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Therapeutic lung lavages in children and adults.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare disease, characterized by excessive intra-alveolar accumulation of surfactant lipids and proteins. Therapeutic whole lung lavages are currently the principle therapeutic option in adults. Not much is known on the kinetics of the wash out process, especially in children. METHODS: In 4 pediatric and 6 adult PAP patients 45 therapeutic half lung lavages were investigated retrospectively. Total protein, protein concentration and, in one child with a surfactant protein C mutation, aberrant pro-SP-C protein, were determined during wash out. RESULTS: The removal of protein from the lungs followed an exponential decline and averaged for adult patients 2-20 g and <0.5 to 6 g for pediatric patients. The average protein concentration of consecutive portions was the same in all patient groups, however was elevated in pediatric patients when expressed per body weight. The amount of an aberrant pro-SP-C protein, which was present in one patient with a SP-C mutation, constantly decreased with ongoing lavage. Measuring the optical density of the lavage fluid obtained allowed to monitor the wash out process during the lavages at the bedside and to determine the termination of the lavage procedure at normal protein concentration. CONCLUSION: Following therapeutic half lung lavages by biochemical variables may help to estimate the degree of alveolar filling with proteinaceous material and to improve the efficiency of the wash out, especially in children.

Adult↗

On systems and control approaches to therapeutic gain.

BACKGROUND: Mathematical models of cancer relevant processes are being developed at an increasing rate. Conceptual frameworks are needed to support new treatment designs based on such models. METHODS: A modern control perspective is used to formulate two therapeutic gain strategies. RESULTS: Two conceptually distinct therapeutic gain strategies are provided. The first is direct in that its goal is to kill cancer cells more so than normal cells, the second is indirect in that its goal is to achieve implicit therapeutic gains by transferring states of cancer cells of non-curable cases to a target state defined by the cancer cells of curable cases. The direct strategy requires models that connect anti-cancer agents to an endpoint that is modulated by the cause of the cancer and that correlates with cell death. It is an abstraction of a strategy for treating mismatch repair (MMR) deficient cancers with iodinated uridine (IUdR); IU-DNA correlates with radiation induced cell killing and MMR modulates the relationship between IUdR and IU-DNA because loss of MMR decreases the removal of IU from the DNA. The second strategy is indirect. It assumes that non-curable patient outcomes will improve if the states of their malignant cells are first transferred toward a state that is similar to that of a curable patient. This strategy is difficult to employ because it requires a model that relates drugs to determinants of differences in patient survival times. It is an abstraction of a strategy for treating BCR-ABL pro-B cell childhood leukemia patients using curable cases as the guides. CONCLUSION: Cancer therapeutic gain problem formulations define the purpose, and thus the scope, of cancer process modeling. Their abstractions facilitate considerations of alternative treatment strategies and support syntheses of learning experiences across different cancers.

Antineoplastic Agents↗

Integrating molecular subtypes, genomics and functional dependencies to identify context-specific therapeutic vulnerabilities in small cell lung cancer.

Small cell lung cancer is one of the most aggressive malignancies, characterized by rapid tumor growth, early metastatic spread and extremely poor survival. Although most patients initially respond to platinum-based chemotherapy, relapse is almost inevitable and treatment options at recurrence remain limited. The recent introduction of immune checkpoint inhibitors has provided only modest clinical benefit, largely due to the fact that these tumors are immunologically cold. These limitations highlight the urgent need to better understand the molecular features of small cell lung cancer in order to identify more effective therapeutic strategies. In this review, we summarize current knowledge of the molecular landscape of small cell lung cancer, with particular emphasis on transcriptome-based classifications that have identified four major molecular subtypes defined by distinct transcriptional regulators and gene expression programs. We discuss how these classifications have improved the biological understanding of the disease and stimulated efforts to develop subtype-specific therapeutic strategies. At the same time, we highlight important limitations of this framework, including the remarkable transcriptional plasticity of tumor cells, which allows dynamic transitions between subtypes and may contribute to therapeutic resistance. To address these challenges, we examine additional molecular features that may represent more stable vulnerabilities, including recurrent genomic alterations, such as the widespread loss of tumor suppressor genes or oncogene amplifications through extrachromosomal DNA. We also discuss emerging approaches aimed at identifying novel context-specific cancer dependencies, including genome-scale functional screens in vitro and in vivo and genetic restraint analyses. Finally, we consider the growing potential of liquid biopsy strategies, which exploit the high level of circulating tumor DNA in patients with this disease to detect clinically relevant genomic alterations and monitor tumor evolution. Overall, this review highlights both the opportunities and challenges associated with molecular stratification in small cell lung cancer. The integration of transcriptional classifications with genomic and functional approaches may help identify more robust therapeutic vulnerabilities and guide the development of more effective treatments for this highly aggressive disease.

