Prediction of renal function improvement in azotemic patients using glomerular filtration rate from 99mTc-DTPA renal scan: An observational study.

ABSTRACT: This study aimed to evaluate the ratio of glomerular filtration rate (GFR) from 99mTc-diethylenetriamine-pentaacetic acid dynamic renal scan (GFRSCAN) to estimated GFR (eGFR) as a predictor of renal function improvement in patients with azotemia.A retrospective review of medical records was conducted to identify consecutive patients with newly discovered or aggravated azotemia who underwent 99mTc-diethylenetriamine-pentaacetic acid renal scan. Significant renal function improvement was defined as ≥100% and ≥10 mL/min improvement of eGFR at 12 weeks compared to eGFR on the day of renal scan (eGFR0). The GFRSCAN/eGFR0 ratio was evaluated as a predictor of significant renal function improvement using logistic regression and receiver operating characteristic (ROC) curve analyses. Added value of the GFRSCAN/eGFR0 ratio in the prediction of significant renal function improvement were demonstrated by adjusting for best clinical predictor variables.The eligibility criteria were met by 224 patients, among whom 22 patients (9.8%) showed significant renal function improvement. The odds ratios of the GFRSCAN/eGFR0 ratio for predicting significant renal function improvement were 1.76 (95% confidence interval [CI]: 1.26-2.45, P < .001) in the univariable analysis and 1.70 (95% CI: 1.19-2.42, P = .003) after adjusting for clinical variables. The area under the ROC curve of the GFRSCAN/eGFR0 ratio for predicting significant renal function improvement was 0.762 (95% CI: 0.648-0.871). The addition of the GFRSCAN/eGFR0 ratio to the best clinical prediction model raised the area under the ROC curve from 0.726 to 0.794, and this increment was statistically significant (P = .02).The GFRSCAN/eGFR ratio can predict renal function improvement in patients with azotemia. Future prospective studies are necessary to validate its potential clinical utilities.

Congenital Tracheobiliary Fistula Shown on 99mTc-EHIDA Hepatobiliary Scintigraphy.

A 1-year 5-month-old male patient had a history of recurrent cough and pneumonia, which required antibiotics and bronchodilators. CT suggested the possibility of congenital tracheobiliary fistula. However, a diagnosis could not be made based on CT alone. A Tc-EHIDA hepatobiliary scintigraphy was then performed, which led to a definite diagnosis of tracheobiliary fistula.

Monitoring Hepatocyte Dysfunction and Biliary Complication After Liver Transplantation Using Quantitative Hepatobiliary Scintigraphy.

The significance of hepatobiliary scintigraphy (HBS) for hepatic graft function assessment was established mostly on retrospective studies and was not widely recognized due to the lack of quantitative data and variation in accuracy. This prospective study was performed to investigate the effectiveness of quantitative HBS for assessing hepatocyte dysfunction and biliary complication in liver transplant recipients.In 57 recipients who had undergone orthotopic liver transplantation, a total of 67 dynamic Tc-EHIDA scans were performed and quantitative parameters including the hepatocyte extraction fraction (HEF), time to maximum hepatic radioactivity (Tmax), and time for peak activity to decrease by 50% (T1/2) were calculated. The scintigraphic results based on the 3 parameters were compared against the final diagnosis. A ROC curve analysis was carried out to identify the cutoff value of Tmax for diagnosis of biliary stricture. Correlation between the parameters of postoperative HBS and conventional biochemical liver function indices were also analyzed.Quantitative Tc-EHIDA HBS had an overall sensitivity of 94.12% (16/17), specificity of 93.33% (42/45), and diagnostic accuracy of 93.55% (58/62) for detecting hepatocyte dysfunction and biliary complication in liver transplant recipients. The recommended cutoff value of Tmax for diagnosis of post-transplant biliary stricture was set at 15.75 min with a sensitivity of 100.0% and a specificity of 94.0%. The scintigraphic parameters (HEF, Tmax) were statistically significantly associated with the conventional liver function parameters.Quantitative Tc-EHIDA HBS offers a noninvasive imaging modality with high sensitivity and specificity to diagnose hepatocyte dysfunction as well as distinguish between patients with or without biliary stricture following liver transplantation. Furthermore, HEF and Tmax values obtained from dynamic HBS show good correlation with conventional liver function parameters.

