Higher Baseline Values Research Articles

749P - Prognostic and predictive factors from the phase III CELESTIAL trial of cabozantinib (C) versus placebo (P) in previously treated advanced hepatocellular carcinoma (aHCC)

749P - Prognostic and predictive factors from the phase III CELESTIAL trial of cabozantinib (C) versus placebo (P) in previously treated advanced hepatocellular carcinoma (aHCC)

Associations between baseline serum biomarker levels and cachexia/precachexia in pretreated non-small cell lung cancer (NSCLC) patients.

3054 Background: We previously reported associations of pretreatment serum biomarkers with clinical outcomes in a cohort of advanced NSCLC patients that progressed on front-line therapy. This study aims to elucidate mechanisms underlying cancer cachexia/ pre-cachexia by evaluating relationships between baseline serum biomarker values and sequential changes in body weight, body mass index (BMI), and neutrophil/lymphocyte ratio (NLR) in NSCLC patients. Methods: We used Luminex immunobead assays to survey 101 protein biomarkers in sera from advanced NSCLC (n = 138) collected prior to their salvage regimen. Serial parameters associated with cancer cachexia included body weight, BMI, and NLR. Outcome variables (progression-free survival (PFS) and overall survival (OS)) were extracted with full IRB-approval. Biomarkers were evaluated as continuous variables with the cachexia surrogates using Pearson correlations, whereas associations of PFS and OS were accomplished with the Cox PH test. Results: High baseline values of BMI and low baseline NLR were associated with both OS and PFS (each p < 0.05), though weight failed to reach significance. PFS and OS were similarly associated with percent changes (relative to baseline) in weight (p < 0.01), BMI (p < 0.01), and NLR (p < 0.001). Thirteen biomarkers were found to be associated (p < 0.05) with baseline BMI values, including positive correlations with leptin, sol.VEGFR2, and c-peptide and inverse correlations with adiponectin, ferritin, ghrelin, IGFBP-1 and IL-8; fifteen biomarkers were associated with baseline NLR (all p < 0.05), including positive correlations with visfatin, insulin, and serum amyloid A and inverse correlations with IGF-II. Fifteen biomarkers were found to be associated (p < 0.05) in common with percent weight and BMI changes, including positive correlations with IGFBP-3 and inverse correlations with insulin, FGF-2, TNF-alpha, and resistin. Only prolactin and placental growth factor were found to be associated (p < 0.05) with percent change in NLR. Conclusions: A series of circulating protein biomarkers primarily connected with metabolic regulation and systemic inflammation/ acute phase response were found to be associated with cachexia/ pre-cachexia in NSCLC patients. Additional cohorts are currently being tested to verify these findings.

Vickers Micro-Hardness of New Restorative CAD/CAM Dental Materials: Evaluation and Comparison after Exposure to Acidic Drink.

CAD/CAM (computer-aided design/computer-aided manufacturing) for indirect restorative materials has been recently introduced in dentistry. The purpose of this study was to evaluate the change of the surface micro-hardness of different restorative CAD/CAM materials after exposure to a carbonated acidic drink (Coca-Cola, Coca-Cola Company, Milan, Italy). One hundred and eighty specimens of identical size (2 mm thickness) were obtained by sectioning each tested CAD/CAM block of four materials: a hybrid ceramic (CERASMART™, GC Corporation, Tokyo, Japan), a resin nano ceramic (Lava™ Ultimate, 3M, Monrovia, CA, USA), a nanohybrid composite (Grandio blocs, VOCO GmbH, Cuxhaven, Germany), and a zirconia-reinforced lithium silicate glass ceramic (VITA SUPRINITY® PC; VITA Zahnfabrik, Bad Sackingen, Germany). Forty-five specimens of each material were tested. Micro-hardness was measured at baseline, after 7 days and after 28 days. The data were analyzed. The micro-hardness of each material varied significantly after immersion in Coca-Cola. The nanohybrid composite had a high initial micro-hardness and the greatest percentage loss after acid exposure. The hybrid ceramic and the resin nano ceramic had similar percentage losses of micro-hardness values even if the second material had higher initial values. The zirconia-reinforced lithium silicate glass ceramic had the highest baseline values and the lowest percentage loss of micro-hardness. The different CAD/CAM materials presented different micro-hardness values before and after acid exposure.

