Simultaneous modelling of mexiletine and hydroxy-methyl-mexiletine data after single- and multiple-dose administration of a sustained-release mexiletine formulation.

The pharmacokinetics of mexiletine and its metabolite hydroxy-methyl-mexiletine have been investigated following single-dose and during multiple-dose administration of a sustained-release form of mexiletine to six post-myocardial infarct patients. Comparison of single-dose and washout pharmacokinetics, after short-term multiple-dose administration, showed significant (p < 0.005), but not systematic, modifications in mexiletine apparent clearance for three patients. Furthermore, for these patients, simulation with both sets of parameters indicated that the steady-state was achieved before washout experiment in two cases. The fraction of mexiletine metabolized to hydroxy-methyl-mexiletine was lower for multiple-dose administration (about 18 per cent) than for the single dose (about 42 per cent). The hydroxy-methyl-mexiletine elimination rate constant was about four times that of mexiletine. Mexiletine clearance could be accounted for by other metabolic pathways. In one patient, hydroxy-methyl-mexiletine was undetectable even during multiple-dose administration, despite a significant increase in mexiletine clearance. However, the observed changes in mexiletine disposition had no therapeutic implications and active plasma levels were achieved by the third day of administration and maintained in the therapeutic range (0.75 to 2 micrograms ml-1) in all patients after a twice daily dosage regimen.

[Contribution of Doppler echocardiography to the evaluation and monitoring of normal and pathologic mitral valve prostheses]. / Apport de l'échocardiographie-Doppler dans l'évaluation et la surveillance des prothèses mitrales normales et pathologiques.

Doppler echocardiographic examinations were performed in 146 patients with normal and 42 patients with pathological (31 regurgitations and 11 obstructions) mitral valve prostheses confirmed by catheterisation and/or surgery. The maximum and mean transprosthetic gradients and pressure half times (PHT) were calculated from continuous wave Doppler recordings and regurgitant signals were searched for by continuous and pulsed wave Doppler. In the group of normal mitral valve prostheses, the mean gradients and PHT were very variable even within the subgroups of the same type and size of prosthesis. The best haemodynamic profile was observed with the St Jude prosthesis (mean gradient = 5 +/- 2 mmHg, PHT = 90 +/- 22 ms, p less than 0.05 vs other prostheses). Minimal mitral regurgitation was detected in 12 per cent of bioprostheses and 20 per cent of mechanical prostheses. No correlations were found between the mean pressure gradient or PHT and the size of the prostheses. Regular Doppler echocardiographic follow-up over 2.4 years was obtained in 25 patients and showed a remarkable stability of the Doppler parameters in 17 patients whereas prosthetic valve dysfunction was diagnosed in the other 8 cases. In the group of pathological mitral valve prostheses, regurgitation (N = 31) was associated with a high early diastolic pressure gradient (20.2 +/- 8 mmHg) and a normal or shortened PHT (84 +/- 28 ms). Obstructed prostheses (N = 11) had high mean pressure gradients (17 +/- 5 mmHg) and increased PHT (195 +/- 53 ms). All cases of obstruction were correctly identified by the Doppler but 4 prosthetic valve regurgitations were missed or underestimated (4 mechanical prostheses).(ABSTRACT TRUNCATED AT 250 WORDS)

[Heart and heart-lung transplantation. 3 years' experience in Timone CHU (Marseilles 1985-1988)]. / Transplantation cardiaque et cardio-pulmonaire. Trois ans d'expérience au CHU Timone (Marseille 1985-1988).

Since December 1985, we have performed 38 transplantations: cardiac (CT) n: 31, cardiopulmonary (CPT) n: 1, or bipulmonary (BPT) n: 6. There were 31 male and 7 female patients, aged 7 to 62, mean 46. In the cardiac group, the cardiomyopathy was primitive in 13, ischemic in 16, valvular in 2. Five patients had undergone one or more previous operations. Three patients had a biventricular assist device (1,6 and 7 days before transplant) for acute cardiac failure. The indication of CPT or BPT was pulmonary artery hypertension (1), silicosis (1), cystic fibrosis (4). There were 4 post-operative deaths in the CT group (12.9%); failure of graft, low cardiac output, pulmonary artery hypertension by multiple pulmonary thrombosis, and 2 deaths in the CPT and BPT groups (28%). The mean post-operative hospital stay was one month. All patients with CT were treated by an initial maintenance bitherapy protocol (cyclosporine, steroids) and observed by myocardial biopsies and echocardiograms. In 40 per cent of the patients, Azathioprine was subsequently added. The patients had 2.1 rejection episode/patient/year, either spontaneously reversed of treated medically. There were two late deaths (2 and 7 months) by refractory rejection. 78 per cent of the patients were alive one year after transplant. All survivors have recovered a normal life, some of them with full-time work.(ABSTRACT TRUNCATED AT 250 WORDS)

