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To assess the overall relative risk of diabetes in individuals with prediabetes based on updated diagnostic criteria, as compared with individuals with normoglycaemia; and to identify the study characteristics associated with the heterogeneity between studies.Meta-analysis, meta-regression.PubMed, CINAHL, British Nursing Index. Search time frame: December 1998-December 2018.The pooled relative risk of developing diabetes among individuals with prediabetes compared with those with normoglycaemia was calculated under a random effects model. Studies reported the natural progression from prediabetes to diabetes were included in this review. Sources of study heterogeneity were examined by a meta-regression.Fifty-nine eligible studies were systematically identified. The pooled relative risk for diabetes among individuals with prediabetes as compared with normoglycaemia was 5.88 (95% CI: 5.02-6.89). The annualized incidence rate (per 1,000 person-year) for diabetes among individuals with prediabetes defined by different criteria varied from 2.20-212.15, with high heterogeneity between studies (IIndividuals with prediabetes had higher risk of developing diabetes than those with normoglycaemia. Races and diagnostic criteria of prediabetes were associated with the magnitude of the estimated risk.Prediabetes is a precursor of diabetes. To screen people with prediabetes as early as possible, practitioners could consider haemoglobin A1c test as an alternative to fasting plasma glucose test. Nurses should educate people especially Asians with prediabetes for the prevention of progression to diabetes.目的: 根据更新的诊断标准,与正常血糖的个体相比,评估糖尿病前期个体患糖尿病的总体相对风险;并确定与研究间异质性相关的研究特征。 设计: 荟萃分析、荟萃回归。 数据来源: PubMed、CINAHL、英国护理学索引。搜索时间范围:1998年12月至2018年12月。 审查方法: 在随机效应模型下,计算了与正常血糖个体相比,糖尿病前期个体患糖尿病的合并相对风险度。研究报告指出,从糖尿病前期发展为糖尿病的自然发展被纳入本审查中。通过荟萃回归检查了研究的异质性来源。 结果: 系统化地确定了59项符合条件的研究。与正常血糖个体相比,糖尿病前期个体患糖尿病的合并相对风险度为5.88(95%置信区间:5.02-6.89)。按不同标准定义的糖尿病前期个体的糖尿病年发病率(每1000人-年)在2.20-212.15不等,研究间异质性较高(I2=96.64%,Q检验:P.001)。在多变量荟萃回归分析中,与白种人相比,亚洲人的相对风险度显著增加。此外,‘糖化血红蛋白A1c升高或空腹血糖受损’的人群与其他类型的糖尿病前期人群相比,相对风险度最高。 结论: 糖尿病前期个体患糖尿病的风险血糖正常个体。糖尿病前期的个体类别和诊断标准与估计的风险量级有关。 影响: 糖尿病前期是糖尿病的前兆。为了尽早筛查糖尿病前期人群,医生可以考虑用血红蛋白A1c测试来代替空腹血糖检测。护士应提醒人们,尤其是糖尿病前期的亚洲人,以防止发展成糖尿病。.

Combined elevated sputum eosinophils+neutrophils in asthma associated with lowest lung function, greater healthcare utilization, and longitudinally, further spirometric loss, implicating cell-cell interactions or overlapping inflammatory pathways while increased eosinophils or neutrophils alone show less effect.

BACKGROUND There were gaps between guidelines and practice when surgery was the only treatment for aortic stenosis (AS). OBJECTIVES This study analyzed the decision to intervene in patients with severe AS in the EORP VHD (EURObservational Research Programme Valvular Heart Disease) II survey. METHODS Among 2,152 patients with severe AS, 1,271 patients with high-gradient AS who were symptomatic fulfilled a Class I recommendation for intervention according to the 2012 European Society of Cardiology guidelines; the primary end point was the decision for intervention. RESULTS A decision not to intervene was taken in 262 patients (20.6%). In multivariate analysis, the decision not to intervene was associated with older age (odds ratio [OR]: 1.34 per 10-year increase; 95% CI: 1.11 to 1.61; P = 0.002), New York Heart Association functional classes I and II versus III (OR: 1.63; 95% CI: 1.16 to 2.30; P = 0.005), higher age adjusted Charlson comorbidity index (OR: 1.09 per 1-point increase; 95% CI: 1.01 to 1.17; P = 0.03), and a lower transaortic mean gradient (OR: 0.81 per 10-mm Hg decrease; 95% CI: 0.71 to 0.92; P < 0.001). During the study period, 346 patients (40.2%, median age 84 years, median EuroSCORE II [European System for Cardiac Operative Risk Evaluation II] 3.1%) underwent transcatheter intervention and 515 (59.8%, median age 69 years, median EuroSCORE II 1.5%) underwent surgery. A decision not to intervene versus intervention was associated with lower 6-month survival (87.4%; 95% CI: 82.0 to 91.3 vs 94.6%; 95% CI: 92.8 to 95.9; P < 0.001). CONCLUSIONS A decision not to intervene was taken in 1 in 5 patients with severe symptomatic AS despite a Class I recommendation for intervention and the decision was particularly associated with older age and combined comorbidities. Transcatheter intervention was extensively used in octogenarians. (J Am Coll Cardiol 2021;78:2131-2143) (c) 2021 by the American College of Cardiology Foundation.

Aim We investigated whether acute carbohydrate ingestion reduced arterial potassium concentration ([K+]) during and after intense exercise and delayed fatigue. Methods In a randomized, double‐blind crossover design, eight males ingested 300 ml water containing 75 g glucose (CHO) or placebo (CON); rested for 60 min, then performed high‐intensity intermittent cycling (HIIC) at 130% V˙O2peak, comprising three 45‐s exercise bouts (EB), then a fourth EB until fatigue. Radial arterial (a) and antecubital venous (v) blood was sampled at rest, before, during and after HIIC and analyzed for plasma ions and metabolites, with forearm arteriovenous differences (a‐v diff) calculated to assess inactive forearm muscle effects. Results Glucose ingestion elevated [glucose]a and [insulin]a above CON (p = .001), being, respectively, ~2‐ and ~5‐fold higher during CHO at 60 min after ingestion (p = .001). Plasma [K+]a rose during and declined following each exercise bout in HIIC (p = .001), falling below baseline at 5 min post‐exercise (p = .007). Both [K+]a and [K+]v were lower during CHO (p = .036, p = .001, respectively, treatment main effect). The [K+]a‐v diff across the forearm widened during exercise (p = .001), returned to baseline during recovery, and was greater in CHO than CON during EB1, EB2 (p = .001) and EB3 (p = .005). Time to fatigue did not differ between trials. Conclusion Acute oral glucose ingestion, as used in a glucose tolerance test, induced a small, systemic K+‐lowering effect before, during, and after HIIC, that was detectable in both arterial and venous plasma. This likely reflects insulin‐mediated, increased Na+,K+‐ATPase induced K+ uptake into non‐contracting muscles. However, glucose ingestion did not delay fatigue., Acute glucose intake substantially elevated insulin, with a systemic K+‐lowering effect evident in arterial and antecubital venous plasma before, during, and post‐exercise. An increased arterio‐venous K+ difference across the relatively inactive forearm musculature with glucose ingestion was consistent with increased K+ uptake in non‐active muscle; this was likely mediated via insulin‐induced activation of sodium‐potassium ATPase.

OBJECTIVES The intermediate-term all-cause mortality rate of real-world patients with multivessel disease (MVD) treated with percutaneous coronary intervention (PCI) with new-generation drug-eluting stents or coronary artery bypass grafting (CABG) remains unknown. We sought to compare the intermediate-term all-cause mortality rates of real-world patients with MVD including left main stem disease, treated with CABG or PCI. METHODS All consecutive all-comer patients with MVD undergoing CABG or PCI with second/third generation drug-eluting stents from 2007 to 2015 in Harefield Hospital, UK were included in this study. The revascularization modality was based on heart team discussions. Primary outcome was all-cause mortality. Mean follow-up of the study was 3.3 years. Cox regression analysis and propensity matching were used. RESULTS Of 6383 patients with MVD, 4230 underwent CABG, whereas 2153 had PCI with new-generation stents. In the CABG group, the mean age was 66.4 ± 10 years, whereas in the PCI group it was 65.3 ± 12.1 years (P CONCLUSIONS In this contemporary cohort of real-world patients with MVD, CABG was associated with increased intermediate-term survival compared to PCI with new-generation drug-eluting stents.

