Biomedical subjects

F Follath

Publications and source records attributed to F Follath.

At least 37 records · Page 2Linked to original sources

PubMed2001

Lethal autoimmune myocarditis in interferon-gamma receptor-deficient mice: enhanced disease severity by impaired inducible nitric oxide synthase induction.

BACKGROUND: Interferon-gamma (IFN-gamma) is an essential cytokine in the regulation of inflammatory responses in autoimmune diseases. Little is known about its role in inflammatory heart disease. METHODS AND RESULTS: We showed that IFN-gamma receptor-deficient mice (IFN-gammaR(-/-)) on a BALB/c background immunized with a peptide derived from cardiac alpha-myosin heavy chain develop severe myocarditis with high mortality. Although myocarditis subsided in wild-type mice after 3 weeks, IFN-gammaR(-/-) mice showed persistent disease. The persistent inflammation was accompanied by vigorous in vitro CD4 T-cell responses and impaired inducible nitric oxide synthase expression, together with evidence of impaired nitric oxide production in IFN-gammaR(-/-) hearts. Treatment of wild-type mice with the nitric oxide synthetase inhibitor N:-nitro-l-arginine-methyl-ester enhanced in vitro CD4 T-cell proliferation and prevented healing of myocarditis. CONCLUSIONS: Our data provide evidence that IFN-gamma protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses.

Adjuvants, Immunologic↗

PubMed2001

Toxicity of amiodarone and amiodarone analogues on isolated rat liver mitochondria.

BACKGROUND: Amiodarone is a well-known mitochondrial toxin consisting of a benzofuran ring (ring A) coupled to a p-OH-benzene structure substituted with 2 iodines and a diethyl-ethanolamine side chain (ring B). AIM: To find out which part of amiodarone is responsible for mitochondrial toxicity. METHODS: Amiodarone, ring A and B without the ethanolamine side-chain and iodines (B0), ring A and B with iodines but no ethanolamine (B2), ring B with 1 iodine and no ethanolamine (C1) and ring B with ethanolamine and 2 iodines (D2) were studied. RESULTS: In freshly isolated rat liver mitochondria, amiodarone inhibited state 3 glutamate and palmitoyl-CoA oxidation and decreased the respiratory control ratios. B0 and B2 were more potent inhibitors than amiodarone and B2 more potent than B0. C1 and D2 showed no significant mitochondrial toxicity. After disruption, mitochondrial oxidases and complexes of the electron transport chain were inhibited by amiodarone, B0 and B2, whereas C1 and D2 revealed no inhibition. Beta-oxidation showed a strong inhibition by amiodarone, B0 and B2 but not by C1 or D2. Ketogenesis was almost unaffected. CONCLUSIONS: Amiodarone, B0 and B2 are uncouplers of oxidative phosphorylation, and inhibit complexes I, II and III, and beta-oxidation. The benzofuran structure is responsible for mitochondrial toxicity of amiodarone and the presence of iodine is not essential.

Amiodarone↗

PubMed2001

Anthracycline-induced acute cardiotoxicity in adults treated for leukaemia. Analysis of the clinico-pathological aspects of documented acute anthracycline-induced cardiotoxicity in patients treated for acute leukaemia at the University Hospital of Zürich, Switzerland, between 1990 and 1996.

BACKGROUND: Acute cardiotoxicity due to anthracyclines is a rare, but life-threatening event. Interindividual sensitivity to anthracyclines is highly variable and cannot be predicted for the individual patient. PATIENTS AND METHODS: This is a retrospective study. Medical charts and autopsy reports of patients treated for acute leukemia between 1990 and 1996 at the University Hospital of Zürich, Switzerland were reviewed and searched for anthracycline-associated acute cardiotoxicity. Patients with pre-existing heart disease known to be associated with cardiotoxicity were excluded. RESULTS: Seven patients treated for leukemia with proven anthracycline-associated acute cardiotoxicity were included. In six patients the direct cause of death was acute cardiotoxicity due to the treatment. One patient recovered from cardiac failure but died a few months later from refractory leukemia. Clinical symptoms were those of a heart failure. Pathological findings were dilatative cardiac hypertrophy and pericardial effusion. Microscopically the typical findings of myocardial fibrosis and perinuclear vacuolisated myocytes were seen. CONCLUSIONS: The awareness of acute adverse effects on cardiac performance by anthracyclines faciliates early recognition and prevention of heart failure. Reliable tests are needed for the early diagnosis of subclinical myocardial damage in order to identify patients at risk.

