ABSTRACT
Gadodiamide is a gadolinium-based chemical element that is considered safe and well tolerated in patients without renal dysfunction and is therefore routinely used as a contrast agent in magnetic resonance imaging. Although radio-opaque, it is not frequently used for coronary angiography due to its less than optimal image quality and prohibitive cost. Our center's previous experience was less than satisfactory but the addition of a power injection system yielded good quality diagnostic images. We report a case of 63 years old male with a known history of severe, life-threatening anaphylactic reaction to previous iodinated dye presenting with persistent angina despite optimal medical therapy. Coronary and bypass graft angiography was performed using 24 cc of undiluted Gadodiamide (OMNISCAN) with a power injector (ACIST®) without any incidents or premedication with an interpretable angiogram.
ABSTRACT
Optimal management of multivessel disease (MVD) is a complex medical decision with significant prognostic implications. Despite the advent of clinical and angiographic scores to aid with treatment delineation, therapy for MVD must be individualized for each patient and his/her clinical presentation. Particularly among patients with MVD, the selection of coronary revascularization with percutaneous coronary intervention versus coronary artery bypass graft surgery versus guideline-directed medical therapy (GDMT) alone is a prognostically important decision. Several patient factors including clinical presentation, severity of coronary artery disease, presence of left ventricular dysfunction and other comorbidities, and the patient's personal preferences should guide the decision making process. In this review, we discuss the management of MVD with regards to decisions of revascularization versus GDMT alone, mode of revascularization, extent of revascularization (i.e., complete versus incomplete), the strategy of angiography- versus ischemia-guided revascularization, and MVD management in the setting of an acute coronary syndrome.
Subject(s)
Cardiovascular Agents/therapeutic use , Coronary Artery Disease/therapy , Percutaneous Coronary Intervention , Cardiovascular Agents/adverse effects , Coronary Angiography , Coronary Artery Bypass/adverse effects , Coronary Artery Bypass/mortality , Coronary Artery Disease/diagnosis , Coronary Artery Disease/mortality , Coronary Artery Disease/physiopathology , Decision Support Techniques , Humans , Patient Preference , Patient Selection , Percutaneous Coronary Intervention/adverse effects , Percutaneous Coronary Intervention/mortality , Predictive Value of Tests , Risk Factors , Severity of Illness Index , Treatment Outcome , Ventricular Function, LeftABSTRACT
The percutaneous revascularization of left main coronary artery stenosis has until recently been reserved for patients at prohibitive surgical risk or for selected emergent cases. This adopted practice of coronary artery bypass grafting, as the standard of care for left main coronary artery stenosis, has largely occurred secondary to disappointing results with bare metal stents implanted in the left main coronary artery. However, in the current era of drug-eluting stents (DES) which significantly reduce restenosis compared to bare metal stents, there has been a renewed interest in examining the role of percutaneous coronary intervention as a means of revascularization of left main disease. This article discusses recent and ongoing studies investigating the role of percutaneous intervention of left main disease, with an emphasis on the use of DES for this purpose.
Subject(s)
Angioplasty, Balloon, Coronary/methods , Coronary Stenosis/therapy , Drug-Eluting Stents , Myocardial Revascularization , Coronary Artery Bypass , Evidence-Based Medicine , Humans , Myocardial Revascularization/methods , Treatment OutcomeABSTRACT
BACKGROUND: The impact of incomplete stent apposition (ISA) after drug-eluting stent implantation determined by intravascular ultrasound (IVUS) on late clinical events is not well defined. OBJECTIVE: To evaluate the clinical impact of ISA after sirolimus-eluting stent (SES) placement during a follow-up period of 4 years. DESIGN: Pooled analysis from the RAVEL, E-SIRIUS and SIRIUS trials, three randomised, multicentre studies comparing SES and bare-metal stents (BMS). METHODS: IVUS at angiographic follow-up was available in 325 patients (SES: n = 180, BMS: n = 145). IVUS images were reviewed for the presence of ISA defined as one or more unapposed stent struts. Clinical follow-up was available for a 4-year period in all patients. Frequency, predictors and clinical sequel of ISA at follow-up after SES and BMS implantation were determined. RESULTS: ISA at follow-up was more common after SES (n = 45 (25%)) than after BMS (n = 12 (8.3%), p<0.001). Canadian Cardiology Society class III or IV angina at stent implantation (odds ratio (OR) = 4.69, 95% CI 2.15 to 10.23, p<0.001) and absence of diabetes (OR = 3.42, 95% CI 1.05 to 11.1, p = 0.041) were predictors of ISA at follow-up after SES placement. Rate of myocardial infarction tended to be slightly higher for ISA than for non-ISA patients. When SES patients only were considered, major adverse cardiac event free survival at 4 years was identical for those with and without ISA at follow-up (11.1% vs 16.3%, p = 0.48). CONCLUSIONS: ISA at follow-up is more common after SES implantation than after BMS implantation. Considering the current very sensitive IVUS definition, ISA appears to be an IVUS finding without significant impact on the incidence of major adverse cardiac events even during long-term follow-up.