Background The survival rates of advanced cancer patients remain low despite clinical therapy advancements. However, physical activity showed promising effects in improving cancer outcomes. This review aimed to systematically evaluate and synthesize the effects on overall mortality of post-diagnosis physical activity in advanced cancer patients. Methods A systematic search of six English databases (PubMed, EMBASE, CINAHL, PsycINFO, The Cochrane Central Register of Controlled Trials, and SPORTDiscus) was conducted from their inception up to 3 February 2021. The association of physical activity with survival was evaluated by combining study-specific hazard ratios with random-effects meta-analysis models. Results Eleven studies were identified. Compared with the reference group, higher-level physical activity was not significantly associated with a lower risk of earlier mortality in advanced cancer patients (InHR = − 0.18, 95% CI, − 0.36 to 0.01). When separated by study type, a higher level of physical activity in non-randomised trials was significantly associated with reduced mortality risk (InHR = − 0.25, 95% CI: − 0.44, − 0.06). However, in randomised trials, engaging in exercise was not significantly associated with a lower mortality risk compared with the control group (InHR = 0.08, 95%CI: − 0.17, 0.32). Conclusions Discrepancies were uncovered in the effect of physical activity on overall survival in randomised and non-randomised trials. In non-randomised trials, a higher level of physical activity was significantly associated with a lower risk of mortality, whereas no significant effect on survival was observed during exercise interventions compared to the control in randomised trials. Considering the wider benefits of physical activity, exercise can still be recommended to improve outcomes for advanced cancer patients. Nevertheless, it might be too late for advanced cancer patients to start exercising for survival improvements, based on findings from randomised controlled trials.

Introduction Percutaneous edge-to-edge mitral repair is a safe treatment method for functional (FMR) and degenerative (DMR) mitral regurgitation. Iatrogenic mitral stenosis remains a concern and periprocedural transoesophageal echocardiography is essential for real-time monitoring of mean mitral pressure gradient (intra-MMPG) and to guide clip deployment. Purpose Published data suggests intra-MMPG predicts clinical outcome and mortality only in DMR patients. We sought to validate these findings in a large high-volume UK center cohort with prolonged follow-up and further explore its use to predict mortality in functional MR patients. Methods All consecutive patients who underwent edge-to-edge mitral repair between 2010 and 2020 were analysed. The intra-MMPG and the severity of MR grade from the transoesophageal echocardiogram post-clip deployment (intra-MRgrade) were collected. Statistical analysis using covariates before and after edge-to-edge repair were compared using paired tests and cox regression models were used to assess the relationship of covariates with all-cause mortality. p Results We analysed data from 246 consecutive patients, 65% were men and mean age was 76±11 years. Pre-procedure LVEF was 49±15%, TAPSE was 16±6 mm, severity of MR was 3.8±0.5, 80% had NYHA III/IV and 45% had FMR. Post procedure, there was a significant reduction in severity of MR grade (3.8±0.5 to 1.7±0.8; p Patients were followed-up for a median of 1021 days (inter-quartile range 289 to 1555) during which 76 patients died. Multivariate survival analysis (see table) showed that the increase in intra-MMPG was independently associated with mortality for FMR, but not for DMR. Furthermore, higher intra-MRgrade was associated with mortality for FMR patients only. Conclusion Intraprocedural mean mitral pressure gradient (intra-MMPG) predicts mortality in percutaneous mitral edge-to-edge repair for FMR, but not for DMR, herby challenging previously published data. Funding Acknowledgement Type of funding source: None

INTRODUCTION: Liver cirrhosis and its complication — hepatocellular carcinoma (HCC) — have been associated with increased exhaled limonene. It is currently unclear whether this increase is more strongly associated with the presence of HCC or with the severity of liver dysfunction. METHODS: We compared the exhaled breath of 40 controls, 32 cirrhotic patients, and 12 cirrhotic patients with HCC using the Breath Biopsy platform. Breath samples were analyzed by thermal desorption–gas chromatography–mass spectrometry. Limonene levels were compared between the groups and correlated to bilirubin, albumin, prothrombin time international normalized ratio, and alanine aminotransferase. RESULTS: Breath limonene concentration was significantly elevated in subjects with cirrhosis-induced HCC (M: 82.1 ng/L, interquartile range [IQR]: 16.33–199.32 ng/L) and cirrhosis (M: 32.6 ng/L, IQR: 6.55–123.07 ng/L) compared with controls (M: 6.2 ng/L, IQR: 2.62–9.57 ng/L) (P value = 0.0005 and 0.0001, respectively) with no significant difference between 2 diseased groups (P value = 0.37). Levels of exhaled limonene correlated with serum bilirubin (R2 = 0.25, P value = 0.0016, r = 0.51), albumin (R2 = 0.58, P value = 5.3e-8, r = −0.76), and international normalized ratio (R2 = 0.29, P value = 0.0003, r = 0.51), but not with alanine aminotransferase (R2 = 0.01, P value = 0.36, r = 0.19). DISCUSSION: Exhaled limonene levels are primarily affected by the presence of cirrhosis through reduced liver functional capacity, as indicated by limonene correlation with blood metrics of impaired hepatic clearance and protein synthesis capacity, without further alterations observed in subjects with HCC. This suggests that exhaled limonene is a potential non-invasive marker of liver metabolic capacity (see Visual abstract, Supplementary Digital Content 1, http://links.lww.com/CTG/A388).

The environment contributes to production diseases that in turn badly affect cow performance, fertility and culling. Oestrus intensity is lower in lame cows, and in all cows 26% potential oestrus events are not expressed (to avoid getting pregnant). To understand these trade-offs, we need to know how animals react to their environment and how the environment influences hypothalamus-pituitary-adrenal axis (HPA) interactions with the hypothalamus-pituitary-ovarian axis (HPO). Neurotransmitters control secretion of GnRH into hypophyseal portal blood. GnRH/LH pulse amplitude and frequency drive oestradiol production, culminating in oestrus behaviour and a precisely-timed GnRH/LH surge, all of which are disrupted by poor environments. Responses to peripheral neuronal agents give clues about mechanisms, but do these drugs alter perception of stimuli, or suppress consequent responses? In vitro studies confirm some neuronal interactions between the HPA and HPO; and immuno-histochemistry clarifies the location and sequence of inter-neurone activity within the brain. In both species, exogenous corticoids, ACTH and/or CRH act at the pituitary (reduce LH release by GnRH), and hypothalamus (lower GnRH pulse frequency and delay surge release). This requires inter-neurones as GnRH cells do not have receptors for HPA compounds. There are two (simultaneous, therefore fail-safe?) pathways for CRH suppression of GnRH release via CRH-Receptors: one being the regulation of kisspeptin/dynorphin and other cell types in the hypothalamus, and the other being the direct contact between CRH and GnRH cell terminals in the median eminence. When we domesticate animals, we must provide the best possible environment otherwise animals trade-off with lower production, less intense oestrus behaviour, and impaired fertility. Avoiding life-time peri-parturient problems by managing persistent lactations in cows may be a worthy trade-off on both welfare and economic terms – better than the camouflage use of drugs/hormones/feed additives/intricate technologies? In the long term, getting animals and environment in a more harmonious balance is the ultimate strategy.