The role of cholescintigraphy in demonstrating delayed post prandial gallbladder motility in cirrhotic patients.

OBJECTIVE: The purpose of this study was to investigate the postprandial gallbladder motility of cirrhotic patients using cholescintigraphy by technetium-99m-ethylhydroiminodiacetic acid ((99m)Tc-EHIDA). SUBJECTS AND METHODS: Sixty two cirrhotic patients (Child-Pugh A: 28 patients; Child-Pugh B: 21 and Child-Pugh C: 13 patients) and 24 normal subjects were included in this study. All patients underwent cholescintigraphy. Mean gallbladder ejection fraction (GBEF) and mean ejection period (EP) were acquired by the region of interest method. In order to evaluate gallbladder contractility of cirrhotic patients, their mean GBEF and EP were compared with the same tests of normal subjects using an independent sample t test. RESULTS: The mean GBEF of cirrhotic patients was lower and their mean ER was longer than that of normal subjects. The means of GBEF and EP of cirrhotic patients were different among different Child-Pugh grade groups. All these differences showed statistical significance. CONCLUSIONS: This study suggests that post prandial cholescintigraphy by (99m)Tc EHIDA demonstrated slower gallbladder motility in cirrhotic patients. The ejection period of cholescintigraphy by (99m)Tc-EHIDA can be used as an index of abnormal gallbladder motility.

Single-photon emission computed tomography/computed tomography as a problem-solving tool in patients with suspected acute cholecystitis.

AIM: The aim of this study was to evaluate our institutional experience with single-photon emission computed tomography/computed tomography (SPECT/CT) hepatobiliary imaging as a problem-solving tool in the workup of suspected acute cholecystitis. METHODS: We queried our radiology information system database for cases in which SPECT/CT had been performed as part of the routine hepatobiliary technetium Tc 99m iminodiacetic acid studies done for the evaluation of acute cholecystitis. Fifty-three consecutive patients who had SPECT/CT after planar imaging were included. This cohort represents cases that were considered problematic by the initial interpreting physician on the basis of planar images. The planar and SPECT/CT images were retrospectively reviewed independently and separately by 2 experienced nuclear medicine specialists who evaluated the planar images for visualization of the gallbladder on a binary scale (yes or no) and rated their level of confidence on an ordinal scale(unsure, somewhat sure, and sure). RESULTS: Single-photon emission CT/CT would have led to change in the management for interpreter 1 in a total of 23 cases (41%), with change from normal to abnormal scan findings (28%) and from abnormal to normal scan findings (13%). Similarly, SPECT/CT would have led to change in the management for interpreter 2 in a total of 23 cases (43%), with change from normal to abnormal scan findings (13%) and from abnormal to normal scan findings (30%). CONCLUSIONS: Although planar hepatobiliary scanning is usually sensitive and specific, there are occasionally problematic cases. In our experience, we found that the addition of SPECT/CT improved the interobserver agreement and may change management in patients with superimposed bowel activity and/or unusual gallbladder anatomy that can confound the planar interpretation.

Predictive models for regional hepatic function based on 99mTc-IDA SPECT and local radiation dose for physiologic adaptive radiation therapy.

PURPOSE: High-dose radiation therapy (RT) for intrahepatic cancer is limited by the development of liver injury. This study investigated whether regional hepatic function assessed before and during the course of RT using 99mTc-labeled iminodiacetic acid (IDA) single photon emission computed tomography (SPECT) could predict regional liver function reserve after RT. METHODS AND MATERIALS: Fourteen patients treated with RT for intrahepatic cancers underwent dynamic 99mTc-IDA SPECT scans before RT, during, and 1 month after completion of RT. Indocyanine green (ICG) tests, a measure of overall liver function, were performed within 1 day of each scan. Three-dimensional volumetric hepatic extraction fraction (HEF) images of the liver were estimated by deconvolution analysis. After coregistration of the CT/SPECT and the treatment planning CT, HEF dose-response functions during and after RT were generated. The volumetric mean of the HEFs in the whole liver was correlated with ICG clearance time. Three models, dose, priori, and adaptive models, were developed using multivariate linear regression to assess whether the regional HEFs measured before and during RT helped predict regional hepatic function after RT. RESULTS: The mean of the volumetric liver HEFs was significantly correlated with ICG clearance half-life time (r=-0.80, P<.0001), for all time points. Linear correlations between local doses and regional HEFs 1 month after RT were significant in 12 patients. In the priori model, regional HEF after RT was predicted by the planned dose and regional HEF assessed before RT (R=0.71, P<.0001). In the adaptive model, regional HEF after RT was predicted by regional HEF reassessed during RT and the remaining planned local dose (R=0.83, P<.0001). CONCLUSIONS: 99mTc-IDA SPECT obtained during RT could be used to assess regional hepatic function and helped predict post-RT regional liver function reserve. This could support individualized adaptive radiation treatment strategies to maximize tumor control and minimize the risk of liver damage.

