1 Department of Clinical Chemistry, 2 Department of Cardiothoracic Surgery, 3 Department of Anaesthesiology and Intensive Care, 4 Department of Neurology and 5 Department of Clinical Neurophysiology, St Antonius Hospital, PO Box 2500, NL-3430 EM, Nieuwegein, The Netherlands. 6 Department of Biomedical Analysis and 7 Centre for Biostatistics, Utrecht University, PO Box 80125, NL-3508 TC, Utrecht, The Netherlands. 8 Department of Anaesthesiology, Academic Hospital Groningen, PO Box 30.001, NL-9700 RB, Groningen, The Netherlands
* Corresponding author. E-mail: edmeejeroen{at}zonnet.nl
Accepted for publication August 10, 2005.
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Abstract |
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Methods. From 69 patients, cerebrospinal fluid and blood samples for biochemical analysis were drawn after the induction of anaesthesia, during the cross-clamp period, 5 min, 2, 4, 6, 8, and 19 h, respectively, after reperfusion. In addition, continuous perioperative recording of motor-evoked potentials after transcranial electrical stimulation (tcMEP) and somatosensory-evoked potentials was carried out. Furthermore, neurological examinations were performed.
Results. In patients with a defined decrease in lower extremity tcMEP during the cross-clamp period, we found that combinations of the serum concentrations of S-100B and tcMEP ratios at 4, 6, and 8 h after reperfusion had a positive and negative predictive value of 100% in predicting adverse neurological outcome after TAA/TAAA surgery. Furthermore, combinations of the serum concentrations of S-100B and NSE or LD at 19 h after reperfusion had both a positive and negative predictive value of 100% in identifying patients with adverse outcome after TAA/TAAA repair.
Conclusions. TcMEP monitoring during TAA/TAAA surgery seems to be an effective but not completely sufficient guide in our protective multi-modality strategy. Combinations of the serum concentrations of S-100B and tcMEP ratios during the early reperfusion period might be associated with adverse neurological complications. Furthermore, biochemical markers could detect central nervous system injury on the first postoperative day and may have prognostic value.
Keywords: blood, protein S-100 ; cerebrospinal fluid ; complications, neurological ; monitoring, evoked potentials ; surgery, aneurysm
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Introduction |
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Patients and methods |
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Anaesthetic technique5
Patients were premedicated with morphine 10 mg and haloperidol 5 mg i.m., 1 h before surgery. After venous cannulation of the right arm and cannulation of the right radial artery, anaesthesia was induced with diazepam 0.20.3 mg kg1 and fentanyl 2030 µg kg1. Subsequently, a low-dose propofol infusion, aiming at a plasma steady state concentration of 0.75 mg litre1, was administered. Tracheal intubation was performed using a left-sided double-lumen tube, after which the position of the tube was verified by fibre-optic bronchoscopy. If necessary, succinylcholine 20 mg was given i.v. to facilitate intubation. Controlled ventilation was adjusted to maintain normocapnia (end-tidal carbon dioxide partial pressure 4.04.5 kPa) and to administer nitrous oxide 50% in oxygen. A pulmonary artery catheter was floated into the pulmonary artery using the cannulated right internal jugular vein. A nasogastric tube, indwelling bladder catheter, rectal thermometer, and muscle thermometer (right tibialis anterior muscle) were placed. The right-sided thenar eminence was used to monitor neuromuscular block. Before a neuromuscular blocking drug was given, the compound muscle action potential (CMAP) was obtained from the thenar eminence after supramaximal stimulation of the median nerve at the wrist using a general evoked response stimulator (SMP 3100, Nihon Kohden) triggered from a personal computer. An infusion of atracurium or mivacurium was used to maintain the first twitch (T1) of the TOF at 4555% of control CMAP. The patient was positioned on a beanbag (Olympic Medical, Seattle, WA, USA) in the right lateral decubitus position and two intrathecal catheters were placed in the second and third lumbar intervertebral spaces. CSF drainage was continued throughout the procedure and at least 24 h after operation in order to maintain intrathecal pressure at less than 10 mm Hg. Routine anaesthetic monitoring for major vascular surgery was performed and stored every 30s (Datex, Helsinki, Finland).
