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Comparative cost-effectiveness analysis of quinidine, procainamide and mexiletine.

Quinidine and procainamide have the potential for major organ toxicity, whereas mexiletine has been reported to have little risk of organ toxicity, serious proarrhythmia or congestive heart failure, but a relatively high incidence of nuisance side effects. In light of the potential adverse effects of all antiarrhythmic agents as highlighted by the Cardiac Arrhythmia Suppression Trial, the relative cost-effectiveness of these 3 agents was assessed. Based on a review of greater than 1,000 published reports, studies included in the analysis examined greater than or equal to 1 of these agents in adults, with adequate efficacy or safety data, or both. The majority of studies assessed patients with symptomatic or malignant arrhythmias, or both. Data were analyzed using a decision analysis/cost-effectiveness model. Probabilities were averaged using techniques of meta-analysis. Costs were obtained from a university medical center cost-accounting system and from expected follow-up visits to university clinics. Thirty-seven separate side effects were included in the analysis. In terms of overall cost, 12 months of mexiletine would engender $875, quinidine $1,239 and procainamide $1,911 of expenses. Mexiletine dominates the older agents in terms of cost per successful drug response, a result that holds over a wide range of efficacy and safety data. Analyses demonstrated no increase in all-cause mortality for quinidine and mexiletine over placebo, but a trend toward higher mortality with procainamide. The results suggest that mexiletine is a cost-saving alternative therapy for ventricular arrhythmias when adverse reactions are considered in addition to pharmaceutical costs and treatment efficacy.

Ambulatory Care↗

Left ventricular hypertrophy.

OBJECTIVE: To review the pathophysiology, epidemiology, patterns, diagnosis, and treatment of left ventricular hypertrophy with emphasis on the elderly. DATA SOURCES: A computer-assisted search of the English-language literature (MEDLINE database) followed by a manual search of the bibliographies of pertinent articles. STUDY SELECTION: Studies on the pathophysiology, epidemiology, patterns, diagnosis, and treatment of left ventricular hypertrophy were screened for review. Studies on left ventricular hypertrophy in the elderly and recent studies were emphasized. DATA EXTRACTION: Pertinent data were extracted from the reviewed articles. Emphasis was on studies involving the elderly. Relevant articles were reviewed in depth. DATA SYNTHESIS: Available data about the pathophysiology, epidemiology, patterns, diagnosis, and treatment of left ventricular hypertrophy with emphasis on studies involving the elderly were summarized. CONCLUSIONS: Left ventricular hypertrophy caused by hypertension or other cardiovascular disease is not only a marker for but also a contributor to cardiovascular morbidity and mortality in elderly and young patients. The question of whether regression of left ventricular mass in patients with hypertension will decrease cardiovascular morbidity and mortality needs to be answered by prospective studies using different types of antihypertensive drugs. Future studies on the efficacy of antihypertensive drugs and on stratification of therapy should include echocardiographic estimates of left ventricular mass index.

Aging↗

Reduction of intimal thickening in canine coronary bypass vein grafts with dipyridamole and aspirin.

The potential benefit of platelet inhibitor drugs on coronary arterial bypass vein grafts was assessed in dogs with magnification-corrected angiographic luminal measurements and quantitative histologic evaluation of the vein grafts. There were 11 control animals and 11 animals treated with dipyridamole, 55 mg/day, plus aspirin, 325 mg/day. Eighteen animals with patent grafts were studied when electively killed 2, 4 or 6 months after grafting. At 14 days, there was greater angiographic narrowing in the most distal 1 cm of vein grafts in control than in treated dogs (P less than 0.01). This same angiographic narrowing persisted in control dogs until they were killed (P less than 0.03). Computer-assisted measurements of the entire area of intimal thickening were done on vein graft cross sections taken 1 cm from the distal anastomosis. The circumference of the vein grafts at the intimal-media junction was measured from the same section and the potential maximal luminal area calculated. The calculated luminal narrowing due to intimal thickening was greater in control than in treated dogs (P less than 0.03). These data correlate well with the demonstrated angiographic narrowing. The findings indicate that the degree of early intimal thickening that persists 2 to 6 months postoperatively in canine coronary bypass vein grafts may be reduced by the platelet inhibitor combination of dipyridamole plus aspirin.