Acute Disease↗

PubMed2001

Metabolism of amiodarone (Part III): identification of rabbit cytochrome P450 isoforms involved in the hydroxylation of mono-N-desethylamiodarone.

1. Amiodarone (AMI) is a potent anti-arrhythmic drug and mono-N-desethylamiodarone (MDEA) is its only known metabolite. It was found recently that in rabbit liver microsomes MDEA was biotransformed to n-3-hydroxybutyl-MDEA (3OH-MDEA). 2. In liver microsomes isolated from the untreated rabbit, the formation of 3OH-MDEA obeyed Michaelis-Menten enzyme kinetics with Km = 6.39 +/- 1.07 microM and Vmax = 0.56 +/- 0.21 nmolmin(-1) mg(-1) protein. 3. Furthermore, (1) among chemicals usually used as inhibitors of cytochrome P450, only midazolam (MDZ), cyclosporin A and ketoconazole inhibited the MDEA hydroxylase activity significantly (>60% inhibition), (2) MDZ, a substrate of CYP3A, inhibited the 30OH-MDEA formation competitively (Ki = 10 +/- 5 microM), (3) the formation rates of 3OH-MDEA correlated positively with those of 1'OH-MDZ (r = 0.81; n = 6), and (4) MDEA hydroxylase activity of microsomes isolated from rabbit rifampicin-induced cultured hepatocytes was 4-fold more active than the control. 4. Since CYP3A6 is mainly induced by rifampicin in rabbit-cultured hepatocytes, the data suggest that this isoform is involved in the biotransformation of MDEA to 3OH-MDEA. 5. Since alpha-naphthoflavone, cimetidine and quinidine also partially inhibited the MDEA hydroxylase activity, it is possible that other CYPs, such as 1A, 2C and 2D, may also be active in the metabolism of amiodarone.

Amiodarone↗

PubMed2001

Metabolism of amiodarone (part I): identification of a new hydroxylated metabolite of amiodarone.

UNLABELLED: Amiodarone (AMI) is a potent antiarrhythmic drug, but its metabolism has not yet been fully documented. Mono-N-desethylamiodarone (MDEA) is its only known metabolite. Our preliminary investigations using rabbit liver microsomes had shown that in vitro AMI was biotransformed to MDEA, and the latter was rapidly further biodegraded to other unknown products. The aim of the present study was to investigate the chemical structure of the biotransformed compound of MDEA. Upon incubation of MDEA with rabbit liver microsomes and NADPH as cofactor, MDEA was biotransformed into three unknown products: X1, X2, and X3. The products were purified using chromatography. The chemical structure of the major product, X1, was investigated in detail. HPLC-ESI-MS revealed that MDEA had been oxygenated. Hydrogen-deuterium exchange experiments showed that the X1 molecule contained one exchangeable hydrogen atom more than its precursor MDEA, indicating that MDEA had been hydroxylated. Further results from ESI-MS/MS analysis indicated that the site of hydroxylation was the n-butyl side chain. NMR analysis (1H NMR, one-dimensional-total correlation spectroscopy, and heteronuclear multiple-bond correlation spectroscopy) established the 3-position (omega-1) of the butyl moiety as the specific carbon atom that is hydroxylated. Rat liver microsomes were also able to catalyze MDEA hydroxylation. Compound X1, as analyzed by HPLC-ESI-MS and ESI-MS/MS, was detected in the liver, heart, lung, and kidney tissue of four rats receiving AMI, suggesting that the hydroxylated MDEA was a secondary metabolite of AMI. CONCLUSION: in mammals, MDEA is hydroxylated to the secondary metabolite of AMI [2-(3-hydroxybutyl)-3-[4-(3-ethylamino-1-oxapropyl)-3,5-diiodobenzoyl]-benzofuran].

Amiodarone↗

PubMed2001

Ischemic versus non-ischemic heart failure: should the etiology be determined?

