RESUMEN

BACKGROUND: Semi-quantitative stenosis assessment by coronary CT angiography only modestly predicts stress-induced myocardial perfusion abnormalities. The performance of quantitative CT angiography (QCTA) for identifying patients with myocardial perfusion defects remains unclear. METHODS: CorE-64 is a multicenter, international study to assess the accuracy of 64-slice QCTA for detecting ≥50% coronary arterial stenoses by quantitative coronary angiography (QCA). Patients referred for cardiac catheterization with suspected or known coronary artery disease were enrolled. Area under the receiver-operating-characteristic curve (AUC) was used to evaluate the diagnostic accuracy of the most severe coronary artery stenosis in a subset of 63 patients assessed by QCTA and QCA for detecting myocardial perfusion abnormalities on exercise or pharmacologic stress SPECT. RESULTS: Diagnostic accuracy of QCTA for identifying patients with myocardial perfusion abnormalities by SPECT revealed an AUC of 0.71, compared to 0.72 by QCA (P = .75). AUC did not improve after excluding studies with fixed myocardial perfusion abnormalities and total coronary arterial occlusions. Optimal stenosis threshold for QCTA was 43% yielding a sensitivity of 0.81 and specificity of 0.50, respectively, compared to 0.75 and 0.69 by QCA at a threshold of 59%. Sensitivity and specificity of QCTA to identify patients with both obstructive lesions and myocardial perfusion defects were 0.94 and 0.77, respectively. CONCLUSIONS: Coronary artery stenosis assessment by QCTA or QCA only modestly predicts the presence and the absence of myocardial perfusion abnormalities by SPECT. Confounding variables affecting the relationship between coronary anatomy and myocardial perfusion likely account for some of the observed discrepancies between coronary angiography and SPECT results.

Asunto(s)

RESUMEN

Non-invasive assessment of plaque volume and composition is important for risk stratification and long-term studies of plaque stabilisation. Our aim was to evaluate dual-source computed tomography (DSCT) and colour-coded analysis in the quantification and classification of coronary atheroma. DSCT and virtual histology intravascular ultrasound (IVUS-VH) were prospectively performed in 14 patients. 22 lesions were compared in terms of plaque volume, maximal per cent vessel stenosis and percentages of fatty, fibrous or calcified components. Plaque characterisation was performed with software that automatically segments luminal or outer vessel boundaries and uses CT attenuation for a colour-coded plaque analysis. Good correlation was found for per cent vessel stenosis in DSCT (53+/-13%) and IVUS (51+/-14%; r(2) = 0.70). Mean volumes for entire plaque and non-calcified atheroma were 68.5+/-33 mm(3) and 56.7+/-30 mm(3), respectively, in DSCT and 60.8+/-29 mm(3) and 55.8+/-26 mm(3), respectively, in IVUS. Mean percentages of fatty, fibrous or calcified components were 28.2+/-6%, 53.2+/-9% and 18.7+/-13%, respectively, in DSCT and 29.9+/-5%, 55.3+/-12% and 14.4+/-9%, respectively, in IVUS-VH. Significant overestimation was present for the entire plaque and the volume of calcified plaque (p = 0.03; p = 0.0004). Although good correlation with IVUS was obtained for the entire plaque (r(2) = 0.76) and non-calcified plaque volume (r(2) = 0.84), correlation proved very poor and insignificant for percentage plaque composition. Interclass correlation coefficients for non-calcified plaque volume and percentages of fatty, fibrous or calcified components were 0.99, 0.99, 0.95 and 0.98, respectively, and intraclass coefficients were 0.98, 0.93, 0.98 and 0.99, respectively. We found that using Hounsfield unit-based analysis, DSCT allows for accurate quantification of non-calcified plaque. Although percentage plaque composition proves highly reproducible, it is not correlated with IVUS-VH.