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Aims CT calcium scoring (CTCS) and CT cardiac angiography (CTCA) are widely used in patients with stable chest pain to exclude significant coronary artery disease (CAD). We aimed to resolve uncertainty about the prevalence of obstructive coronary artery disease and long-term outcomes in patients with a zero-calcium score (ZCS). Methods and results Consecutive patients with stable cardiac symptoms referred for CTCS or CTCS and CTCA from chest pain clinics to a tertiary cardiothoracic centre were prospectively enrolled. In those with a ZCS, the prevalence of obstructive CAD on CTCA was determined. A follow-up for all-cause mortality was obtained from the NHS tracer service. A total of 3914 patients underwent CTCS of whom 2730 (69.7%) also had a CTCA. Half of the patients were men (50.3%) with a mean age of 56.9 years. Among patients who had both procedures, a ZCS was present in 52.2%, with a negative predictive value of 99.5% for excluding ≥70% stenosis on CTCA. During a mean follow-up of 5.2 years, the annual event rate was 0.3% for those with ZCS compared with 1.2% for CS ≥1. The presence of non-calcified atheroma on CTCA in patients with ZCS did not affect the prognostic value (P = 0.98). Conclusion In patients with stable symptoms and a ZCS, obstructive CAD is rare, and prognosis over the long-term is excellent, regardless of whether non-calcified atheroma is identified. A ZCS could reliably be used as a ‘gatekeeper’ in this patient cohort, obviating the need for further more expensive tests.

There are limited contemporary studies comparing coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) for isolated proximal left anterior descending (LAD) disease. Increasing stent length and decreasing stent diameters are associated with increased risk of restenosis and adverse outcomes after PCI. Whether these parameters influence outcomes when comparing CABG and PCI is unclear. We compared CABG and PCI in 3,473 patients who underwent revascularization for isolated proximal LAD disease from 2004 to 2015 at Harefield Hospital, UK; 3,078 patients (89%) had PCI and 384 patients had CABG (11%). We analyzed all-cause mortality at 3 years. The unadjusted mortality rates were similar (PCI vs CABG: 9.5% vs 7.0%, p = 0.109). PCI was associated with comparable mortality (hazard ratio [HR] 1.15, 95% confidence interval [CI] 0.70 to 1.89, p = 0.593), even when stratified to bare-metal stents (HR 1.58, 95% CI 0.89 to 2.80, p = 0.121); first-generation drug-eluting stents (FDES; HR 1.16, 95% CI 0.67 to 2.02, p = 0.597); and second-generation DES (SDES; HR 0.98, 95% CI 0.53 to 1.82, p = 0.946). Stent diameters did not influence outcomes, but PCI was associated with higher mortality when stent length ≥30 mm (HR 2.12, 95% CI 1.12 to 4.03, p = 0.022). There was a linear association between stent length and mortality, and for every 1-mm increase in stent length, the 3-year mortality increased by 0.32%. In conclusion, for patients with isolated proximal LAD disease, PCI and CABG were associated with similar mortality. Increasing stent length was progressively associated with worse outcomes with PCI. For longer segments of disease requiring stent lengths ≥30 mm, CABG may be associated with better outcomes.

Background Cangrelor, an intravenous, reversible P2Y12 antagonist, is approved for use in patients undergoing percutaneous coronary intervention (PCI). Objectives This study sought to evaluate the efficacy and safety of cangrelor compared with clopidogrel in subgroups that did and did not receive glycoprotein IIb/IIIa inhibitors (GPIs). Methods This pooled, patient-level analysis of the 3 CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) trials analyzed all randomized patients who underwent PCI and received the study drug (n = 24,902). Only bailout/rescue GPI use was permitted, except in CHAMPION PCI, in which routine or bailout/rescue GPI use was at the site investigator’s discretion. The primary efficacy endpoint was the composite of all-cause mortality, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h after randomization. Results Overall, 3,173 patients (12.7%) received a GPI, most commonly eptifibatide (69.4%). Despite variation in indications for GPIs, baseline characteristics were well balanced between the cangrelor and clopidogrel arms in subsets receiving and not receiving GPIs. Rates of the primary composite endpoint were lower with cangrelor compared with clopidogrel in patients who did (4.9% vs. 6.5%; odds ratio [OR]: 0.74; 95% confidence interval [CI]: 0.55 to 1.01) or did not receive a GPI (3.6% vs. 4.4%; OR: 0.82; 95% CI: 0.72 to 0.94; Pint = 0.55). Cangrelor did not increase the primary safety endpoint, GUSTO-defined severe/life-threatening bleeding, in patients who did (0.4% vs. 0.5%; OR: 0.71; 95% CI: 0.25 to 1.99) or did not receive GPIs (0.2% vs. 0.1%; OR: 1.56; 95% CI: 0.80 to 3.04; Pint = 0.21). GPI use was associated with increased risk of bleeding in both treatment arms. Conclusions Cangrelor’s efficacy in reducing ischemic complications in patients undergoing PCI was maintained irrespective of GPI administration. GPI use was associated with substantially higher bleeding rates, regardless of the randomization to cangrelor or clopidogrel. (A Clinical Trial to Demonstrate the Efficacy of Cangrelor [PCI]: NCT00305162 ; Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition [PLATFORM]: NCT00385138 ; A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX] [CHAMPION]: NCT01156571 )

Introduction: Fibroblast growth factor (FGF23), sclerostin, osteocalcin, and osteoprotegerin are important factors that control mineral bone metabolism. End-stage renal disease is associated with the pronounced dysregulation of mineral bone metabolism; however, the impact and clearance of mineral bone metabolism factors during dialysis remain largely undescribed. Methods: In a cross-sectional study, 10 chronic hemodialysis patients were treated with hemodialysis for 8 h using a high-flux filter and a dialysate bath of 50% calculated total body water continuously recycled at a rate of 500 mL/min. Plasma and dialysate concentrations of FGF23, sclerostin, osteoprotegerin, and osteocalcin were measured at 1, 2, 4, 6, and 8 h permitting the estimation of dialysis clearance. Results: Clearance of FGF23 was 7.7 mL/min, of sclerostin was 7.6 mL/min, of osteoprotegerin was 1.2 mL/min, and of osteocalcin was 19.7 mL/min. Clearance of FGF23 was correlated to sclerostin and osteoprotegerin clearance and also to the ultrafiltration rate. Although, osteocalcin blood concentrations decreased during dialysis, they rebounded within 6 h. Overall, no significant changes in blood concentrations of the measure mineral bone metabolism factors were observed. Conclusions: The intradialytic clearance of osteocalcin, FGF23, sclerostin, and osteoprotegerin occurs; however, only clearance of FGF23 is directly correlated with the ultrafiltration rate. The effects of dialytic clearance on mineral bone metabolism are, however, uncertain and intradialytic plasma concentrations of the studied substrates remained largely unchanged.

Despite advances in cardiopulmonary resuscitation, functional survival remains low after out-of-hospital cardiac arrest (OOHCA). Intra-aortic balloon pump (IABP) therapy has recently been shown to augment cerebral blood flow. Whether IABP therapy in the post-resuscitation period improves functional outcomes is unknown.We analysed 174 consecutive patients who were successfully resuscitated from an OOHCA between 2011-2013 at Harefield Hospital, London. We analysed functional status at discharge and mortality up to one year.A total of 55 patients (32.1%) received IABP therapy. Comparing those receiving IABP with those not receiving IABP, there was no difference in favourable functional status at discharge (49.1% vs. 57.1%, p=0.321); and mortality at one year (45.5% vs. 35.5%, p=0.164). Multivariable analyses identified IABP therapy as a strong independent predictor for favourable functional status at discharge (OR=7.51, 95% CI: 2.15-26.14, p=0.002) and this association was maintained in propensity-score adjusted analyses (OR=9.90, 95% CI: 2.11-46.33, p=0.004) and inverse probability treatment weighted analyses (OR=10.84, 95% CI: 2.75-42.69, p0.001). However, IABP therapy was not an independent predictor for mortality at one year (HR=0.93, 95% CI: 0.52-1.65, p=0.810) and this was confirmed in both propensity-score adjusted and inverse probability treatment weighted analyses.In this observational analysis of patients surviving an OOHCA, the use of IABP therapy in the post-resuscitation period was associated with improved functional outcomes. This warrants further evaluation in larger prospective studies.