CD4/CD8 ratio improvement in HIV-1-infected patients receiving dual antiretroviral treatment.

The CD4/CD8 ratio is an indirect marker of immune activation, immune senescence, and inflammation in HIV infection. We performed a prospective study of the CD4/CD8 ratio evolution in 245 virally-suppressed (median, 55 months) HIV-infected patients (29% females) who had switched to four dual antiretroviral regimens. At baseline, the median CD4/CD8 ratio was 0.71 (interquartile range, IQR, 0.46-0.97), associated with duration of HIV infection, nadir CD4+ cell count, and AIDS diagnosis. It was lower in the case of hepatitis C virus coinfection and cardiovascular disease (p = 0.09), but the ratio was higher in patients with chronic kidney disease, proteinuria, or osteoporosis. At 48 weeks, the median CD4/CD8 ratio increased by 3% (+0.02; IQR, -0.07, +0.09; p = 0.07); greater improvement was observed in patients with lower baseline ratios and previous AIDS diagnosis. The slope of increase was slower in patients with the highest baseline values. Also, there were no differences in the CD4/CD8 ratio increase according to type of dual regimen, after adjusting for baseline and HIV-related values. In conclusion, CD4/CD8 ratio increase is observed during suppressive dual regimens, and its extent is related to baseline values and previous HIV-related factors. Longer duration on antiretroviral therapy and drug toxicity could affect the evolution of this marker in the presence of comorbidities.

Metabolic improvements during weight loss: The RNPC® cohort

Background/AimBody weight loss is essential to lower risk factors for type 2 diabetes and cardiovascular diseases in overweight patients. Therefore, we examined the effectiveness of the Rééducation Nutritionnelle et Psycho-Comportementale (RNPC®) program, designed to improve metabolic parameters during weight loss, among different patient groups. MethodsThe RNPC® program, used in 54 French centers, starts with an energy-restricted 800–1000 kcaL/day high-protein, low-carbohydrate, and low-fat diet comprising real foods and meal replacement products. The 89% (n = 10,809) of the patients completing the ∼15-week weight loss phase had a median 11% of initial body weight loss and was included in the study. The weight stabilization phases of the program were not included as metabolic risk markers were only sporadically measured in those phases. ResultsA total of 70.3% were obese and 30.3% classified as having the metabolic syndrome. Without differences in weight loss, improvements in fasting glucose were 0.1 mmoL/L (95% CI -0.2; -0.03, P < 0.05), 0.6 mmoL/L (95% CI -0.7; -0.5, P < 0.001), 3.0 mmoL/L (95% CI -3.6; -2.5, P < 0.001) and 2.0 mmoL/L (95% CI -3.1; -0.8, P < 0.05) for men with pretreatment fasting glucose of <5.6, 5.6–6.9, ≥7.0, or receiving diabetic medication, respectively. Similarly, the largest improvements in triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and alanine transaminase levels were found among male patients with the worst baseline level. Comparable results were obtained for females. ConclusionWeight loss during the RNPC® program is followed by overall metabolic improvement that is mainly driven by substantial improvements in specific metabolic risk markers among those with highest baseline values.

Effects of aging on corneal parameters measured with Pentacam in healthy subjects