[Acute, severe liver insufficiency caused by extrahepatic biliary atresia in a newborn]. / Akut, svær leverinsufficiens forårsaget af binyretumor hos nyfødt.

A newborn female was hospitalized due to metabolic acidosis and conjugated hyperbilirubinaemia. Extrahepatic biliary atresia (EHBA) was suspected why a (99m)Tc-mebrofenin cholescintigraphy was performed. It showed poor hepatocyte tracer uptake and no drainage to the gut. The hepatocyte dysfunction was caused by an obstructing adrenal gland neuroblastoma later visualised by ultrasound and MRI. The cholescintigraphy is a non-invasive modality to exclude or confirm the suspicion of EHBA. Furthermore neonatal conjugated hyperbilirubinaemia demands the use of a multimodality imaging strategy for differential diagnosis to EHBA.

Comparative evaluation of intragastric bile acids and hepatobiliary scintigraphy in the diagnosis of duodenogastric reflux.

AIM: To assess the diagnostic value of a combination of intragastric bile acids and hepatobiliary scintigraphy in the detection of duodenogastric reflux (DGR). METHODS: The study contained 99 patients with DGR and 70 healthy volunteers who made up the control group. The diagnosis was based on the combination of several objective arguments: a long history of gastric symptoms (i.e., nausea, epigastric pain, and/or bilious vomiting) poorly responsive to medical treatment, gastroesophageal reflux symptoms unresponsive to proton-pump inhibitors, gastritis on upper gastrointestinal (GI) endoscopy and/or at histology, presence of a bilious gastric lake at > 1 upper GI endoscopy, pathologic 24-h intragastric bile monitoring with the Bilitec device. Gastric juice was aspirated in the GI endoscopy and total bile acid (TBA), total bilirubin (TBIL) and direct bilirubin (DBIL) were tested in the clinical laboratory. Continuous data of gastric juice were compared between each group using the independent-samples Mann-Whitney U-test and their relationship was analysed by Spearman's rank correlation test and Fisher's linear discriminant analysis. Histopathology of DGR patients and 23 patients with chronic atrophic gastritis was compared by clinical pathologists. Using the Independent-samples Mann-Whitney U-test, DGR index (DGRi) was calculated in 28 patients of DGR group and 19 persons of control group who were subjected to hepatobiliary scintigraphy. Receiver operating characteristic curve was made to determine the sensitivity and specificity of these two methods in the diagnosis of DGR. RESULTS: The group of patients with DGR showed a statistically higher prevalence of epigastric pain in comparison with control group. There was no significant difference between the histology of gastric mucosa with atrophic gastritis and duodenogastric reflux. The bile acid levels of DGR patients were significantly higher than the control values (Z: TBA: -8.916, DBIL: -3.914, TBIL: -6.197, all P < 0.001). Two of three in the DGR group have a significantly associated with each other (r: TBA/DBIL: 0.362, TBA/TBIL: 0.470, DBIL/TBIL: 0.737, all P < 0.001). The Fisher's discriminant function is followed: Con: Y = 0.002TBA + 0.048DBIL + 0.032TBIL - 0.986; Reflux: Y = 0.012TBA + 0.076DBIL + 0.089TBIL - 2.614. Eighty-four point zero five percent of original grouped cases were correctly classified by this method. With respect to the DGR group, DGRi were higher than those in the control group with statistically significant differences (Z = -5.224, P < 0.001). Twenty eight patients (59.6%) were deemed to be duodenogastric reflux positive by endoscopy, as compared to 37 patients (78.7%) by hepatobiliary scintigraphy. CONCLUSION: The integrated use of intragastric bile acid examination and scintigraphy can greatly improve the sensitivity and specificity of the diagnosis of DGR.

