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In this multicenter trial, higher-risk adults undergoing on-pump CABG (with or without valve surgery) were randomly assigned to preconditioning with transient arm ischemia and reperfusion or sham conditioning. Remote ischemic preconditioning did not improve clinical outcomes. Coronary heart disease is the leading cause of death and disability worldwide. For patients with multivessel coronary artery disease, the treatment of choice for many is revascularization by means of coronary-artery bypass grafting (CABG) surgery. As a result of the aging of the population, an increased prevalence of coexisting conditions (e.g., diabetes, obesity, and hypertension), and a growing need for concomitant valve surgery, higher-risk patients are undergoing CABG surgery (with or without valve surgery); the clinical outcomes in such patients have been worse than the outcomes in patients without so many problems. 1 , 2 Thus, novel cardioprotective interventions are indicated to . . .

Background:Remote ischaemic preconditioning (RIPC) induced by brief ischaemia and reperfusion of the arm reduces myocardial injury in coronary artery bypass (CABG) surgery patients receiving predominantly cross-clamp fibrillation for myocardial protection. However, cold-blood cardioplegia is the more commonly used method world wide.Objective:To assess whether RIPC is cardioprotective in CABG patients receiving cold-blood cardioplegia.Design:Single-centre, single-blinded, randomised controlled trial.Setting:Tertiary referral hospital in London.Patients:Adults patients (18–80 years) undergoing elective CABG surgery with or without concomitant aortic valve surgery with cold-blood cardioplegia. Patients with diabetes, renal failure (serum creatinine >130 mmol/l), hepatic or pulmonary disease, unstable angina or myocardial infarction within the past 4 weeks were excluded.Interventions:Patients were randomised to receive either RIPC (n = 23) or control (n = 22) after anaesthesia. RIPC comprised three 5 min cycles of right forearm ischaemia, induced by inflating a blood pressure cuff on the upper arm to 200 mm Hg, with an intervening 5 min reperfusion. The control group had a deflated cuff placed on the upper arm for 30 min.Main outcome measures:Serum troponin T was measured preoperatively and at 6, 12, 24, 48 and 72 h after surgery and the area under the curve (AUC at 72 h) calculated.Results:RIPC reduced absolute serum troponin T release by 42.4% (mean (SD) AUC at 72 h: 31.53 (24.04) μg/l.72 h in controls vs 18.16 (6.67) μg/l.72 h in RIPC; 95% CI 2.4 to 24.3; p = 0.019).Conclusions:Remote ischaemic preconditioning induced by brief ischaemia and reperfusion of the arm reduces myocardial injury in CABG surgery patients undergoing cold-blood cardioplegia, making this non-invasive cardioprotective technique widely applicable clinically.Trial registration number:NCT00397163.

Objective Cyclosporin-A (CsA) has been reported to reduce myocardial infarct size in both the experimental and clinical settings. This protective effect is dependent on its ability to prevent the opening of the mitochondrial permeability transition pore, a critical determinant of cell death in the setting of acute ischaemia-reperfusion injury. Whether CsA can reduce the extent of peri-operative myocardial injury (PMI) in patients undergoing coronary artery bypass graft (CABG) surgery is unknown, and is investigated in this randomised controlled clinical trial. Methods 78 adult patients undergoing elective CABG surgery were randomised to receive either an intravenous bolus of CsA (2.5 mg/kg) or placebo administered after induction of anaesthesia and prior to sternotomy. PMI was assessed by measuring serum cardiac enzymes, troponin T (cTnT) and CK-MB at 0, 6, 12, 24, 48 and 72 h after surgery. Results There was no significant difference in mean peak cTnT levels between control (n=43) and CsA treatment (n=40) patients (0.56±0.06 ng/mL with control vs 0.35±0.05 ng/mL with CsA; p=0.07). However, in higher-risk patients with longer cardiopulmonary bypass times, there was a significant reduction in PMI with CsA therapy (p=0.049), with a reduced postoperative cTnT rise by 0.03 ng/mL for every 10 min, when compared with control. Conclusions In patients with longer cardiopulmonary bypass times, a single intravenous bolus of CsA administered prior to CABG surgery reduced the extent of PMI.