Techniques of tcMEP and SEP monitoring
The techniques of tcMEP and SEP monitoring have been described previously.5 15 TcMEP responses were acquired every 5 min before and during surgery, and every 10 min in the intensive care unit (ICU) until 8 h and at 19 h after reperfusion, that is the first postoperative morning. During the first postoperative day, most patients would awake from anaesthesia so that 19 h after reperfusion was the last time point in the study protocol. From every tcMEP response the latency of onset, amplitude and area under the curve (AUC) were derived. Subsequently,
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In the operating room (OR), we used the AUC as parameter of the tcMEP response of the lower extremity. In order to reduce the false-positive results of intraoperative tcMEP recording, the influence of the anaesthetic and neuromuscular blocking agents on the tcMEP registration was kept low. The recording of muscle responses to six-pulse transcranial electrical stimulation during low-dose propofol/fentanyl/nitrous oxide 50% anaesthesia and a neuromuscular block aimed at T1 of 4555% seems to be a good combination of sensitivity and clinical usefulness.16 As in the ICU we were not informed on the influences of anaesthetics and neuromuscular blocking agents administered during surgery, the lower extremity tcMEP AUC was not a useful parameter. Instead, we used the tcMEP ratio. The tcMEP ratio rules out the hampering effects of anaesthetics and neuromuscular blocking on the tcMEP registration.
SEP responses were obtained every minute before and during surgery, and in the ICU until 8 h and at 19 h after reperfusion. From every SEP response, the mean amplitude was derived. For neurophysiological evaluation,
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Surgical technique5
A posterolateral thoracotomy in the fifth or sixth intercostal space was performed, extending in a median or paramedian laparatomy after arcus costae transsection. Simultaneously, the left common femoral artery was dissected free. After opening the pericardium, the left atrium (or left inferior pulmonary vein) and left femoral artery were cannulated, connected to the Biomedicus pump and bypass commenced. The mean proximal arterial pressure was maintained between 60 and 100 mm Hg, and the mean distal arterial line pressure was maintained higher than 60 mm Hg by adjusting bypass flows and intravascular volume and with nitroprusside infusion. Spontaneous hypothermia on bypass was tolerated (3234°C, as measured by a rectal probe). When aneurysm configuration allowed us to do so, we used staged clamping to maximize the beneficial effect of the distal perfusion with the left-heart bypass procedure. After incision of the aneurysm, large intercostal arteries localized within the aneurysm were temporarily occluded with a balloon catheter. A woven Dacron vascular prosthesis (Intervascular, La Ciotat, France) was used. In 68 patients, the proximal anastomosis was created first; in the remaining patient it was preferable to construct the distal anastomosis before the proximal one. After testing the first anastomosis, large intercostal and lumbar arteries, especially between T-8 and L-2, were re-implanted into the prosthesis and reperfused. Re-warming to a rectal temperature of 3637°C was done while the distal anastomosis (and in one patient the proximal anastomosis) was being performed and after reperfusion of all re-implanted intercostal and lumbar vessels. After terminating the left-heart bypass procedure, the blood was re-transfused into the left atrium whenever possible. The cleaned aneurysm wall was closed over the graft for additional protection.
Multi-modality strategy
Brain and spinal cord protection was achieved by means of a multi-modality approach: moderate hypothermia (32°C rectal temperature), left-heart bypass, staged aortic clamping, re-implantation of intercostal and lumbar arteries, and CSF drainage. In addition, when tcMEP of the lower extremity decreased more than 50% of baseline after a few minutes of excluding a particular aneurysmal segment, the intercostal and lumbar arteries within this segment were considered to be critical to the spinal circulation and were promptly reattached. At the same time, higher perfusion pressures and more CSF drainage were accomplished.