The effect of lipophilicity on the hepatobiliary properties of iminodiacetic acid derivatives in the conditions of hyperbilirubinemia.

The partition coefficients (log P) of theoretically possible alkyliodinated iminodiacetic acid (IDA) derivatives and commercial IDA derivatives were calculated using two computer programs: ChemSketch Log P and ChemOffice Ultra. Newly synthesized ligands (DIETHYLIODIDA and DIISOPROPYLIODIDA) with the highest calculated log P were labeled with technetium-99m. The biodistribution and the influence of bilirubin on their biokinetics were investigated in rats and compared to corresponding results for commercial (99m)Tc-BROMIDA. Log P of (99m)Tc-complexes of synthesized ligands were determined experimentally as well as the protein binding. In comparison to (99m)Tc-BROMIDA, (99m)Tc-DIETHYLIODIDA has: (a) better biliary excretion (2.76±0.15%ID/g versus 1.83±0.10%ID/g); (b) faster hepatic clearance (2.90±0.21%ID/g versus 7.47±0.70%ID/g) and decreased biliary excretion (for 14% versus 22%) in conditions of hyperbilirubinemia after 15min. It is proved that (99m)Tc-DIISOPROPYLIODIDA has a prolonged hepatic transit time and decreased biliary excretion.

Gallbladder motility disorders estimated by non-invasive methods.

BACKGROUND/AIMS: The aim is to compare the radionuclide (DC) and ultrasonographic (US) method in the assessment of gallbladder (GB) motility. METHODOLOGY: The study was performed in 15 controls (C), 10 patients with acute cholecystitis (AC), 20 patients with chronic acalculous cholecystitis (CAC), 26 patients with chronic cholecystitis with calculosis (CCC) as well as in 15 patients with GB dyskinesia (D). GB emptying period (EP), ejection fraction (EF) and ejection rate (ER) were estimated with dynamic cholescintigraphy (DC) and US. RESULTS: The DC and US finding in the patients with AC was typical in all the patients, i.e. GB was not visualized at all on DC, while on US, stone was visible in the cystic duct. There were significant differences (p<0.05) between the EF and ER values obtained between C and the three groups of patients CAC, CCC and D, using both methods. However, there were no significant differences in EF, EP and ER values among CAC, CCC and D (p>0.05). There was also high correlation between the results obtained with both methods in all the groups of patients studied. CONCLUSIONS: The results obtained by both methods are valuable for the assessment of GB motility. Although there are no significant differences and there is a high correlation between the values, radionuclide method is more precise, because it can register motility continuously.

The value of radionuclide hepatobiliary scintigraphy in combination with determination of bilirubin from duodenal drainage in differential diagnosis of infantile persistent jaundice.

The aim of this study was to investigate the value of technetium etifenin injection (99mTc-EHIDA) hepatobiliary scintigraphy in combination with determination of bilirubin from duodenal drainage in differential diagnosis between infantile hepatitis syndrome and biliary atresia. 99mTc-EHIDA hepatobiliary scintigraphy in combination with duodenal fluid examination was used for evaluation in 84 infants with persistent infantile jaundice. For diagnosing biliary atresia, the sensitivity and specificity of scintigraphy were 100% and 74.5%, respectively; the sensitivity and specificity of scintigraphy in combination with duodenal fluid examination were 100% and 100%, respectively. In conclusion, hepatobiliary scintigraphy, which is a noninvasive, safe, valuable examination method, in combination with examination of duodenal fluid, is of value for the differential diagnosis between infantile hepatitis syndrome and biliary atresia.

Interventions used with cholescintigraphy for the diagnosis of hepatobiliary disease.

Since the early 1980s interventions have been used in conjunction with (99m)Tc-iminodiacetic acid (IDA) radiopharmaceuticals in many different clinical situations, eg, to prepare the patient for the study, to reduce the time of a study, to improve its diagnostic accuracy, and to make diagnoses not otherwise possible. Interventions all have underlying physiological rationales. Some of these interventions are as simple as having the patient fast before the study or eat a meal with high fat content. However, most are pharmacologic interventions, eg, morphine sulfate, cholecystokinin, and phenobarbital. Although these are probably the most common interventions used today, numerous other interventions have been used during the years and likely will be in the future. Interventions have aided in the diagnosis of acute cholecystitis, chronic cholecystitis, biliary obstruction, and sphincter of Oddi dysfunction. This review will discuss in detail the interventions commonly is use today and in somewhat less detail many that have been successfully used on an investigational basis and may have some larger role in the future.