Ischemic postconditioning (IPost) has been demonstrated to reduce myocardial injury in patients undergoing primary coronary angioplasty for an acute myocardial infarction.Pre-clinical animal studies suggest that pro-survival protein kinases of the Reperfusion Injury Salvage Kinase (RISK) pathway such as Akt and Erk1/2 mediate the cardioprotective effect of IPost. Whether IPost can protect human myocardial tissue ex vivo and whether it recruits the RISK pathway in human myocardium are both not known. To investigate this, atrial appendages were harvested from patients undergoing cardiac surgery. From these samples atrial trabeculae were isolated and mounted on a superperfusion apparatus and subjected to 90 min of hypoxia followed by 120 min of reoxygenation at the end of which function expressed as a percentage of the recovery of baseline contractile function was determined. Atrial trabeculae were randomized to control, hypoxic preconditioning (HPre), hypoxic postconditioning comprising either four 30-s (HPost-30) or 60-s (HPost-60) episodes of alternating hypoxia and reoxygenation, and HPost in the presence or absence of UO126 (a MEK1/2 inhibitor) or LY294002 (a PI3K inhibitor). HPre and HPost-60 improved the recovery of baseline contractile function (45.4+/-3.2% with HPre and 45.2+/-2.2% with HPost-60 vs 26.7+/-2.1 % in control: N>or=6/group: P<0.05), whereas HPost-30 failed to cardioprotect (28.3+/-3.4% with HPost-30 vs 26.7+/-2.1 % in control: N>or=6/group: P>0.05). The cardioprotective effect of HPost-60 was abolished in the presence of either LY (28.1+/-2.5% with HPost-60+LY vs 45.2+/-2.2% with HPost-60: N>or=6/group: P<0.05) or UO (32.7+/-1.8% with HPost-60+UO vs 45.2+/-2.2% with HPost-60:N=7/group: P<0.05). The kinase inhibitors alone had no effect on functional recovery (28.2+/-3.6% with LY and 30.1+/-4.8% with UO vs 26.7+/-2.1 % in control: N>or=5/group: P>0.05). In conclusion, we demonstrate for the first time that postconditioning protects human myocardium ex vivo and that this effect is dependent on the activation of the RISK pathway.

Background and purposes: Erythropoietin (EPO) has been shown to protect against myocardial infarction in animal studies by activating phosphatidylinositol‐3 kinase (PI3K)/Akt and ERK1/2. However these pro‐survival pathways are impaired in the diabetic heart. We investigated the ability of EPO to protect human atrial trabeculae from non‐diabetic and diabetic patients undergoing coronary artery bypass surgery, against hypoxia‐reoxygenation injury. Experimental approach: Human atrial trabeculae were exposed to 90min hypoxia and 120min reoxygenation. EPO was administered throughout reoxygenation. The developed force of contraction, calculated as a percentage of baseline force of contraction, was continuously monitored. The involvement of PI3K and ERK1/2 and the levels of activated caspase 3(AC3) were assessed. Key results: EPO improved the force of contraction in tissue from non‐diabetic patients (46.7+/‐1.7% vs. 30.2+/‐2.2% in control, p<0.001). These beneficial effects were prevented by the PI3K inhibitor, LY294002 and the ERK1/2 inhibitor, U0126. EPO also significantly improved the force of contraction in the diabetic tissue, although to a lesser degree. The levels of activated caspase 3 were significantly reduced in EPO treated trabeculae from both non‐diabetic and diabetic patients, relative to their respective untreated controls. Conclusions and implications: EPO administered at reoxygenation protected human myocardial muscle by activating PI3K and ERK1/2 and reducing the level of activated caspase 3. This cardioprotection was also observed in the diabetic group. This data supports the potential of EPO being used as a novel cardioprotective strategy either alone or as an adjunct in the clinical setting alongside existing reperfusion therapies. British Journal of Pharmacology (2008) 153, 50–56; doi:10.1038/sj.bjp.0707461; published online 22 October 2007

The National Pectus multi-disciplinary team (MDT) meeting was commissioned by NHS England in April 2023 to review all cases of pectus excavatum (PE) being considered for surgical management. In cases of severe PE, the chest wall compresses the heart and lungs, which may result in cardiac or respiratory function compromise on exercise, measured during cardio-pulmonary exercise testing (CPET). This MDT has led to a further ongoing study on the impact of the timing of surgery on patient-reported improvement in quality of life, and improvement in CPET parameters (the RESTORE trial).All patients discussed in the MDT require prior CPET and pulmonary function testing (PFT) to assess for physiological limitation and investigate for other potential causes. The majority of PE patients have restrictive spirometry, however a subset of 28 patients potentially had an obstructive spirometry pattern (table 1), with a mean FEV1/FVC 0.72. This population was predominantly male (85.7%) with an average age of 22.3 years.Prior to surgical intervention, we propose these patients undergo further investigation to exclude undiagnosed obstructive airways disease, and in event of a diagnosis being made, receive a trial of treatment which may alleviate the need for an invasive surgical procedure.Abstract P255 Table 1Demographics (N=28)

Distinct genes are mutated in different regions of a single patient’s tumor. Point mutations seem to have less adverse effect on relapse-free survival than copy-number heterogeneity. Chromosome instability appears to be an important adverse prognostic factor. Lung cancer is the leading cause of cancer-related death worldwide, 1 , 2 with non–small-cell lung cancer (NSCLC) being the most common type. Large-scale sequencing studies have revealed the complex genomic landscape of NSCLC 3 – 6 and genomic differences between lung adenocarcinomas and lung squamous-cell carcinomas. 7 However, in-depth exploration of NSCLC intratumor heterogeneity (which provides the fuel for tumor evolution and drug resistance) and cancer genome evolution has been limited to small retrospective cohorts. 8 , 9 Therefore, the clinical significance of intratumor heterogeneity and the potential for clonality of driver events to guide therapeutic strategies have not yet been defined. Tracking Non–Small-Cell Lung Cancer . . .