Based on the results of our previous study by van Dongen and colleagues,5 we used a decrease of more than 50% of baseline in lower extremity tcMEP AUC as the threshold for interventions. We assumed that a decrease in lower extremity tcMEP AUC more than two times the coefficient of variation (2025%) would provide optimal detection of beginning cerebral and spinal cord malfunction.5 Therefore, we divided the patients into two different risk groups for adverse neurological outcome, based on the AUC of the lower extremity tcMEP during aortic cross-clamping (AXC) (Table 1). Group 1 consisted of patients with a tcMEP AUC of the lower extremity during AXC more than 50% of baseline, whereas the patients of Group 2 had a lower extremity tcMEP AUC during AXC 50% of baseline.
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The patients were divided into two outcome groups. Group a (adverse neurological outcome) consisted of patients with a postoperative ASIA impairment scale (AIS, Appendix 2) of A, B, C, or D and patients who were not testable according to the protocol of ASIA because of severe neurological injury, such as coma and stroke. Group b (no adverse neurological outcome) included all patients with a postoperative AIS of E, one patient with pre- and postoperative AIS of D because of the preoperative presence of anterior cord syndrome and one patient with pre- and postoperative AIS of C as a result of the preoperative existence of cauda equina syndrome.
Sample collection and biochemical measurements
CSF and blood samples were drawn after the induction of anaesthesia and haemodynamic stabilization, during the cross-clamp period of the critical aortic segment, 5 min, 2, 4, 6, 8, and 19 h, respectively, after reperfusion. After centrifuging the samples immediately at 2800 g and 4°C for 10 min the supernatants were stored at less than 70°C until analysis. Visibly haemolysed samples were rejected for the determinations of the (catalytic) concentrations of NSE and LD. Furthermore, CSF samples visibly contaminated with blood were discarded for the measurements of the catalytic concentrations of LD.
Determinations of the concentrations of S-100B and NSE in CSF and serum were performed on a LIAISON® Random Access Analyzer (DiaSorin SpA, Saluggia, Italy). The detection limit for Liaison® Sangtec®100 was 0.02 µg litre1, both intra-assay and inter-assay variation were less than 11%. For NSE, the intra- and inter-assay variation was less than 6%. Kinetic methods were used for the measurements of the catalytic concentrations of LD in CSF [Cobas Fara II® analyzer (Roche Diagnostics, Basel, Switzerland)]19 and plasma [Cobas Integra 700 analyzer (Roche Diagnostics)].20 21 For plasma, mean total reproducibility was 2.1%. In CSF, total reproducibility was less than 12%.19 In this paper, the catalytic concentrations of LD are abbreviated to simply concentrations of LD.
Statistical analysis
Data analysis was performed using SPSS 12.0. Categorical variables were presented as percentages and were analysed by the exact 2 test when appropriate. For continuous variables, medians and ranges (1090th percentile) were summarized. The exact MannWhitney U-test was used to assess differences in the protective measures applied in patients of Group 2. For all tests, P-values
0.05 were considered statistically significant. To compare the results of the biochemical measurements and evoked potential responses, we calculated the median values of the parameters of the last four (or in the ICU last two) tcMEP responses and the median values of the last 20 SEP ratios before the CSF and blood sample collection time points. As the number of patients with adverse outcome was very small, descriptive statistics were used to summarize data on prediction and diagnosis. In order to emphasize the longitudinal character of the data, the time courses of the biochemical markers were expressed as a median line for all patients without adverse neurological complications and individual lines for the patients with an adverse neurological outcome. Scatterplots were made to estimate sensitivity (sens), specificity (spec) and positive and negative predictive value (PPV and NPV) for all parameters and their combinations at the different time points. Cut-off values were determined with receiver operating characteristic (ROC) curves and based on giving 100% sensitivity for detecting adverse outcome. The AUC is a quantitative index describing a ROC curve. Values higher than 0.6 were considered to be informative.