[Preoperative evaluation of liver function using 99mTc-diethyl iminodiacetic acid based on single photon emission computed tomography].

OBJECTIVE: To establish a three-dimentional liver function evaluation system using 99mTc-diethyl iminodiacetic acid (99mTc-EHIDA) scintigraphy based on single photon emission computed tomography (SPECT). METHODS: Totally 16 patients with liver lesions were divided into cirrhosis group and non-cirrhosis group. SPECT was performed 2 days before operation and 5 days after operation. Serum liver functions were examined on the same day of scintigraphy. SPECT images of areas of interest of heart and liver were aquired. Time of the peak of EHIDA density in liver (Tpeak), five-minutes heart liver index (HLI5), blood clearance index (HH15), receptor index (LHL15), and the predictive values were calculated. RESULTS: Tpeak was not significantly different between two groups, while HLI5, HH15, and LHL15 were significantly different (P = 0.033, P = 0.001, and P = 0.005). HLI, and LHL15 were significantly correlated with preoperative total protein and prealbumin levels (P = 0.003, P = 0.015, P = 0.022, P = 0.038) and post-operative prealbumin (P = 0.037, P = 0.042). The predictive values of HLI5 and LHL15 correlated well with postoperative HLI5 and LHL15 (r = 0.675, P = 0.016; r = 0.629, P = 0.028). CONCLUSION: The three-dimentional liver function evaluation system using 99mTc-EHIDA based on liver SPECT may facilitate the further studies of risks of liver surgery.

Biliary leak in a child after liver transplant and value of delayed images.

A 2-year-old child underwent liver transplant and was referred for postsurgical abdominal pain. Hepatobiliary scintigraphy with Tc-99m iminodiacetic acid (IDA) was performed and with the help of 24-hour delayed images, the diagnosis of biliary leak at the site of anastomosis was made possible. This case report confirms the value of delayed images to facilitate the diagnosis in unequivocal situations and reminds us of the usefulness of this noninvasive method, especially in pediatrics.

Preoperative evaluation of liver function using 99mTc-diethyl iminodiacetic acid based on single photon emission computed tomography / 中国医学科学院学报

<p><b>OBJECTIVE</b>To establish a three-dimentional liver function evaluation system using 99mTc-diethyl iminodiacetic acid (99mTc-EHIDA) scintigraphy based on single photon emission computed tomography (SPECT).</p><p><b>METHODS</b>Totally 16 patients with liver lesions were divided into cirrhosis group and non-cirrhosis group. SPECT was performed 2 days before operation and 5 days after operation. Serum liver functions were examined on the same day of scintigraphy. SPECT images of areas of interest of heart and liver were aquired. Time of the peak of EHIDA density in liver (Tpeak), five-minutes heart liver index (HLI5), blood clearance index (HH15), receptor index (LHL15), and the predictive values were calculated.</p><p><b>RESULTS</b>Tpeak was not significantly different between two groups, while HLI5, HH15, and LHL15 were significantly different (P = 0.033, P = 0.001, and P = 0.005). HLI, and LHL15 were significantly correlated with preoperative total protein and prealbumin levels (P = 0.003, P = 0.015, P = 0.022, P = 0.038) and post-operative prealbumin (P = 0.037, P = 0.042). The predictive values of HLI5 and LHL15 correlated well with postoperative HLI5 and LHL15 (r = 0.675, P = 0.016; r = 0.629, P = 0.028).</p><p><b>CONCLUSION</b>The three-dimentional liver function evaluation system using 99mTc-EHIDA based on liver SPECT may facilitate the further studies of risks of liver surgery.</p>

A Case of Cholethorax following Percutaneous Transhepatic Cholangioscopy / 결핵및호흡기질환

Cholethorax (bilious pleural effusion) is an extravasation of bile into the thoracic cavity via a pleurobiliary fistula (and also a bronchobiliary fistula). It is an extremely rare complication of thoraco-abdominal injuries. It can be caused by congenital anomaly and also by hepatobiliary trauma, severe infection or iatrogenic procedures. The definitive diagnosis is made with aspiration of bilious fluid from the pleural space during thoracentesis, by finding a fistulous tract during endoscopic retrograde cholangiopancreatography (ERCP) or cholagioscopy, or with finding an abnormal pleural accumulation of radioisotope during hepatobiliary nuclear imaging. Its symptoms include coughing, fever, dyspnea and pleuritc chest pain. Herein we report on a case of cholethorax following performance of percutaneous transhepatic cholangioscopy (PTCS) to remove incidentally discovered common bile duct (CBD) stones.