Asunto(s)

RESUMEN

To assess HU-based color mapping for characterization of coronary plaque, using intravascular ultrasound virtual histology (IVUS-VH) as a standard of reference. Dual-source computed tomography and IVUS-VH were prospectively performed in 13 patients. In five lesions, HU thresholds of the color-coding software were calibrated to IVUS-VH. In a 15-lesion verification cohort, volumes of vessel, lumen and plaque or percentages of lipid, fibrous and calcified components were obtained through use of pre-set HU cut-offs as well as through purely visual adjustment of color maps. Calibrated HU ranges for fatty or fibrous plaque, lumen and calcification were -10-69, 70-158, 159-436 and 437+. Using these cut-offs, HU-based analysis achieved good agreement of plaque volume with IVUS (47.0 vs. 51.0 mm(3)). Visual segmentation led to significant overestimation of atheroma (61.6 vs. 51.0 mm(3); P = 0.04) Correlation coefficients for volumes of vessel, lumen and plaque were 0.92, 0.87 and 0.83 with HU-based analysis or 0.92, 0.85 and 0.71 with visual evaluation. With both methods, correlation of percentage plaque composition was poor or insignificant. HU-based plaque analysis showed good reproducibility with intra-class correlation coefficients being 0.90 for plaque volume and 0.81, 0.94 or 0.98 for percentages of fatty, fibrous or calcified components. With use of optimized HU thresholds, color mapping allows for accurate and reproducible quantification of coronary plaque.

Asunto(s)

RESUMEN

PURPOSE: To determine if percutaneously applied radio frequency (RF) combined with percutaneous ethanol instillation (PEI) can increase the extent of ablation in rat breast tumors. MATERIALS AND METHODS: R3230 mammary adenocarcinoma was implanted bilaterally in the mammary fat pads of 18 female rats. The tumor nodules measured 1. 2-1.5 cm. Eight tumors each were treated with (a) conventional, monopolar RF (96 mA +/- 28; 70 degrees C for 5 minutes); (b) PEI (250 microL of ethanol infused over 1 minute); (c) combined therapy of PEI immediately followed by RF ablation; or (d) combined therapy of RF ablation immediately followed by PEI. Four tumors were not treated and served as controls. Histopathologic examination included staining for mitochondrial enzyme activity. Resultant coagulation necrosis was compared between treatment groups. RESULTS: Coagulation necrosis was observed only within treated tumors. Tumors treated with RF alone had 6.7 mm +/- 0.6 of coagulation surrounding the electrode, and those treated with PEI alone had 6.4 mm +/- 0.6 of coagulation around the instillation needle (not significant). Significantly increased coagulation of 10.1 mm +/- 0.9 (P: <.001) was observed with the combined therapy of PEI followed by RF. RF followed by PEI did not increase coagulation (6.4 mm +/- 0.8 around the needle; not significant). CONCLUSION: PEI followed by RF ablation therapy increases the extent of induced coagulation necrosis in rat breast tumors, as compared with either therapy alone.

Asunto(s)

Asunto(s)

RESUMEN

We recently experienced a high frequency of biliary complications after orthotopic liver transplantation in rats (22 of 25 cases (88%): biloma, 20 cases; biliary peritonitis, 2 cases). These complications seemed to be rare in general, but some researchers reported such cases and addressed them mainly through rearterialization. The biliary complications we encountered were found to be associated with necrosis of the donor bile duct and an opportunistic infection of Enterobacteriaceae. After administering appropriate antibiotics, the complications significantly diminished (2 of 25 cases (8%), P = 0.0001). The nonarterialized bile duct, which becomes ischemic soon after liver transplantation, appears to be susceptible to infections. Such opportunistic infections may prevent the development of arterial collaterals, causing bile duct necrosis and the subsequent leakage of bile juice. When biliary complications frequently occur after nonarterialized liver transplantation in rats, the possibility of an opportunistic infection should thus be considered.

Asunto(s)