Our purpose was to prospectively analyze the age-related changes of corneal Scheimpflug parameters in healthy subjects. Thirty-five eyes of 35 volunteers (age 14–67 years) were investigated with an average interval of 3.6 years. Changes of corneal parameters (flattest keratometric reading at anterior (K1F) and posterior surface (K1B), steepest keratometric reading at anterior (K2F) and posterior surface, anterior astigmatism, posterior astigmatism (AstigB), flat axis of anterior and posterior astigmatism (AxisB), thinnest pachymetric value (PachyMin), corneal volume (CV10-mm)) were analyzed. K1F and K2F decreased significantly during observation and showed stronger decrease in younger than in older individuals. Higher values proved to be more stable. K1B decreased significantly and the degree of decrease was dependent on its baseline value and age: in young subjects low values increased, high values decreased. AstigB decreased significantly and showed a baseline-dependent significant increase from lower and a significant decrease from higher initial values. Over time, the mean AxisB shifted significantly. PachyMin and CV decreased significantly with age, especially from higher baseline values in younger subjects. The results of this longitudinal study suggest that both corneal surfaces change significantly with age. We demonstrate for the first time that age and baseline values influence age-related changes of corneal parameters.

Closing the gap:

BACKGROUND&#x0D; Interventions to improve performance of global programs in the HIV cascade of care are widespread and increasing the focus of implementation science. At present, however, there is no clear consensus on how to conceptualize their improvement at the program level. The commonly used measures of association, based on ratios of probabilities (or odds), have well-known defects in public health applications. They yield large effect sizes even when the absolute effects, and therefore the public health impact, are small. On the other hand, risk differences create problems because settings with higher baseline values are penalized. We aim to examine ways of quantifying improvement in each health center of a cluster-randomized trial in Uganda to accelerate antiretroviral therapy initiation among HIV-infected adults.&#x0D; METHODS&#x0D; We formalize the concept of the ‘improvement index,’ defined as the fraction of gaps closed as a metric of improvement, and suggest that it has unique features and strengths when compared to risk ratios and risk differences.&#x0D; RESULTS&#x0D; Overall agreement between the different indices was not high, especially among health centers that were among the top 5 or 10. However, all ranking showed broad similarities at the far ends of the spectrum. On scatter plots, there was a positive linear relationship between the metrics, and the Bland Altman (B-A) plots were in agreement.&#x0D; CONCLUSION&#x0D; The improvement index can be used as an alternative measure of association in implementation science interventions. It can be useful for public health purposes as it demonstrates how much can be covered from the baseline.

Liver steatosis and dyslipidemia after HCV eradication by direct acting antiviral agents are synergistic risks of atherosclerosis

AimWe comprehensively analyzed how hepatitis C virus (HCV) eradication by interferon (IFN)-free direct-acting-antiviral-agents (DAAs) affects liver steatosis and atherogenic risk.MethodsPatients treated with IFN-free-DAAs who underwent transient elastography before and at 24-weeks post-treatment, including controlled attenuation parameter (CAP), and achieved sustained viral response (SVR) were enrolled. The association between changes in liver steatosis, lipid-metabolism, and genetic and clinical factors was analyzed.ResultsA total of 117 patients were included. The mean CAP and low-density lipoprotein cholesterol (LDL-C) levels were significantly elevated at SVR24. However, baseline LDL-C and CAP values were significantly negatively correlated with changes in these values after HCV eradication, indicating that in patients with high baseline values, the values generally decreased after HCV eradication. Mean small-dense LDL-C (sdLDL-C), which has greater atherogenic potential, was significantly elevated only in patients with both dyslipidemia (LDL-C >140 mg/dL) and liver steatosis (CAP >248 dB/m) at SVR24. Those patients had significant higher baseline BMI, LDL-C, and total-cholesterol levels.ConclusionsGenerally, successful HCV eradication by IFN-free-DAAs decreases CAP and LDL-C in patients with high baseline values. However, elevated LDL-C was accompanied with elevated sdLDL-C only in patients with liver steatosis and dyslipidemia at SVR24; therefore, those patients may require closer monitoring.

High Proportion of Subjective Component to the Disease Activity Score is Associated with Favorable Response to Abatacept in Rheumatoid Arthritis.