IntroductionIsolated mediastinal lymphadenopathy (IML) is a common presentation to respiratory physicians and mediastinoscopy is traditionally considered the gold-standard investigation when a pathological diagnosis is required. EBUS-TBNA is established as an alternative to mediastinoscopy in patients with lung cancer. However, the utility and healthcare costs of EBUS-TBNA in patients with IML is unknown.MethodsThis prospective clinical trial recruited 77 consecutive patients with IML who were referred for mediastinoscopy from five centres between April 2009 and March 2011. All patients underwent EBUS-TBNA. If the results from EBUS-TBNA were not conclusive, patients underwent mediastinoscopy. The co-primary endpoints were the proportion of mediastinoscopies saved and NHS costs. The Bonferroni correction was applied to the type 1 error to account for multiple significance testing. Economic evaluation of the EBUS-TBNA strategy (where negative EBUS-TBNA is followed by mediastinoscopy) vs mediastinoscopy alone from an NHS perspective was carried out using a decision tree model and univariate threshold sensitivity analysis.ResultsEBUS-TBNA prevented 87% of mediastinoscopies (97.5% CI 78 to 96%, p<0.001) but failed to provide a diagnosis in 10 patients, all of whom underwent mediastinoscopy (Abstract S56 figure 1). Mediastinoscopy provided a specific diagnosis in 6 cases while the remaining four patients had clinical and radiological follow-up of at least 6 months duration. The sensitivity and negative predictive value of EBUS-TBNA in patients with IML was 92% (95% CI 83 to 95) and 40% (95% CI 12% to 74%) respectively. No significant complications of EBUS-TBNA or mediastinoscopy were observed. The patients included in the trial were similar to a historical control group of 68 patients with IML undergoing mediastinoscopy in 2008. The cost of the EBUS-TBNA strategy was £1871 per patient while a strategy of mediastinoscopy alone was £3268 per patient (p<0.001). Threshold sensitivity analysis demonstrated that the EBUS-TBNA strategy was less costly than mediastinoscopy if the cost per EBUS-TBNA procedure was <£2828.Abstract S56 Figure 1Flowchart of patients in the REMEDY trial.ConclusionsEBUS-TBNA is a safe, highly sensitive and cost-saving initial investigation in patients with IML being referred for mediastinoscopy. The low negative predictive value of EBUS-TBNA in this setting indicates that mediastinoscopy should be performed in cases of negative EBUS-TBNA.Trial registrationclinicaltrials.gov NCT00932854.

Objectives Remote ischaemic preconditioning (RIPC), using brief cycles of limb ischaemia/reperfusion, is a non-invasive, low-cost intervention that may reduce perioperative myocardial injury (PMI) in patients undergoing cardiac surgery. We investigated whether RIPC can also improve short-term clinical outcomes. Methods One hundred and eighty patients undergoing elective coronary artery bypass graft (CABG) surgery and/or valve surgery were randomised to receive either RIPC (2–5 min cycles of simultaneous upper arm and thigh cuff inflation/deflation; N=90) or control (uninflated cuffs placed on the upper arm and thigh; N=90). The study primary end point was PMI, measured by 72 h area under the curve (AUC) serum high-sensitive troponin-T (hsTnT); secondary end point included short-term clinical outcomes. Results RIPC reduced PMI magnitude by 26% (−9.303 difference (CI −15.618 to −2.987) 72 h hsTnT-AUC; p=0.003) compared with control. There was also evidence that RIPC reduced the incidence of postoperative atrial fibrillation by 54% (11% RIPC vs 24% control; p=0.031) and decreased the incidence of acute kidney injury by 48% (10.0% RIPC vs 21.0% control; p=0.063), and intensive care unit stay by 1 day (2.0 days RIPC (CI 1.0 to 4.0) vs 3.0 days control (CI 2.0 to 4.5); p=0.043). In a post hoc analysis, we found that control patients administered intravenous glyceryl trinitrate (GTN) intraoperatively sustained 39% less PMI compared with those not receiving GTN, and RIPC did not appear to reduce PMI in patients given GTN. Conclusions RIPC reduced the extent of PMI in patients undergoing CABG and/or valve surgery. RIPC may also have beneficial effects on short-term clinical outcomes, although this will need to be confirmed in future studies. Trial registration number ClinicalTrials.gov ID: NCT00397163.