In epidemiological surveys and in large-scale therapeutic trials, the prognosis of patients with ischemic heart failure is worse than in patients with a non-ischemic etiology. Even heart transplant candidates may respond better to intensified therapy if they have non-ischemic heart failure. The term 'non-ischemic heart failure' includes various subgroups such as hypertensive heart disease, myocarditis, alcoholic cardiomyopathy and cardiac dysfunction due to rapid atrial fibrillation. Some of these causes are reversible. The therapeutic effect of essential drugs such as angiotensin-converting enzyme inhibitors, beta-blockers and diuretics does not, in general, significantly differ between ischemic and non-ischemic heart failure. However, in some trials, response to certain drugs (digoxin, tumor necrosis factor-alpha, inhibition with pentoxifylline, growth hormone and amiodarone) was found to be better in non-ischemic patients. Patients with ischemic heart failure and non-contracting ischemic viable myocardium may, on the other hand, considerably improve following revascularization. In view of prognostic and possible therapeutic differences, the etiology of heart failure should be determined routinely in all patients.

Adrenergic beta-Antagonists↗

PubMed2000

[Cost effectiveness of bisoprolol in treatment of heart failure in Germany. An analysis based on the CIBIS-II study].

OBJECTIVES: Economic analysis of bisoprolol plus standard therapy versus placebo plus standard therapy in the treatment of chronic heart failure in Germany. MATERIALS AND METHODS: Prospective analysis of resource use and costs by way of integration into the international, randomized, double-blind CIBIS (Cardiac Insufficiency Bisoprolol Study)-II clinical trial, which treated 1,327 patients with bisoprolol and 1,320 with placebo. Two hundred and fifteen German patients were included in CIBIS-II (bisoprolol: 112, placebo: 103). The German health economic subpopulation comprised 97 patients (bisoprolol: 52, placebo: 45). The economic base analysis valued the resource use of every single patient of this subpopulation in monetary terms, from the perspective of Germany's third party payer (statutory sick funds). RESULTS: Mean observation time was 1.3 years. During this time hospitalization costs of DM 783.--were saved in the bisoprolol group. Total direct medical costs amounted to DM 7,651.--in the bisoprolol group and DM 8,905.--in the placebo group. This means savings of DM 1,254.--per patient, or a 14.1% cost reduction. If mean data of all German CIBIS-II patients are used as a broader basis, bisoprolol therapy saves DM 1,203.--per patient. Bisoprolol therapy induced a mortality rate reduction from 17% to 12% in the overall clinical CIBIS-II population (n = 2,647). This difference is statistically highly significant (p < 0.0001). Altogether 74 lives could be saved by bisoprolol therapy. Saved life years amounted to 0.03 per patient after 65 weeks of therapy (460 days), and to 0.12 per patient after 130 weeks (30 months). As bisoprolol therapy leads to net savings, a formal cost-effectiveness analysis, which would relate incremental clinical efficiency to additional costs, is not needed. CONCLUSION: The use of bisoprolol in the therapy of chronic heart failure is not only clinically effective, it also saves net costs.

Aged↗

PubMed2000

[Diagnosis and course of myocarditis: a survey in the medical clinics of Zurich University Hospital 1980 to 1998].