BackgroundResponse prediction of certain biologic agents for the treatment of rheumatoid arthritis (RA) remains an unmet need in real-world clinical practice. The contribution of patient-reported components to the 28-joint Disease Activity Score (DAS28) was termed DAS28-P and investigated as a predictor of response to biologic agents, mostly tumor necrosis factor inhibitors. We aimed to evaluate DAS28-P as a predictor of the European League Against Rheumatism (EULAR) response to abatacept in patients with RA.MethodsThe study population was a prospective, observational, multicenter cohort of Korean patients with RA, who were followed up for a nationwide post-marketing surveillance study of abatacept. Correlation of DAS28-P with DAS28, change of DAS28, and EULAR response groups were evaluated. Logistic regression analysis was used to predict good-to-moderate EULAR response to abatacept in the study population.ResultsA total of 341 patients were involved in the analysis stratified on the EULAR response criteria. Presence of comorbidities, previous exposure to biologic agents, baseline DAS28, three of its components (tender joint counts, global health visual analog scale, erythrocyte sedimentation rate), and baseline DAS28-P were significantly associated with EULAR response to abatacept at 6 months. Stratified upon EULAR response, a group with good-to-moderate response had a higher baseline value and lower interval change for DAS28-P. Logistic regression analysis showed that a DAS28-P cut-off of > 0.44 was more positively associated with good-to-moderate EULAR response with abatacept treatment than naivety to biologic agents.ConclusionsThe DAS28-P could be predictive of response to abatacept. A higher baseline DAS28-P is associated with a favorable therapeutic response to abatacept.Trial registrationTrial name, Korean Post-marketing Surveillance for Orencia®. Trial registration number, NCT01583244. Registered on April 20, 2012.Electronic supplementary materialThe online version of this article (10.1007/s40271-018-0347-z) contains supplementary material, which is available to authorized users.

Effect of Bronchoscopy on Gas Exchange and Respiratory Mechanics in Critically Ill Patients With Atelectasis: An Observational Cohort Study

Background: Atelectasis frequently develops in critically ill patients and may result in impaired gas exchange among other complications. The long-term effects of bronchoscopy on gas exchange and the effects on respiratory mechanics are largely unknown.Objective: To evaluate the effect of bronchoscopy on gas exchange and respiratory mechanics in intensive care unit (ICU) patients with atelectasis.Methods: A retrospective, single-center cohort study of patients with clinical indication for bronchoscopy because of atelectasis diagnosed on chest X-ray (CXR).Results: In total, 101 bronchoscopies were performed in 88 ICU patients. Bronchoscopy improved oxygenation (defined as an increase of PaO2/FiO2 ratio > 20 mmHg) and ventilation (defined as a decrease of > 2 mmHg in partial pressure of CO2 in arterial blood) in 76 and 59% of procedures, respectively, for at least 24 h. Patients with a low baseline value of PaO2/FiO2 ratio and a high baseline value of PaCO2 were most likely to benefit from bronchoscopy. In addition, in intubated and pressure control ventilated patients, respiratory mechanics improved after bronchoscopy for up to 24 h. Mild complications, and in particular desaturation between 80 and 90%, were reported in 13% of the patients.Conclusions: In selected critically ill patients with atelectasis, bronchoscopy improves oxygenation, ventilation, and respiratory mechanics for at least 24 h.

Prognostic and predictive factors for angiosarcoma patients receiving paclitaxel once weekly plus or minus bevacizumab: an ancillary study derived from a randomized clinical trial

BackgroundWe report here a correlation analysis conducted along with a phase II trial assessing bevacizumab in combination with weekly paclitaxel.MethodsCirculating pro/anti-angiogenic factors were assessed on day 1 (D1) and day 8 (D8). The prognostic value for progression-free survival (PFS) was evaluated using a Cox model with biomarkers as continuous variables.ResultsAmong the 51 patients enrolled and treated in this trial, biomarker analysis was performed for 42: 18 in Arm A (single-agent) and 24 in Arm B (combination). With a median follow-up of 46 months, PFS was 5.5 versus 5.7 months, respectively (p = 0.75). According to univariate analysis, factors associated with a poor PFS were as follows: visceral angiosarcoma, de novo angiosarcoma, and high PlGF and low VEGF-C baseline values. In multivariate analysis, de novo angiosarcoma (HR = 2.5; p = 0.024) and baseline VEGF-C value (HR = 0.7; p = 0.003) were significant prognostic factors. We observed a significant increase in circulating PlGF (< 0.001) and a decrease in VEGF (< 0.001) during bevacizumab treatment. An increase in FGF was associated with a poor outcome.ConclusionsDe novo angiosarcoma and a low baseline level of VEGF-C were found to be associated with a poor prognosis. Addition of bevacizumab induces major changes in circulating biomarkers (VEGF and PlGF) in a short timeframe without impacting PFS.Trial registrationRetrospectively registered on EudraCT N° 2009–017020-59 and NCT01303497 (February 24, 2011).

