[Surgical treatment of urethral prolapse]. / Chirurgische Therapie des Urethralprolaps.

Urethral prolapses in humans are rare. Urethral caruncula are more frequent. Caruncula originate from the dorsal external layer of the urethral meatus. We report on the surgical approach used for the resection of a huge urethral prolapse in a postmenopausal woman with chronic constipation using the four-quadrants resection technique. After the procedure, the patient was quickly relieved from pain and micturition was improved. The patient was fully continent. Alternative treatments to surgical resection include conservative approaches with sitz baths and oestrogen cremes, manual reduction under general anaesthesia and ligation of the prolapse around a transurethral bladder catheter.

An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer.

The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.

[The G8 questionnaire as a geriatric screening tool in urooncology]. / Der G8-Fragebogen als geriatrisches Screening-Tool in der Uroonkologie.

The G8 questionnaire is a geriatric screening tool recommended by the SIOG and the EAU. To save time and resources, it can precede a comprehensive geriatric assessment (CGA) in a two-step evaluation. Based on our experience, this 8-item questionnaire is easy and fast to perform (4 - 5 minutes), even by medical staff untrained in geriatrics. The G8 questionnaire has become an established screening tool also in geriatric oncology. It has been shown in several studies that it provides an independent prognostic indicator for the overall survival of cancer patients. However, some critical aspects remain: its low specificity (60 %), its focus on nutritional aspects, and possible interobserver differences. These aspects should be known and taken into account by clinicians.

Utility of the EORTC risk tables and CUETO scoring model for predicting recurrence and progression in non-muscle-invasive bladder cancer patients treated with routine second transurethral resection.

PURPOSE: Routine second transurethral resection (TUR) for non-muscle-invasive bladder cancer (NMIBC) is common practice in Germany. Applicability of European Organization for Research and Treatment of Cancer (EORTC) and Spanish Urological Club for Oncological Treatment (CUETO) models in NMIBC patients is still controversial. Aim of the study was to assess the performance of EORTC and CUETO predictive models in NMIBC patients treated with second TUR. METHODS: 479 NMIBC patients with routine second TUR were analyzed retrospectively between 2003 and 2011, and investigated with clinical and pathological variables in regard to tumor recurrence and progression. Furthermore, recurrencefree survival (RFS) and progression-free survival (PFS) were evaluated according to EORTC and CUETO, and the discrimination of the models assessed. RESULTS: With a median follow-up of 60 months, prior recurrence rate, grade, and second TUR pathology were independent prognostic factors for the risk of disease recurrence and progression. The concordance index of the EORTC and the CUETO model was 0.563 and 0.516 for recurrence and 0.681 and 0.702 for progression, respectively. The positive pathology after second TUR was significantly associated with risk of disease recurrence and progression. EORTC and CUETO risk models estimated progression better than recurrence, especially with higherscore groups. CONCLUSIONS: Improved predictive tools should be developed for optimal treatment selection.

[Intra- and postoperative complications classified according to the Clavien-Dindo classification in patients > 80 years after transurethral resection of the urinary bladder]. / Intra- und postoperative Komplikationen klassifiziert nach Clavien Dindo bei Patienten > 80 J. nach transurethraler Resektion der Harnblase.

INTRODUCTION: Urothelial carcinoma of the urinary bladder is a tumour of advanced age. The demographic change increases the number of very old patients ( > 80 years) subjected to TUR-B. MATERIAL AND METHODS: In a retrospective analysis, perioperative complications in 89 patients (> 80 years), who underwent a transurethral resection of the bladder between 2013 and 2016 in our department, were recorded and evaluated using the Clavien-Dindo grading system. RESULTS: Mean patient age was 87 years (82 - 94). 81 patients (91 %) were treated with oral anticoagulants (32 × ASA, 24 × NOACs, 25 × Marcumar). A histological examination revealed no tumour in 25/89 (28 %) patients, pTa in 28/89 (31 %), pT1 in 22/89 (25 %) and pT2 or higher in 14/89 patients (16 %), respectively. A total of 36/89 (40 %) patients experienced complications according to the Clavien-Dindo classification. 21/89 (23 %) of patients had a prolonged bladder irrigation due to macrohaematuria, 5/89 (6 %) needed surgical reintervention. 14 (12.4 %) patients needed a blood transfusion, 6 (5.3 %) of them preoperatively. According to the Clavien-Dindo classification, 4/89 (4 %) patients were graded as I, 21/89 (24 %) as II, 5/89 (6 %) as IIb and 3/89 (3 %) as IVa, respectively. Three patients (3 %) died postoperatively (Clavien-Dindo V). One of them died as a result of aspiration pneumonia (86 y, ASA IV), one as a result of pulmonary embolism (90 y, ASA IV) and one as a result of multiorgan failure (84 y, ASA III). In multivariate analyses, a tumour stage > T2 was confirmed as a significant predictor of the occurrence of postoperative complications (odds ratio of 9.541 (95 % CI 1.14 - 84.67 p = 0.032). For oral anticoagulants the odds ratio was 4.10 (95 % CI, 41.00 - 1.23, p = 0.050). CONCLUSION: Overall, the data show that a TUR-B is feasible in patients > 80 years with an increased complication rate in comparison to younger patients. Prolonged macrohaematuria and a high transfusion rate are attributable to the high percentage of orally anticoagulated patients.

