage.Lithium metal foil  was stored in a dry room (Relative Humidity <0.1% at 20 °C) together with all the other chemicals mentioned in this paper. rocedure  and drie3.2.−2 M AgTFSI  -PYR14TFSI. The reference electrode potential was checked vs. lithium, and the working potentials are reported vs. the Li+/Li couple. A Pt wire was used as a counter electrode. The voltammetric scans were corrected for the ohmic drop evaluated by impedance spectroscopy in the 10 kHz–1 Hz range. These tests were performed using a VSP multichannel potentiostat/galvanostat/electrochemical impedance analyser, .The oxygen redox reaction was investigated by cyclic voltammetry (CV) using a glassy carbon electrode , in a 5-mL cell, which was thermostated at 30 °C by a K40 thermocryostat . The reference electrode was a silver wire in 6 × 103.3.ca. 1 cm2.All cell assembly procedures were performed inside the dry room. Pouch bags were manufactured using two 100 μm “coffee-bag” sheets and Ni current collectors (thickness: 20 μm). Lithium foil strips were then folded around the current collectors to ensure electrical contact and separated by a glass fiber separator impregnated with the electrolyte. The cells thus fabricated had an active area of 3.4.T = ±0.1 °C  at three different temperatures  and electrochemical impedance measurements were acquired daily to track the changes in interfacial resistance over time. For this purpose, the range spanning from 65 kHz to 10 MHz was investigated, using a Solartron 1287 potentiostat/galvanostat coupled to a Solartron 1260 frequency response analyzer .Some of the pouch cells were subjected to a one-week thermal conditioning, by storing them in a MK53 climatic chamber Δ3.5.−2 current density that was reversed every 60 min. Cut-off voltages of 0.5 and −0.5 V were used. Thermal equilibration was ensured by inserting a 12-h rest step before performing each test.All pouch cells were galvanostatically cycled using a battery cycler  by applying a 0.1 mA·cm3.6.® microscope, Zeiss, Oberkochen, Germany). The sample surfaces were made conductive by using a turbo-pumped gold sputter/coater . The current applied was 45 mA for 30 s.The morphology of the glass fiber separators was analyzed via high-resolution scanning electron microscopy . This phenomenon is slowed down by the formation of an outer polymeric SEI that promotes the stabilization of the Li/electrolyte interface and leads to a delayed clogging of the electrode, as less degradation products are generated during cycling. The stabilization of SEI becomes more effective at higher temperatures, an effect that is enhanced by the faster Li+ ion transport within the electrolyte. The study of two different glass fiber separators with the same chemical composition also showed that the porosity and morphology of the separator can influence the “native” SEI’s open circuit evolution and the electrode clogging upon cycling. These features pave the way to the usage of ionic liquid electrolytes in next-generation electrochemical energy storage technologies, such as Lithium–air batteries. The long-term cyclability that IL-based electrolytes ensure, together with the peculiar physico-chemical properties, like negligible volatility and wide electrochemical stability, are key enabling factors to the deployment of such novel electrochemical power sources into the market.In this work, we showed that it is possible to achieve cycling efficiencies as high as 96.5% through plating/stripping tests of lithium metal electrodes in a Pyr


After three years of excessive confidence, overoptimistic expectations and performance of 15 to 20,000 renal denervation procedures in Europe, the failure of a single well-designed US trial—Symplicity HTN-3—to meet its primary efficacy endpoint has cast doubt on renal denervation as a whole. The use of a sound methodology, including randomisation and blinded endpoint assessment was enough to see the typical 25–30 mmHg systolic blood pressure decrease observed after renal denervation melt down to less than 3 mmHg, the rest being likely explained by Hawthorne and placebo effects, attenuation of white coat effect, regression to the mean and other physician and patient-related biases. The modest blood pressure benefit directly assignable to renal denervation should be balanced with unresolved safety issues, such as potentially increased risk of renal artery stenosis after the procedure , unclear long-term impact on renal function and lack of morbidity–mortality data. Accordingly, there is no doubt that renal denervation is not ready for clinical use. Still, renal denervation is supported by a strong rationale and is occasionally followed by major blood pressure responses in at-risk patients who may otherwise have remained uncontrolled. Upcoming research programmes should focus on identification of those few patients with truly resistant hypertension who may derive a substantial benefit from the technique, within the context of well-designed randomised trials and independent registries. While electrical stimulation of baroreceptors and other interventional treatments of hypertension are already “knocking at the door”, the premature and uncontrolled dissemination of renal denervation should remain an example of what should not be done, and trigger radical changes in evaluation processes of new devices by national and European health authorities. Accordingly, at 6 months the between-group difference in office blood pressure averaged 33/11 mmHg (P < 0.0001) [In 2009, Krum and colleagues  publisheStill, in this sunny landscape, many shadows remained. Only a minority of patients with resistant hypertension were found to be eligible for RDN , 6, 7•. As early as 2012, we and others , 15 haveDespite these