Machine-learning facilitates selection of a novel diagnostic panel of metabolites for the detection of heart failure.

The metabolic derangement is common in heart failure with reduced ejection fraction (HFrEF). The aim of the study was to check feasibility of the combined approach of untargeted metabolomics and machine learning to create a simple and potentially clinically useful diagnostic panel for HFrEF. The study included 67 chronic HFrEF patients (left ventricular ejection fraction-LVEF 24.3 ± 5.9%) and 39 controls without the disease. Fasting serum samples were fingerprinted by liquid chromatography-mass spectrometry. Feature selection based on random-forest models fitted to resampled data and followed by linear modelling, resulted in selection of eight metabolites (uric acid, two isomers of LPC 18:2, LPC 20:1, deoxycholic acid, docosahexaenoic acid and one unknown metabolite), demonstrating their predictive value in HFrEF. The accuracy of a model based on metabolites panel was comparable to BNP (0.85 vs 0.82), as verified on the test set. Selected metabolites correlated with clinical, echocardiographic and functional parameters. The combination of two innovative tools (metabolomics and machine-learning methods), both unrestrained by the gaps in the current knowledge, enables identification of a novel diagnostic panel. Its diagnostic value seems to be comparable to BNP. Large scale, multi-center studies using validated targeted methods are crucial to confirm clinical utility of proposed markers.

Anti-inflammatory effects of atorvastatin treatment in chronic obstructive pulmonary disease. A controlled pilot study.

UNLABELLED: Observational studies have suggested that statins may have beneficial effects on outcomes in chronic obstructive pulmonary disease (COPD) patients. These effects may be mediated through an anti-inflammatory effect of statins. The purpose of this pilot-study was to determine whether statins have an anti-inflammatory effect on the lungs of COPD patients. We conducted randomized, controlled, parallel group pilot-study to compare the effects of atorvastatin (n=12) or placebo (n=6) on lung inflammation in patients with mild to moderate COPD. The primary endpoint was change in CD45+ cells expression measured by immunohistochemistry and changes in expression of genes measured using microarrays in lung biopsy (TBB) samples before and after 12 weeks of treatment with atorvastatin 40 mg/day. All subjects had spirometry, lung volumes, diffusing capacity of the lungs for carbon monoxide (DLCO), St George's Respiratory Questionnaire (SGRQ), 6 minute walk distance (6 MWD), serum lipids, hs-CRP, induced sputum (IS), bronchoscopy and TBB carried out at baseline and after treatment. TBB specimens were processed for histology, immunohistochemistry and genome-wide association studies (GWAS) profiling. Seventeen subjects completed the study. There was a significant improvement in SGRQ with mean SGRQ decreased by 12 points after treatment with atorvastatin (P=0.012). Atorvastatin treatment produced a significant 34% reduction in sputum neutrophil count, and a 57% reduction in CD45+ cells in lung biopsies (expressed as integrated optical density -IOD; median IOD 62.51% before, 27.01% after atorvastatin treatment, P=0.008). In patients' lung tissue atorvastatin treatment produced downregulation of key genes involved in inflammatory processes, immune response, and leukocyte activation. These data demonstrate the pulmonary anti-inflammatory effects of atorvastatin in COPD patients with the potential for beneficial clinical effects. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01748279.

Usefulness of automatic measurement of contrast flow intensity: an innovative tool in contrast-enhanced ultrasound imaging of atherosclerotic carotid plaque neovascularization. A pilot study.