[Epidemiologic aspects of polyarterial pathology]. / Aspects épidémiologiques de la pathologie polyartérielle.

UNLABELLED: With the considerable technical progress in vascular investigations made in the last decade, evaluation of multifocal ischemic pathology (MIP) has become easier and allows better assessment of strategy for reperfusion. In vascular surgery, 50% of post-operative mortality and morbidity are related to coronary heart disease (CHD). Epidemiologic data, not biased by specific recruitment of medical and surgical departments, are needed to assessing the real incidence of MIP. Different clinical date have already shown the problem of MIP: the post-operative cardiac mortality rate in vascular surgery has been evaluated at between 0.9% and 3.5% for abdominal aortic aneurysms and 0.3% and 3.2% for peripheral vascular disease (PVD) according to recent statistics (2, 7, 10, 12, 21) (Table I). The total cardiac mortality rate is between 1% and 2% for vascular surgery and is 0.2% for general surgery (8). Thus, though early post-operative over-risk in vascular surgery is not very high, the long term-prognosis is far more impaired: 25% to 55% of patients will die within 10 years after vascular surgery (4, 10, 13, 20). Hertzer, using systematic pre-operative coronary angiograms, found significant coronary stenosis in 57% of patients referred for vascular surgery (11). POPULATION AND METHODS: This study was performed in a representative sample taken from an ongoing prospective survey of 10,446 council employees in Marseille (5,177 men (M.), 5,269 women (W.)). This sample of 1,883 M. and 1,212 W. (mean age: 42.3 +/- 9 for M., 44.9 +/- 11 for W., range 25-65 years) was submitted to a detailed questionnaire on personal and family history of CHD, risk factors and symptoms of CHD (22), and to a physical examination including height, weight and blood pressure measurements. Every subject underwent an ECG recording and a dietetic (5) and psychologic (1) interview, and a blood sample was taken for plasma glucose, total cholesterol and lipoprotein assay. According to epidemiologic data, the prevalence of MIP appears to be lower as compared to clinical data. Undoubtedly, clinical data from surgical departments overestimate the true prevalence of MIP since patients referred for surgical therapy are usually suffering from more advanced pathology. Epidemiology, mainly based on non invasive data probably underestimates the prevalence of MIP but confirms the highest prevalence of CHD as compared to prevalence of other localisations of atherosclerosis and shows CHD as being the earliest localisation of vascular ischemic lesions in most cases. When unifocal ischemic pathology (UIP) and MIP are compared, risk factors are the same, although different proportions of patients are concerned with some of them: in MIP, age is still the major risk factor, whereas smoking in M. and overweight in W. seem to be more frequent than in UIP. RESULTS: Sixty-eight cases (5%) of ischemic pathology were found in men and 47 cases (4%) in women, with 4.1% cases of unifocal ischemic pathology (UIP) in M. and 3.3% in W...

[Diagnostic approach in coronary disease in vascular surgery. Role of myocardial scintigraphy]. / Approche diagnostique de la coronaropathie en chirurgie vasculaire. Place de la scintigraphie myocardique.

Dipyridamole thallium scintigraphy (tomo SMTD) (fig. 2) and a bicycle stress-testing ECG were performed in a prospective study of 102 patients (Tabl. VIII) referred for aortic reconstruction surgery with aortic cross-clamping (fig. 1), carried out without knowledge of tomo SMTD results. A clinical coronary artery disease (CAD) was suspected in 45 patients (44%). The exercise test (tabl. IV) was inadequate in 78%, normal in 11% and abnormal in 11% of patients. Tomo SMTD (tabl. VI et X) was normal in 60 patients (59%), abnormal with persistent defect in 21 (20.5%) and abnormal with transient defect in 21 (20.5%). Post-operative cardiac events (tabl. I) occurred in 4 patients (3.9%): 2 deaths, 1 non-fatal myocardial infarction and 1 rest angina; but only 2 of these had documented CAD. All 4 had abnormal tomo SMTD (3 with transient, 1 with persistent defect). It is concludes that abnormal tomo SMTD had a significant pronostic value (p less than 0.03) in predicting post-perative cardiac events (tabl. XI, fig. 3) after abdominal aortic surgery with cross-clamping. This test facilitates selection of patients for coronary angiography.