The clinical picture of myocarditis/myopericarditis is of importance in differential diagnosis, especially in younger patients with suspected myocardial infarction. Myocarditis/myopericarditis commonly presents with chest pain, and the diagnosis is usually established on clinical grounds. However, endomyocardial biopsy is necessary to confirm the diagnosis. We evaluated the characteristics of acute myocarditis over the years 1980-1998 in 54 patients of the Department of Medicine of the University Hospital, Zurich. Two to 6 patients per year were hospitalised with this diagnosis. In most cases the diagnosis was established by a combination of criteria, such as a preceding infection of the upper respiratory tract, thoracic pain, ST segment elevations in different precordial leads followed by T wave inversions, arrhythmias, elevation of cardiac enzymes, reversible hypokinesia by echocardiography and normal coronary arteries. At least 3 of 5 criteria were requested. In a first step we analysed retrospectively all patients with acute myocarditis/myopericarditis in the years 1980-1993. Among 30 cases of acute myocarditis/myopericarditis the following causes could be identified: one influenza B, one Toxoplasma gondii infection, 2 Epstein-Barr infections and one bacterial myocarditis with gram-negative rods. The aetiology of the other 25 cases remained unknown. The majority of myocarditis/myopericarditis healed without complications. One patient with Epstein-Barr myocarditis and one with Toxoplasma gondii infection died. Two patients developed dilated cardiomyopathy. In a second phase we analysed prospectively all cases with acute myocarditis/myopericarditis over the period 1994-1998: 24 patients with acute myocarditis/myopericarditis were hospitalised. At that time coronary angiography and endomyocardial biopsies were performed more frequently. We found 2 patients with giant cell myocarditis and 2 with Toxoplasma gondii infection and HIV, all of whom died. In addition, there were 2 patients with eosinophilic myocarditis, one with Lyme carditis, one with Epstein-Barr myocarditis, one with myopericarditis after Campylobacter enteritis and one histologically proven myocarditis after pneumonia with Haemophilus influenzae. The aetiology of the remaining 13 cases with myocarditis/myopericarditis could not be established. Three patients with probable viral myocarditis developed cardiogenic shock requiring intraaortic balloon pump, and fully recovered. The patient with Lyme carditis manifested with total atrioventricular block and was treated with a temporary pacemaker. One patient with lymphocytic myocarditis required heart transplantation because of terminal heart failure and one female patient with histologically proven diffuse lympho-monocytic myocarditis died of cardiogenic shock. All the other cases healed without complications. Serologies are of little diagnostic value and should be restricted to serologies with therapeutic implications. We believe that the apparent increase in myocarditis/myopericarditis in recent years is a result of better diagnostic tools, such as more specific cardiac enzyme tests, coronary angiography and endomyocardial biopsies. In most cases the therapy remains symptomatic. In elected, severe cases steroids and other immunosuppressive drugs are sometimes used.

Acute Disease↗

PubMed2000

[Medical treatment of heart failure: an analysis of actual treatment practices in outpatients in Switzerland. The Swiss "IMPROVEMENT of HF" Group].

BACKGROUND: From several studies in Europe and the USA there is evidence that drug treatment of patients with congestive heart failure (CHF) could be improved. There are only sparse data on the treatment of this population in Switzerland. METHODS: In the context of a European Study (IMPROVEMENT of HF Study), in 1999, the treatment of 474 patients with symptomatic CHF was recorded by chart review with primary care physicians throughout Switzerland. The effect of potential predictors of drug treatment was tested using multivariate logistic regression. RESULTS: Mean age of the study population was 75 +/- 12 years. Overall, angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) were prescribed to 65% of the study population. Beta-blockers, loop diuretics/thiazides, spironolactone and digitalis were prescribed to 25%, 73%, 13% and 31% respectively. Compared with CHF patients < 65 years of age, the odds ratio of ACE-I/ARB prescription in patients aged 65-74, 75-84, and > or = 85 years was 0.80, 0.58 and 0.40 respectively (p < 0.001). The respective odds ratios for beta blocker treatment were 0.37, 0.21 and 0.06 (p < 0.001). In addition, NYHA classification, comorbid conditions such as renal failure and contraindications strongly predicted drug prescription. Gender and geographical area were not associated with drug selection. CONCLUSIONS: Overall drug prescription among CHF patients in Swiss primary care appears to be satisfactory. However, prescription of ACE-I/ARB and beta-blockers falls steeply with increasing age, independent of measured comorbid conditions and contraindications. Thus, improvement of treatment should focus on a more consistent use of these drugs in the segment of elderly CHF patients.

Adrenergic beta-Antagonists↗

PubMed2000

[Cost-effectiveness of primary PTCA and thrombolysis in the treatment of acute myocardial infarction].

Clinical studies have shown a favourable outcome for primary PTCA compared with thrombolysis in the treatment of acute myocardial infarction. No data are available in Switzerland on the logistic and economic implications of treating more acute myocardial infarction patients by PTCA. The present paper sets out to assess all published studies comparing the cost-effectiveness of the two treatment modalities. A Medline search identified seven original cost and cost-effectiveness studies conducted between 1989 and 1999. According to these studies emergency PTCA generates costs similar to thrombolysis in the treatment of acute myocardial infarction if the infrastructure is available and there is high volume output. Better clinical results, as suggested by the literature, would result in a favourable cost-effectiveness ratio for primary PTCA.