Animals↗

[Ventricular arrhythmia and late potentials in patients with hypertrophic cardiomyopathy].

Holter monitoring (48 h) and registration of signal-averaged late potentials (method of Simson, high pass filter 40 Hz) were performed in outpatiens with hypertrophic cardiomyopathy. A prevalence of spontaneous ventricular arrhythmias could be determined in 51 patients; the results of 45 patients not taking antiarrhythmic drugs are presented here. 96% of these showed ventricular premature beats, 76% had multiform extrasystoles, 27% showed pairs of ectopic beats and 20% had runs of ventricular tachycardia (more than 3 QRS complexes). Absolute counts of premature beats were low in most patients, but important interindividual differences could be observed: M = 34 extrasystoles/24 h (0-4943). Ventricular tachycardias were of short duration (maximum 11 QRS) with heart rate ranging from 120 to 200/min. All patients were asymptomatic during tachycardia. Signal-averaged late potentials could be registered in 30 patients, 28 of them without antiarrhythmic drug therapy. Mean QRS duration (QRSdur) was 108 +/- 12 ms, mean duration of low amplitude signals (less than 40 microV) in the terminal portion of the QRS (LAdur) was 27 +/- 13 ms, and mean amplitude of the last 40 ms of the filtered QRS (LAamp) was 65 +/- 43 microV. A patient was considered to show late potentials if two of the following criteria were present: QRSdur greater than 120 ms, LAdur greater than or equal to 40 ms, LAamp less than 20 microV. This was found in four patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Concept of an antiatherosclerotic efficacy of calcium entry blockers. INTACT Investigators.

Animal experiments suggest an inhibitory effect of calcium entry blockers on arterial calcinosis and the formation of atherosclerotic plaques. Experiments with isolated tissues suggest various mechanisms for an antiatherosclerotic effect of calcium entry blockers. INTACT, the International Nifedipine Trial on Antiatherosclerotic Therapy, is the first study investigating, with a prospective, placebo-controlled, randomized, double-blind design, the influence of a calcium entry blocker (nifedipine 80 mg/day) on the progression of coronary atherosclerosis in patients with proven coronary artery disease. Study endpoints were changes of established coronary stenoses (diameter reduction greater than or equal to 20%), as well as the formation of new stenoses as documented by coronary angiography. Standardized coronary angiograms were taken before and after a treatment period of 3 years. The angiograms were quantitatively analyzed with the computer-assisted edge detection system CAAS. Of the 425 patients included in the study, 282 patients (134 on nifedipine and 148 on placebo) revealed no protocol violations. In the inclusion angiograms of these patients, 893 coronary stenoses were detected which were not significantly influenced in their development by nifedipine. However, 196 entirely new coronary lesions, 185 stenoses and 11 occlusions, were found in the follow-up angiograms. There were 78 lesions in 54 patients (40%) on nifedipine (0.58 new lesions/patient) and 118 lesions in 73 patients (49%; n.s.) on placebo (0.8 new lesions/patient; p = 0.031). In two other studies on the inhibiting effect of dihydropyridine calcium entry blockers on the progression of coronary artery disease in man defining angiographic endpoints, the drugs were also shown to reduce the number of newly formed significant coronary lesions. If further trials in man confirm a protective role of calcium entry blockers against the formation of atherosclerotic coronary lesions, a new strategy in the prevention of coronary artery disease has to be considered.

Animals↗

Effect of carbamazepine treatment on EEG changes induced by different cortical activation patterns in newly referred epileptic patients.

Sixteen epileptic patients suffering from focal epilepsy who underwent antiepileptic drug treatment with carbamazepine (CBZ) for the first time were studied. The EEG was recorded at rest with eyes closed, during blocking reaction (BR), fixation (FIX) and mental arithmetic tasks. The computerized EEG study, performed before and after CBZ therapy, utilized spectral analysis. Data underwent statistical evaluation through Anova and correlation analysis. The parameters evaluated were the mean frequency and the mean absolute and relative power. The results have shown that after CBZ treatment there is a decrease in the alpha reactivity during BR and FIX, while a significant increase in beta activity was observed during all tasks. The effect of CBZ therapy on EEG activity during cortical activation patterns are discussed.