Subject(s)
Coronary Restenosis/prevention & control , Coronary Thrombosis/etiology , Drug-Eluting Stents , Angioplasty, Balloon, Coronary/adverse effects , Coronary Angiography/methods , Coronary Restenosis/diagnostic imaging , Coronary Thrombosis/diagnostic imaging , Drug-Eluting Stents/adverse effects , Epidemiologic Methods , Female , Humans , Male , Middle Aged , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Sirolimus/administration & dosage , Time Factors , Tubulin Modulators/administration & dosage , Ultrasonography, Interventional/methodsSubject(s)
Angioplasty, Balloon, Coronary/methods , Cardiology/trends , Drug Delivery Systems , Stents , Angioplasty, Balloon, Coronary/instrumentation , Coronary Restenosis/prevention & control , Drug Delivery Systems/instrumentation , Humans , Paclitaxel/administration & dosage , Sirolimus/administration & dosageABSTRACT
Aims To assess whether coronary flow velocity reserve following stent implantation is predictive of the subsequent need of target lesion revascularization. Methods and Results The outcome was examined of 417 patients enrolled in a multicentre prospective randomized study (DESTINI), who received a successful single vessel stent implantation in native coronary arteries and in whom coronary flow velocity reserve was measured. Logistic regression analysis and the receiver operator characteristic curve were used. When compared with 358 patients not requiring target lesion revascularization, 59 patients (14%) who underwent target lesion revascularization had a lower final coronary flow velocity reserve (2.33 +/- 0.87 vs 2.48+/- 0.80, P= 0.20) and smaller final minimal lumen diameter (2.62 +/- 0.66 mm vs 2.73+/- 0.60, P= 0.19); however, those differences were not statistically significant. Patients with a coronary flow velocity reserve of < 2.0 (n=109, 26%) exhibited a significantly higher target lesion revascularization rate than patients with a coronary flow velocity reserve of > or = 2.0 (22% vs 11%, P= 0.010). This difference remained significant (odds ratio=2.01, 95% CI=1.11 to 3.66) after adjustment for other variables that were also correlated with the incidence of target lesion revascularization. Conclusion The presence of a final coronary flow velocity reserve of < 2.0 is an independent predictor of the need for target lesion revascularization after stent implantation in native coronary artery lesions.
Subject(s)
Coronary Circulation/physiology , Coronary Restenosis/physiopathology , Myocardial Revascularization , Stents/adverse effects , Blood Flow Velocity , Female , Humans , Likelihood Functions , Male , Middle Aged , Prospective Studies , ROC CurveABSTRACT
We report an ostial lesion with negative remodeling. Coronary angiography revealed a 60% stenosis at the ostium of the left circumflex artery (LCX). Intravascular ultrasound (IVUS)-guided directional atherectomy followed by stenting was planned. However, IVUS images revealed no significant stenosis and negative remodeling at the ostium of the LCX. The lesion did not undergo intervention.