Effect of L-citrulline supplementation on blood pressure: a systematic review and meta-analysis of randomized controlled trials.

The objective of this study was to systematically investigate the efficacy of oral L-citrulline supplementation on systolic and diastolic blood pressure. Studies were identified by a search of electronic databases from inception to April 2018, and combined and stratified analyses were used. Fifteen trials were identified, and data from 424 participants were included. Pooled analysis showed significant reductions in systolic blood pressure by -7.54 mmHg (95% confidence interval (CI): -9.44, -5.63; P < 0.001, I2 = 14%) and diastolic blood pressure by -3.77 mmHg (95% CI: -5.67, -1.86, P < 0.001, I2 = 42%) following oral supplementation of L-citrulline or a watermelon extract. No changes were detected in controls. Significant heterogeneity (I2 = 42%, P = 0.04) was found for diastolic blood pressure, and subgroup analysis showed significant improvements in systolic and diastolic blood pressure, particularly for study durations: ≥6 weeks, lower doses: ≤4 g/day, and in participants with higher baseline values: ≥130/85 mmHg. In conclusion, L-citrulline improves systolic and diastolic blood pressure and may be more efficacious in pre-hypertensive and hypertensive populations.

C3-epimerization of 25-hydroxyvitamin D increases with increasing serum 25-hydroxyvitamin D levels and shows a high degree of tracking over time

ObjectiveEvaluate the effects of serum 25-hydroxyvitamin D (25(OH)D) levels, vitamin D binding protein (DBP) and genetic factors on C3-epimerization of 25(OH)D and follow the tracking of the epimer during one year. DesignCross-sectional and longitudinal study. MethodsData from eight previously conducted, Tromsø based studies (3 observational, 5 randomized controlled trials) were combined. 25(OH)D serum samples were re-analyzed with a LC-MS/MS method that also resolves and measures the metabolite C3-epi-25(OH)D3. Data on vitamin D binding protein (DBP) phenotype (based on single nucleotide polymorphisms (SNPs) rs4588 and rs7041) and genetic determinants for serum 25(OH)D (SNPs rs2282679, rs10741657, rs3829251 and rs6013897) were collected where available. Results2219 subjects were included. Median (5th, 95th percentiles) baseline serum values of 25(OH)D3, C3-epi-25(OH)D3, and %-C3-epi-25(OH)D3 were 49.1 (22.1, 92.8) nmol/L, 2.3 (0.9, 6.0) nmol/L and 4.4 (2.7, 8.4) %, respectively. The highest baseline values were 230.5 nmol/L for 25(OH)D3, 79.7 nmol/L for C3-epi-25(OH)D3 and 48.2% for %-C3-epi-25(OH)D3. There was a strong correlation between serum 25(OH)D3 and C3-epi-25(OH)D3. The %-C3-epi-25(OH)D3 value increased with increasing serum 25(OH)D3, but leveled off at ~7% at a 25(OH)D3 concentration of ~120–140 nmol/L. There was a significant degree of tracking for %-C3-epi-25(OH)D3 (correlation coefficient rho between baseline and 1-year values 0.39, P < 0.001). The %-C3-epi-25(OH)D3 level was not related to serum DBP level, DBP phenotype nor to SNPs related to serum 25(OH)D3 level. The serum 25(OH)D3 level could explain less than 3% of %-C3-epi-25(OH)D3 variation. ConclusionsThere are considerable individual and reproducible differences in percent C3-epimerization of uncertain clinical importance.