Adult↗

Ventricular late potentials: another expression of cardiotoxicity of cytostatic drugs in children?

With the aim of finding a sensitive method to detect early anthracycline-induced myocardial damage ultimately resulting in cardiomyopathy, we studied the occurrence of ventricular late potentials, using a signal averaged electrocardiogram, in 68 children with cancer during or after chemotherapy. Ten (15%) of the children showed late potentials; in addition, patients treated with cytostatic drugs had significantly lower voltages of the last 40 ms of the QRS complex (RMS40) and a longer duration of low amplitude signals in the terminal QRS (LAS) than control patients. The occurrence of late potentials was not significantly correlated with anthracycline therapy or dosage, nor with the presence of echocardiographic abnormalities; in none of the patients we found late potentials during therapy with anthracyclines. We therefore conclude that late potentials are not helpful for early detection of myocardial injury. The occurrence of late potentials, however, does show another expression of cardiotoxicity not specifically related to anthracycline therapy. The occurrence of these late potentials may have prognostic significance with regard to the risk of ventricular arrhythmias during longer follow-up of these patients.

Action Potentials↗

Benzodiazepines in the treatment of schizophrenia: a review and reappraisal.

OBJECTIVE: Benzodiazepines, either alone or added to neuroleptics, have been studied extensively as treatments for schizophrenia, but no consensus regarding their efficacy has been reached. The authors review the double-blind trials in the literature and relate the findings to the neurobiology of benzodiazepine actions. METHOD: The clinical review included all double-blind studies through 1989 that could be identified by means of Index Medicus and computer-assisted searches and by the cross-referencing of articles. The findings from the 14 studies of benzodiazepines used alone and the 16 studies of adjunctive therapy are presented separately. RESULTS: The studies reviewed suggest that 1) response is highly variable, and about one-third to one-half of patients improve; 2) benzodiazepines are potentially most useful as adjuncts to neuroleptics in the acute management of psychotic agitation, although actual antipsychotic effects have also been observed in some patients; 3) relatively higher doses of benzodiazepines may be associated with better response; and 4) therapeutic effects, when seen, develop rapidly but diminish after several weeks in some patients. The authors explore the neurobiological bases of benzodiazepine action, which presumably underlie their efficacy in schizophrenia and may help explain the variability of response. CONCLUSIONS: Future research on benzodiazepines in the treatment of schizophrenia should focus on features that predict response, the relation of dopamine or other neurotransmitter systems to therapeutic effects, the schizophrenic symptoms most amenable to benzodiazepine treatment, changes in neuroleptic dose during benzodiazepine augmentation, the role of benzodiazepines in maintenance therapy, and the optimal characteristics of benzodiazepine treatment.

Antipsychotic Agents↗

[Effect of amiodarone on signal-averaged and long-term ECG].

This prospective study examined the influence of long-term amiodarone therapy on the parameters of the signal-averaged ECG and their relation to simultaneously derived Holter monitoring data. For this purpose, 23 patients with angiographically confirmed dilated cardiomyopathy or coronary heart disease and high-grade ventricular arrhythmias, in whom an average of four class I antiarrhythmic drugs had proven ineffective, were stabilized on amiodarone. Before the beginning of therapy, as well as after 2 months and, subsequently, every 3 months, a resting ECG, a signal-averaged ECG by Simson's method, and Holter monitoring were performed. Compared to the initial measurement, we found a significant increase in the duration of the total filtered QRS complex from an average of 114 +/- 24 ms to 127 +/- 35 ms, while the change in voltage did not reach the significance level. The incidence of late potentials remained largely constant under amiodarone; 10 patients showed a constant late potential, 12 patients had no late potential, and one patient with coronary heart disease developed a new late potential. In the long-term follow-up, we ascertained a relatively high responder rate under amiodarone between 41% and 81%. No relation could be detected between the results of the signal-averaged ECG and those of 24-h Holter monitoring.

Aged↗

Prospective detection of vulnerability to sustained ventricular tachycardia in patients awaiting cardiac transplantation.