RESUMEN

PURPOSE: To develop a computerized algorithm for pulsed, high-current percutaneous radiofrequency (RF) ablation, which maximally increases the extent of induced coagulation necrosis. MATERIALS AND METHODS: An automated, programmable algorithm for pulsed-RF deposition was designed to permit high-current deposition by periodically reducing current for 5-30 seconds during RF application. Two strategies for pulsed-RF deposition were evaluated: (i) constant peak current (900-1,800 mA) of variable duration and (ii) variable peak current (1,200-2,000 mA) for a specified minimum duration. The extent of induced coagulation was compared to results obtained with continuous (lower current) RF application. Trials were performed in ex vivo calf liver (n = 115) and in vivo porcine liver (n = 30) and muscle (n = 18) with use of 2-4-cm tip, internally cooled electrodes. RESULTS: For 3-cm electrodes in ex vivo liver, applying pulsed-RF with constant peak current for 12 minutes produced 3.5 cm +/- 0.2 of necrosis. Greater necrosis was produced with use of the variable current strategy, in which 4.5 cm +/- 0.2 of coagulation was achieved with use of an initial current > or =1,500 mA (minimum peak-RF duration of 10 sec, with 15 sec of reduced current to 100 mA between peaks; P < .01). This variable peak current algorithm also produced 3.7 cm +/- 0.6 of necrosis in in vivo liver, and 6.5 cm +/- 0.9 in in vivo muscle. Without pulsing, a maximum of 750 mA, 1,100 mA, and 1,500 mA could be applied in ex vivo liver, in vivo liver, and in vivo muscle, respectively, which resulted in 2.9 cm +/- 0.2, 2.4 cm +/- 0.2, and 5.1 cm +/- 0.4 of coagulation (P < .05, all comparisons). CONCLUSIONS: A variable peak current algorithm for pulsed-RF deposition can increase coagulation necrosis diameter over other ablation strategies. This innovation may ultimately enable the percutaneous treatment of larger tumors.

Asunto(s)

RESUMEN

OBJECTIVE: The purpose of this study was to compare the effectiveness of iliac angioplasty and outcomes in diabetic patients and nondiabetic patients with limb-threatening ischemia. MATERIALS AND METHODS: Records of 91 consecutive patients with limb-threatening ischemia (rest pain, nonhealing ulceration, or gangrene) who, during a 6-year period, underwent iliac angioplasty of hemodynamically significant lesions were reviewed. Stents were placed in patients with suboptimal findings at angioplasty. Sixty-eight (75%) of the 91 patients were diabetic. Life table analysis and log-rank significance tests were used to compare rates of primary iliac artery patency, primary and secondary graft patency, limb salvage, and survival in diabetic patients versus nondiabetic patients. RESULTS: One hundred seven iliac lesions were treated with percutaneous angioplasty. Ten iliac stents were placed because of suboptimal results at angioplasty. The mean time of follow-up was 20 months (range, 2-62 months). Sixty-eight patients (75%) underwent peripheral reconstruction. Outcomes were comparable in both patient groups for primary iliac patencies at 4 years (diabetic patients, 85%; nondiabetic patients, 76%; p = .5), primary and secondary graft patencies at 4 years (diabetic patients, 65% and 73%, respectively; nondiabetic patients, 74% and 100%, respectively; p = .7 and .19, respectively), 4-year limb-salvage rates (diabetic patients, 93%; nondiabetic patients, 79%; p = .07). Major complications of angioplasty occurred in four patients (4.4%). CONCLUSION: Outcomes of iliac angioplasty and limb-salvage rates were comparable for diabetic patients and nondiabetic patients who underwent current methods of iliac angioplasty and infrainguinal reconstruction.

Asunto(s)

RESUMEN

Chemoembolization of the liver for unresectable malignancy, although controversial, is being used with increasing frequency. Chemoembolization can be difficult, and there is great potential for causing complications. There are also findings after chemoembolization, particularly on computed tomographic scans, that may appear to indicate complications but are common and of no concern. Chemoembolization requires an understanding of the congenital and acquired variations of arterial anatomy that may be seen supplying the liver. Assessment of the patency of the portal vein is also required. An abnormal portal vein demands significant changes in technique to allow safe chemoembolization. Partial or complete occlusion of the portal vein is associated with significantly decreased survival but does not prevent a worthwhile response to chemoembolization and is not an absolute contraindication. The presence of chemoembolization material in the gallbladder is not uncommon; with the technique used by the authors, the chemoembolization material infrequently causes cholecystitis or gallbladder infarction. Extrahepatic chemoembolization material is commonly seen in other organs but usually does not cause problems, presumably because the dose deposited outside the liver is small compared with the dose delivered to the liver. Other complications include pseudocirrhosis, liver infarction and abscess formation, carcinoid crisis, hepatorenal syndrome, and liver rupture.