Subject(s)
Coronary Stenosis , Coronary Vessels/pathology , Models, Cardiovascular , Coronary Angiography , Coronary Stenosis/diagnosis , Diagnostic Errors , Humans , Male , Middle Aged , Ultrasonography, InterventionalABSTRACT
BACKGROUND: It is believed that restenosis following coronary interventions is the result of endothelial denudation that leads to thrombus formation, vascular remodeling, and smooth muscle cell proliferation. Low-power red laser light (LPRLL) irradiation enhances endothelial cell growth in vitro and in vivo, and reduces restenosis in animal models. The present study investigated the optimal dose of intravascular LPRLL therapy in the prevention of in-stent stenosis in a porcine coronary stent model. METHODS AND RESULTS: Selected right coronary artery segments were pretreated with a LPRLL balloon, delivering a dose of 0 mW during 1 min (group 1, n = 10), 50 mW during 1 min (group II, n = 10), or 100 mW during 1 min (group III, n = 10) before stenting. Quantitative coronary analysis of the stented vessel was performed before stenting, immediately after stenting, and at 6 weeks follow-up. The pigs were sacrificed, and histologic and morphometric analyses were conducted. At 6 weeks, minimal luminal stent diameter was significantly narrower in the control group compared to the 50-mW dose group (p < 0.05). These results were confirmed by morphometric analysis. Neointimal area was also significantly decreased in the 50-mW dose group. CONCLUSIONS: Intravascular LPRLL contributes to reduction of angiographic in-stent restenosis and neointimal hyperplasia in this animal model. The optimal dose using the LPRLL balloon system seems to be approximately 5 mW delivered during 1 min.
Subject(s)
Coronary Restenosis/prevention & control , Endothelium, Vascular/radiation effects , Low-Level Light Therapy , Stents , Animals , Dose-Response Relationship, Radiation , Models, Animal , SwineABSTRACT
BACKGROUND: Neointimal hyperplasia after PTCA is an important component of restenosis. METHODS AND RESULTS: Cultures of rabbit endothelial cells and smooth muscle cells (SMCs) were irradiated with different doses of nonablative infrared (1064-nm) radiation. Normalized viability index detected with nondestructive Alamar Blue assay and direct cell count were studied. Our experiments demonstrated dose-dependent cytostatic or cytotoxic effects of laser irradiation. We also evaluated the long-term effect of endoluminal nonablative infrared laser irradiation on neointimal hyperplasia in a rabbit balloon injury model. PTCA of both iliac arteries of 23 New Zealand White rabbits was performed. One iliac artery was subjected to intra-arterial subablative infrared irradiation via a diffuse tip fiber. The contralateral vessel served as control. The diet was supplemented with 0.25% cholesterol and 2% peanut oil for 10 days before and 60 days after PTCA. Morphometry after 60 days showed that intimal areas were 0.76+/-0.18 and 1.85+/-0.30 mm(2) in the laser and control arteries, respectively (P=2.2x10(-11)). CONCLUSIONS: We conclude that nonablative infrared laser inhibited neointimal hyperplasia after PTCA in cholesterol-fed rabbits for up to 60 days.
Subject(s)
Angioplasty, Balloon, Coronary/adverse effects , Endothelium, Vascular/radiation effects , Hyperplasia/prevention & control , Infrared Rays/therapeutic use , Muscle, Smooth, Vascular/radiation effects , Tunica Intima/radiation effects , Animals , Catheterization/instrumentation , Cell Count , Cell Division/radiation effects , Cell Survival/radiation effects , Cells, Cultured , Disease Models, Animal , Dose-Response Relationship, Radiation , Endothelium, Vascular/cytology , Fiber Optic Technology/instrumentation , Hyperplasia/etiology , Hyperplasia/pathology , Iliac Artery/pathology , Iliac Artery/radiation effects , Iliac Artery/surgery , Laser Therapy , Muscle, Smooth, Vascular/cytology , Rabbits , Treatment Outcome , Tunica Intima/injuriesABSTRACT
OBJECTIVES: The purpose of the study was to determine whether cutting balloon angioplasty (CBA) has advantages over other modalities in treatment of in-stent restenosis (ISR). BACKGROUND: Controversies exist regarding optimal treatment for ISR. Recently, CBA emerged as a tool in management of ISR. METHODS: A total of 648 lesions treated for ISR were divided into four groups according to the treatment strategy: CBA, rotational atherectomy (ROTA), additional stenting (STENT), and percutaneous transluminal coronary angioplasty (PTCA). Following the matching process, 258 lesions were entered into the analysis. RESULTS: Baseline clinical and angiographic characteristics were similar among the groups (p = NS). Acute lumen gain was significantly higher in the STENT group (2.12 +/- 0.7 mm), whereas in the CBA group the gain was similar to one achieved following ROTA and following PTCA (1.70 +/- 0.6 vs. 1.79 +/- 0.5 mm and 1.56 +/- 0.7 mm, respectively; p = NS). The lumen loss at follow-up was lower for the CBA versus ROTA and versus STENT (0.63 +/- 0.6 vs. 1.30 +/- 0.8 mm and 1.36 +/- 0.8 mm, respectively; p < 0.0001), yielding a lower recurrent restenosis rate (20% vs. 35.9% and 41.4%, respectively; p < 0.05). By multivariate analysis, CBA (odds ratio [OR] = 0.17; confidence interval [CI], 0.06 to 0.51; p = 0.001) and diffuse restenosis type at baseline (OR = 2.07; CI, 1.15 to 3.71; p = 0.02) were identified as predictors of target lesion revascularization. CONCLUSIONS: We conclude that CBA is a safe and efficient technique for treatment of ISR, with immediate results similar to atheroablation and better clinical and angiographic outcomes at follow-up. This approach might be implemented as a viable option in management of focal ISR and to prepare diffuse ISR for brachytherapy treatment.