AIM: Contrast-enhanced ultrasound imaging of the carotid arteries (CECU) permits direct, real-time visualization of neovascularization in atherosclerotic plaques and is a confirmed predictor of unstable atheromatous lesions. The aim of the study was the assessment of a new, automatically measured index of intensity in quantitative estimation of the contrast flow through the carotid plaque (till now assessed only visually). METHODS: Forty-four patients (mean age 70.4±11.4) with ultrasound diagnosed significant stenosis of internal carotid artery (ICA), after cerebrovascular or cardiovascular events, qualified for carotid artery stenting (CAS) were examined. The carotid ultrasound examinations with contrast agent Sonovue were performed. RESULTS: Visually in 22 patients (50%) contrast flow through the atherosclerotic plaques was found. In 17 patients (38.6%) massive, calcified atherosclerotic plaques were present. Patients with preserved contrast flow through the plaque more frequently had a history of cerebral stroke (P=0.04). Massive calcifications of atherosclerotic plaques correlated with a previous MI (P=0.03) and the degree of advancement of coronary artery disease (P=0.04), but not with a previous cerebral stroke. Contrast flow through the atherosclerotic plaque positively correlated with values of the index of intensity (r=0.69, P<0.00001). In patients with preserved contrast flow the mean value of the index of intensity was 22.24±3.55 dB as compared with 12.37±7.67 dB - a value present in patients without preserved contrast flow. No significant relation for the degree of calcifications and the value of the index of intensity was found. CONCLUSION: The assessment of the index of intensity is a novel, simple and automatic method to estimate the degree of contrast flow through the carotid plaque. The values of the index of intensity correlate with the contrast flow through the atherosclerotic plaque, but not with its calcification.

Myocardial perfusion and intima-media thickness in patients with subclinical hypothyroidism.

PURPOSE: The data concerning the relation between subclinical hypothyroidism (SH) and the risk of cardiovascular disease are divergent. We aimed to assess myocardial perfusion in contrast-enhanced echocardiography and intima-media thickness (IMT) in patients with SH. MATERIAL/METHODS: Forty females with SH without symptoms of coronary artery disease and 15 healthy female volunteers were examined. Echocardiographic evaluation of the left ventricle function as well as carotid and femoral IMT complex measurements were performed at baseline. Thereafter, dobutamine stress echocardiography with myocardial perfusion assessment at rest and on the peak of stress test was performed. SonoVue® intravenous bolus as a contrast medium was used. The myocardial perfusion was assessed by quantitative method using Q-LAB Philips software (ROI modality). The perfusion index was calculated (a number of left ventricle segments with improved perfusion/a number of all segments). RESULTS: A mean IMT value in the SH group was significantly higher than in the controls (0.7 mm vs. 0.38 mm, p=0.001). Myocardial perfusion at rest and at the peak of stress test was significantly lower in the SH patients as compared to the controls (at rest 120 Db in SH vs. 181 Db in controls, p=0.039 and at the peak of stress 115 Db and 188 Db, p=0.01, respectively). The perfusion index was not significantly worse in the SH group (p=0.6). IMT values negatively correlated with the myocardial perfusion index at the peak of stress (r=-0.54, p=0.014). CONCLUSIONS: In patients with SH contrast-enhanced echocardiographic examination revealed myocardial hypoperfusion and increased IMT. Our results may suggest that the patients with SH are at risk of the development of cardiovascular disease.

Effect of on-pump versus off-pump coronary bypass surgery on cardiac function assessed by intraoperative transesophageal echocardiography.

PURPOSE: To compare cardiac function assessed by intraoperative transesophageal echocardiography in patients undergoing cardiac revascularization with or without cardiopulmonary bypass. MATERIAL AND METHODS: Forty-one patients scheduled for elective, isolated cardiac revascularization (21 on-pump and 20 off-pump) were prospectively analyzed. Patients were matched for demographic (age and gender), anthropometric (BMI), clinical (co-morbidities, EuroScore) and laboratory variables (blood counts, renal function, left ventricular function). Transesophageal echocardiography was performed after induction of anesthesia, protamine sulfate administration, and chest closure. Left ventricular wall motion score index, end-diastolic area, fractional area change, right ventricular area change and end-diastolic area were assessed. Troponin I and C-reactive protein concentrations were measured. RESULTS: Regarding echocardiographic parameters of left and right ventricular function no significant differences between on-pump and off-pump groups at any point-of-time measurements were found. Troponin I and C-reactive protein were higher in on-pump as compared to off-pump group (p=0.001 and p=0.002; p=0.003 and p=0.001, respectively). CONCLUSIONS: In elective patients scheduled for cardiac revascularization there were no difference in cardiac performance assessed by intraoperative echocardiography regardless of surgical method used.

The importance of intima-media thickness (IMT) measurements in monitoring of atherosclerosis progress after myocardial infarction.