Background Patients with acute, decompensated severe mitral regurgitation (MR) are poorly served by surgical or medical treatments and is associated with high mortality. Percutaneous edge-to-edge mitral valve repair (PMVR) with the MitraClip system is potentially a less-invasive life-saving procedure. While PMVR has demonstrated efficacy in stable patients with severe MR, there is limited evidence for its use in patients suffering from prolonged cardiogenic shock, recurrent or persistent pulmonary oedema, and haemodynamic instability. Purpose The aim of this study was to evaluate the effectiveness of emergency PMVR in haemodynamically unstable patients with decompensated MR who were unsuitable for surgical intervention. Methods We performed a retrospective review of all patients who underwent emergency PMVR from January 2015 to January 2019 in a single centre. Inclusion criteria were patients with acute decompensated severe MR and shock (defined at the time of procedure as dependence on one or more of: intravenous (IV) inotropes; afterload reduction for persistent pulmonary oedema; mechanical circulatory support; and invasive respiratory support). Outcome measures were pre- and post-procedural MR severity grade, mortality at six months, and incidence of further mitral valve intervention. Results Of 183 consecutive patients undergoing PMVR, 14 (8%) patients fulfilled the inclusion criteria. Median age was 70 (range 55–88, IQR 23), and 8 were female. At the time of admission, 7 (50%) were in cardiogenic shock and 7 were in persistent pulmonary oedema. MR was functional in 7 (50%) patients and degenerative in 7, of which 4 were secondary to acute papillary muscle rupture. All patients had Grade 4 MR at presentation and were considered too high-risk for surgery by the Heart Team. Median Euroscore II was 14.4 (8.1–54.6, IQR 9.1). Post-procedure, 13 patients (93%) of patients had Grade 3 MR or less. Eleven (79%) patients were successfully weaned from mechanical support and intravenous drugs. The remaining three patients died of persistent arrhythmia, stroke or heart failure within 4 weeks. At six-months, 9 out of 12 patients (75%) were alive and 2 were lost to follow-up. No patients underwent further mitral valve intervention. Conclusions This small case-series suggests that PMVR may be a feasible and life-saving procedure in patients presenting with acute, decompensated severe MR who were unsuitable for surgery. It was associated with reversal of cardiogenic shock and good short-term survival in the majority of patients. These patients are typically considered critically unwell with very high mortality. These promising results may inform larger, prospective studies to manage this otherwise under-served patient cohort.

Stress influences the activity of the reproductive system at several sites. One of the most significant effects is at level of the GnRH secretory system to reduce GnRH pulsatility and thus LH pulsatility. This in turn reduces the oestradiol signal that stimulates the GnRH-LH surge in the follicular phase. Three sequential phases have been identified in the induction of the GnRH-LH surge by oestradiol: (i) activation, (ii) transmission and (iii) surge secretion. There is evidence that administration of endotoxin prevents activation but not transmission, hypoglycaemia blocks both activation and transmission, whereas truck transport is effective during the late, but not early, transmission phase. Opioids mediate the suppressive effects of hypoglycaemia on both LH pulsatility and the delayed onset of the LH surge in ewes. The exact neurocircuitry used in sheep is yet to be identified but many of the connections that are proposed as important in rats are present in sheep. Corticotrophin-releasing hormone (CRH) neurones in the paraventricular nucleus that project axons to the median eminence probably do not directly inhibit GnRH, but either afferent or parallel central pathways are involved. New members of the CRH peptide and receptor families have been identified, but roles in the control of reproduction have yet to be determined.

Transport of post-partum cows or sheep before an oestradiol-induced LH surge delayed gonadotrophin secretion possibly by affecting hypothalamic activity but not via an opioid mediated mechanism as the effect could not be reversed by naloxone. In addition, reduced LH responses to GnRH were observed in cattle during transport. In sheep, adrenocorticotrophic hormone (ACTH) also diminished the LH response to GnRH, but only when GnRH was administered 3 h after ACTH, not after 0.5 h. This finding suggests that very early suppression of LH secretion by stressors is not mediated by ACTH action at the pituitary but that immediate activation of the sympathetic nervous system may be involved. In ewes during the breeding season, repeated exposure to GnRH at intervals of 2 h during transport resulted in lower LH responses to the second and third injections. When anoestrous ewes were treated with oestradiol and GnRH while being restrained and isolated, the onset of the LH surge was delayed. The effects of hypothalamus-pituitary-adrenal hyperactivity on LH release may involve suppression of GnRH receptor activity, a reduction in releasable LH, or both factors. Studies in vitro with perifused ovine pituitaries showed that ACTH or corticotrophin releasing hormone markedly suppressed LH secretion in response to the second of two exposures to GnRH. This occurred with pituitaries obtained from anoestrous ewes irrespective of prior treatment with oestradiol, suggesting that compounds from the hypothalamus-pituitary-adrenal do not exert effects on the oestradiol-sensitizing mechanisms on the pituitary. In conclusion, stressors affect reproductive function via actions at the hypothalamus as well as impairing pituitary LH release induced by GnRH.

INTRODUCTION: Patients with both severe mental illness (SMI) and type II diabetes (T2DM) have lower life expectancy than patients with T2DM alone, partly due to poor control of cardiovascular risk factors in comorbid patients. AIM: To compare levels of cholesterol, HbA1c and blood pressure in T2DM patients with and without SMI. METHOD: We analysed longitudinal clinical records of 30,353 people with T2DM (657 with SMI;29,696 controls without SMI) between 2001 and 2013 using the Clinical Practice Research Datalink (CPRD). We used mixed effects regression models to compare cardiovascular risk factors between SMI and controls. RESULTS: Patients with SMI had lower mean systolic blood pressure (SBP) (β -2.49; SE=0.45 P=

Worldwide, colorectal cancer is the fourth leading cause of death from cancer and the incidence is projected to increase. Many countries are exploring the introduction of organized screening programs, but there is limited information on the resources required and guidance for cost-effective implementation. To facilitate the generating of the economics evidence base for program implementation, we collected and analyzed detailed program cost data from 5 European members of the International Colorectal Cancer Screening Network. The cost per person screened estimates, often used to compare across programs as an overall measure, varied significantly across the programs. In addition, there were substantial differences in the programmatic and clinical cost incurred, even when the same type of screening test was used. Based on these findings, several recommendations are provided to enhance the underlying methodology and validity of the comparative economic assessments. The recommendations include the need for detailed activity-based cost information, the use of a comprehensive set of effectiveness measures to adequately capture differences between programs, and the incorporation of data from multiple programs in cost-effectiveness models to increase generalizability. Economic evaluation of real-world colorectal cancer-screening programs is essential to derive valuable insights to improve program operations and ensure optimal use of available resources.

The mechanisms and prognosis of secondary mitral regurgitation (MR) may be different in patients (pts) with ischemic (ICM) and nonischemic cardiomyopathy (NICM). Whether transcatheter mitral valve repair with MitraClip is equally effective in ICM and NICM is unknown. In COAPT, 614 pts with heart

Intense exercise induces pronounced hyperkalemia, followed by transient hypokalemia in recovery. We investigated whether the β2 agonist salbutamol attenuated the exercise hyperkalemia and exacerbated the postexercise hypokalemia, and whether hypokalemia was associated with impaired cardiac repolarization (QT hysteresis). Eleven healthy adults participated in a randomized, counterbalanced, double-blind trial receiving either 1,000 µg salbutamol (SAL) or placebo (PLAC) by inhalation. Arterial plasma potassium concentration ([K+]a) was measured at rest, during 3 min of intense rowing exercise, and during 60 min of recovery. QT hysteresis was calculated from ECG ( n = 8). [K+]a increased above baseline during exercise (rest, 3.72 ± 0.7 vs. end-exercise, 6.81 ± 1.4 mM, P < 0.001, mean ± SD) and decreased rapidly during early recovery to below baseline; restoration was incomplete at 60 min postexercise ( P < 0.05). [K+]a was less during SAL than PLAC (4.39 ± 0.13 vs. 4.73 ± 0.19 mM, pooled across all times, P = 0.001, treatment main effect). [K+]a was lower after SAL than PLAC, from 2 min preexercise until 2.5 min during exercise, and at 50 and 60 min postexercise ( P < 0.05). The postexercise decline in [K+]a was correlated with QT hysteresis ( r = 0.343, n = 112, pooled data, P = 0.001). Therefore, the decrease in [K+]a from end-exercise by ~4 mM was associated with reduced QT hysteresis by ~75 ms. Although salbutamol lowered [K+]a during exercise, no additive hypokalemic effects occurred in early recovery, suggesting there may be a protective mechanism against severe or prolonged hypokalemia after exercise when treated by salbutamol. This is important because postexercise hypokalemia impaired cardiac repolarization, which could potentially trigger arrhythmias and sudden cardiac death in susceptible individuals with preexisting hypokalemia and/or heart disease. NEW & NOTEWORTHY Intense rowing exercise induced a marked increase in arterial potassium, followed by a pronounced decline to hypokalemic levels. The β2 agonist salbutamol lowered potassium during exercise and late recovery but not during early postexercise, suggesting a protective effect against severe hypokalemia. The decreased potassium in recovery was associated with impaired cardiac QT hysteresis, suggesting a link between postexercise potassium and the heart, with implications for increased risk of cardiac arrhythmias and, potentially, sudden cardiac death.