Open-label study of ademetionine for the treatment of intrahepatic cholestasis associated with alcoholic liver disease.

The effect of oral and/or parenteral ademetionine (500 mg intravenous [IV] and tablet formulation) on clinical symptoms and biochemical markers of intrahepatic cholestasis (IHC) was investigated in subjects with alcoholic liver disease (ALD) and compensated liver function. Prospective, multicenter, open-label study consisting of a screening period and an 8-week treatment period and performed in subjects (18-75 years) with compensated ALD and confirmed IHC. Subjects with a baseline serum conjugated bilirubin value above normal range were initially treated with IV ademetionine for two weeks (500-800 mg daily) and continued with oral ademetionine 1500 mg daily for a further six weeks. Subjects with a baseline serum conjugated bilirubin value within normal range were treated with oral ademetionine for eight weeks. A total of 72 subjects were treated; 41 initially with IV ademetionine and 31 with oral ademetionine. Clinical symptoms status improved from baseline to end of treatment with an increase in the proportion of subjects with no symptoms. Ademetionine showed significant improvements in primary efficacy parameters alkaline phosphatase (ALP) and γ-glutamyltransferase (γGT) (P<0.0001). Although decreases of ALP were higher for subjects initially treated with IV ademetionine, these subjects also had higher baseline values. No safety concerns with ademetionine arose with respect to the severity or frequency of adverse events (AEs) during the treatment period, laboratory parameters, and vital signs. Administration of oral or IV/oral ademetionine step-therapy for 8 weeks to subjects with IHC due to ALD was safe and provided a significant improvement of disease burden.

High serum levels of C-reactive protein (CRP) predict beneficial decrease of visceral fat in obese females after sleeve gastrectomy

Background & aimsGender-related differences represent an emerging investigation field to better understand obesity heterogeneity and paradoxically associated cardiovascular (CV) risk. Here, we investigated if high-sensitivity C-reactive protein (hs-CRP) might differently affect adiposity and predict the clinical response to bariatric surgery in obese males and females. Methods and resultsIn 110 morbidly obese patients undergoing laparoscopic sleeve gastrectomy, hs-CRP as well as anthropometric assessment of adiposity, completed by electric bioimpedance and ultrasonography quantification of visceral fat area (VFA), were measured before and one year after surgery. As compared to males, obese female showed less severe overweight and prevalent subcutaneous fat deposition, but higher circulating hs-CRP. In obese females, hs-CRP was associated with VFA at baseline, independently of body mass index (BMI) and visceral adiposity index (OR 1.022 [95% CI 1.001–1.044]; p = 0.039). Based on decreases and increases in hs-CRP levels after surgery, two distinct subgroups of females were identified. Post-surgery decreases in hs-CRP was predominantly observed in patients with higher baseline levels of hs-CRP and associated with greater reduction of weight, BMI, fat and lean mass, VFA and visceral to subcutaneous fat ratio. Finally, we observed that high baseline values of hs-CRP were able to predict VFA reduction one-year after surgery, independently of BMI and visceral adiposity index (VAI) loss (OR 1.031 [95% CI 1.009–1.053]; p = 0.005). ConclusionIn obese females, hs-CRP levels might be a promising biomarker of visceral fat amount and dysfunction, in addition to predict the effectiveness of bariatric surgery in terms of loss of VFA one-year after surgery.

New approaches to address dyslipidemia.

Although lipid-lowering treatment with statins, ezetimibe, and PCSK9 inhibitors is a very successful strategy to prevent cardiovascular events, there is a need for further drug developments. Not all patients respond sufficiently to the available therapy (very high baseline values, intolerance). Furthermore, patients may be characterized by dyslipidemias not accessible to available drugs such as patients with homozygous familial hypercholesterolemia, chylomicronemia syndrome, or elevated lipoprotein(a). A number of drugs are being developed to close these gaps. The focus is on new antibodies, antisense oligonucleotides, and small molecules that address different aspects of lipid metabolism. Many of these developments are promising as they decrease LDL-cholesterol and/or non-HDL-cholesterol and/or triglycerides and/or lipoprotein(a) in patients who so far cannot be treated sufficiently. These drugs are currently in different stages of development and being tested in clinical trials. Some of the new lipid-lowering drugs have a very promising profile. However, eventually phase 3 and outcome trials will be required to prove the usefulness of these compounds in clinical practice. Furthermore, it is unlikely that they will change the primary lipidological approach (statin and ezetimibe) even if they prove successful.