PURPOSE: Intima-media thickness (IMT) assessed in peripheral arteries correlates with presence and progression of atherosclerosis in coronary arteries. IMT measurements may help to select high risk patients and evaluate the efficacy of the therapy used. AIM: The aim of the study was to assess the usefulness of ultrasonographic measurement of IMT in atherosclerosis progress monitoring in patients after myocardial infarction (MI). PATIENTS AND METHODS: 70 men (mean age 52.8 ± 8.4) treated with PCI due to acute myocardial infarction, were enrolled in the study. All subjects underwent ultrasound examination of the IMT complex of: common carotid artery (CCA), carotid bulb and common femoral artery (CFA) during hospitalization and follow-up period (3.83 ± 1.29 years). RESULTS: During the follow-up 3 patients (4.3%) were not on any medications, 8 pts (11.4%) were on reduced doses of ß-blocker, statin or ACE-I (non-compliant pts.). The others (compliant) - 59 pts (84.3%) received standard pharmacological treatment after MI. Nevertheless, an increase of IMT complex value after follow-up compared to initial IMT values of all examined peripheral arteries was observed (respectively: IMT CCA - 0.91 ± 0.26 vs 1.10 ± 0.36, p=0.002, IMT of carotid bulb - 1.31 ± 0.55 vs 1.82 ± 0.69, p=0.012, IMT CFA - 1.38 ± 0.64 vs 1.97 ± 0.75, p=0.014). Non-compliant patients had statistically significant higher IMT values after follow-up when compared to compliant subjects (1.62 vs 1.20, p= 0.017). Patients with higher IMT values were reported to have cardiac events more frequently during the follow-up (p<0.05). CONCLUSIONS: Our results provide evidence that ultrasonographic IMT complex assessment of peripheral arteries in everyday clinical practice allows monitoring efficacy of pharmacological therapy in CAD patients after MI. They also suggest treatment intensification if necessary.

Real-time myocardial contrast echocardiography as a useful tool to select candidates for coronary revascularization among patients with end-stage renal disease - a 3-year follow-up study.

PURPOSE: To evaluate a real-time myocardial contrast echocardiography (MCE) as a tool to select candidates for coronary revascularization among patients with ESRD and to assess the rate of revascularization and mortality. MATERIAL/METHODS: 58 ESRD patients were screened for CAD using MCE. We analyzed the rate of coronary revascularization during 3-year follow-up. Patients with and without perfusion disturbances on MCE were compared. RESULTS: CAD was found in 46.2% patients out of 39 who underwent coronary angiography. 11 (39.3%) patients out of 28 from the group with perfusion defects on MCE underwent revascularization procedure (21.4% - PCI, 17.9% - CABG). No one from the group without perfusion defects had revascularization procedure. Perfusion defect (OR 1.37 CI 1.37-1.86, p=0.022) was related to revascularization in multivariant analysis (OR 12.87, CI 1.86-89.21, p=0.025). There was no difference in mortality between the group which underwent invasive procedures and treated conservatively (p=0.6643). In ROC analysis defects on MCE and CAD on angiography were equally good in anticipating combined end-point (AUC 0.716, CI 95% 0.544-0.851 and AUC 0.747, CI 95% 0.577-0.875, p=0.701) and death (AUC 0.752, CI 95% 0.582-0.878 and AUC 0.729, CI 95% 0.558-0.861, p=0.805). CONCLUSIONS: Our results indicate that MCE is a safe and uncomplicated method which may help along with other methods to select candidates for coronary revascularization among ESRD patients. In our study coronary revascularization procedures were successful but they did not improve patients' survival on 3-year follow-up.

Early and long-term prognosis of patients with coronary artery disease treated with percutaneous coronary interventions in 2005. Experience of single large-volume PCI center.