Subject(s)
Angioplasty, Balloon, Coronary/methods , Atherectomy, Coronary , Coronary Disease/therapy , Stents , Aged , Coronary Angiography , Coronary Disease/diagnostic imaging , Female , Humans , Male , Middle Aged , Multivariate Analysis , Recurrence , Treatment Outcome , Ultrasonography, InterventionalABSTRACT
We report five cases treated with brachytherapy through the internal mammary artery (IMA) for in-stent restenosis at the distal anastomosis (n = 3) and in the left anterior descending coronary artery beyond the distal anastomosis (n = 2). After angioplasty, catheter-based gamma radiation was performed. There was no delivery failure of the radiation system. All cases had angiographic success and no procedural or in-hospital complications.
Subject(s)
Brachytherapy , Graft Occlusion, Vascular/etiology , Graft Occlusion, Vascular/radiotherapy , Mammary Arteries/diagnostic imaging , Stents/adverse effects , Aged , Female , Humans , Male , Middle Aged , RadiographyABSTRACT
The assessment of left ventricular electromechanical activity using a novel, nonfluoroscopic 3-dimensional mapping system demonstrates considerable differences in electrical and mechanical activities within regions of myocardial infarction or ischemia. We sought to determine whether these changes correlate with indexes of myocardial perfusion, viability, or ischemia. A 12-segment comparative analysis was performed in 61 patients (45 men, 61 +/- 12 years old) with class III to IV angina, having reversible and/or fixed myocardial perfusion defects on single-photon emission computed tomographic perfusion imaging. A dual-isotope protocol was used, consisting of rest and 4-hour redistribution thallium images followed by adenosine technetium-99m sestamibi imaging. Average rest endocardial unipolar voltage (UpV) and local shortening (LS) mapping values were compared with visually derived perfusion scores. There was gradual and proportional reduction in regional UpV and LS in relation to thallium-201 uptake score at rest (p = 0.0001 and p = 0.0002, respectively) and redistribution studies (p = 0.0001 and p = 0.003, respectively). UpV > or = 7.4 mV and LS > or = 5.0% had a sensitivity of 78% and 65%, respectively, with a specificity of 68% and 67% for detecting viable myocardium. UpV values of 12.3 and 5.4 mV had 90% specificity and sensitivity, respectively, to predict viable tissue. UpV, but not LS, values differentiated between normal segments and those with adenosine-induced severe perfusion defects (11.8 +/- 5.3 vs 8.8 +/- 4.1 mV, p = 0.005). Catheter-based left ventricular assessment of electromechanical activity correlates with the degree of single-photon emission computed tomographic perfusion abnormality and can identify myocardial viability with a greater accuracy than myocardial ischemia.