Baseline and stress-induced blood properties of male and female Darwin’s small ground finch (Geospiza fuliginosa) of the Galapagos Islands

Birds are renowned for exhibiting marked sex-specific differences in activity levels and reproductive investment during the breeding season, potentially impacting circulating blood parameters associated with stress and energetics. Males of many passerines often do not incubate, but they experience direct exposure to intruder threat and exhibit aggressive behaviour during the nesting phase in order to defend territories against competing males and predators. Nesting females often have long bouts of inactivity during incubation, but they must remain vigilant of the risks posed by predators and conspecific intruders approaching the nest. Here, we use 33 free-living male (n = 16) and female (n = 17) Darwin's small ground finches (Geospiza fuliginosa) on Floreana Island (Galapagos Archipelago) to better understand how sex-specific roles during the reproductive period impact baseline and stress-induced levels of plasma corticosterone (CORT), blood glucose and haematocrit. Specifically, we hypothesise that males are characterised by higher baseline values given their direct and relatively frequent exposure to intruder threat, but that a standardised stress event (capture and holding) overrides any sex-specific differences. In contrast with expectations, baseline levels of all blood parameters were similar between sexes (13.4 ± 1.9 ng ml−1 for CORT, 13.7 ± 0.4 mmol l−1 for glucose, 58.3 ± 0.8% for haematocrit). Interestingly, females with higher body condition had lower baseline haematocrit. All blood parameters changed with time since capture (range 1.2–41.3 min) in both sexes, whereby CORT increased linearly, haematocrit decreased linearly, and glucose increased to a peak at ∼20 min post-capture and declined to baseline levels thereafter. Our results do not support the hypothesis that sex-specific roles during the reproductive period translate to differences in blood parameters associated with stress and energetics, but we found some evidence that blood oxygen transport capacity may decline as finches increase in body condition.

The effect of pre-operative methylprednisolone on early endothelial damage after total knee arthroplasty: a randomised, double-blind, placebo-controlled trial.

We wished to evaluate whether inhibition of the systemic inflammatory response by a single pre-operative dose of methylprednisolone reduced markers of early endothelial damage after fast-track total knee arthroplasty. We randomly allocated 70 patients undergoing elective unilateral total knee arthroplasty (1:1) to receive either pre-operative intravenous methylprednisolone 125 mg (methylprednisolone group) or isotonic saline (control group). All procedures were performed under spinal anaesthesia without a tourniquet, using a standardised multimodal analgesic regime. The outcomes included changes in Syndecan-1 concentrations, a marker of glycocalyx degradation, markers of endothelial cell damage and activation (plasma soluble thrombomodulin and sE-Selectin), and permeability by vascular endothelial growth factor, as well as C-reactive protein concentrations. Blood samples were collected at baseline and 2 h, 6 h and 24 h after surgery, with complete sampling from 63 patients for analyses. Methylprednisolone significantly reduced markers of endothelial damage at 24 h following surgery compared with saline (methylprednisolone group vs. control group, adjusted means (SEM)) expressed by circulating Syndecan-1: 11.6 (1.0) ng.ml-1 vs. 13.4 (1.1) ng.ml-1 p = 0.046; soluble thrombomodulin: 5.1 (0.1) ng.ml-1 vs. 5.7 (0.2) ng.ml-1 , p = 0.009; sE-Selectin: 64.8 (1.8) ng.ml-1 vs. 75.7 (1.9) ng.ml-1 , p = 0.001, and vascular endothelial growth factor: 35.3 (2.7) ng.ml-1 vs. 58.5 (2.8) ng.ml-1 , p < 0.001. The effect of the intervention increased with time for soluble thrombomodulin, sE-Selectin and vascular endothelial growth factor, and was more pronounced in patients with high baseline values. Finally, methylprednisolone reduced the C-reactive protein response 24 h postoperatively; 31.1 (1.1) mg.l-1 vs. 68.4 (1.1) mg.l-1 , p < 0.001. Pre-operative administration of methylprednisolone 125 mg reduced circulating markers of endothelial activation and damage, as well as the systemic inflammatory response (C-reactive protein) early after fast-track total knee arthroplasty. These findings may have a positive effect on surgical outcome, but require studies in major surgery.