Asunto(s)

RESUMEN

Antiangiogenic tumor therapies have recently attracted intense interest for their broad-spectrum action, low toxicity, and, in the case of direct endothelial targeting, an absence of drug resistance. To promote tumor regression and to maintain dormancy, antiangiogenic agents need to be chronically administered. Gene therapy offers a potential way to achieve sustained therapeutic release of potent antiangiogenic substances. As a step toward this goal, we have generated recombinant adeno-associated virus (rAAV) vectors that carry genes coding for angiostatin, endostatin, and an antisense mRNA species against vascular endothelial growth factor (VEGF). These rAAVs efficiently transduced three human tumor cell lines tested. Transduction with an rAAV-encoding antisense VEGF mRNA inhibited the production of endogenous tumor cell VEGF. Conditioned media from cells transduced with this rAAV or with rAAV-expressing endostatin or angiostatin inhibited capillary endothelial cell proliferation in vitro. Antiangiogenic rAAVs may offer a novel gene therapy approach to undermining tumor neovascularization and cancer progression.

Asunto(s)

RESUMEN

PURPOSE: Reduced intrahepatic perfusion that occurs during contrast angiography performed after administration of halothane anesthesia is thought to result from halothane-induced systemic hemodynamic alterations, such as reduced splanchnic blood flow, rather than intrahepatic microvascular alterations. The authors postulate that intrinsic hepatic effects caused by inhalational anesthetic agents rather than contrast materials, further reduce liver perfusion. MATERIALS AND METHODS: With use of dynamic video microscopy, intrahepatic microvascular flow rates and patterns, hepatic cord/sinusoidal diameters, portal venous pressure changes, and quantitative and qualitative Kupffer cell phagocytic activity were continuously recorded in isolated perfused rat livers before and during exposure to 1.5% halothane in O2/CO2, with and without the addition of iothalamate meglumine. RESULTS: Exposure of livers to halothane resulted in intrahepatic portovenous shunting secondary to obstruction to sinusoidal outflow, diminished sinusoidal perfusion, and a mean elevation in terminal portal venous pressure of 12.8 mm Hg. Kupffer cell phagocytic activity was reduced even when normalized for flow within sinusoids. None of these changes were attributed to use of contrast material. CONCLUSIONS: Alterations in hepatic blood flow during exposure to halothane result, in part, from increased intrinsic hepatic vascular resistance, sinusoidal outflow obstruction, and portovenous shunting, and not only from systemic hemodynamic changes. Iothalamate meglumine produced no microvascular alterations.

Asunto(s)

RESUMEN

PURPOSE: To evaluate the intratumoral distribution of liposome-encapsulated doxorubicin. MATERIALS AND METHODS: Tumor-bearing livers of 24 mice were studied with in vivo fluorescence and electron microscopy after injection of liposomal doxorubicin in the hepatic artery, portal vein, or tail vein. Distribution and uptake of liposomes and doxorubicin in tumors were compared at 5, 30, and 60 minutes after injection. In vitro evaluation of uptake of doxorubicin in Kupffer cells and in human colorectal cancer cells incubated under normoxic and hypoxic conditions for 5, 30, and 60 minutes was performed with fluorescence microscopy. RESULTS: Doxorubicin autofluorescence was seen in tumors 30 minutes after intraarterial and intraportal injection and was statistically significantly greater at 60 minutes (P < .001). Liposomes were observed in small tumors (diameter < 300 microns) and were trapped in Kupffer cells around larger, hypovascular tumors. Electron microscopy findings confirmed intracytoplasmic, perinuclear uptake of liposomes in tumor cells. In vitro, a higher proportion of doxorubicin was seen in cancer cells (92%) than in Kupffer cells (75%) after 60 minutes incubation. CONCLUSION: Liposomal doxorubicin can be reliably delivered to liver metastases via the hepatic artery, eliminating need for tumor embolization. Further evaluation is warranted, and the drug may be useful for treating patients with unresectable liver metastases.