This prospective study tested the hypothesis that abnormal signal-averaged electrocardiograms (ECGs) and inducible ventricular arrhythmias identify patients awaiting cardiac transplantation who are prone to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Thirty-seven patients with advanced symptoms of heart failure and a mean left ventricular ejection fraction of 20 +/- 7 were studied. In response to programmed ventricular stimulation using up to 3 extrastimuli, sustained monomorphic VT was induced in 8 (22%) and polymorphic VT or VF was induced in 5 patients (13%). Patients with inducible arrhythmias underwent drug therapy guided by results of programmed ventricular stimulation or implantation of a defibrillator. Patients in whom ventricular arrhythmias could not be induced were not treated for arrhythmias. The signal-averaged ECG was abnormal and sustained VT or VF was induced in 10 patients (27%). Follow-up ranged from 1 to 33 months (mean 12). Four patients (11%) died suddenly and 4 (11%) had nonfatal sustained VT or VF. The positive predictive value for sudden death or nonfatal VT/VF was 27% for the signal-averaged ECG, 38% for programmed ventricular stimulation, and 50% if both tests were abnormal. The negative predictive values for these tests were 87, 88 and 88%, respectively. The actuarial incidence of arrhythmic events was significantly higher in patients with inducible ventricular arrhythmias (p = 0.017) and in patients in whom both the results of signal-averaged electrocardiographic analysis and the response to programmed ventricular stimulation were abnormal (p = 0.002). This study demonstrates that results of signal-averaged electrocardiographic analysis and the response to programmed ventricular stimulation improve risk stratification for sudden cardiac death in patients awaiting cardiac transplantation.

Actuarial Analysis↗

Evaluation of antiarrhythmic drug effects with simultaneous analysis of single ventricular premature contractions, couplets and salvos.

To improve the clinical value of ambulatory Holter electrocardiographic (ECG) monitoring as a tool of antiarrhythmic therapy control, a new statistical model was developed. In a patient group at increased risk of sudden cardiac death, the spontaneous variability of ventricular arrhythmias was assessed, with simultaneous consideration of single ventricular premature complexes, couplets and salvos. The study included 100 patients who suffered from coronary heart disease or idiopathic dilated cardiomyopathy and for whom greater than 30 ventricular premature complexes/h and couplets had been demonstrated on the last Holter ECG before the study. Between 3 and 12 Holter recordings were made for each patient in a drug-free state; the mean follow-up period was 260 days (maximum 1,403). The mean hourly values of the ectopic events (EE) were assessed separately for ventricular premature complexes, couplets and salvos. The spontaneous variability (SV) was calculated for single ventricular premature complexes, couplets and salvos as SV = log (EEday 2 + 0.01/EEday 1 + 0.01) and linked in one, two and three dimensions. Compared with the consideration of only one type of arrhythmia (one-dimensional model), the simultaneous use of two or three types of arrhythmia (two- or three-dimensional model) resulted in considerably lower reduction and aggravation rates as sufficient proof of drug effects. With control intervals up to 1 week, the one-dimensional model yielded reduction rates for ventricular premature complexes, couplets and salvos of -63%, -90% and -95%, respectively. In contrast, with the three-dimensional model, the rates were -28%, -72% and -88%. The corresponding aggravation values were +370, +1,114% and +2,189% versus +38%, +256% and +747%.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Arrhythmia Agents↗

Analysis of the mechanisms underlying the changes in left ventricular filling dynamics during oral nisoldipine therapy in patients with anterior myocardial infarction.

The aim of this study was to clarify the mechanisms responsible for the increase in early filling rate observed during oral nisoldipine therapy in patients with ischaemic left ventricular (LV) dysfunction. For that purpose, the global and regional LV function was analysed before and after 2 months of double-blind monotherapy with nisoldipine (10 mg twice daily) or a placebo, in 17 patients with a previous anterior myocardial infarction. The baseline LV ejection fraction ranged from 34-51% and no patient had heart failure. Compared to the placebo, nisoldipine significantly lowered LV systolic pressure and end-diastolic pressure (-3 mmHg vs +6 with the placebo; P less than 0.01) and the LV pressure at the time of mitral opening (-2.0 +/- 3.4 mmHg vs +3.5 +/- 3.0; P less than 0.01). Despite this reduction in driving pressure, the global LV early peak filling rate improved with nisoldipine only and this improvement was related to a selective increase in expansion rate of the anterior areas, from 1010 +/- 360 to 1339 +/- 496 mm2.s-1 (P less than 0.001). The time to regional peak filling rate (-8%; P less than 0.01), the asynchrony of diastolic wall motion and the regional ejection fraction (33 +/- 10 to 38 +/- 12%; P less than 0.001) also improved in the anterior areas with nisoldipine but not with the placebo. In contrast, in the inferior, control zones, the regional ejection fraction and filling rate remained unchanged, both when compared to baseline and to the placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