Cancer vulnerabilities↗

Group therapeutic factors on an alcohol in-patient unit.

Seventy consecutive patients admitted to an alcohol unit were given a modified version of Yalom's therapeutic factor questionnaire at various points during the therapeutic programme. This programme consists of a two-week introductory programme, followed by a treatment programme, which includes psychodynamic groups, life-history reviews and intensive cognitive-therapy sessions. Internal agreement of ranking order of therapeutic factors was high among all patients and was independent of time spent in group therapy. Patients valued most an existential factor (which embraces concepts of personal responsibility and isolation), self-understanding and cohesiveness; they least valued guidance and identification. Therapists also completed the questionnaire: their ranking of therapeutic factors correlated highly with that of patients, but they ranked an existential factor much lower.

Adaptation, Psychological↗

Potentially neuroprotective and therapeutic properties of nitrous oxide and xenon.

Despite the beneficial effects of prototypical glutamatergic receptor antagonists in animal models, the pharmacological attempts by the use of such agents have met with very limited clinical success because these compounds produce adverse side effects and possess an intrinsic neurotoxicity at neuroprotective and therapeutic concentrations. Interestingly, nitrous oxide and xenon, which are anesthetic gases with a remarkably safe clinical profile, have been shown to be effective inhibitors of the NMDA receptor. We briefly review accumulating evidence that nitrous oxide and xenon at subanesthetic concentrations may have potentially neuroprotective and therapeutic properties, with a particular focus on their beneficial effects on ischemia-induced neuronal death and amphetamine-induced sensitization. Nitrous oxide at 75-vol% and xenon up to 70-vol% reduce ischemia-induced neuronal death induced by occlusion of the middle cerebral artery in rodents, and decrease NMDA-induced Ca2+ influx in neuronal cell cultures, a critical event involved in excitotoxicity. Nitrous oxide at 75-vol% and xenon at 50-vol% further reduced amphetamine-induced locomotor sensitization in rodents. However, at a higher concentration of 75-vol%, xenon shows potentially neurotoxic properties and adverse side effects. Because both agents are rapidly eliminated from the body, it is plausible that their administration at appropriate subanesthetic neuroprotective and therapeutic concentrations may not be associated, in contrast with prototypical NMDA receptor antagonists, with adverse side effects and potentially neurotoxicity. Finally, the possible therapeutic implications in humans are discussed.

Anesthetics, Inhalation↗

Raf: a strategic target for therapeutic development against cancer.

The mitogen-activated protein kinase (MAPK) signaling pathway plays a critical role in transmitting proliferative signals generated by cell surface receptors and cytoplasmic signaling elements to the nucleus. Several important signaling elements of the MAPK pathway, particularly Ras and Raf, are encoded by oncogenes, and as such, their structures and functions can be modified, rendering them constitutively active. Because the MAPK pathway is dysregulated in a notable proportion of human malignancies, many of its aberrant and critical components represent strategic targets for therapeutic development against cancer. Raf, which is an essential serine/threonine kinase constituent of the MAPK pathway and a downstream effector of the central signal transduction mediator Ras, is activated in a wide range of human malignancies by aberrant signaling upstream of the protein (eg, growth factor receptors and mutant Ras) and activating mutations of the protein itself, both of which confer a proliferative advantage. Three isoforms of Raf have been identified, and therapeutics targeting Raf, including small-molecule inhibitors and antisense oligodeoxyribonucleotides (ASON), are undergoing clinical evaluation. The outcomes of these investigations may have far-reaching implications in the management of many types of human cancer. This review outlines the structure and diverse functions of Raf, the rationale for targeting Raf as a therapeutic strategy against cancer, and the present status of various therapeutic approaches including ASONs and small molecules, particularly sorafenib (BAY 43-9006).