caveats, publication of the Symplicity studies , 2••, 3 Based on mostly small, purely observational studies, RDN was associated with ancillary benefits such as decreased left ventricular mass , arteriahttp://www.tctmd.com/show.aspx?id=123265) stunned the medical community and device industry as a deep shock, and was quickly followed by definitive or temporary stopping of large ongoing research programmes (http://www.reuters.com/article/2014/01/24/us-covidien-divestment-idUSBREA0N18B20140124). A rapid opinion shift from excessive optimism to deep mistrust ensued [Symplicity HTN-3 ••, a lart ensued .P < 0.001 for both comparisons of the change from baseline). This corresponds to a modest 2.39 mmHg advantage in favour of the technique, lower than the preset superiority margin of 5 mmHg [p = 0.006) compared to a non-significant (p = 0.51) -3 mmHg in 25 patients from control group [p < 0.001 for both) [In contrast with Symplicity HTN-2 ••, the mf 5 mmHg ••. Discoor both) •• , at higher cardiovascular risk (slightly higher proportion of type 2 diabetes and dyslipidemia) and took more diuretics (99 vs. 89 %) and aldosterone antagonists (23 vs. 17 %). Furthermore, as expected in a US population, the Symplicity HTN-3 cohort included one-fourth of patients of African descent [The huge discrepancy between Symplicity HTN-3 on one side and most other studies including Symplicity HTN-2 on the other side raises concern. Can a single large US trial challenge all previous studies? Who is right? Symplicity HTN-2, Symplicity HTN-3, or both? Compared to Symplicity HTN-2 •• were m descent ••, while descent •• was th descent ••.blinded, while other studies were randomised but unblinded (Symplicity HTN-2) or purely observational [The aforementioned differences in study populations and in the RDN procedure itself may partly account for the less important blood pressure decrease in RDN-treated patients from Symplicity HTN-3 •• comparvational ••, 42••.vational . In othevational . As detavational , the Symvational , 19••. Cvational , 15. In vational .Some of the most enthusiastic exponents of RDN are already ready to “seek redemption” for RDN , withoutThe key message of Symplicity HTN-3 •• is simOn the other side, reason takes back her rights. All previous discrepancies are now easily understandable. If the blood pressure decrease observed in previous studies is mostly related to patient and physician-related biases, it is not unexpected that blood pressure outcome may critically depend on the expertise of centres, the way in which blood pressure is measured, and/ or the individual characteristics and psychology of patients. It is obvious that ambulatory blood pressure, which minimises observer-related bias and placebo effect , will behttp://www.tctmd.com/show.aspx?id=123265). At first sight, this may convey the impression that the Simplicity HTN-3 investigators have achieved at least one of their aims after all, and thus mitigate our disappointment. However, it should be pointed out that the primary safety endpoint—a composite of major adverse events, including death, endstage renal disease, an embolic event resulting in end-organ damage, renal-artery or other vascular complications, hypertensive crisis within 30 days or new renal-artery stenosis of more than 70 % within 6 months [The first announcement of the failure of Symplicity HTN-3 •• to ach6 months ••—was an6 months , in the 6 months .http://www.tctmd.com/show.aspx?id=120456), respectively. If confirmed on a larger scale, this frequency is not negligible, especially in view of the modest efficacy of the technique [Up to now, at least 13 cases of significant, de novo renal artery stenosis have been documented 3 to 6 months after RDN performed using four different renal ablation systems ••, 55–65echnique ••, 42••.echnique , some of2, a twofold to eightfold larger decrease than in other contemporary trials including patients at high cardiovascular risk (median follow-up: 29 to 56 months) [Long-term evolution of renal function is also a matter of concern. While glomerular filtration rate (GFR) at 6 months was similar in both RDN and control groups in Symplicity HTN-2 , in the  months) –70. WhetIn patients with resistant hypertension as a whole, the efficacy of RDN has been largely overestimated ••. OveraThe proportion of patients in whom RDN appears as the single option is thus very low (probably < 1 %) , 73. Furrationale [2 [While, as stated in a recent editorial, the “RDN bubble” has exploded  and overationale . Most inationale . Hence, ationale , but mayationale ••, whileonale [2 ••. Theseonale [2 .Identification of determinants of response to RDN should be done within the context of properly designed randomised controlled trials and independent registries. Selection criteria should be much stricter than previously. Candidates to RDN should undergo an in-depth screening in order to rule out secondary and white coat hypertension. Elderly patients, patients with isolated systolic hypertension and altered renal function  are unliRDN may find its place in the therapeutic arsenal of resistant hypertension and some other diseases characterised by sympathetic overactivity. It will never be a “miracle cure” of hypertension, or even the standard treatment for all patients with resistant hypertension , 44. In rationale [Different factors have jointly contributed to the uncontrolled and premature deployment of RDN in Europe: (1) the attractive underlying ationale ; (2) theationale ; (5) theationale • and theationale ; (6) theationale , 86; andationale .Thriving on what is viewed as the failure of RDN to meet its expectations, new treatment approaches of resistant hypertension such as electrical stimulation of baroreceptors  or creat