Background Studies comparing coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) have largely been performed in the bare-metal stent (BMS) and first-generation drug eluting stent (F-DES) era. Second-generation DES (S-DES) have shown improved outcomes when compared to F-DES, but data comparing CABG with PCI using S-DES is limited. We compared mortality following CABG versus PCI for patients with multivessel disease and analyzed different stent types. Methods A total of 6,682 patients underwent multivessel revascularization at Harefield Hospital, UK. We stratified CABG patients into single arterial graft (SAG) or multiple arterial grafts (MAG); and PCI patients into BMS, F-DES or S-DES groups. We analyzed all-cause mortality at 5 years. Results 4,388 patients had CABG (n[SAG] = 3,358; n[MAG] = 1,030) and 2,294 patients had PCI (n[BMS] = 416; n[F-DES] = 752; n[S-DES] = 1,126). PCI had higher 5-year mortality with BMS (HR = 2.27, 95% CI:1.70–3.05, p

AIMS We aimed to investigate why many patients with ST-segment elevation myocardial infarction (STEMI) initially present to non-primary percutaneous coronary intervention (PPCI) equipped hospitals in a region that offers a 24-hour direct access Heart Attack Centre. METHODS AND RESULTS A retrospective stratified consecutive case analysis was performed for 180 inter-hospital transfer (IHT) and 201 direct access PPCI patients. IHT and direct patients had similar age (61±1.8 years vs. 62±1.9 years, p=0.42), gender (76% vs. 78% male, p=0.64), and cardiovascular risk profile (hypertension 53% vs. 46%, p=0.18; hypercholesterolaemia 32% vs. 25%, p=0.22; and smoking 38% vs. 35%, p=0.56), though there were more diabetic patients in the IHT group (15% vs. 8%, p

ObjectiveTo evaluate the prognosis of primary percutaneous coronary intervention (PPCI) and medical therapy (MT) in elderly patients presenting with ST-elevation myocardial infarction (STEMI).MethodsA total of 238 STEMI patients aged above 80 and treated with PPCI (n=186) and MT (n=52) at Harefield Hospital, London were included in this study. Patients who did not have true STEMI based on non-diagnostic electrocardiogram (ECG) for STEMI and negative troponin, who presented with left bundle branch block (LBBB) and had normal coronaries were excluded from this study. Primary PCI was defined as any use of a guidewire for more than diagnostic purposes in patients with STEMI, whereas conventional MT was defined as treatment of patients with anti-platelets and anti-thrombotic medications without thrombolysis.ResultsThe survival rate of PPCI patients was 86% (n=160) at month 1 followed by 83.9% (n=156) at month 6, and 81.2% (n=151) at month 12. The survival rate of MT patients was 44.2% (n=23) at month 1 followed by 36.5% (n=19) at month 6, and 34.6% (n=18) at month 12. Compared to MT, significantly fewer comorbidities were found in the PPCI group. Ventricular fibrillation (VF) (4.8%) and consequent admission to intensive care unit (7%) were the major complications of the PPCI group.ConclusionPPCI has a higher survival rate and, compared to MT, fewer comorbidities were observed in the PPCI group of elderly patients presenting with STEMI.

Disruption of the rest-activity rhythm in patients with lung cancer can accelerate cancer progression and affect survival. Rest-activity rhythm changes with age. Therefore, we investigated the effects of rest-activity rhythm and age on patients' survival. A total of 84 patients with lung cancer were recruited, then separated into two groups; younger patients aged under 65 years or elderly patients aged 65 and over. The dichotomy index (I

In the ewe, steroid hormones act on the hypothalamic arcuate nucleus (ARC) to initiate the GnRH/LH surge. Within the ARC, steroid signal transduction may be mediated by estrogen receptive dopamine-, β-endorphin- or neuropeptide Y (NPY)-expressing cells, as well as those co-localising kisspeptin, neurokinin B (NKB) and dynorphin (termed KNDy). We investigated the time during the follicular phase when these cells become activated (i.e., co-localise c-Fos) relative to the timing of the LH surge onset and may therefore be involved in the surge generating mechanism. Furthermore, we aimed to elucidate whether these activation patterns are altered after lipopolysaccharide (LPS) administration, which is known to inhibit the LH surge. Follicular phases of ewes were synchronised by progesterone withdrawal and blood samples were collected every 2 h. Hypothalamic tissue was retrieved at various times during the follicular phase with or without the administration of LPS (100 ng/kg). The percentage of activated dopamine cells decreased before the onset of sexual behaviour, whereas activation of β-endorphin decreased and NPY activation tended to increase during the LH surge. These patterns were not disturbed by LPS administration. Maximal co-expression of c-Fos in dynorphin immunoreactive neurons was observed earlier during the follicular phase, compared to kisspeptin and NKB, which were maximally activated during the surge. This indicates a distinct role for ARC dynorphin in the LH surge generation mechanism. Acute LPS decreased the percentage of activated dynorphin and kisspeptin immunoreactive cells. Thus, in the ovary-intact ewe, KNDy neurones are activated prior to the LH surge onset and this pattern is inhibited by the administration of LPS.

The recent revisions of the Organisation for Economic Co-operation and Development (OECD) genetic toxicology test guidelines emphasize the importance of historical negative controls both for data quality and interpretation. The goal of a HESI Genetic Toxicology Technical Committee (GTTC) workgroup was to collect data from participating laboratories and to conduct a statistical analysis to understand and publish the range of values that are normally seen in experienced laboratories using TK6 cells to conduct the in vitro micronucleus assay. Data from negative control samples from in vitro micronucleus assays using TK6 cells from 13 laboratories were collected using a standard collection form. Although in some cases statistically significant differences can be seen within laboratories for different test conditions, they were very small. The mean incidence of micronucleated cells/1000 cells ranged from 3.2/1000 to 13.8/1000. These almost four-fold differences in micronucleus levels cannot be explained by differences in scoring method, presence or absence of exogenous metabolic activation (S9), length of treatment, presence or absence of cytochalasin B or different solvents used as vehicles. The range of means from the four laboratories using flow cytometry methods (3.7-fold: 3.5-12.9 micronucleated cells/1000 cells) was similar to that from the nine laboratories using other scoring methods (4.3-fold: 3.2-13.8 micronucleated cells/1000 cells). No laboratory could be identified as an outlier or as showing unacceptably high variability. Quality Control (QC) methods applied to analyse the intra-laboratory variability showed that there was evidence of inter-experimental variability greater than would be expected by chance (i.e. over-dispersion). However, in general, this was low. This study demonstrates the value of QC methods in helping to analyse the reproducibility of results, building up a 'normal' range of values, and as an aid to identify variability within a laboratory in order to implement processes to maintain and improve uniformity.