[Prevention of deep venous thrombosis of the leg by a very low molecular weight heparin fraction (CY 222) in patients with hemiplegia following cerebral infarction: a randomized pilot study (30 patients)]. / Prévention des thromboses veineuses profondes des membres inférieurs par une fraction d'héparine de très bas poids moléculaire (CY 222) chez des patients porteurs d'une hémiplégie secondaire à un infarctus cérébral: étude pilote randomisée (30 patients).

The effectiveness and safety of a very low molecular weight heparin fraction were evaluated in the prevention of deep-vein thrombosis in patients confined to bed due to hemiplegia consecutive to a recent cerebral infarction. CY 222 was administered within 48 hours of the stroke by one single daily subcutaneous injection of 0.6 ml (= 15,000 U AXa IC) during 14 days. This randomized pilot study involved 30 patients. The effects of CY 222 were assessed in a group of 15 patients compared with a control group of 15 untreated patients. No deep-vein thrombosis was detected by the labelled fibrinogen test in the treated group, as against 12 patients in the control group. Six patients (3 in each group) died during the study. One case of lethal pulmonary embolism was observed and confirmed at autopsy in the control group. In the remaining 5 patients, no systematic autopsy which would have asserted the absence of pulmonary embolism or drug-induced haemorrhage was performed. Numerous standard laboratory tests confirmed that CY 222 was well tolerated.

[Exploratory strategy in venous thromboembolic disease]. / Stratégie des explorations dans la maladie thrombo-embolique veineuse.

It is currently accepted that the clinical signs are not very reliable in the diagnosis of deep venous thromboses (DVT). For this reason, various methods, more objective, are used in daily practice. Anatomical methods permitting direct visualization of the thrombus: one is invasive: phebography, the other is non-invasive: ultrasonography, which is quite competitive with the previous one and presents the advantage of evaluating the surrounding structures and providing functional informations when associated with a Doppler test. Haemodynamic functional methods, less reliable, permitting an indirect evaluation of the venous return: the Doppler analyzes the blood velocity, qualitatively and subjectively, plethysmography, more objective, studies the variations of the blood volume, artificially created by venous obstruction. Isotopic methods, using radioactive materials incorporated in the coagulation factors resulting in the formation of a thrombus, such as iodine 125 labelled fibrinogen. Biological methods, reflecting the formation and dissolving of a thrombus: it consists in the plasma titration of D-Dimer, specific disintegration product of fibrin. The advantages, limitations and indications of each technique are discussed. Selection of the exploration method must take into consideration the prevalence of DVTs and the value of the tests according to various clinical situations: presence or not of thrombogenic circumstances (ambulatory patient, hospitalized patient), presence or not of clinical manifestations (high-risk asymptomatic patient, symptomatic patient). Haemodynamic and isotopic tests have been substituted for phlebography. The current tendency leans toward Ultrasonography-Doppler, a very reliable method in symptomatic patients, but its value still has not been properly determined under other circumstances.

[Detection of acute rejection by Doppler echocardiography in orthotopic cardiac transplantation. Prospective comparative study with endomyocardial biopsy]. / Détection du rejet aigu par échocardiographie doppler dans la transplantation cardiaque orthotopique. Etude prospective comparative avec la biopsie endomyocardique.