Molecular Markers Increase Precision of the European Association of Urology Non-Muscle-Invasive Bladder Cancer Progression Risk Groups.

Purpose: The European Association of Urology (EAU) guidelines for non-muscle-invasive bladder cancer (NMIBC) recommend risk stratification based on clinicopathologic parameters. Our aim was to investigate the added value of biomarkers to improve risk stratification of NMIBC.Experimental Design: We prospectively included 1,239 patients in follow-up for NMIBC in six European countries. Fresh-frozen tumor samples were analyzed for GATA2, TBX2, TBX3, and ZIC4 methylation and FGFR3, TERT, PIK3CA, and RAS mutation status. Cox regression analyses identified markers that were significantly associated with progression to muscle-invasive disease. The progression incidence rate (PIR = rate of progression per 100 patient-years) was calculated for subgroups.Results: In our cohort, 276 patients had a low, 273 an intermediate, and 555 a high risk of tumor progression based on the EAU NMIBC guideline. Fifty-seven patients (4.6%) progressed to muscle-invasive disease. The limited number of progressors in this large cohort compared with older studies is likely due to improved treatment in the past two decades. Overall, wild-type FGFR3 and methylation of GATA2 and TBX3 were significantly associated with progression (HR = 0.34, 2.53, and 2.64, respectively). The PIR for EAU high-risk patients was 4.25. On the basis of FGFR3 mutation status and methylation of GATA2, this cohort could be reclassified into a good class (PIR = 0.86, 26.2% of patients), a moderate class (PIR = 4.32, 49.7%), and a poor class (PIR = 7.66, 24.0%).Conclusions: We conclude that the addition of selected biomarkers to the EAU risk stratification increases its accuracy and identifies a subset of NMIBC patients with a very high risk of progression. Clin Cancer Res; 24(7); 1586-93. ©2018 AACR.

Prognostic Impact of a 12-gene Progression Score in Non-muscle-invasive Bladder Cancer: A Prospective Multicentre Validation Study.

BACKGROUND: Progression of non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is life-threatening and cannot be accurately predicted using clinical and pathological risk factors. Biomarkers for stratifying patients to treatment and surveillance are greatly needed. OBJECTIVE: To validate a previously developed 12-gene progression score to predict progression to MIBC in a large, multicentre, prospective study. DESIGN, SETTING, AND PARTICIPANTS: We enrolled 1224 patients in ten European centres between 2008 and 2012. A total of 750 patients (851 tumours) fulfilled the inclusion and sample quality criteria for testing. Patients were followed for an average of 28 mo (range 0-76). A 12-gene real-time qualitative polymerase chain reaction assay was performed for all tumours and progression scores were calculated using a predefined formula and cut-off values. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured progression to MIBC using Cox regression analysis and log-rank tests for comparing survival distributions. RESULTS AND LIMITATIONS: The progression score was significantly (p<0.001) associated with age, stage, grade, carcinoma in situ, bacillus Calmette-Guérin treatment, European Organisation for Research and Treatment of Cancer risk score, and disease progression. Univariate Cox regression analysis showed that patients molecularly classified as high risk experienced more frequent disease progression (hazard ratio 5.08, 95% confidence interval 2.2-11.6; p<0.001). Multivariable Cox regression models showed that the progression score added independent prognostic information beyond clinical and histopathological risk factors (p<0.001), with an increase in concordance statistic from 0.82 to 0.86. The progression score showed high correlation (R2=0.85) between paired fresh-frozen and formalin-fixed paraffin-embedded tumour specimens, supporting translation potential in the standard clinical setting. A limitation was the relatively low progression rate (5%, 37/750 patients). CONCLUSIONS: The 12-gene progression score had independent prognostic power beyond clinical and histopathological risk factors, and may help in stratifying NMIBC patients to optimise treatment and follow-up regimens. PATIENT SUMMARY: Clinical use of a 12-gene molecular test for disease aggressiveness may help in stratifying patients with non-muscle-invasive bladder cancer to optimal treatment regimens.