PURPOSE: The progress which has been made in interventional cardiology contributes to the gradual improvement of the results of CHD (coronary heart disease) therapy. The aim of the study was the assessment of early and long-term prognosis in all the patients with CHD treated invasively in one large-volume PCI center in 2005. MATERIAL AND METHODS: 1390 consecutive patients with CHD treated with PCI in 2005 were included in the analysis. Patients with ST-elevation myocardial infarction (STEMI) accounted for 50% of cases, patients with stable angina (SA) amounted to 25%, and patients with non-ST elevation acute coronary syndromes (NSTE-ACS) constituted 25%. Mean follow-up was 738 (±237) days. RESULTS: The highest mortality during the hospitalization was noted within the STEMI group(SA vs. NSTE-ACS vs. STEMI; 0% vs. 0.3% vs. 4.1%, respectively; p<0.001). The highest mortality during a 2-year follow-up was also observed in the STEMI group (SA vs. NSTE-ACS vs. STEMI, 6.3% vs. 8.5% vs. 13.8%, respectively; p<0.001). Multiple regression model showed that independent risk factors for death during the follow-up were: age, glycaemia at admission, heart rate, blood pressure, ejection fraction, STEMI, ineffective PCI (R=0.3613; F(10.131)=19.672; p<0.0001 for the model). CONCLUSIONS: The highest relative increase of mortality after the discharge of patients with CHD undergoing PCI referred to the patients with NSTE-ACS. However, in the real life PCI practice STEMI patients have the worst hospital and long-term prognosis. Well recognized risk factors for death in patients with CHD are still of great importance in negative prognosis of patients undergoing PCI.

Blood pressure in relation to neurogenic, inflammatory and endothelial dysfunction biomarkers in patients with treated essential arterial hypertension.

PURPOSE: Clinical relevance of relations among blood pressure (BP), inflammation, endothelial dysfunction and sympathetic activation is unknown. Study aimed, whether in patients with diagnosed and treated essential arterial hypertension (HTN) biomarkers of inflammation (hs-C-reactive protein, hs-CRP), endothelial dysfunction (endothelin-1, ET-1), and sympathetic nervous system modulation (epinephrine, E and norepinephrine, NE) could be related to BP values. MATERIAL AND METHODS: In 62 patients with diagnosed and treated HTN (mean time of disease 5±3.2 years), serum hs-CRP and ET-1 as well as plasma E and NE concentrations were measured. 24-hour ambulatory blood pressure measurement device (ABPM) was used to estimate efficacy of treatment. RESULTS: A positive correlation between epinephrine and norepinephrine concentrations was found (r=0.246, p=0.05), however such a statistically significant correlation neither to hs-CRP, nor ET-1 were found. Patients with the highest hs-CRP and NE concentrations had the highest systolic (SBP) and diastolic (DBP) blood pressure values. Similar relation was found in subgroup of patients with suboptimal blood pressure values (SPB l 130mmHg, DBP l 80mmHg). In a group of optimal treated patients, elevated levels of ET-1 and NE related to increased blood pressure values. ROC analysis identified ET-1 as statistically significant to diagnose elevated blood pressure: 0.665 (95% Confidence interval 0.512 to 0.796). CONCLUSIONS: In patients with diagnosed and treated arterial hypertension, there are relations among measurements of hs-CRP, ET-1, NE and blood pressure values in spite of treatment, which may improve understanding of mechanisms involving inflammation, endothelial dysfunction and sympathetic nerve activation and may identify patients with refractory hypertension.

Silent pulmonary embolism in a patient with acute myocardial infarction and type B acute aortic dissection - a case report.

A 69-year-old man while being treated for type B aortic dissection was also found to have acute myocardial infarction. The patient initially was treated conservatively. Prophylactic anticoagulant treatment of potential thrombosis was not given because of aortic dissection. Stent-graft implantation to the thoracic aorta was considered at the time. Unexpectedly, elective computer tomography (CT), revealed 2 large thrombi at the bifurcation of the pulmonary trunk. The patient did not show any symptoms of pulmonary embolism. Heparin therapy was initiated immediately. The patient responded well to the therapy and on transesophageal echocardiography and subsequent CT no embolic material was found. Since that time, the patient is receiving oral anticoagulation. The case we present raises the question of anticoagulation prophylaxis in the presence of aortic dissection in bedridden patients. Failure to use such therapy in our patient could have resulted in an unfavorable clinical outcome.

Trends in the incidence of the free wall cardiac rupture in acute myocardial infarction. observational study: experience of a single center.