The aim of this study was to investigate how acute insulin-induced hypoglycaemia (IIH) alters the activity of cells containing oestradiol receptor α (ERα) or somatostatin (SST) in the arcuate nucleus (ARC) and ventromedial nucleus (VMN), and ERα cells in the medial preoptic area (mPOA) of intact ewes. Follicular phases were synchronized with progesterone vaginal pessaries. Control animals were killed at 0 h or 31 h (n = 5 and 6, respectively) after progesterone withdrawal (PW; time zero). At 28 h, five other animals received insulin (INS; 4 iu/kg) and were subsequently killed at 31 h. Hypothalamic sections were immunostained for ERα or SST each with c-Fos, a marker of neuronal transcriptional activation. Insulin did not alter the percentage of activated ERα cells in the ARC; however, it appeared visually that two insulin-treated animals (INS responders, with no LH surge) had an increase in the VMN (from 32 to 78%) and a decrease in the mPOA (from 40 to 12%) compared to no increase in the two INS non-responders (with an LH surge). The percentage of activated SST cells in the ARC was greater in all four insulin-treated animals (from 10 to 60%), whereas it was visually estimated that activated SST cells in the VMN increased only in the two insulin responders (from 10 to 70%). From these results, we suggest that IIH stimulates SST activation in the ARC as part of the glucose-sensing mechanism but ERα activation is unaffected in this region. We present evidence to support a hypothesis that disruption of the GnRH/LH surge may occur in insulin responders via a mechanism that involves, at least in part, SST cell activation in the VMN along with decreased ERα cell activation in the mPOA.

Background. The TT approach has significantly improved the outcome of multiple myeloma (MM) by combining new drugs with a regimen that comprises induction, tandem autologous stem cell transplantation (ASCT), consolidation and maintenance. However, a group of 15% of patients with high risk multiple myeloma (HRMM) have derived little benefit despite similar response rates to induction chemotherapy and ASCT when compared to low risk MM. The poor outcome of HRMM is explained by early relapse post ASCT resulting in a short progression free survival (PFS) with only 15-20% of patients surviving long-term. Daratumumab (Dara) is a human IgG1k anti-CD38 monoclonal antibody that has shown favorable results in early single-arm studies and more recently in phase III studies for relapsed/refractory and newly diagnosed MM. In TT7, we introduced Dara during all phases of therapy, including immune consolidation early post ASCT, to improve responses rate and PFS in HRMM. Methods. Patients had newly diagnosed HRMM as defined by high risk cytogenetic abnormalities, presence of extramedullary disease, >3 focal lesions on CT-PET, elevated LDH due to MM, or ISS II/III with cytogenetic abnormality. Dara (16mg/kgx1) was added to induction with KTD-PACE (carfilzomib, thalidomide, dexamethasone; and four-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide). Conditioning for tandem autologous stem cell transplantation (ASCT) was with fractionated melphalan (50mg/m2x4) (fMEL) based on prior observations that patients with adverse cytogenetics fare better with fMEL rather than single high dose MEL200mg/m2.In the inter tandem ASCT period immunological consolidation with Dara (16mg/kg) alone for 2 doses was followed by Dara (16mg/kg) on day 1 combined with K (36mg/m2) and D (20mg) weekly for 2 cycles. DaraKD was administered to avoid treatment free periods allowing for myeloma regrowth. The 2nd ASCT was followed by further immunological consolidation with Dara (16mg/k) for 2 doses, and maintenance therapy for 3 yrs with 3-months block of alternating Dara-KD (dara 16mg/kg day 1; K 36mg/m2 and dex 20mg weekly) and Dara-lenalidomide (R)D (dara 16mg/kg day 1; R 15mg day 1-21 q28 and D 20mg weekly). Results. TT7 enrolled 43 patients thus far. The median follow-up was 11 months (range: 1-22). The median age was 61 yrs (range 44-73). Sixteen patients were ≥65 yrs (37.2%). A mean of 29.4x106 CD34+ cells/kg (range: 4.6-86.4) were collected. 36 patients completed ASCT #1 (83.7%) and 18 (41.9%) ASCT #2, whilst 14 patients have proceeded to the maintenance phase. R-ISS II/III or metaphase cytogenetic abnormalities were present in 85.1 and 58.1% of patients, respectively. Elevated LDH or >3FL on CT-PET were noted in 30 and 41.8%. The 1-yr cumulative incidence estimates for reaching VGPR and PR were 87 and 83%, respectively. A CR or sCR was achieved in 68 and 46%. The 1-yr estimates of PFS and OS were 91.6 and 87.2%. 40 subjects are alive, whilst 5 progressed on study therapy and 3 subsequently died. 38 patients are progression free at the time of reporting. Dara was well-tolerated and no subjects discontinued therapy due to dara-related side effects. The CR and sCR rates compared favorably to the predecessor HRMM TT5 protocol where CR and sCR rates were 59 and 27%. Conclusion. The early results of TT7 point to increased response rates of HRMM to a dara-based TT regimen with especially higher rates of CR and sCR. Longer follow-up is required to determine if these early results translate into superior PFS and OS. Figure Disclosures van Rhee: Karyopharm Therapeutics: Consultancy; Kite Pharma: Consultancy; Adicet Bio: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy. Walker:Celgene: Research Funding. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding.

There are no randomized clinical trials on efficacy of Entecavir in Fulminant Hepatic Failure (FHF) due to Hepatitis B Virus (HBV). Definitive treatment of FHF remains Liver Transplant. However, availability of cadaveric donor organs is limited, and many of the patients with FHF may not be candidates for Liver Transplantation. There are only few case reports on beneficial effects of Entecavir in FHF due to HBV. We present 2 cases of FHF due to HBV. Both patients had severe liver cell damage among which one was immunocompromised. Transaminases were elevated up to 200 times the normal. Both were not transplant candidates, and were successfully treated with Entecavir resulting in significant clinical and transaminases improvement within 7 days of starting Entecavir. DOI: http://dx.doi.org/10.3126/jaim.v2i2.8780 Journal of Advances in Internal Medicine 2013;02(02):67-70

Spontaneous left main coronary artery dissection is a rare cause of acute coronary events or sudden cardiac death, constituting less than 1% of all epicardial coronary artery dissections. It is often fatal and is mostly recognized at post-mortem examination in young victims of sudden death. More than 70% of the reported cases occurred in women, particularly during pregnancy and the peripartum period and those on oral contraceptives. The clinical presentation is highly variable and prognosis varies widely, depending predominantly on the speed of diagnosis. Treatment options include medical therapy, revascularization with coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) and mechanical circulatory support in cases of cardiogenic shock. We report a case of spontaneous dissection of the left main stem coronary artery, with extension into the left coronary territory, which occurred in a 41-year-old lady, complicated by profound cardiogenic shock requiring recovery with extracorporeal mechanical circulatory support after salvage myocardial revascularization.

Background More than half of the patients undergoing percutaneous coronary intervention (PCI) have multivessel disease. Whether complete revascularization impacts long-term mortality or whether selected patients or those with specific coronary anatomy benefit from complete revascularization is unclear. Methods A total of 14,452 patients underwent PCI between 2004 and 2015 at Harefield Hospital, UK. Of these, 7,076 patients had multivessel disease. We excluded 321 patients with left main-stem stenosis ≥50%, with 6,755 patients included in the analysis (936 patients had complete revascularization). Results The unadjusted 3-year mortality rates were lower with complete revascularization (10.8% vs 13.1%, P = 0.047). However, multivariable-adjusted analyses indicated that complete revascularization was not independently associated with mortality (HR = 1.01, 95% CI: 0.78–1.31, P = 0.939). These findings were unchanged when addressing measured confounding using propensity-matched analyses (HR = 1.16, 95% CI: 0.81–1.65, P = 0.417) and inverse probability treatment weighted analyses (HR = 1.01, 95% CI: 0.77–1.33, P = 0.950); and unmeasured confounding using instrumental variable analyses (Δ = 0.9%, 95% CI: −2.5%, 4.3%, P = 0.958). There was no association with mortality and untreated LAD disease (HR = 0.92, 95% CI: 0.72–1.17, P = 0.482) and LCx disease (HR = 0.90, 95% CI: 0.74–1.10, P = 0.999). However, untreated proximal LAD disease (HR = 1.23, 95% CI: 1.06–1.51, P = 0.045) and RCA disease (HR = 1.36, 95% CI: 1.08–1.65, P = 0.007) was associated with increased mortality, particularly in patients with ST-elevation acute coronary syndrome (STEACS). Conclusions In this study of unselected patients undergoing PCI, complete revascularization did not confer a mortality benefit. However, the presence of untreated proximal LAD and RCA disease was prognostic in patients with STEACS. Thus, complete revascularization may be considered in select patient groups with anatomical subsets of coronary disease.