In a prospective study of 23 patients who had undergone orthotopic heart transplantation we tried to assess the value of doppler-echocardiography in the detection of acute graft rejection. For this purpose, 220 echocardiographic records were compared with the results of endomyocardial biopsies performed at an interval of less than 12 hours. The parameters investigated by TM and two-dimensional echocardiography were: morphological parameters (including septal echodensity), left ventricular mass and systolic function parameters. Diastolic parameters (isovolumetric relaxation time [IVR], transmitral gradient half-decrease time [T 1/2] and proto-end-diastolic mitral velocity ratio [E/A] were measured by TM echocardiography and pulsed doppler velocimetry. The best doppler-echocardiographic criteria for graft rejection were a more than 15 ms reduction of IVR, a more than 15 p. 100 increase of myocardial mass, and a more than 30 p. 100 increase of teh E/A ratio, the corresponding sensitivities for histological rejection being 82, 76 and 74 p. 100 respectively. In contrast, T 1/2 and systolic function studies seemed to be disappointing. Finally, the increase of septal echodensity enabled rejection to be diagnosed with an excellent (92 p. 100) specificity but an insufficient sensitivity. Thus, none of the parameters measured were sensitive enough, taken separetely, to replace endomyocardial biopsy. However, the combined use of the most sensitive of them should make it possible to reduce the frequency of systematic biopsies.

[Is home thrombolysis of myocardial infarct realistic?]. / La thrombolyse à domicile de l'infarctus du myocarde est-elle réaliste?

Based on a 19-month experience of intravenous thrombolysis performed at home during the acute phase of myocardial infarction, we feel it is a realistic procedure, since it did not result in too many unnecessary calls: in 648 calls which seemed attributable to a coronary emergency by the Emergency Medical Services, this diagnosis was ruled out in 119 instances (18.4%) and confirmed in 529 instances (81.6%); diagnostic errors were not too frequent: 3.8 p. cent of false positive and 5.8 p. cent of false negative; it was not very hazardous: one death only from cardiogenic shock; it permitted to save time by decreasing by 30 minutes the start of the treatment; it avoided excessive costs by using already established structures.

Mexiletine in acute myocardial infarction. Simulation of a theoretical protocol and validation in six patients.

A mexiletine (Mexitil, MEX) administration schedule was established by simulation, in order to maintain MEX at therapeutic levels in plasma during the transition from parenteral to slow-release MEX (SR MEX) administration. This protocol was made valid in 6 patients with acute myocardial infarction (AMI) admitted to a coronary care unit, 24 h after the onset of pain. From both the i.v. and oral plasma level data, the pharmacokinetic parameter alterations of MEX and its hydroxymethylmexiletine metabolite (OH MEX) were evaluated over a week's period. The results presented here demonstrate that a twice daily oral SR MEX administration, starting at the end of MEX infusion, maintains the therapeutic concentrations of MEX (750-2000 ng/ml) previously achieved by infusion therapy (at 48 h, end of infusion, mean +/- SD = 1393 +/- 325 ng/ml; at 60 h, mean +/- SD = 1434 +/- 376 ng/ml; at 96 h, mean +/- SD = 1423 +/- 367 ng/ml. No evidence of either clinical side-effects or malignant arrhythmias was observed. MEX and OH MEX pharmacokinetic parameters were estimated by fitting the i.v. infusion data (phase I) and the oral data after the last SR MEX administration (phase II)beta to a linear compartment model. The terminal half-life t1/2 MEX was longer in phase I than in phase II (28.4 +/- 12.1 h (betaI) versus 14.06 +/- 4.47 h (II); p less than 0.01). This prolonged t1/2 MEX was probably due to a decrease of total plasma clearance Cl MEX (3.723 +/- 1.534 ml.kg-1min-1 (I) versus 5.031 +/- 1.28 ml.kg-1min-1 (II).(ABSTRACT TRUNCATED AT 250 WORDS)

[Pulsed Doppler echography in the quantification of aortic insufficiency in adults]. / Apport de l'échographie Doppler pulsé dans la quantification des insuffisances aortiques de l'adulte.