Subject(s)
Myocardial Ischemia/diagnostic imaging , Myocardial Ischemia/physiopathology , Adenosine , Adult , Aged , Angina Pectoris/diagnostic imaging , Angina Pectoris/physiopathology , Cohort Studies , Electrophysiology , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Radiography , Sensitivity and Specificity , Technetium Tc 99m Sestamibi , Thallium Radioisotopes , Tomography, Emission-Computed, Single-Photon , United States , Ventricular Dysfunction, Left/diagnostic imagingABSTRACT
Rotational atherectomy is used to debulk calcified or complex coronary stenoses. Whether aggressive burr sizing with minimal balloon dilation (<1 atm) to limit deep wall arterial injury improves results is unknown. Patients being considered for elective rotational atherectomy were randomized to either an "aggressive" strategy (n = 249) (maximum burr/artery >0.70 alone, or with adjunctive balloon inflation < or = 1 atm), or a "routine" strategy (n = 248) (maximum burr/artery < or =0.70 and routine balloon inflation > or =4 atm). Patient age was 62 +/- 11 years. Fifty-nine percent routine and 60% aggressive strategy patients had class III to IV angina. Fifteen percent routine and 16% aggressive strategy patients had a restenotic lesion treated; lesion length was 13.6 versus 13.7 mm. Reference vessel diameter was 2.64 mm. Maximum burr size (1.8 vs 2.1 mm), burr/artery ratio (0.71 vs 0.82), and number of burrs used (1.9 vs 2.7) were greater for the aggressive strategy, p <0.0001. Final minimum lumen diameter and residual stenosis were 1.97 mm and 26% for the routine strategy versus 1.95 mm and 27% for the aggressive strategy. Clinical success was 93.5% for the routine strategy and 93.9% for the aggressive strategy. Creatine kinase-myocardial band (CK-MB) was >5 times normal in 7% of the routine versus 11% of the aggressive group. CK-MB elevation was associated with a decrease in rpm of >5,000 from baseline for a cumulative time >5 seconds, p = 0.002. At 6 months, 22% of the routine patients versus 31% of the aggressive strategy patients had target lesion revascularization. Angiographic follow-up (77%) showed minimum lumen diameter to be 1.26 mm in the routine group versus 1.16 mm in the aggressive group, and the loss index 0.54 versus 0.62. Dichotomous restenosis was 52% for the routine strategy versus 58% for the aggressive strategy. Multivariable analysis indicated that left anterior descending location (odds ratio 1.67, p = 0.02) and operator-reported excessive speed decrease >5,000 rpm (odds ratio 1.74, p = 0.01) were significantly associated with restenosis. Thus, the aggressive rotational atherectomy strategy offers no advantage over more routine burr sizing plus routine angioplasty. Operator technique reflected by an rpm decrease of >5,000 from baseline is associated with CK-MB elevation and restenosis.
Subject(s)
Angioplasty, Balloon, Coronary , Atherectomy, Coronary , Coronary Disease/therapy , Aged , Atherectomy, Coronary/adverse effects , Atherectomy, Coronary/instrumentation , Coronary Angiography , Coronary Artery Bypass , Coronary Disease/diagnostic imaging , Emergencies , Female , Humans , Male , Middle Aged , Myocardial Infarction/etiology , Myocardial Infarction/mortality , Treatment OutcomeABSTRACT
BACKGROUND: Although the frequency of restenosis after coronary angioplasty is reduced by stenting, when restenosis develops within a stent, the risk of subsequent restenosis is greater than 50 percent. We report on a multicenter, double-blind, randomized trial of intracoronary radiation therapy for the treatment of in-stent restenosis. METHODS: Of 252 eligible patients in whom in-stent restenosis had developed, 131 were randomly assigned to receive an indwelling intracoronary ribbon containing a sealed source of iridium-192, and 121 were assigned to receive a similar-appearing nonradioactive ribbon (placebo). RESULTS: The primary end point, a composite of death, myocardial infarction, and the need for repeated revascularization of the target lesion during nine months of follow-up, occurred in 53 patients assigned to placebo (43.8 percent) and 37 patients assigned to iridium-192 (28.2 percent, P=0.02). However, the reduction in the incidence of major adverse cardiac events was determined solely by a diminished need for revascularization of the target lesion, not by reductions in the incidence of death or myocardial infarction. Late thrombosis occurred in 5.3 percent of the iridium-192 group, as compared with 0.8 percent of the placebo group (P=0.07), resulting in more late myocardial infarctions in the iridium-192 group (9.9 percent vs. 4.1 percent, P=0.09). Late thrombosis occurred in irradiated patients only after the discontinuation of oral antiplatelet therapy (with ticlopidine or clopidogrel) and only in patients who had received new stents at the time of radiation treatment. CONCLUSIONS: Intracoronary irradiation with iridium-192 resulted in lower rates of clinical and angiographic restenosis, although it was also associated with a higher rate of late thrombosis, resulting in an increased risk of myocardial infarction. If the problem of late thrombosis within the stent can be overcome, intracoronary irradiation with iridium-192 may become a useful approach to the treatment of in-stent restenosis.