Angioplasty, Balloon, Coronary↗

PubMed2000

The Euro Heart Failure Survey of the EUROHEART survey programme. A survey on the quality of care among patients with heart failure in Europe. The Study Group on Diagnosis of the Working Group on Heart Failure of the European Society of Cardiology. The Medicines Evaluation Group Centre for Health Economics University of York.

BACKGROUND: The EUROHEART programme is a rolling programme of cardiovascular surveys among the member nations of the European Society of Cardiology (ESC). These surveys will provide information on the nature of cardiovascular disease and its management. This manuscript describes a survey into the nature and management of heart failure. AIMS: The EuroHeart Failure survey aims to describe the quality of hospital care, diagnostic and therapeutic, for patients with suspected or confirmed heart failure in ESC member countries. Patients will be interviewed subsequent to hospital discharge to assess their understanding of their condition, side effects from and their compliance with therapy and their satisfaction with the management for heart failure. The quality of management will be judged against the recommendations contained in the ESC guidelines on diagnosis and treatment of heart failure. Outcome will be further assessed by repeat interviews in 6-12 months time. A further survey of heart failure in 2001/2002 is also planned. METHODS: A prospective survey of all deaths and discharges from medical (cardiology, internal medicine and geriatric medicine) and cardiac surgical wards to identify patients with heart failure, suspected or confirmed. Approximately 70 hospital clusters, comprising two to six hospitals in each cluster, in 24 member countries of the ESC are conducting the study. At the time of writing, approximately 30000 deaths and discharges have been screened and approximately 4000 patients have been enrolled. CONCLUSIONS: The EuroHeart Survey will allow actual practice to be compared to ESC guidelines on the diagnosis and treatment of heart failure. The surveys and guidelines should prove mutually informative. The main EuroHeart Failure project will be completed by late 2000. However, new centres volunteering to participate in the study (contact corresponding author) may be accepted providing they have the necessary research personnel and provided funding can be agreed for statistical support and administration.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2000

Management of heart failure in Switzerland.

Similar to other countries, heart failure is a major cause of morbidity and mortality in Switzerland. Among heart failure patients admitted to a Swiss university hospital in 1998, admission therapy included: ACE inhibitors/AT-II blockers in approximately two-thirds; diuretics in approximately 70%; and beta-blockers in approximately one-third. Easy access to diagnostic tests and limited results of surveys suggest that quality of care of heart failure patients is satisfactory in Switzerland. However, results from ongoing studies are required to assess more reliably the quality of diagnosis and therapy of this high-risk population in Switzerland.

Heart Failure↗

PubMed2000

[Heart failure].

Explore the source record for details and available documents.

Age Distribution↗

PubMed2000

[Ischemic vs nonischemic heart failure--does etiology matter?].

In most large scale trials the prognosis of ischemic heart failure is worse than in patients with non-ischemic etiology. The therapeutic effect of essential drugs such as ACE-inhibitors, betablockers and diuretics is similar, but response to some other drugs (amiodarone, amlodipine, digoxin, growth hormone) is better in non-ischemic heart failure. Of great practical importance is the recognition of hibernating myocardium in coronary artery disease, since revascularisation may significantly improve left ventricular function. Specific therapeutic interventions are possible in hypertensive heart disease, alcoholic cardiomyopathy and LV-dysfunction to tachyarrhythmias. The etiology of heart failure should therefore be cleared in all patients.

Arteriosclerosis↗

PubMed2000

Epidemiology of drug exposure and adverse drug reactions in two swiss departments of internal medicine.