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Results |
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All four patients with adverse neurological complications (Group a) had a lower extremity tcMEP AUC during AXC 50% of baseline and belonged to Group 2. Table 2 demonstrates the relationship between the risk Groups 1 and 2 and the outcome Groups a and b. The two outcome groups seemed to differ in lower extremity tcMEP responses during AXC (P<0.01) and in the presence of rupture (P=0.02, Table 2). Furthermore, the two different risk groups for adverse neurological outcome may vary in aneurysm types (P=0.04, Table 1) and two of the four patients with adverse neurological complications underwent surgery for a type II TAAA (Table 2).
During AXC, 22 patients had a lower extremity tcMEP AUC 50% of baseline (Group 2), which resulted in adjusting the total strategy. Four of these patients (18.2%), however, had an adverse neurological outcome afterwards (Table 2). Table 3 summarizes the protective measures applied in the patients of Group 2. Most vessels were re-implanted between the level of T-8 and L-2: 16.5% at T-8, 21.5% at T-9, 9.9% at T-10, 9.9% at T-11, 8.3% at T-12, 6.6% at L-1 and 2.5% at L-2. The median number of reattached intercostal and lumbar arteries was lower (P=0.05) in the four patients with adverse neurological complications than in the 18 patients without (Table 3).
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All four patients with an adverse neurological outcome died within 30 days of the operation or before discharge. The overall operative mortality rate was 13% (nine patients). The causes of death of the other five patients were multiple organ failure (two), pneumonia (two), and ventricular fibrillation (one). Four of these five patients had a lower extremity tcMEP AUC during AXC more than 50% of baseline and belonged to Group 1. Three of these patients demonstrated the same biochemical time courses as the patients without adverse neurological complications. The other two, however, displayed higher serum concentrations of S-100B at 4, 6, 8, and 19 h after reperfusion than the 90th percentile of patients without adverse neurological complications [4 h: median 0.51 µg litre1 (0.211.04 µg litre1), 6 h: median 0.44 µg litre1 (0.180.90 µg litre1), 8 h: median 0.35 µg litre1 (0.160.78 µg litre1) and 19 h: median 0.33 µg litre1 (0.170.76 µg litre1)]. In addition, the patient with a lower extremity tcMEP AUC during AXC 50% of baseline also demonstrated higher CSF concentrations of S-100B at 19 h after reperfusion than the 90th percentile of patients without adverse neurological complications [median 2.7 µg litre1 (1.44.9 µg litre1)].
Tables 4 and 5 summarize the predictive and diagnostic values of different parameters at different time points for adverse neurological outcome after TAA/TAAA surgery for patients belonging to Group 2 (Table 1). Cut-off values were determined with ROC curves (Fig. 2). Since there was no data on tcMEP recording in the direct postoperative period, we were looking for optimal cut-off values of the tcMEP ratios and did not utilize the threshold of the lower extremity tcMEP AUC used during surgery. TcMEP ratio at 19 h after reperfusion and all combinations of tests presented in Tables 4 and 5 demonstrated AUCs for ROC curves of 1. Table 4 illustrates that the combinations of the serum concentrations of S-100B and tcMEP ratios at 4, 6, and 8 h after reperfusion had both a PPV and NPV of 100% in predicting adverse neurological outcome. In addition, at 19 h after reperfusion, the serum concentrations of S-100B, NSE, and LD seemed to have higher PPVs and specificities than their CSF concentrations in identifying patients with adverse neurological complications after TAA/TAAA surgery (Table 5). Both the combinations of the serum concentrations of S-100B and NSE or LD, and tcMEP ratios less than 50% had a PPV and NPV of 100% in detecting adverse neurological complications after this type of surgery. Furthermore, for patients belonging to Group 2, the PPVs and specificities of the serum concentrations of S-100B at 4, 6, 8, and 19 h after reperfusion and the CSF concentrations of S-100B, NSE, and LD at 19 h after reperfusion were slightly higher for operative mortality than for adverse neurological complications. The NPVs and sensitivities were 100% as well. Combinations of the serum concentrations of S-100B greater than 0.35 µg litre1 and NSE greater than 9.0 µg litre1 or LD greater than 478 u litre1 at 19 h after reperfusion had both a PPV and NPV of 100% in predicting operative mortality.