Asunto(s)

RESUMEN

OBJECTIVE: The purpose of this study was to determine retrospectively the effectiveness of thrombolysis of occluded infrapopliteal bypass grafts and to identify factors affecting success. MATERIALS AND METHODS: The records of 52 consecutive patients (52 grafts) who underwent selective urokinase thrombolysis of grafts to the pedal or tibial arteries were reviewed. The need for subsequent surgery and the influence of diabetes on outcome were analyzed. RESULTS: There were 43 vein and nine Goretex (W-L Gore, Flagstaff, AZ) and vein composite grafts inserting into tibial and peroneal arteries (n = 28) or pedal arteries (n = 24). Mean time of follow-up was 19 months. All grafts were entered, and technical success was achieved in 73% of patients. Twenty-six patients required some form of graft revision. Overall patency at 30 days was 76%. Thirty-day limb-salvage and mortality rates were 82% and 4%, respectively. No significant difference was found in 1-yr outcomes between diabetic and nondiabetic patients or between pedal and tibial grafts. Major complications occurred in eight patients (15%). CONCLUSION: Thrombolysis of occluded grafts that insert into the pedal or tibial vessels was as effective as thrombolysis of more proximal grafts and native arterial thrombolysis, which have reported 30-day limb-salvage rates that range between 80% and 90%. Diabetes and grafting to foot vessels did not adversely affect response to thrombolysis. Surgery was often required to correct an underlying lesion revealed by thrombolysis. Despite the small size of the arteries to which the grafts were anastomosed, selective thrombolysis of occluded infrapopliteal bypass grafts proved to be an effective procedure.

Asunto(s)

RESUMEN

The chemical shifts of 31P and 1H in thulium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phosphonate) (TmDOTP5-) are approximately two orders of magnitude more sensitive to temperature than are water proton and 19F shifts. In the physiologically relevant pH range, the 31P and 1H chemical shifts of TmDOTP5- are linear functions of temperature between 25 and 47 degrees C. The results indicate that using TmDOTP5- can provide measurements of temperature in vivo that are significantly more accurate than methods based on water and fluorocarbon chemical shifts.

Asunto(s)

RESUMEN

PURPOSE: To determine the efficacy of the transfemoral vein approach to repositioning malpositioned central venous catheters. METHODS: During a 4(1/2)-year period, malpositioned central venous catheters were repositioned 91 times in 83 patients via the transfemoral vein approach. All repositioning was initially attempted with a Grollman catheter or other pigtail catheter and a tip-deflecting wire. If these techniques failed or the venous anatomy was unfavorable, gooseneck or long loop snares were used. RESULTS: During 48 repositionings, rotating a pigtail-type catheter alone was used successfully in 39 (81%). In 6 of 9 failures, the addition of a tip-deflecting wire also failed. A Grollman catheter and tip-deflecting wire were used initially in 39 repositionings (6 failures; 85% success). Successful repositioning required a snare in 8 (4 as the primary repositioning technique) and a long-loop technique in 5. All repositionings were ultimately successful and there were no complications. CONCLUSION: Central venous catheters can be repositioned consistently by the transfemoral route. Pigtail catheters or tip-deflecting wires alone are successful in over 80% of cases.

Asunto(s)

RESUMEN

PURPOSE: To evaluate the transjugular intrahepatic portosystemic shunt (TIPS) as primary treatment in patients with cirrhosis and severe ascites. MATERIALS AND METHODS: A TIPS placement was attempted in 54 consecutive patients with intractable ascites. Clinical assessment findings, shunt patency, complications, and survival were analyzed. RESULTS: A TIPS was successfully placed in 50 patients (93%). Follow-up for clinical effectiveness in 51 patients was a mean of 285 days (range, 1-981 days). Forty patients (78%) gained clinical benefit from the shunt. Of these, 29 (57%) had a complete response (required no further paracentesis) and 11 patients (22%) had a partial response (required less frequent but additional paracentesis for control of ascites). The absence of preprocedure renal insufficiency (creatinine < 1.5 mg/dL [< 130 mumol/L]) was the only characteristic identified as an indicator of clinical success (P < .05). Eleven patients (22%) required shunt revision during follow-up to gain or prolong control of symptoms. Cumulative survival in the population evaluated for clinical efficacy was 53% at 6 months and 48% at 1 year. A complete response was the only variable that indicated increased survival (P < .05; R2 = 12%) with a 6-month survival rate of 76% and a 1-year rate of 71%. CONCLUSION: TIPS placement appears to be effective as a primary treatment of patients with cirrhosis and severe ascites.