Since several methods based on doppler-echocardiography have been suggested to quantify aortic valve regurgitation, we compared two of these methods--left ventricular diastolic jet mapping and evaluation of blood flow in the descending aorta--with the results of left heart catheterization in 82 patients with aortic regurgitation. The invasive quantification rested on the degree of left ventricular opacification after contrast injection into the supra-sigmoid aorta, the results being classified into 3 grades. Left ventricular mapping was carried out using pulsed doppler ultrasound by the apical route; results were expressed as 3 grades of increasing severity. Blood flow in the aorta was recorded using pulsed doppler velocimetry by the suprasternal route at the level of the aortic isthmus where we measured the diastolic to systolic velocity integrals ratio (D/S). Apical mapping could be performed in 81 of the 82 patients, whereas suprasternal planimetry could be performed in only 56 patients (68 p. 100). Mapping provided good correlations with catheterization in 65 patients (80 p. 100); discordances were observed mainly in patients with aortic leakage due to prosthetic valve dysfunction (4/8 prosthetic valves) or with major left ventricular dilatation (found in 7 out of 9 cases of underestimation of leakage by the doppler system). The D/S ratio values obtained by the suprasternal route ranged from 16 to 28 p. 100 for mild angiographic leakage, from 34 to 66 p. 100 for moderate leakage, and from 52 to 155 p. 100 for severe leakage. "Borderline" values of 30 and 60 p. 100 respectively enabled the various degrees of aortic regurgitation to be separated. Despite their limitations, the non-invasive methods used in combination are effective in quantifying aortic regurgitation in most cases; mapping offers the advantage of simplicity: the suprasternal study is more accurate but cannot be performed in all patients.

[Slow-release verapamil 240 mg and treatment of mild to moderate hypertension]. / Vérapamil 240 mg à libération prolongée et traitement de l'HTA essentielle légère à modérée.

The study was carried out in association with medical practitioners who were responsible for observing the patients. Its aim was to determine the effective dosage of slow release verapamil (V) in the treatment of mild to moderate hypertension and to compare plasma concentrations of V with blood pressure effects. The study comprised a 2-week placebo period and a 3-month active treatment period with V, during which patients were examined, 20-24 h after last intake of V, at the end of the first (D30) and of the third (D90) month of treatment. Active treatment started with 240 mg of V (once a day); at D-30 if diastolic blood pressure (DBP) remained above 90 mmHg the dosage of V was increased to 480 mg (t.d.s.). At each examination blood pressure, body weight and heart rate were registered, electrocardiogram and routine biochemical tests were carried out; plasma concentration of V was measured at D30 for every patient and at D90 for those receiving 480 mg. of V. Thirty patients (11 men and 19 women) aged from 29 to 80 years (mean : 61.7) took part in the study. Treatment needed to be stopped in one patient; results are based on the other 29. At D30 systolic blood pressure (SBP) fell from 179.4 +/- 5.9 to 156.2 +/- 5,5 mmHg and DBP from 101.3 +/- 1.8 to 88.3 +/- 3 mmHg; DPB became normal (less than 90 mmHg) in 23 subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Lisinopril versus slow-release nifedipine in the treatment of mild to moderate hypertension: a multicentre study. The Cooperative Study Group.

The antihypertensive effects of lisinopril 20 mg once daily and slow-release nifedipine 20 mg twice daily were compared in a double-blind, parallel group, 10-week study involving 274 patients with mild to moderate hypertension. During the first 6 weeks of treatment, slow-release nifedipine and lisinopril produced similar reductions in lying and standing blood pressure (BP), except for lying systolic BP (SBP) which was reduced to a greater extent by lisinopril. After 6 weeks of double-blind treatment, hydrochlorothiazide 25 mg once daily was added if BP remained uncontrolled (lying DBP greater than or equal to 95 mmHg); a significantly greater proportion of patients in the nifedipine group than in the lisinopril group required additional diuretic treatment (29% versus 14%, respectively; P = 0.005). Moreover, after a further 4 weeks of treatment BP was adequately controlled (lying DBP less than 95 mmHg) in significantly more lisinopril-treated patients than in the nifedipine group (91.4% versus 78.3%, respectively; P = 0.006). Lisinopril was better tolerated than slow-release nifedipine. The frequency of drug-related events was significantly lower (threefold) for lisinopril than for nifedipine (P = 0.001) and the number of withdrawals from treatment with nifedipine was more than three times that in the lisinopril treatment group (P = 0.009). Lisinopril appears to provide an effective once-daily antihypertensive treatment which is at least as effective as, and better tolerated than, slow-release nifedipine.

Plasma plasminogen activator inhibitor-1 in angina pectoris. Influence of plasma insulin and acute-phase response.