Salbutamol inhalation is permissible by WADA in athletic competition for asthma management and affects potassium regulation, which is vital for muscle function. Salbutamol effects on arterial potassium concentration ([K+]a) during and after high-intensity continuous exercise (HIcont) and intermittent exercise comprising repeated, brief sprints (HIint), and on performance during HIint are unknown and were investigated. Seven recreationally active men participated in a double-blind, randomised, cross-over design, inhaling 1000 µg salbutamol or placebo. Participants cycled continuously for 5 min at 40 % $$ {\dot{\text{V}}} $$ O2peak and 60 % $$ {\dot{\text{V}}} $$ O2peak, then HIcont (90 s at 130 % $$ {\dot{\text{V}}} $$ O2peak), 20 min recovery, and then HIint (3 sets, 5 × 4 s sprints), with 30 min recovery. Plasma [K+]a increased throughout exercise and subsequently declined below baseline (P

The National Heart, Lung, and Blood Institute Severe Asthma Research Program (SARP) has characterized over the past 10 years 1,644 patients with asthma, including 583 individuals with severe asthma. SARP collaboration has led to a rapid recruitment of subjects and efficient sharing of samples among participating sites to conduct independent mechanistic investigations of severe asthma. Enrolled SARP subjects underwent detailed clinical, physiologic, genomic, and radiological evaluations. In addition, SARP investigators developed safe procedures for bronchoscopy in participants with asthma, including those with severe disease. SARP studies revealed that severe asthma is a heterogeneous disease with varying molecular, biochemical, and cellular inflammatory features and unique structure–function abnormalities. Priorities for future studies include recruitment of a larger number of subjects with severe asthma, including children, to allow further characterization of anatomic, physiologic, biochemical, and genetic factors related to severe disease in a longitudinal assessment to identify factors that modulate the natural history of severe asthma and provide mechanistic rationale for management strategies.

Acute insulin administration causes a disparity between the onset of estrous behavior and the LH surge in ovary-intact ewes. To examine the considerable variation in responses, in the present study we used a large number of animals to confirm findings with insulin, and examine whether endotoxin has the same effect. During the breeding season, follicular phases of intact ewes were synchronized with progesterone vaginal pessaries and received saline vehicle (n=22; controls), insulin (4 IU/kg; n=21 ewes) or endotoxin (LPS; 100 ng/kg; n=10) at 28 h after progesterone withdrawal (time zero). In controls, the LH surge onset occurred at 36.5±5.7 h and were first mounted by a ram at 38.2±1.8 h, but there was a delay of 17.6 h (P0.001) and 7.2 h (P0.05), respectively, in half the insulin-treated animals ('insulin-delayed') but not in the other half; and a delay of 22.5 h (P0.001) and 20.7h (P0.001), respectively, in all LPS-treated animals. Plasma estradiol concentrations decreased after both stressors, and remained low for a period of time equivalent to the LH surge delay (P0.001; Rs-q=78%). Cortisol increased for 12h after treatment in both insulin subgroups and the LPS group (P0.05); whereas progesterone increased in the insulin-delayed and LPS groups from 4.0±0.5 ng/ml and 5.3±1.0 ng/ml to a maximum of 5.7±0.3 ng/ml and 8.8±1.6 ng/ml, respectively (P0.05 for both comparisons). Plasma triglycerides were measured to assess insulin resistance, but concentrations were similar before and after treatment (0.25±0.01 mmol/l versus 0.21±0.01 and 0.25±0.01 mmol/l versus 0.26±0.01 mmol/l in the insulin-non delayed and insulin delayed subgroups, respectively). Therefore, we hypothesize that a) when an acute stressor is applied during the late follicular phase, the duration of the LH surge delay is related to the duration of estradiol signal disruption b) cortisol is not the key disruptor of the LH surge after insulin, c) insulin (but not LPS) can separate the onsets of LH surge and estrus by approximately 10h, providing a model to identify the specific neuronal systems that control behavior distinct from those initiating the GnRH surge.

The objective of this study was to examine the effect of a chronic stressor, lameness, on reproductive parameters. Seventy cows 30–80 days post-partum were scored for lameness and follicular phases synchronized with GnRH followed seven days later by prostaglandin (PG). Fifteen Lame animals did not respond to GnRH ovarian stimulation. Milk progesterone for 5 days prior to PG was lower in the remaining Lame cows than Healthy herdmates. Fewer Lame cows ovulated (26/37 versus 17/18; P = 0.04) and the interval from PG to ovulation was shorter in Lame cows. In Subset 1 (20 animals), the LH pulse frequency was similar in ovulating animals (Lame and Healthy) but lower in Lame non-ovulators. An LH surge always preceded ovulation but lameness did not affect the interval from PG to LH surge onset or LH surge concentrations. Before the LH surge, estradiol was lower in non-ovulating cows compared to those that ovulated and estradiol concentrations were positively correlated with LH pulse frequency. In Subset 2 (45 cows), Lame ovulating cows had a less intense estrus than Healthy cows, although Lame cows began estrus and stood-to-be-mounted earlier than Healthy cows. In conclusion, we have identified several parameters to explain poor fertility in some chronically stressed animals. From 30 to 80 days post-partum, there was a graded effect that ranged from 29% Lame cows with absence of ovarian activity, whereas another 21% Lame cows failed to express estrus or ovulate a low estrogenic follicle; in 50% cows, many reproductive parameters were unaffected by lameness.

Vandetanib (ZD6474) is an orally available inhibitor of 3 signaling pathways important in tumor progression: vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection tyrosine kinase activity. Current development of vandetanib is focused on the treatment of non-small-cell lung cancer and other tumor types, including thyroid cancer. This study was conducted as a requirement for regulatory submission for vandetanib in China.To determine the pharmacokinetics of vandetanib in Chinese patients with advanced, solid, malignant tumors and to compare these with data obtained in Japanese and Western populations.Phase I consisted of a nonrandomized, open-label, single-center study conducted in Guangzhou, China. Adult patients (12 per treatment) who had tumors refractory to standard treatments or for whom no appropriate therapies existed received oral vandetanib (100 mg every other day, 100 mg once daily, or 300 mg once daily) until disease progression or discontinuation in the study. The initial cohort was dosed at 100 mg every other day. Once at least 3 patients had received this dose of vandetanib for 28 days without experiencing dose-limiting toxicity, a second cohort at 100 mg once daily was started. Following the same criteria, the third cohort received 300 mg once daily. Pharmacokinetics, tolerability, and tumor response were assessed. The pharmacokinetics of vandetanib in Chinese, Western, and Japanese patients were compared through a combined population pharmacokinetic model. Tolerability was assessed by recording adverse events and monitoring physical examination, body weight, performance status, vital signs, urinalysis, biochemistry, hematology, and 12-lead electrocardiogram.Thirty-six patients were enrolled (age range 21-82 years, 56% male, body mass index range 17.6-33.0 kg/m(2)). Thirty-three of 36 patients (92%) were World Health Organization performance status 0-1. Vandetanib pharmacokinetics were linear over the dose range studied with AUC(ss) for the 300 mg once daily group (38611 ng/h/mL) being 3.6-fold higher than that for the 100 mg once daily group (10826 ng/h/mL). Absorption was relatively slow following a single 100- or 300-mg dose, with T(max) ranging from 2 to 10 hours. Interpatient variability in C(max SS) and AUC(SS) was relatively high, with the coefficient of variation ranging from 29.1% to 40.6%. Vandetanib plasma clearance was slow (7.8-9.2 L/h) and was independent of dose. The most common drug-related adverse events were rash (42%) and diarrhea (39%). No QT(C) prolongation was observed. Hypertension was reported as an adverse event in 3 patients. There were no clinically relevant changes in hematology, urinalysis, or World Health Organization performance status. Elevation of alanine aminotransferase was reported as an adverse event in 1 patient. One patient with medullary thyroid cancer showed a partial tumor response. Population pharmacokinetic analysis suggests that vandetanib pharmacokinetics appear to be comparable in Chinese, Western, and Japanese patients.The pharmacokinetic properties of vandetanib in these Chinese patients were characterized by low plasma clearance of approximately 8 L/h, a long half-life of approximately 8 to 10 days, and an accumulation of approximately 8-fold to 15-fold on multiple dosing. In these Chinese patients, the pharmacokinetic profile of vandetanib appeared to be comparable with that observed in Japanese and Western populations. Oral doses up to 300 mg once daily appeared to be well tolerated.