Urinary transcript quantitation of CK20 and IGF2 for the non-invasive bladder cancer detection.

PURPOSE: Cytokeratin 20 (CK20) and insulin-like growth factor 2 (IGF2) were previously proposed to be elevated in clinical samples from patients with bladder cancer (BCa). A two cohort design validation study was used to assess the relevance for BCa detection by transcript quantitation of both markers in urine samples. Their diagnostic value was assessed in comparison with voided urine cytology (VUC). METHODS: RNA isolation was carried out using cellular sediments of urine samples from 196/103 histologically positive BCa patients, as well as 97/50 control subjects for the test (TC) and validation cohort (VC), respectively. Urinary transcript levels of CK20 and IGF2 were determined by qPCR. RESULTS: Relative transcript levels were significantly elevated 3.4/11-fold for CK20 and 188/64-fold for IGF2 (p < 0.001) in urine sediments of BCa patients compared to controls in the TC and VC, respectively. In a combined analysis, the resulting sensitivity (SN) (SNTC: 77.9; SNVC: 90.3%) and specificity (SP) (SPTC: 88.0; SPVC: 84.0%) were similar to that of VUC. The sensitivity of VUC in combination with CK20 and IGF2 was considerably increased (SNTC: 94.6; SNVC: 93.2%) while specificity was reduced (SPTC: 72.0; SPVC: 82.0%) compared to VUC alone in the test and validation cohort. CONCLUSIONS: Transcript levels of IGF2 and CK20 enabled the detection of BCa with a diagnostic performance similar to VUC. Combined analysis of voided urine cytology together with altered transcript levels of CK20 and IGF2 enhanced sensitivity, but did not improve overall test performance.

Evaluation of Plasmatic Kisspetin-10 as a Biomarker for Malignancy and Subtype Differentiation in Small Renal Tumours.

OBJECTIVE: To evaluate Kisspeptin-10 (Kiss-10) in patients with small renal tumours (SRTs) and controls. MATERIAL AND METHODS: Kiss-10 was measured in preoperative plasma samples in a cohort of 143 patients with unilateral renal tumours smaller than or equal to 4 cm and 40 age-matched controls by a competitive ELISA test kit. The cohort of patients included 56 patients with clear cell renal cell carcinoma (ccRCC), 43 with papillary RCC (pRCC), 12 with chromophobe RCC (chRCC) and 32 with oncocytomas. RESULTS: Kiss-10 was detected in all patients and controls. SRT patients revealed significantly higher Kiss-10 levels than controls (mean value 10.04 vs. 6.37 pmol/l, p < 0.001). In SRT patients, Kiss-10 was detected at significantly different concentrations between the subgroups (p = 0.021). The highest concentration was observed in those with oncocytomas (11.50 pmol/) followed by chRCC, pRCC and ccRCC patients (9.89, 10.01 and 9.25 pmol/l, respectively). Receiver operating characteristic curve analyses revealed an area under the curve (AUC) of 0.82 for the comparison of all tumours vs. controls (p < 0.001) and an AUC of 0.671 for all malignant tumours vs. oncoytomas (p = 0.003). CONCLUSION: This study shows that Kiss-10 levels are significantly altered by malignancy and tumour subtypes even in patients with SRTs. Kiss-10 therefore deserves further attention as a plasmatic biomarker for renal tumours.

Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma.

Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal- and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.

Prevalence and Management of Lower Urinary Tract Symptoms Related to Benign Prostatic Obstruction in a Contemporary Series of Renal Transplant Recipients.