EEG-brain mapping. A method to optimize therapy in schizophrenics using absolute power and center frequency values.

In this study EEG-spectral parameters like mean alpha-power values and center frequency values are computed as maps and compared using significant probability mapping. The parameters are used to describe changes of the functional state of the brain after neuroleptic depot injection (Haldol-Decanoate) in schizophrenic patients. The absolute alpha-power increased significantly (p < 0.01), especially within the first week after injection mostly in the left hemispheric regions. The center frequency decreased most significantly (p < 0.02) between the first and second week after haldol depot injection at the right occipital regions. Both parameters are efficient to describe functional changes correlated with clinical symptomatology, even 3-5 days earlier. Thus, EEG power and center frequency mapping can be used very efficiently to estimate the optimal time between sequential neuroleptic depot injections.

Adult↗

Accuracy of drug infusion pumps under computer control.

Prototype systems implementing algorithms for automated drug infusions are typically constructed by coupling a microcomputer to a drug infusion pump through a serial communications interface. Infusion rates demanded of the infusion pump in many computed-controlled drug delivery applications are made to change at intervals much shorter than those encountered under routine clinical use. Because the ability of infusion pumps to maintain accurate flow rates during high frequency rate changes has not been documented, the purpose of this study was to validate the volumetric accuracy of three commercially available infusion pumps operating in a demanding computer-controlled application. In independent 2-h evaluations, the infusion rate demanded of each pump changed as often as every 5, 10, or 15 s using an algorithm for computer-controlled pharmacokinetic model-driven intravenous infusion. Accuracy of the infusion devices was determined gravimetrically. At all measurement times, each of the infusion pumps was accurate to within approximately +/- 5% of the expected volumetric output under each of the infusion rate intervals tested. Flow rate accuracy of +/- 5% is equal to the nominal expected accuracy of these infusion pumps in conventional clinical use.

Algorithms↗

Computer-assisted review of digoxin therapy in the elderly.

Current practice with digoxin was assessed in a group of 42 elderly patients by comparing plasma digoxin concentrations attained on previously established maintenance doses with those generated by a computer programme designed to calculate dosage schedules to suit individual patients. Discrepancies between measured and computed plasma levels and between established and computed doses dictated withdrawal of the drug or revision of dosage in 26 patients (62%), with obvious clinical benefit. An important determinant of dosage was renal function; reduction in creatinine clearance provided good evidence for the loss of ability of the elderly kidney to eliminate digoxin. Simple bedside methods are available which permit a reliable estimate of creatinine clearance without a 24-hour urine collection, provoding a rational basis for the choice of digoxin dosage in the elderly.

Aged↗

Computers in healthcare: overview and bibliography.

OBJECTIVE: The objective of this article is to provide an overview of computer technology and an associated bibliography, emphasizing institutional-based healthcare applications and pharmacoinformatics. DATA SOURCES: References were selected from the authors' files and from a computerized search over the last five years on computers in healthcare/medical informatics and in pharmacy. STUDY SELECTION: Articles selected for review and discussion were considered to be important contributions to the respective areas listed in the bibliography and representative of advancements in computer applications in healthcare and pharmacy. DATA SYNTHESIS: The computer has become an important support tool for healthcare professionals. Medical informatics and the discipline related to pharmacy, called pharmacoinformatics, have evolved from the cognitive underpinnings of medicine, pharmacy, and computer science. Recent developments in computer technology have resulted in computers that are fast, increasingly portable, and user friendly. Hospital information systems employ computers in various ways to deal with the vast amount of information used by various departments. Standards for electronic data exchange are being developed to increase the integration potential of these systems. Hospital pharmacists have used computers for drug distribution, financial analysis and inventory control, drug interaction detection, pharmacokinetic dosing, drug information, and drug therapy monitoring. Expert systems are being developed in several areas of drug therapy. Pharmacy educators have developed interactive courseware to help students learn problem-solving skills in the areas of calculations, therapeutics, and drug information. CONCLUSIONS: Pharmacists need to become more involved with applications of technology to pharmacy. Properly implemented, computers can provide more time for pharmacists to use their cognitive skills in the delivery of pharmaceutical care.