Animals↗

Interaction of therapeutic process and alliance during psychological assessment.

Utilizing a collaborative therapeutic assessment (TA) model proposed by Finn and Tonsager (1997), we examined the interaction between therapeutic alliance and in-session process during the assessment phase of treatment. This study compares the utility of the TA model (n = 38) versus a traditional information gathering model (n = 90) of assessment. The results of this study indicate that the use of a TA model may decrease the number of patients who terminate treatment against medical advice. The Session Evaluation Questionnaire (Stiles & Snow, 1984), Combined Alliance Short Form (Hatcher & Barends, 1996), and Penn Helping Alliance Questionnaire-Revised (Barber & Crits-Christoph, 1996) can reliably measure the patient's experience of the assessment. The psychological assessment process may impact the patient's experience of assessment feedback and aid in the development of a therapeutic alliance. The therapeutic alliance developed during the assessment was found to be related to alliance early in psychotherapy. We discuss the theoretical, clinical, and research implications of these findings.

Adult↗

MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD.

OBJECTIVE: To assess the feasibility of using MRI measurements as a surrogate endpoint for disease progression in a therapeutic trial for AD. METHODS: A total of 362 patients with probable AD from 38 different centers participated in the MRI portion of a 52-week randomized placebo-controlled trial of milameline, a muscarinic receptor agonist. The therapeutic trial itself was not completed due to projected lack of efficacy on interim analysis; however, the MRI arm of the study was continued. Of the 362 subjects who underwent a baseline MRI study, 192 subjects underwent a second MRI 1 year later. Hippocampal volume and temporal horn volume were measured from the MRI scans. RESULTS: The annualized percent changes in hippocampal volume (-4.9%) and temporal horn volume (16.1%) in the study patients were consistent with data from prior single-site studies. Correlations between the rate of MRI volumetric change and change in behavioral/cognitive measures were greater for the temporal horn than for the hippocampus. Decline over time was more consistently seen with imaging measures, 99% of the time for the hippocampus, than behavioral/cognitive measures (p < 0.001). Greater consistency in MRI than behavioral/clinical measures resulted in markedly lower estimated sample size requirements for clinical trials. The estimated number of subjects per arm required to detect a 50% reduction in the rate of decline over 1 year are: AD Assessment Scale-cognitive subscale 320; Mini-Mental Status Examination 241; hippocampal volume 21; temporal horn volume 54. CONCLUSION: The consistency of MRI measurements obtained across sites, and the consistency between the multisite milameline data and that obtained in prior single-site studies, demonstrate the technical feasibility of using structural MRI measures as a surrogate endpoint of disease progression in therapeutic trials. However, validation of imaging as a biomarker of therapeutic efficacy in AD awaits a positive trial.

Adolescent↗

Cardiac emergency triage and therapeutic decisions using whole blood rapid troponin T test for patients with suspicious acute coronary syndrome.

Emergency triage and therapeutic decisions using the recently developed whole blood rapid troponin T test were evaluated and compared with conventional electrocardiographic (ECG) diagnosis in a total of 155 patients with chest pain who visited 16 emergency outpatient clinics in the Tokyo metropolitan area. Thirty-seven patients (23.9%) had a final diagnosis of acute myocardial infarction or high-risk unstable angina requiring emergency coronary intervention and these events were defined as acute coronary syndrome. Diagnostic values using the second-generation rapid troponin T test were evaluated according to 3 time-windows in 85 patients. The sensitivity of the test was 10% for patients assessed within 3 h after the onset, 62.5% for 3-6 h after, and 75% for more than 6h, whereas conventional ECG diagnosis had 100% sensitivity at any time-window. In contrast, the specificity of the rapid troponin T test was 100%, 100%, and 97.4%, whereas that of conventional ECG diagnosis was 25%, 57.1%, and 42.2%, respectively for the 3 time-windows. The positive predictive value of ECG diagnosis was inferior to the rapid troponin T test, which reflected the prudent attitude of physicians taking ECG decisions as positive when myocardial ischemia was suspected. The diagnostic efficacy of the rapid troponin T test was remarkable in patients with the non-ST elevation type of acute coronary syndrome. A questionnaire survey on therapeutic decisions revealed that only 10% of Tokyo outpatient institutes performed prehospital thrombolytic therapy, 30-33% administered aspirin or nitrate, and 16.7% gave heparin. The rapid troponin T test is extremely useful for cardiac emergency triage and therapeutic decision making. There is a requirement for practical guidelines for the primary therapeutic decisions for patients with suspicious acute coronary syndrome.