Asunto(s)

Asunto(s)

RESUMEN

PURPOSE: The distribution of different ethiodized oil-doxorubicin mixtures within and around hypovascular liver metastases in athymic nude mice was compared following either intraarterial or intraportal injections. MATERIALS AND METHODS: Six different mixtures of doxorubicin and ethiodized oil in water-soluble contrast material, shaken for 5, 10, 15, and 30 minutes, respectively, were prepared and the size of the oil droplets in the mixtures evaluated. Intraarterial and intraportal injections of mixtures shaken for 10 and 15 minutes were performed in mice bearing hypovascular hepatic colorectal metastases. In vivo video microscopy was used to evaluate microvascular flow and the biodistribution and the size of the oil droplets within and around the tumors. RESULTS: Oil droplets smaller than 20 microns in diameter were taken up by tumor nodules. There was no significant difference in oil droplet accumulation within the tumor between intraarterial and intraportal injections. Oil droplets larger than 20 microns occluded small and medium portal branches. The optimum combination was 0.1 mL of ethiodized oil in 2 mL of diatrizoate sodium meglumine (Renografin-76) shaken for 15 minutes at 800 rpm, which formed droplets smaller than 20 microns (92%). CONCLUSION: Avascular regions of hepatic metastases may be embolized with ethiodized oil-anticancer drug mixtures containing oil droplets smaller than 20 microns. Since these droplets penetrate to the tumor interstitium with either intraarterial or intraportal injections, chemoembolization via the arterial route seems preferable for treatment of unresectable hypovascular hepatic metastases since it is easier to perform. The conclusions drawn from this study are limited to the animal model for experimental hypovascular hepatic metastases.

Asunto(s)

RESUMEN

OBJECTIVES: To review the experience of the treatment of hepatocellular carcinoma by a single multimodality team during a 6-year period, including all patients who were referred for possible surgical intervention, to evaluate prognostic factors at presentation, and to determine the results of the different modalities of treatment that were used. DESIGN: Retrospective study of 154 patients who were referred to our Hepatobiliary Surgical Unit with the diagnosis of hepatocellular carcinoma from January 1988 through August 1995. SETTING: Tertiary care center. RESULTS: Methods of treatment included surgical resection (n=49), transplantation (n=22), hepatic artery chemoembolization (n=30), systemic chemotherapy (n=25), and no treatment (n=22). Predictive prognostic factors included coexisting cirrhosis, symptoms at presentation, and abnormal liver function test results. Unfavorable tumor characteristics were size (diameter, >5 cm) and multicentricity. For patients who underwent surgical exploration, advanced staging according to the manual of the American Joint Committee on Cancer, vascular invasion, and a margin of less than 1 cm in the group for patients who underwent resection impacted negatively on the prognosis. The median survival (42.4 months) for the group of patients who underwent resection was significantly higher than that for the groups of patients who did not undergo resection. Chemoembolization was associated with significantly better survival results than was systemic chemotherapy. CONCLUSIONS: Hepatic resection offers the best chance at cure for patients with hepatocellular carcinoma. The high association between hepatocellular carcinoma and cirrhotic liver disease makes surgical resection, even in favorable tumor types, a difficult task based on low hepatic reserve whose tumors are considered unresectable can be considered for chemoembolization. Liver transplantation should be reserved for selected patients with cirrhotic liver disease who have tumors (diameter, <5 cm) in the contest of neoadjuvant protocols.

Asunto(s)

RESUMEN

OBJECTIVE: The purpose of this study was to retrospectively compare two-dimensional time-of-flight MR angiography with other imaging procedures in the evaluation of the portal venous system in 152 consecutive patients. MATERIALS AND METHODS: The findings on MR angiography performed on 152 patients to depict breath-hold, two-dimensional time of flight MR angiography. Selective arterial presaturation, bolus tracking, and three-dimensional reconstruction were used routinely. Findings were correlated with findings on sonography (104 patients), CT (8 patients), and conventional digital subtraction angiography (19 patients) as well as surgery (23 patients). RESULTS: Agreement between results of MR angiography and alternative types of imaging was excellent (99%). Agreement with sonography (100 of 104), CT (8 of 8), conventional angiography (18 of 19), and surgery (23 of 23) was good. Visualization of varices and spontaneous shunts by MR angiography was superior to that by other imaging techniques. CONCLUSION: Our experience shows that time-of-flight MR angiography is reliable and accurate for depicting portal venous anatomy. MR angiography shows vessels that are not visible with sonography. Complicated pathology is clearly visualized in a way that is not possible with other techniques.

Asunto(s)