BACKGROUND: The kidney is the most frequently transplanted human organ worldwide. In patients with end-stage renal failure, renal transplantation improves both quality of life and life expectancy. The current literature indicates that the numbers of renal recipients over 60 years of age has increased in recent years. OBJECTIVES: To evaluate the prevalence and management of lower urinary tract symptoms (LUTS) related to benign prostatic obstruction (BPO) in a contemporary series of male renal transplant (RTx) recipients. MATERIALS AND METHODS: We retrospectively evaluated 150 consecutive transplant recipients at the University of Jena 12 months postoperatively for the presence and treatment of LUTS related to BPO. RESULTS: The mean age of the patients was 59 years (range 27 - 82 years). By 12 months postoperatively, 91% (n = 137/150) were off dialysis with a functioning kidney graft. Two patients died during follow up. Six patients had undergone treatment for prostate cancer prior to RTx. Of the remaining 131 patients, 47% (n = 62/131) were considered as patients with BPO 12 months after RTx. Six percent (n = 8/131) of the patients experienced urinary retention due to BPO and 6% (n = 8/131) had a transurethral resection of the prostate (TURP) during the first year after RTx. No major complications were observed in those patients. A significant increase was noted in the use of α-blocker therapy after RTx (P = 0.004). CONCLUSIONS: We observed a high prevalence of LUTS related to BPO in our cohort of patients. Due to the increasing age of transplant recipients, more attention should be paid to the evaluation and treatment of BPO prior to RTx.

High-grade Carcinoma of the Proximal Ureter With Negative Nephroureteroscopy Detected by a Positive FISH Test: A Rare Case Report.

Upper tract urothelial carcinomas in the proximal ureter are an uncommon disease. We present a case in which it was firstly detected by fluorescence in situ hybridization and not by endoscopy and radiologic imaging. Consequently, a radical nephroureterectomy with excision of the bladder cuff was performed as the gold standard treatment.

FISH analysis of washing urine from the upper urinary tract for the detection of urothelial cancers.

INTRODUCTION: To evaluate FISH analysis of washing urine from the upper urinary tract (UUT) in comparison with cytology (Cyt) for the detection of urothelial cancers. PATIENTS AND METHODS: In 82 patients with symptoms or abnormalities of the UUT sampling of washing urine for FISH and Cyt and a stepwise diagnostic work-up (e.g. retrograde ureteropyelography, ureterorenoscopy and endoscopic biopsy) were performed. In case of endoscopically and/or histologically proven malignancy patients either underwent nephroureterectomy, partial ureterectomy or local treatment. Sensitivity and specificity for FISH and Cyt as well as its combination were determined. RESULTS: Urothelial cancer of the UUT was detected in 20 patients. Eleven patients underwent nephroureterectomy, six partial ureterectomy and three endoscopic tumour treatment. This revealed nine pTa, three pT1 and seven muscle-invasive tumours. Twelve tumours were classified as low and seven as high-grade tumours. In one patient with a macroscopic unequivocal finding of tumour, endoscopic laser ablation without histologic confirmation was performed. FISH was evaluable in 76 patients and detected 16 tumours with a sensitivity and specificity of 84.2 and 91.1 %, respectively. Cyt was performed in 79 and was evaluable in 78 patients. It detected ten tumours with a sensitivity and specificity of 52.6 and 91.4 %, respectively. Cyt and FISH together detected 19 tumours with (sensitivity 100 % and specificity 83.6 %). CONCLUSION: FISH was more sensitive than and equally specific to Cyt in the detection of urothelial cancers of the UUT. Both markers in combination revealed the best sensitivity, making it a possible approach in future settings.

Prospective evaluation of fluorescence-guided cystoscopy to detect bladder cancer in a high-risk population: results from the UroScreen-Study.