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Discussion |
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The present study has shown that using our multi-modality strategy, the incidence of adverse neurological complications was low (5.8%). All four patients with an adverse neurological outcome in this series had a lower extremity tcMEP AUC during AXC 50% of baseline and belonged to Group 2. This confirms the results of our previous study by van Dongen and colleagues5 to use a decrease of more than 50% of baseline in lower extremity tcMEP AUC as the threshold. We assume that patients with a lower extremity tcMEP AUC during AXC
50% of baseline are at increased risk for an adverse neurological outcome. In order to reduce the risk for neurological deficits in this patient group, it is essential to reattach more intercostal and lumbar arteries into the prosthesis and to accomplish higher perfusion pressures and more CSF drainage.5 In this study, less intercostal and lumbar arteries were re-implanted in the four patients who developed adverse neurological complications in comparison with the 18 patients who did not (Table 3). Based on previous studies, the extent and urgency of the repair, age and the lack of re-implantation of intercostal and lumbar arteries have been the best predictors of paraplegia3 4 28 but not of stroke.4
The results of this study confirmed our previous finding that not all the patients with a lower extremity tcMEP AUC 50% of baseline during surgery demonstrated adverse neurological outcome afterwards, suggesting reversible phenomena in most of the patients.5 So, tcMEP monitoring during surgery seemed to be an effective but not completely sufficient guide in our protective multimodality strategy. Besides, since tcMEP monitoring is expensive and requires specialized equipment and very well-trained investigators and technicians for efficient operation, an appropriate biochemical marker would be a desirable alternative. Furthermore, in emergency situations tcMEP monitoring is not possible, and suitable biochemical markers could be of value.
In this study, we found that the serum concentrations of S-100B increased in all patients during the surgical procedure (Fig. 1). These early increases, with the highest concentrations at 2 h after reperfusion, were not correlated to neurological damage but were probably attributable to S-100B release from nonnervous tissues (muscle, fat, bone marrow) by surgical trauma.29 The biological half-life of S-100B is only 25 min.30 Therefore, to avoid extracerebral contamination of S-100B samples, appropriate sampling times should be chosen (2 h after possible contamination, so from 4 h after reperfusion). Furthermore, cardiotomy suction and postoperative autotransfusion, other potential extracerebral sources for S-100B release to blood, were not used.31 Besides, none of the included patients suffered severe renal impairment.26
Moreover, we did not observe that the CSF concentrations of S-100B and the CSF and serum concentrations of NSE and LD at AXC, 5 min and 2 h, respectively, after reperfusion could be associated with either silent neurological damage or adverse neurological complications after TAA/TAAA surgery. Any haemolysis during surgery will falsely increase the serum concentrations of NSE and LD.26 In order to overcome this problem, we rejected all haemolysed samples for the determinations of those concentrations. Furthermore, since CSF drainage was only performed when the intrathecal pressure was above 10 mm Hg, the amount of CSF drained varied between patients. The CSF concentrations of the biochemical markers would be falsely lowered in a complex relation to the amount of CSF drained.32 It would be very helpful if this complex relationship could be clarified so that we would be able to correct the CSF concentrations of the different biochemical markers for the variable amounts of CSF drained. Until now, we and also other investigators were not able to elucidate this relationship.
So, unfortunately, we did not notice that the biochemical markers S-100B, NSE and LD could replace or add information to the tcMEP monitoring during surgery. However, for patients with a lower extremity tcMEP AUC during AXC 50% (Group 2), we observed that combinations of the serum concentrations of S-100B and tcMEP ratios during the early reperfusion period might be associated with adverse neurological complications after TAA/TAAA surgery (Table 4). In patients at risk for adverse neurological outcome, it is especially important to accomplish an optimal perfusion pressure of the CNS. In our recent experience, when tcMEP ratios and serum concentrations of S-100B in the early reperfusion period are outside their suggested limits, artificially elevating MAP, preventing abnormal cardiac rhythms and draining more CSF are suggestive of a better final outcome. TcMEP ratios are acquired every 10 min and biochemical test results are always available within 1 h after sampling and in time to institute further management techniques. In order to provide even more rapid results, bedside assays for S-100B have been developed and are presently available. Although, the appropriateness of those assays for the above mentioned purposes has to be evaluated before they can be used in clinical practice. Furthermore, tcMEP ratios and serum concentrations of S-100B could be used to assess the efficacy of new neuroprotective adjuncts.