Acute Disease↗

A therapeutic alliance can exist without face-to-face contact.

We examined the therapeutic alliance in 64 parents who completed treatment with a non-professional telephone coach in a paediatric psychosocial and behavioural intervention study called Family Help. The mean total Working Alliance Inventory score was 242.7 (95% confidence interval [CI]: 240.2, 245.2). Overall, the total scores were very high regardless of coach/parental age or gender, socioeconomic class/educational level of the parent, severity or type of the child's mental health disorder or modality of treatment delivery. The results were compared with normative data reported from other studies, which suggested that the distance therapeutic alliance scores were at least similar to face-to-face therapeutic alliance scores. The present study provides evidence that a strong, positive therapeutic alliance can exist in the absence of face-to-face contact using non-professional telephone coaches.

Adult↗

Thermochemotherapy with cis-platinum, CCNU, BCNU, chlorambucil and melphalan on murine marrow and two tumours: therapeutic gain for melphalan only.

The magnitude of potentiation by whole body hyperthermia (45 min at 41 degrees C) of cis-platinum (DDP), CCNU, BCNU, chlorambucil and melphalan (Mel) on two tumours was compared with that on marrow in C3H mice. Drug damage was assayed in the KHT tumour by growth delay and in the RIF-1 tumour by clonogenic cell survival 24 h after treatment and/or by growth delay. Toxicity to marrow stem cells was assayed 24 h after treatment, by the spleen colony technique. When drug was given at the start of heating, all drugs were potentiated both in tumour and marrow to varying degrees. However, there was no therapeutic gain for the combined treatment with DDP on RIF-1, with CCNU or BCNU on KHT, or with CHL on either RIF-1 or KHT. Therapeutic ratios for Mel of 1.9 to 2.0 for KHT and of 1.1 to 1.8 in RIF-1 were measured over the dose range 7.5 to 15.0 mg/kg in unheated animals, indicating net therapeutic gain under these conditions. An absolute therapeutic gain was found for Mel in KHT when Mel was given 30 min before the start of heat.

Animals↗

[The therapeutic impact of (18)F-FDG whole body PET. A radiooncologist's view].

AIMS: An explorative analysis of the diagnostic as well as therapeutic impact of (18)F-FDG whole body PET on patients with various tumours in the setting of an university hospital radiation therapy was performed. PATIENTS AND METHODS: 222 FDG PET investigations (148 initial stagings, 74 restagings) in 176 patients with diverse tumour entities (37 lung carcinoma, 15 gastrointestinal tumours, 38 head and neck cancer, 30 lymphoma, 37 breast cancer, 19 sarcoma and 16 other carcinomas) were done. All PET scans were evaluated in an interdisciplinary approach and consecutively confirmed by other imaging modalities or biopsy. Unconfirmed PET findings were ignored. Proportions of verified PET findings, additional diagnostic information (diagnostic impact) and changes of the therapeutic concept intended and documented before PET with special emphasis on radiooncological decisions (therapeutic impact) were analysed. RESULTS: 195/222 (88%) FDG-PET findings were verified, 104/222 (47%) FDG-PET scans yielded additional diagnostic information (38 distant, 30 additional metastasis, 11 local recurrencies, 10 primary tumours and 15 residual tumours after chemoptherapy). The results of 75/222 (34%) scans induced changes in cancer therapy and those of 58/222 (26%) scans induced modifications of radiotherapeutic treatment plan (esp. target volumes). CONCLUSION: (18)F-FDG whole body PET is a valuable diagnostic tool for therapy planning in radiooncology with a high impact on therapeutic decisions in initial staging as well as in restaging. Especially in a curative setting it should be used for definition of target volumes.

Biopsy↗

Novel therapeutic strategies for leiomyomas: targeting growth factors and their receptors.