PURPOSE: Free wall cardiac rupture (CR) is one of the most common cause of in-hospital death in acute myocardial infarction (AMI). The early diagnosis of CR and selection of the patients predisposed to CR become an important clinical tool. AIM: assessing the occurrence of CR in patients with AMI, to determine the factors which could help to identify the patients threatened with CR. MATERIAL AND METHODS: 2320 consecutive patients with AMI. CR was proved by autopsy or by echocardiography performed during cardio-pulmonary resuscitation (CPR). RESULTS: In-hospital mortality was 11% (254 patients). 50 patients (2%) died from CR. CR was the cause of 20% of total in-hospital death. Patients with CR were older than survivors (72 vs 60 years, p<0.0001). Women prevailed in CR group: (62% in CR group vs 27% in the survivors, p<0.01). 29% of patients were treated with thrombolytics (Th+). Out of 58 patients from Th (+) group who died, 17 (29.31%) died because of CR. CR occurred in 33 (16.8%) patients out of 196 died in Th (-) group. In the logistic regression analysis only age and sex remained as predictors of CR. 16 patients died from CR during first 24 h from admission (ECR). In 34 patients CR occurred >24 h (LCR). In ECR group were no prevalence of women, while in LCR women constituted 68%. In ECR group all but one patient had no previous history of MI (p=0.06). Frequency of thrombolythic therapy was equal. CONCLUSIONS: Advanced age patients, particularly women with first AMI are at risk of CR. Decision of thrombolytic treatment in this group of patients must be very cautious.

Low dose rofecoxib, inflammation and prostacyclin synthesis in acute coronary syndromes.

PURPOSE: To assess the influence of low dose rofecoxib on inflammatory mediators and prostacyclin synthesis in patients with acute coronary syndromes (ACS) in a short-term follow up. MATERIAL AND METHODS: Twenty nine patients with ACS without ST elevation were randomized to simvastatin alone or together with low dose rofecoxib. Serum levels of interleukin 6 (IL-6), 6-keto-PGF-1alpha--stable product of prostacyclin (PGT2) and hs-C-reactive protein (hs-CRP) were assessed on enrollment and after 30-day follow up. RESULTS: Combination of rofecoxib with statin significantly decreased levels of hs-CRP after one month therapy (5.21 mg/l +/- 4.12 vs 2.11 mg/l +/- 2.1; p=0.0092). This effect was not evident in a group on statin alone (3.95 mg/l +/- 3.33 vs 2.48 mg/l +/- 2.39; p=0.31). 6-keto-PGF-1alpha increased not significantly in both groups. IL-6 concentration has not changed during follow up. CONCLUSIONS: Low dose of selective COX-2 inhibitor exerts significant anti-inflammatory effect and does not diminish PG12 synthesis in study group of patients with ACS.

Prognostic factors in medically treated patients with chronic pulmonary embolism.

OBJECTIVE: To evaluate risk factors in medically treated patients with chronic pulmonary embolism (CPE) who are not suitable candidates for definitive surgical therapy. STUDY DESIGN: A total of 53 consecutive patients with angiographically confirmed CPE were involved. Four patients underwent pulmonary endarterectomy, and 49 patients received continuous anticoagulation therapy and were followed up over an average period of 18.7 months (range, 6 to 72 months). RESULTS: Sixteen patients died during the follow-up period, mostly from progressive right ventricle failure. Among the nonsurvivors, 12.5% had distal CPE and 87.5% had proximal CPE (p = 0.03). The survivors had a higher (mean +/- SD) level of PaO(2) (59.3 +/- 11 mm Hg) than the nonsurvivors (50.8 +/- 9 mm Hg; p = 0.02), a lower mean pulmonary artery pressure (mPAP; 30.3 +/- 15 mm Hg vs 51 +/- 21 mm Hg; p = 0.0004), a lower hematocrit value (40.0 +/- 6 vs 44.2 +/- 6; p = 0.03), and better exercise tolerance (4.8 +/- 3 multiples of resting O(2) consumption [METs] vs 2.5 +/- 1 METs; p = 0.02) achieved during the maximal symptom-limited exercise. The patients with coexisting COPD had a higher mortality rate (62.5%) than those without COPD (37.5%; p = 0.04). Independent risk factors in the Cox analysis were as follows: mPAP (p = 0.04), exercise tolerance (p = 0.02), and COPD (p = 0.04). In the Kaplan-Meier analysis, the patient group with lower mortality achieved > 2 METs (p = 0.02) and had mPAP < 30 mm Hg (p = 0.04). CONCLUSION: The prognosis for the medically treated CPE patients, particularly those with pulmonary hypertension, was unfavorable. The prognostic factors for these patients were mPAP, coexistence of COPD, and severe exercise intolerance.