Besides, we noticed that on the first postoperative day, the serum and CSF concentrations of S-100B were higher in respectively two and three of the four patients with adverse neurological complications than the 90th percentile of patients with no adverse neurological outcome (Fig. 1). This finding is consistent with the results of both Anderson and colleagues7 and Kunihara and co-workers.8 Our results show that the CSF concentrations of the biochemical markers investigated in this study could be of less value in detecting adverse neurological complications than their serum concentrations (Table 5). Possible explanations are first, asymptomatic patients can also show late increases in CSF concentrations of S-100B and NSE.7 Secondly, the CSF concentrations could have been influenced by the different amounts of CSF drained between patients.32
Moreover, we observed that both the combinations of the serum concentrations of S-100B and NSE or LD and tcMEP ratios less than 50% at 19 h after reperfusion could be of value in identifying patients with adverse neurological complications after TAA/TAAA surgery. Anderson and colleagues7 also found high serum concentrations of S-100B and NSE in patients with neurological complications (stroke, paraplegia) on the first postoperative day. Unfortunately, at this time brain and spinal cord injury are already manifest and irreversible and biochemical markers or tcMEP monitoring add little valuable information for the clinician when treating a patient with adverse neurological complications. However, at least two diagnostic challenges can be discerned in such patients.26 First, the sedated patient on ventilator support after surgery is unable to undergo a neurological investigation. At present the best way to monitor brain and spinal cord damages is a CT- and/or MRI-scan, which normally poses practical problems when transferring the patient to the radiology unit. Furthermore, it is much easier in the ICU to take a blood sample and analyse it than to perform tcMEP monitoring. In this study, there were some missing values in tcMEP ratios due to technical or logistic problems in the ICU. Secondly, although the incidence of paraplegia and paraparesis is 227%3 and of stroke 4.5%4 after TAA/TAAA surgery, this minority of patients often consume both time and resources in the ICU. Previous studies have shown that serum concentrations of S-100B at 48 h after surgery, especially in combination with any CNS complication, could predict mortality after cardiac surgery.33 34 In this study, all four patients with adverse neurological complications had serum concentrations of S-100B at 19 h after reperfusion above 0.35 µg litre1 and died within 30 days of the operation or before discharge. Furthermore, we observed for patients belonging to Group 2, that combinations of the serum concentrations of S-100B and NSE or LD might be associated with operative mortality after TAA/TAAA surgery.
One important limitation of our study was the small number of patients with adverse outcome. Therefore, we used no more than descriptive statistics to summarize data on prediction and diagnosis. In some cases, individual or combinations of tests resulted in sensitivities, specificities, positive and negative predictive values of 100%. The ROC curves (Fig. 2) demonstrate that one little change can decrease sensitivity to 75% and also specificity and positive and negative predictive value. The results of this study apply to the study population that satisfied the inclusion criteria and confirmation is needed in an independent prospective study with a larger number of patients with adverse outcome, regarding the predictive values of the proposed cut-off levels for an adverse neurological outcome and operative mortality.
Notwithstanding the limitations of this study, we believe that some observations may be potentially very relevant and worthwhile reporting to the anaesthesiological and cardiovascular surgical community. TcMEP monitoring during TAA/TAAA surgery seems to be an effective but not completely sufficient guide in our protective multi-modality strategy. The biochemical markers investigated in this study (S-100B, NSE, and LD) could not replace or add information to the tcMEP monitoring during surgery. However, combinations of the serum concentrations of S-100B and tcMEP ratios during the early reperfusion period might be associated with adverse neurological complications. Furthermore, biochemical markers could detect CNS injury on the first postoperative day and may have prognostic value.
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Appendices |
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Acknowledgments |
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References |
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