Effects of nitrate supplementation in trained and untrained muscle are modest with initial high plasma nitrite levels.

Nitrate (NO3-) supplementation resulting in higher plasma nitrite (NO2-) is reported to lower resting mean arterial blood pressure (MAP) and oxygen uptake (VO2 ) during submaximal exercise in non-athletic populations, whereas effects in general are absent in endurance-trained individuals. To test whether physiologic effects of NO3- supplementation depend on local muscular training status or cardiovascular fitness, male endurance-trained cyclists (CYC, n=9, VO2 -max: 64±3mL/min/kg; mean±SD) and recreational active subjects serving as a control group (CON, n=8, 46±3mL/min/kg), acutely consumed nitrate-rich beetroot juice ([NO3-] ~9mmol) (NIT) or placebo (PLA) with assessment of resting MAP and energy expenditure during moderate intensity (~50% VO2 -max) and incremental leg cycling (LEG-ex) and arm-cranking exercise (ARM-ex). NIT increased (P<.001) resting plasma NO3- by ~1200% relative to PLA. Plasma NO2- increased ~25% (P<.01) with a significant change only in CYC. LEG-ex VO2 (~2.60L/min), ARM-ex VO2 (~1.14L/min), and resting MAP (~87mm Hg) remained unchanged for CYC, and similarly for CON, no changes were observed for LEG-ex VO2 (~2.03L/min), ARM-ex VO2 (~1.06L/min), or resting MAP (~85mm Hg). VO2 -max was not affected by supplementation, but incremental test peak power was higher (P<.05) in LEG-ex for CYC in NIT relative to PLA (418±47 vs 407±46W). In both CYC and CON, high initial baseline values and small increases in plasma NO2- after NIT may have lowered the effect of the intervention implying that muscular and cardiovascular training status is likely not the only factors that influence the physiologic effects of NO3- supplementation.

An exploratory analysis of the association between levels of hormones implied in steroid biosynthesis and activity of abiraterone in patients with metastatic castration-resistant prostate cancer.

Abiraterone acetate, approved for patients with metastatic castration-resistant prostate cancer (mCRPC), blocks androgen byosinthesis. We aimed to describe changes determined by abiraterone in hormones implied in steroid biosynthesis, exploring association between hormonal levels and drug activity. Patients with mCRPC, receiving standard abiraterone + prednisone after docetaxel failure, were studied. We determined serum levels of progesterone, 17OH-progesterone, cortisol, ACTH, DHEA-sulphate, androstenedione, testosterone, sex hormone-binding globulin, aldosterone, plasma renin activity, and cholesterol, baseline and every 12 weeks. For each hormone, association with treatment activity was tested 1) comparing baseline values in responders vs. non-responders; 2) comparing progression-free survival (PFS) of patients with baseline low vs. high values; 3) comparing values after 12 weeks in responders vs. non-responders. Forty-nine patients were analyzed; 26 patients (53.1%) experienced PSA response. Baseline values of all hormones were not statistically different between responders and non-responders. For all hormones, PFS difference of patients with low vs. high baseline values was not statistically significant. Several hormones showed significant and sustained changes vs. baseline, but all significant changes were similar between responders and non-responders. This analysis does not suggest a significant association between baseline hormonal values, or changes induced by abiraterone, and treatment activity.