Leiomyomas (fibroids) are benign smooth-muscle cell (SMC) tumors of the uterus and are the most common pelvic tumors in women. These tumors occur primarily during the reproductive years and are the most common indication for hysterectomy in women. Unfortunately the only effective treatments for leiomyomas and the associated abnormal uterine bleeding are surgical, involving either hysterectomy, myomectomy, or hysteroscopic removal of the tumors. The goal of this paper is to discuss recent research findings that support the idea of using therapeutic compounds that block the actions of specific growth factors as therapeutic agents for treatment of leiomyomas and abnormal uterine bleeding. Most of the studies were carried out using cell cultures of leiomyoma or myometrial SMCs. Primary cultures of SMCs provide a system for investigation of the roles of growth factors and their receptors in proliferation of normal myometrial and leiomyoma SMCs. Several growth factors have been shown to be present and to have regulatory roles in the proliferation of uterine SMCs. Bioassay and Western blotting of fast protein liquid chromatography fractions of tissue extracts identified platelet-derived growth factor, heparin-binding epidermal growth factor, hepatoma-derived growth factor, and basic fibroblast growth factor in normal myometrium and fibroid tumors. The presence of heparin-binding growth factors suggests a possible focus for therapeutic agents. RG13577 (a heparinlike compound) and halofuginone (an alkyloid) reversibly inhibited DNA synthesis of normal myometrial and leiomyoma cells without toxic effects. Pirfenidone, a known antifibrotic drug, inhibited DNA synthesis and synthesis of collagen type I mRNA in normal and fibroid cells, and decreased collagen type III mRNA only in normal myometrial cells. Another hopeful therapeutic candidate, interferon-Alpha, significantly inhibited growth factor-stimulated proliferation in both normal and leiomyoma cells. These results suggest that future nonsurgical treatments for leiomyomas may include compounds that block the actions of specific growth factors that regulate proliferation and collagen production by uterine SMCs.

Antineoplastic Agents↗

The therapeutic relationship: dead or merely impeded by technology?

The ways in which current nurse education is delivered, combined with rapid increases in technological advances in health care, are having a major impact on the delivery of care to patients. This article focuses on one aspect of that care: the establishment, development and maintenance of the therapeutic relationship. The authors argue that the changes in education delivery and the rapid introduction of technologies are contributing to the possible demise of the contemporary nurse-patient relationship and, therefore, the loss of that essence of nursing which is essential to the patients' well-being and the nurses' professional satisfaction. The article explores the requisite knowledge and skills competences essential for the formation of the therapeutic relationship and asks whether these are being impeded by simulated educational activities and the advent of ubiquitous computing. The authors acknowledge the difficulties associated with the assessment of an effective therapeutic relationship and suggest a possible framework in which a performance of understanding of the formation of a therapeutic relationship can be established.

Clinical Competence↗

Therapeutic recreation treats depression in the elderly.

Therapeutic recreation can be an effective method to treat depression in elderly home care patients. Home care is the fastest growing component in the Medicare budget. The co-occurrence of physically limiting conditions and depression in the elderly is well documented. Untreated depression carries an enormous risk and cost. Therapeutic recreation is an ideal psychosocial treatment for use in the home care setting because of its effectiveness and versatility. Certified therapeutic recreation specialists use various interventions such as poetry, music, and exercise as part of a treatment team. In addition to effectively managing depression, therapeutic recreation can be beneficial in reducing the effects of many concurrent physical conditions.

Aged↗

[Relationship experiences and therapeutic outcome in inpatient psychotherapy].

OBJECTIVES: Inpatient psychotherapy includes the patient's manifold contacts with different therapists, nurses and fellow patients. The present study investigated the association between these multiple relationships and therapy outcome. METHODS: Pre-post measures of symptom load (Brief Symptom Inventory), interpersonal problems (IIP) and self-efficacy (SEB) were used to define three groups with positive (N=129), unchanged (N=44) or negative (N=40) outcome. These groups were compared 1) by their alliance with an individual therapist, their relationship to the therapeutic team, their experience of cohesion and climate concerning fellow patients in the ward (measured weekly by the "Stationserfahrungsbogen" SEB), and 2) by their differences in mean correlations between the courses of relationship experiences and symptom load. RESULTS AND CONCLUSIONS: Cohesion and relationship to the therapeutic team were not associated with therapy outcome. Therapeutic alliance with the individual therapist and climate among fellow patients turned out to be moderate indicators of the therapeutic outcome. It is recommended to include these process parameters systematically into the process diagnostics of inpatient psychotherapy.