[Hepatobiliary scintigraphy in evaluation of liver transplant function].

The aim of the study is evaluation of hepatocellular function, as well as morphology and patency of the biliary three of the liver transplants by dynamic hepatobiliary scintigraphy. The study was performed in 10 controls and 10 patients after orthotopic transplantation (up to two years). Sixty minutes dynamic acquisition (1 frame/min) was performed with scintillation camera after injection of 360 MBq 99mTc-diethyl- IDA. Hepatobiliary scintigrams were analysed for morphology, and parenchymal and hepatobiliary TA curves were generated and analysed as regard to the time to maximal acitivity (Tmax) and the time to half of maximum acitivity (T1/2). Uptake of the radiopharmaceutical was slightly but not significantly delayed (Tmax=18.5 +/- 2.9 min) in comparison to the controls (Tmax=14.2 +/- 3.4min), while excretion was significantly prolonged (T1/2=59.5 +/- 12.1 min) than physiological (Tmax=34.2 +/- 4.1min). Intrahepatic bile flow was nonsignificantly prolonged (Tmax=31.3 +/- 3.7 min) in comparison to the controls (Tmax=25.7 +/- 3.5 min) while extrahepatic one is high significantly prolonged (T1/2=89.0 +/- 14.3 min) than physiological (T1/2 =45.0 +/- 7.2 min). Biliary phase of hepatobiliary scintigraphy showed increased accumulation of radiopharmaceutical in the left (n=1) or right (n=2) hepatic duct. Radionuclide methods are noninvasive, and apear to be sensitive and valuable for the monitoring of liver transplants.

Relationship of hepatic functional imaging to irinotecan pharmacokinetics and genetic parameters of drug elimination.

PURPOSE: The marked variability of irinotecan (Ir) clearance warrants individualized dosing based on hepatic drug handling. The aims of this trial were to identify parameters from functional hepatic nuclear imaging (HNI) that correlate with (1) Ir pharmacology, and (2) single-nucleotide polymorphisms (SNPs) for the ABCB1 (P-glycoprotein) and UGT-1A1 genes, known to influence Ir handling. METHODS: Patients underwent genotyping for ABCB1 SNPs and UTUGT-1A1*28 carriage and HNI with 99mTc-DIDA (acetanilidoiminodiacetic acid)/99mTc-DISIDA (disofenin) and MIBI (99mTc-sestamibi) scans, probes for biliary transport proteins ABCC1 and -2, and ABCB1 function. HNI data were analyzed by noncompartmental and deconvolutional analysis to provide hepatic extraction and biliary excretion parameters. Patients received Ir, fluorouracil, and folinic acid using a weekly x2, every-3-weeks schedule. Plasma was taken for Ir and SN-38 analysis on day 1, cycle 1. RESULTS: Of the 21 patients accrued, Ir pharmacokinetics data were obtained from 16 patients. 99mTc-DIDA/DISIDA percent retention at 1 hour (1-hour RET) correlated to baseline serum bilirubin (P = .008). Both 99mTc-DIDA/DISIDA and MIBI 1-hour RET correlated with SN-38 area under the curve (AUC; P < .01). On multiple regression analysis, SN-38 AUC = -215 + 18.68 x bilirubin + 4.27 x MIBI 1-hour RET (P = .009, R2 = 44.2%). HNI parameters did not correlate with Ir toxicity or UGT1A1*28 carriage. MIBI excretion was prolonged in patients with the ABCB1 exon 26 TT variant allele relative to wild-type (P = .015). CONCLUSION: Functional imaging of hepatic uptake and excretory pathways may have potential to predict Ir pharmacokinetics. Evaluation of a larger cohort as well as polymorphisms in other biliary transporters and UGT1A1 alleles is warranted.