[Echocardiographic assessment of pathologic geometry in the left left ventricle with aneurysm before and after endoventricular plasty]. / Echokardiograficzna ocena zaburzen geometrii lewej komory z tetniakiem przed i po operacji metoda plastyki wewnatrzkomorowej.

UNLABELLED: Large LV aneurysm (LVA) leads to progressive distortion of ventricular geometry. Endoventricular plasty (EVP) maintains LV original shape and size and may restrain this process. AIMS: Echocardiographic estimation of LVA size. Assessment of the results of EVP regarding operative technique. Assessment if the initial parameters of LV function and LVA size could predict the choice of surgical technique. MATERIAL AND METHOD: 33 patients with LVA underwent EVP: 18 with patch (group A), 15 without patch (group B). Echocardiography was performed before and after surgical procedure. LVA-area, LVA-volume, its proportion to LV area and volume (LVA-area/LV-EDA, LVA-volume/LV-EDV) were determined apart from routine parameters of LV function. RESULTS: Mean LVA-area was 15 cm2, LVA-volume was 50 mL. Mean LVA-areal LV-EDA was 0.38 LVA-volume/LV-EDV was 0.35. LVA exceeding 0.4 of LV area/volume was considered as a large. After surgery LV-EDV diminished +/- 40 mL, LVLd decreased +/- 1.5 cm. EF improved from 44% to 54%. Patients in group A had larger LVA-volume (60 vs 39 ml, p = 0.02) as well as LV-EDV (160 vs 120 ml, p = 0.03), and lower EF (41% vs 51% p = 0.002). Only 2 patients with LVA-volume greater than 56 ml were operated on without patch. After surgery echocardiographic parameters did not differ between the groups: in group A operation was much more extensive. SUMMARY: 1.) Echocardiographic parameters concerning size (LVA-area, LVA-area/LV-EDA) and volume (LVA-volume, LVA-volume/LV-EDV) of LVA provides information about disturbances in LV geometry, are valuable in planning operative method. 2.) EVP with or without patch provides significant improvement of LV geometry and function in echocardiographic investigation.

[Cardiac rupture in acute myocardial infarction]. / Pekniecie wolnej sciany serca w swiezym zawale.

Free wall rupture of the heart is the most common cause of death following pump failure. The incidence of death is 10-16% of all deaths because of acute myocardial infarction (AMI). In respect of time between the onset of AMI to Cardiac Rupture (CR), early (80%) and late CR are distinguished. Other clinical classification distinguishes acute and subacute CR. CR is considered subacute if the time between the onset of typical symptoms of CR and irreversible shock is longer as 30 min. There are three problems to solve: 1) selection of patient particularly threatened with CR, 2) defining the prodroms of CR and early diagnosis, 3) advancing the methods of surgical treatment. CR occurs more often in women, hypertensive patients and patient > 60 years old sustaining the first infarction. Thrombolytic agents diminish overall mortality in AMI, but do not influence frequency of CR. There are three mechanisms of CR incidence: 1) blood effusion into the ischemic zone resulting in the loss of tissue strength, 2) influence of thrombolytic therapy on degradation and inhibition collagen synthesis, 3) absorption of collagen by lymphocyte infiltration in infarction zone. Cardiac insufficiency with cardiogenic shock and rapid increase of pericardial effusion in echo examination and electro-mechanical discordance are considered to be clinical signs of CR and tamponade. CRP is an independent marker of subacute CR. Surgical treatment is possible only in case of subacute CR. Pericardiocentesis and bloodletting could temporary diminish cardiac tamponade and allow transfer to the operating room.

[Difficulties in distinguishing left ventricular aneurysm from pseudoaneurysm. Case report]. / Trudnosci w róznicowaniu rzekomego i prawdziwego tetniaka sciany dolnej serca. Opis przypadku.

A case of 51-year old female with large inferior left ventricular aneurysm developed 3 months after myocardial infarction is presented. The patient demonstrated advanced congestive heart failure and angina. Coronarography revealed amputation of the distal part of 3 coronary vessels without possibility of revascularisation. In ventriculography large inferior wall aneurysm was found. Echocardiography strongly suggest the presence of pseudoaneurysm. During the operation very large real aneurysm arising from inferior wall and apex was found. Postoperative period was complicated by many cardiac and non cardiac events. Authors discuss the problems of proper diagnostic and its influence on decision about surgical management.