Adult↗

Is the sildenafil product information adequate to facilitate informed therapeutic decisions?

BACKGROUND: Optimal therapeutics and the prevention of adverse drug effects begin with complete information. When new drugs are released, the manufacturer's product information is the main and often only readily available source of drug information and, therefore, greatly influences treatment strategies. Thus, it is vital that the information in the package insert is not only complete, but also as relevant as possible for the great diversity of patients that physicians encounter. OBJECTIVE: To review the product information for sildenafil for comprehensiveness and accuracy, with respect to whether the information is sufficient to facilitate optimal therapeutics and to prevent avoidable adverse events in the wide diversity of patients with erectile dysfunction seen in clinical practice. DATA SOURCES: Sildenafil package inserts, unpublished information provided by the manufacturer, Food and Drug Administration reports, and articles retrieved through MEDLINE through March 2000. DATA SYNTHESIS: Deficiencies or inaccuracies persist in the sildenafil product information regarding sildenafil's effects on blood pressure; potential drug interactions with cimetidine, protease inhibitors, some antihypertensive drugs, alcohol, and drugs that may competitively inhibit cytochrome P450 pathways; and recommended sildenafil doses for older patients. CONCLUSIONS: For physicians to practice optimal therapeutics, adequate, clinically relevant drug information is required. Several brief changes and additions in the sildenafil product information would assist physicians in making therapeutic decisions regarding the use of sildenafil in a very diverse patient population and in avoiding preventable adverse events.

Aged↗

Diagnostic accuracy and therapeutic impact of transthoracic and transesophageal echocardiography in mechanically ventilated patients in the ICU.

STUDY OBJECTIVES: To assess the respective diagnostic accuracy of transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) and their therapeutic implications in mechanically ventilated patients, in the intensive care unit (ICU). DESIGN: A prospective study. SETTINGS: Intensive care units of two tertiary referral teaching hospitals. PATIENTS: One hundred eleven ICU patients (81 men and 30 women; mean age 57 +/- 16 years). Fifty-seven percent were hospitalized for medical illnesses, 16.5 percent after thoracic surgery, 10.5 percent after other surgery, and 16.0 percent for multiple trauma. Their Simplified Acute Physiologic Score was 16 +/- 5. INTERVENTIONS: The echocardiograms were performed in order to solve well-defined clinical problems. TTE was the first step of the procedure and TEE was performed only when (1) TTE did not solve the clinical problems, and (2) TTE yielded unsuspected findings requiring TEE. During each echocardiographic study, the following were noted: ventilatory mode, clinical problems, imaging quality, results, consequence on acute care, duration of the procedure, and potential complications of TEE. Diagnostic accuracy was defined as the proportion of solved problems, and therapeutic impact was defined as changes on acute care that resulted directly from the procedure. MEASUREMENTS AND RESULTS: One hundred twenty-eight consecutive TTE and 96 TEE were performed. TTE solved 60 of 158 clinical problems (38 percent), whether positive end-expiratory pressure (> 4 cm H2O) was present or not (28 of 74 vs 32 of 84: p > 0.50). TTE allowed evaluation of left ventricular function in 77 percent of cases and pericardial effusion in every case, but it did not solve most of the other clinical problems. Indeed, the diagnostic accuracy of TEE was markedly superior (95/98 vs 60/158: p < 0.001), but TEE required a physician's presence longer (43 +/- 17 min vs 27 +/- 12 min: p < 0.001). When TTE and TEE were scheduled (n = 96), TEE yielded an additional diagnosis or excluded with more certitude a suspected diagnosis, except in two cases. TEE had a therapeutic impact more frequently than TTE (35/96 vs 20/128: p < 0.001). Cardiovascular surgery was prompted by echocardiographic findings in ten patients. TEE was well tolerated in all patients; there were no complications. CONCLUSIONS: TEE is a valuable well-tolerated imaging technique in mechanically ventilated patients. For the assessment of left ventricular systolic function and pericardial effusion; however, TTE continues to be an excellent diagnostic tool, even when positive end-expiratory pressure is present. Both TTE and TEE have a therapeutic impact in approximately 25 percent of cases.

Echocardiography↗