Clinical Pharmacy Information Systems↗

Decision analysis as a quality-assurance screening tool.

BACKGROUND: The purpose of this pilot study was to examine whether the technique of decision analysis, including sensitivity analysis, could be used in a clinical quality-assurance program. METHODS: This research was performed in a family practice residency clinical practice. A computerized decision analysis model was developed for selection of initial drug therapy for hypertension. The medical records of 52 resident-managed patients with hypertension were then reviewed. The residents' drug prescribing was evaluated by faculty reviewers and also by the decision analysis model, including a sensitivity analysis. RESULTS: Faculty reviewers rated the residents' drug choices as "most appropriate" or "acceptable" in 59.6% of cases. There was good agreement between faculty reviewers and the computerized decision analysis model. For example, in those cases in which the resident chose the computer model's first-choice drug, faculty deemed the management as "most appropriate" or "acceptable" 93.3% of the time. When residents selected the computer model's third or fourth choice, faculty judged the residents' therapy as "inappropriate" or "an alternate drug would have been more desirable" in 61.9% of cases. CONCLUSION: The results suggest that computerized decision analysis techniques may be a useful adjunct to other clinical quality-assurance procedures in residency training programs.

Adult↗

Kinetics and dynamics of acute rejection after heterotopic heart transplantation.

Right cervical, heterotopic heart transplantation was performed in 18 mongrel dogs. Study design was based on three different groups (n = 3 x 6). Standard immunosuppression consisted of triple drug therapy in all dogs. Groups II and III received high dose steroids during acute rejection. In group III the native hearts of previous recipients (groups I and II) were used as donors for heterotopic transplantation ("domino" principle). The hearts were examined by daily transmural biventricular biopsies and graded according to Billingham classification. Cytoimmunologic monitoring (n = 345; activation index from peripheral and coronary sinus blood) and fast Fourier transformation ECG (n = 80; area under the curve; surface recordings) served as daily noninvasive methods. Optionally antimyosin scintigraphy (n = 25; single photon emission computed tomography; heart-to-lung ratio) was performed and immunohistologically confirmed by peroxidase staining of the antibody (n = 61). Kinetics of rejection was not uniform in group I (onset after 5.7 days) and biphasic in group II (clear rejection-free interval: 6.8 days). Group III developed a continuously persisting rejection, despite repeated high-dose steroids, with an early onset (3.2 days). The invasive data, consisting of 587 punch biopsies, showed no significant difference between right and left ventricular rejection. Clearly focal rejection appeared in 51.5% of the cases, with subendocardial involvement in 54%. Cytoimmunologic monitoring significantly (p less than 0.001) correlated with daily biopsies in groups I and II. The activation index from coronary sinus blood was two times higher than in peripheral blood. Fast Fourier transform ECG identified the onset of rejection with great accuracy (p less than 0.01). The heart-to-lung ratio of antimyosin scintigraphy corresponded exactly to the various stages of rejection (p less than 0.001). High-dose steroids led to a clear reduction of the ratio in 26% cases. Peroxidase staining showed typical locations of the antibody, depending on the grade of rejection (p less than 0.001). Considering the results of pathology in this transplantation model, relying on endomyocardial biopsy alone in a clinical setting may not seem advisable. Although the results of this study must be confirmed clinically, the simultaneous use of cytoimmunologic monitoring and fast Fourier transformation ECG may prove to be valuable to day-to-day monitoring for acute rejection in the early postoperative course. If both methods indicate the onset of an acute rejection, antimyosin scintigraphy and endomyocardial biopsy, respectively, should be performed to confirm and grade the suspected diagnosis.

Animals↗