AIMS: To explore drug exposure, frequency of adverse drug reactions (ADRs), types of ADRs, predisposing risk factors and ADR-related excess hospital stay in medical inpatients. METHODS: Structured data regarding patient characteristics, 'events' (symptoms, laboratory results), diagnoses (ICD10) and drug therapy were collected using a computer-supported data entry system and an interface for data retrieval from electronic patient records. ADR data were collected by 'event monitoring' to minimize possible bias by the drug monitor. The causality of each event was assessed in relation to disease(s) and drug therapy. RESULTS: The analysis included 4331 (100%) hospitalizations. The median observation period was 8 days. The median number of different drugs administered per patient and day was 6 and varied between 4 (Q1 ) and 9 (Q3 ) different drugs in 50% of all hospital days. In 41% of all hospitalizations at least one disease-unrelated event could be possibly attributed to drug therapy. Clinically relevant ADRs occurred in 11% of all hospitalizations. In 3.3% of all hospitalizations ADRs were the cause of hospital admission. The incidence of possibly ADR-related deaths was 1.4. Factors predisposing for clinically relevant ADRs were female gender and polypharmacy. ADR-related excess hospital stay accounted for 8. 6% of hospital days. CONCLUSIONS: These data demonstrate the feasibility of the developed 'event monitoring' system for quantitative analysis of ADRs in medical inpatients. With increasing numbers of recorded patients the pharmacoepidemiological database provides a valuable tool to study specific questions regarding drug efficacy and safety in hospitalized patients.

Adverse Drug Reaction Reporting Systems↗

PubMed1999

[Lipid-lowering therapy in patients with coronary disease: proportion of patients requiring treatment according to recommendations of the Swiss Society of Cardiology].

BACKGROUND: Recent studies have confirmed that treatment with lipid-lowering drugs decreases cardiovascular morbidity and mortality in primary as well as secondary prevention of cardiovascular diseases. In 1999, new Swiss recommendations for treatment with lipid-lowering drugs have been published. We therefore performed a study to estimate the proportion of patients with coronary artery disease requiring lipid-lowering drugs. METHODS: We included 637 patients with coronary heart disease who were referred for coronary angiography during 1991-1993. We calculated the proportion of patients requiring lipid-lowering drugs according to the new Swiss guidelines, and compared them with European and US guidelines. RESULTS: According to the 1999 Swiss recommendations, 79% of the study population would have qualified for lipid-lowering treatment (males 80%, females 78%; patients aged up to 69 years 80%, patients aged 70 years and over 73%). Agreement with both the Recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention, and the ACC/AHA Guidelines for Management of Patients with Acute Myocardial Infarction, was 96% (Kappa 0.79 and 0.83 respectively). CONCLUSION: A large proportion of patients with coronary artery disease qualifies for treatment with lipid-lowering drugs. The new Swiss recommendations closely agree with European and US guidelines.

Aged↗

PubMed1999

[Internal medicine in academic centers: what future?].

The rapid increase in medical knowledge and the introduction of new diagnostic and therapeutic techniques has also led to increasing specialisation in the field of internal medicine. For this reason controversy has arisen, particularly in university centres, about the importance and role of "general" internal medicine compared to the medical specialties. In this paper the most important tasks of internal medicine in patient care, in graduate and postgraduate training and in clinical research are analysed. The prime task of internal medicine is comprehensive care for the increasing number of elderly patients with multiple co-existing diseases. In this respect generalists cannot be adequately replaced by specialists. Mutual critical co-operation between internists and specialists also reduces the risk of overuse of medical technology and leads to a corresponding reduction in hospital costs. In medical schools internists have a major task in teaching bedside clinical examination and a general approach in the diagnosis and treatment of the most relevant medical disorders, while specialised knowledge becomes more important during the postgraduate training period. Hospital-based internal medicine remains an essential basis for clinical training not only for general internists and family physicians but also for all medical sub-specialties. In continuous medical education internists have the task of synthesising and transmitting new knowledge from the various special fields, including their application in a non-selected broad patient population. Also in clinical research several tasks remain for internists, such as clinical epidemiology, cost-benefit analysis and critical evidence-based assessment of diagnostic and therapeutic methods. Discontinuance or drastic reduction of internal medicine in university centres would not be justified and could lead to a negative balance between general internists and specialists, with negative consequences for health care, as experienced in the USA. Instead of fragmentation and rivalry for positions and resources, better co-ordination and co-operation between internists and specialists is needed in university centres, if possible in integrated medical departments.

Delivery of Health Care↗

PubMed1999

Prognostic significance of oxygen uptake kinetics during low level exercise in patients with heart failure.

Oxygen uptake kinetics during low-intensity exercise were investigated in 48 patients with congestive heart failure to assess their prognostic value compared with established predictors of prognosis including neurohumoral stimulation. Mean response time of oxygen uptake during low-intensity exercise, which does not require the patient's maximal effort, appears to be an important predictor of prognosis in these patients.

Adult↗