Plasminogen activator inhibitor-1 (PAI-1) is an important physiological inhibitor of fibrinolysis. It circulates in blood both in free active form and in inactive form complexed with tissue type plasminogen activator (t-PA). Control mechanisms for its synthesis and release from hepatocytes and endothelial cells are important in the pathogenesis of thrombosis. Possible risk factors for myocardial infarction include high insulin and PAI-1 levels, which correlate with one another in healthy subjects, and fibrinogen, which together with PAI-1, is an acute-phase reactant. We therefore studied the interrelationships between PAI-1, plasma insulin, and acute-phase proteins in 67 patients with angina pectoris. Plasma insulin correlated strongly (r = 0.59, p less than 0.001) with PAI activity, free PAI-1 antigen (r = 0.60, p less than 0.001), and total PAI-1 antigen (r = 0.58, p less than 0.001). The acute-phase proteins, fibrinogen and C-reactive protein, correlated significantly with t-PA antigen, total PAI-1 antigen, and PAI-1/t-PA complexes but not with PAI activity or free PAI-1. The results suggest that insulin stimulates synthesis and release of free PAI-1 (probably via hepatocytes as previously shown with cell culture) and that endothelial cell synthesis and release of t-PA, together with PAI-1, reflects a nonspecific acute-phase response to chronic vascular disease. Hyperinsulinemia found in patients with angina pectoris could play a role in the development of myocardial infarction via the induction of high plasma PAI-1 activity.

[Calcium channel blockers in ischemic cardiopathies]. / Les inhibiteurs du canal calcique lent dans les cardiopathies ischémiques.

Calcium-entry blockers are the drugs of choice in coronary spasm, unstable angina, and when patients do not have any effort limitation. However, beta-blockers, without sympathomimetic activity, remain the treatment of angina pectoris. When clinical situation is difficult to control, association calcium blockers and bêta-blockers are more efficient than monotherapy. In myocardial infarction, results are controversial: calcium channel blockers should be administered only with beta-blockers.

[Double mitral valve orifice. Apropos of a case discovered by echocardiography]. / Orifice mitral double. A propos d'un cas de découverte échocardiographique.

The authors report a case of isolated double orifice mitral valve in a 20-year old pregnant woman. This exceptional and seldom isolated anomaly is usually discovered at autopsy or surgery. In this particular case it was diagnosed by pulsed doppler ultrasound combined with echocardiography. Data from the literature are reviewed on that occasion, and the echocardiographic images of the malformation are described. Despite its rarity, double orifice mitral valve deserves to be known and its presence should be looked for by echocardiography, notably in patients with complete or partial atrioventricular canal.

[Diagnostic value of exercise tomoscintigraphy with thallium 201 in patients with complete left branch block]. / Valeur diagnostique de la tomoscintigraphie d'effort au thallium 201 chez les patients porteurs d'un bloc de branche gauche complet.

Eighteen patients with rate-dependent (n = 5) or chronic (n = 13) left bundle branch block underwent thallium 201 exercise SPECT and selective coronary arteriography. 15 patients showed significant septal or anteroseptal perfusion defects on the exercise scintigrams, but in only 4 of them did the coronary disease involve the left anterior descending artery (LAD) (n = 3) or the left main coronary artery (n = 1). Among patients with normal scintigrams, one had right coronary artery stenosis. Test performance in detecting individual coronary artery stenosis greater than 70 p. 100 was: sensitivity 80 p. 100 (4/5) and specificity 15 p. 100. In patients with left bundle branch block, T1 201 SPECT was indeterminate for LAD disease due to reversible septal perfusion defect. We conclude that the usefulness of stress thallium 201 SPECT in patients with left bundle branch block is very limited.

[Carcinoid cardiopathy: value of ultrasonography and MRI. Apropos of a case related to bronchial tumor. Review of the literature]. / Cardiopathie carcinoïde: intérêt de l'ultrasonographie et de l'IRM. A propos d'un cas lié à une tumeur bronchique. Revue de la littérature.

A case of carcinoid cardiopathy (C.C.) of the right heart, related to liver metastases secondary to a bronchial tumor, is reported. Non-invasive investigative methods have enabled an easy diagnosis of C.C.: liver metastases by scan and abdominal sonogram, restrictive myocardiopathy with typical tricuspid lesions by echocardiography and MRI, magnitude of the tricuspid regurgitation by cardiac Doppler. These extremely performing methods must allow an early diagnosis at a stage when the patient may be still operable, since C.C. is the most frequent cause of death in patients with carcinoid tumors.