Subject(s)
Brachytherapy , Coronary Disease/prevention & control , Iridium Radioisotopes/therapeutic use , Stents , Angioplasty, Balloon, Coronary , Brachytherapy/adverse effects , Combined Modality Therapy , Coronary Disease/mortality , Coronary Disease/therapy , Coronary Thrombosis/etiology , Dose-Response Relationship, Radiation , Double-Blind Method , Female , Gamma Rays/therapeutic use , Humans , Male , Middle Aged , Multivariate Analysis , Myocardial Infarction/etiology , Myocardial Infarction/prevention & control , Platelet Aggregation Inhibitors/therapeutic use , Radiotherapy Dosage , Secondary PreventionABSTRACT
Patients may develop simultaneous symptoms of atherosclerotic vascular disease from different arterial beds. A concurrent minimally invasive approach to the management of these clinical situations may be an advantage over conventional surgical procedures. This study describes two separate case series of patients undergoing coronary/peripheral (n = 38) and peripheral/peripheral procedures (n = 10). Technical and clinical success was achieved in all patients. There were two periprocedural complications (retroperitoneal bleed and septicemia) in the coronary/peripheral series and no complications in the peripheral/peripheral series. We also present five case reports to illustrate the utility of hybrid procedures in various clinical settings. This study suggests that the use of simultaneous or sequential minimally invasive procedures appears to be a safe and feasible strategy for the treatment of patients with symptoms from more than one vascular bed. Cathet Cardiovasc Intervent 2001;52:154-161.
Subject(s)
Arterial Occlusive Diseases/surgery , Arteriosclerosis/surgery , Cardiac Surgical Procedures , Aged , Carotid Stenosis/diagnostic imaging , Carotid Stenosis/surgery , Female , Humans , Male , Middle Aged , Minimally Invasive Surgical Procedures , Radiography , Renal Artery Obstruction/surgery , Stents , Subclavian Artery/surgeryABSTRACT
A 64-year-old male with unstable angina underwent direct stenting in the proximal and mid-left anterior descending coronary artery (LAD) lesions. Although coronary angiography showed a good result, intravascular ultrasound imaging revealed a dissection flap protruding through the struts of the stent in the proximal LAD. Another stent was deployed in the first stent (stent-in-stent) to seal it. The patient's in-hospital course was uneventful. Subacute stent thrombosis was not observed.
Subject(s)
Angina, Unstable/surgery , Stents/adverse effects , Angina, Unstable/complications , Angina, Unstable/therapy , Angiography , Constriction, Pathologic/etiology , Constriction, Pathologic/surgery , Coronary Vessels/surgery , Humans , Male , Middle Aged , Ultrasonography, InterventionalABSTRACT
There is an increasing trend to rely on duplex ultrasound rather than angiography to measure an internal carotid artery stenosis. The aim of this study was to determine the validity of ultrasound assessment of carotid stenosis performed in community based vascular laboratories. We compared ultrasound with angiography in 225 patients referred to us for carotid intervention. Mild lesions were diagnosed by ultrasound with a sensitivity of 54%, specificity of 89%, and a positive predictive value of 89% compared with angiography. Severe lesions had a sensitivity of 93%, a specificity of 67%, and a positive predictive value of 45%. Receiver operator characteristic curves demonstrated the optimal ultrasound cut-off value of 66% stenosis as a predictor of >60% stenosis measured angiographically, is associated with a false positive rate of 38%, and a false negative rate of 9%. Similarly, if a cut-off of 76% on ultrasound is used to predict >70% stenosis measured angiographically, it would be associated with a 29% false positive rate and a false negative rate of 11%. Despite the value of non-invasive testing for carotid disease, duplex ultrasonography performed in non-accredited and some accredited laboratories may produce highly variable results. Using ultrasound as the sole diagnostic test to determine the severity of a carotid stenosis may result in a high number of inappropriate operations and a large proportion of patients who may not be offered treatment due to false negative diagnoses.