The aim of this study was to determine the neuronal responses following insulin administration during the late follicular phase. Intact ewes were given either saline or insulin (5 IU/kg, i.v.) at 35 h after progesterone withdrawal and killed 3 h later. There was a marked increase in the number of Fos-positive noradrenergic neurones in the caudal brainstem of insulin-treated ewes. In the hypothalamic paraventricular nucleus, insulin treatment increased the presence of Fos-positive corticotrophin-releasing hormone neurones (from 2% to 98%) and Fos-positive arginine vasopressin parvocellular neurones (from 2% to 46%). Interestingly, after insulin treatment, despite a general increase in Fos-positive neurones in the arcuate nucleus (ARC), there was a marked reduction (from 47% to 1%) in Fos-positive β-endorphin neurones. Similarly, colocalized Fos and oestradiol receptor (ER) α-positive neurones decreased in the ARC after insulin (from 7% to 3%). Conversely, in the ventromedial nucleus, ERα-positive neurones with Fos increased (from 7% to 22%) alongside a general increase in Fos-positive neurones. Overall, a complex system of neurones in brainstem and hypothalamus is activated following insulin administration during the late follicular phase.

Vandetanib, an oncology drug being evaluated in phase III clinical trials, undergoes significant renal and hepatic excretion. The objective of these two studies was to investigate the single-dose pharmacokinetics of vandetanib in subjects with renal or hepatic impairment in comparison with healthy subjects.Two open-label, parallel-group studies were conducted at a single centre in Germany. Subjects aged 18-75 years with a body mass index of 18-32 kg/m2 were eligible. The renal impairment study recruited subjects with normal renal function and mild, moderate and severe renal impairment according to creatinine clearance calculated from a 24-hour urine collection pre-dose. The hepatic impairment study recruited subjects with normal hepatic function and mild, moderate and severe hepatic impairment according to the Child-Pugh classification. All subjects received a single 800 mg oral vandetanib dose. Blood samples for measurement of vandetanib, N-desmethylvandetanib and vandetanib N-oxide were collected before and at various timepoints after vandetanib administration for up to 63 days. Pharmacokinetic parameters were determined using noncompartmental methods.Thirty-two subjects were recruited for the renal impairment study (ten with normal renal function and six, ten and six with mild, moderate and severe impairment, respectively). Thirty subjects were recruited for the hepatic impairment study (eight with normal hepatic function and eight, eight and six with mild, moderate and severe impairment, respectively). The area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) values of free vandetanib increased by approximately 46%, 62% and 79% in subjects with mild, moderate and severe renal impairment, respectively. These increases were statistically significant, with the increase in the severe renal impairment group having the possibility of being double the value observed in subjects with normal renal function (geometric least squares [GLS] mean ratio [renal impairment : normal renal function] of 1.79; 90% CI 1.39, 2.31). Peak plasma concentrations of free vandetanib increased slightly by approximately 7%, 9% and 11% in subjects with mild, moderate and severe renal impairment, respectively. Total plasma clearance of free vandetanib decreased with all degrees of renal dysfunction. Hepatic impairment did not have a statistically significant effect on the AUC(infinity) of total vandetanib. Peak plasma concentrations of total vandetanib were reduced in subjects with all classifications of hepatic impairment compared with normal hepatic function, with a statistically significant effect in the severe hepatic impairment group (GLS mean ratio 0.71; 90% CI 0.53, 0.96). Increased exposure to both metabolites was seen in subjects with renal impairment. Exposure to N-desmethylvandetanib was reduced in subjects with hepatic impairment, while exposure to vandetanib N-oxide was increased in subjects with severe hepatic impairment. Vandetanib was well tolerated and had a similar tolerability profile in subjects with renal or hepatic impairment compared with healthy subjects.Exposure to vandetanib was increased by about 46%, 62% and 79% in subjects with mild, moderate and severe renal impairment, respectively. A doubling in exposure could be ruled out in subjects with mild or moderate renal impairment but not for those with severe renal impairment. The possibility of dose reductions in patients with severe renal impairment will need to be assessed when the safety and tolerability profile is fully defined. Exposure to vandetanib was not altered in subjects with hepatic impairment, and no dose adjustment would be expected in patients with hepatic impairment.

The objectives of the present study were to quantify the effects of a biological chronic stressor (lameness) on the duration and frequency of different oestrous behaviours in parallel with milk hormone profiles. Dairy cows 51.8 +/- 1.4 days postpartum (n = 59), including 18 non-lame control cows, were scored for lameness and closely observed for signs of oestrus having had their follicular phases synchronized by administration of gonadotrophin-releasing-hormone (GnRH) followed by prostaglandin F(2alpha) (PG) 7 days later. Lameness shortened the period when herd-mates attempted to mount the lame cows (1.83 +/- 0.69 h vs 5.20 +/- 1.53 h; p = 0.042) but did not affect the overall duration of total behaviours (lame 12.3 +/- 1.3 h vs non-lame 15.2 +/- 1.3 h). Lameness also lowered the intensity of oestrus [1417 +/- 206 points (n = 18) vs 2260 +/- 307 points (n = 15); p = 0.029]. Throughout the synchronized oestrous period, lame cows mounted the rear of herd-mates less frequently (p = 0.020) and tended to chin rest less (p = 0.075). Around the period of maximum oestrous intensity, lameness also diminished the proportion of cows mounting the rear of another cow and chin resting (p = 0.048, p = 0.037, respectively). Furthermore, lame cows had lower progesterone values during the 6 days before oestrous (p < or = 0.05). Fewer lame cows were observed in oestrus following PG (non-lame 83%, lame 53%; p = 0.030); however, if prior progesterone concentrations were elevated, lame cows were just as likely to be observed in oestrus. In conclusion, following endogenous progesterone exposure, lameness shortens the period when herd-mates attempt to mount lame cows but does not affect the incidence of oestrous. However, lame cows are mounted less frequently and express oestrus of lower intensity. This is associated with lower progesterone prior to oestrus but not with abnormal oestradiol or cortisol profiles in daily milk samples.

This study investigated possible integrated links in the neuroanatomical pathways through which the activity of neurones in the paraventricular nucleus and arcuate nucleus may modulate suppression of gonadotrophin-releasing hormone (GnRH) secretion during stressful situations. Double-label immunofluorescence and laser scanning confocal microscopy were used to examine the hypothalamic sections from the follicular phase ewes. Noradrenergic terminals were in close contact with 65.7 ± 6.1% corticotrophin-releasing hormone (CRH) and 84.6 ± 3.2% arginine vasopressin (AVP) cell bodies in the paraventricular nucleus but not with β-endorphin cell bodies in the arcuate nucleus. Furthermore, γ-amino butyric acid (GABA) terminals were close to 80.9 ± 3.5% CRH but no AVP cell bodies in the paraventricular nucleus, as well as 60.8 ± 4.1%β-endorphin cell bodies in the arcuate nucleus. Although CRH, AVP and β-endorphin cell terminals were identified in the medial pre-optic area, no direct contacts with GnRH cell bodies were observed. Within the median eminence, abundant CRH but not AVP terminals were close to GnRH cell terminals in the external zone; whereas, β-endorphin cells and terminals were in the internal zone. In conclusion, neuroanatomical evidence is provided for the ewe supporting the hypothesis that brainstem noradrenergic and hypothalamic GABA neurones are important in modulating the activity of CRH and AVP neurones in the paraventricular nucleus, as well as β-endorphin neurones in the arcuate nucleus. These paraventricular and arcuate neurones may also involve interneurones to influence GnRH cell bodies in medial pre-optic area, whereas the median eminence may provide a major site for direct modulation of GnRH release by CRH terminals.