OBJECTIVE: To prospectively evaluate the role of fluorescence-guided cystoscopy in a high-risk bladder cancer population undergoing screening based on a multi-marker panel of urine-tests (UroScreen-study). PATIENTS AND METHODS: UroScreen was conducted as a validation study for tumor markers within the frame of a health surveillance program of workers with occupational exposure to aromatic amines. Voluntary annual screens were done in 1,609 men. Cytology, quantitative NMP22® assay, and UroVysion (FISH) were applied to 7091 urine samples. Subjects with at least one positive urine-based tumor marker and/or persisting microscopic hematuria were offered fluorescence-guided (PDD) instead of white light cystoscopy. In case of suspicious findings histopathological evaluation by transurethral biopsy was performed. Data were statistically summarized and compared to tumors found by the standard algorithm of the screening study. RESULTS: Twenty-two subjects with a mean age of 58 years (39-72) underwent PDD cystoscopy. Of those 3 had positive NMP22 tests, 14 positive FISH tests and 9 suspicious cytologies. Two had persisting microscopic hematuria only. PDD cystoscopy revealed enhanced unifocal fluorescence in 14. All had subsequent transurethral biopsy or resection. In total, 1 urothelial carcinoma (pTaG1, low grade) was diagnosed. In the other participants urothelial cancer of the bladder was ruled out. Chronic cystitis was revealed in 8 of 14 biopsies. No higher detection rate was found using PDD than with the standard algorithm of the UroScreen study in which 17 tumors were detected by white light cystoscopy. CONCLUSION: The use of PDD does not lead to a higher cancer detection rate in a high-risk screening population. Larger sample sizes may be needed to ultimately asses the value of PDD for bladder cancer screening.

Bladder cancer discussed on the internet: a systematic analysis of gender differences of initial posters on an online discussion board.

OBJECTIVES: To evaluate gender differences of initial posters in threads dealing with bladder cancer on an online discussion board. METHOD: 529 threads opened between 09/2005 and 03/2012 were screened on the largest German speaking bladder cancer online discussion board. 366 threads fulfilled the requirements for this study. Gender, age, number, status of concern and oncological situation of initiating posters as well as their motives and language style were analyzed following a standardized protocol. RESULTS: Threads were initiated in 45% (164/366) by men and in 55% (202/366) by women. Mean age of male initiating posters was 50 years and of female posters 44 years (p < 0.001). Of males 80% (132/164) were concerned patients and 20% (32/164) relatives or friends. Of females they were 39% (78/202) and 61% (124/202), respectively (p < 0.001). In general motives for initial posting were focused on medical information and did not differ between both genders. 81% of the posters asked for medical information or therapeutic recommendations regarding diagnosis, treatment and prognosis. However, women significantly more often expressed their wish for emotional support (p = 0.034) and in tendency wanted to share their experiences with others (p = 0.057). Language analysis revealed that women significantly more often used a tentative language style than men (p = 0.003). CONCLUSION: Even though women are less often affected by bladder cancer, they are more active -especially for their concerned family members - on the evaluated discussion board than men. Whereas both genders equally often ask for medical information, women more often want to share their experiences and look for emotional support.

Prospective comparison between the AirSeal® System valve-less Trocar and a standard Versaport™ Plus V2 Trocar in robotic-assisted radical prostatectomy.

BACKGROUND AND PURPOSE: To prospectively compare the AirSeal® System valve-less Trocar with a standard Versaport™ Plus V2 Trocar as assistant insufflating port in transperitoneal and extraperitoneal robotic-assisted radical prostatectomy (t-RARP/e-RARP). PATIENTS AND METHODS: Two consecutive cohorts of patients undergoing RARP using either a 12 mm AirSeal valve-less Trocar (n=19 [14 t-RARP/5 e-RARP]) or a 12 mm Versaport Plus V2 Trocar (n=17 [11 t-RARP/6 e-RARP]) were prospectively evaluated. Age, body mass index, tumor characteristics, and surgical approach were similar in both cohorts. Besides relevant clinical data, episodes of pressure loss (<8 mm Hg), the number of necessary trocar manipulations, the frequency of camera cleaning, and overall carbon dioxide (CO2) consumption were recorded and compared. RESULTS: Mean surgical time was 175 minutes in the AirSeal and 166 minutes in the Versaport group (p=0.55). Whereas in the AirSeal group, only one episode of pressure loss <8 mm Hg was observed; this occurred in mean 38 times in the Versaport group (p<0.0001). No trocar manipulations for specimen or needle retrieval were necessary in the AirSeal group in contrast to in mean 15 in the Versaport group (p<0.0001). Otherwise, no appreciable differences regarding overall operating time, blood loss, camera cleaning, or overall CO2 consumption were observed for the present study. Patient CO2 absorption was not evaluated. CONCLUSIONS: In the present study, the AirSeal Trocar offered a more stable pneumocavity and facilitated specimen retrieval and needle extraction.

Pre- and postoperative urodynamic findings in patients after a bulbourethral composite suspension with intraoperative urodynamically controlled sling tension adjustment for postprostatectomy incontinence.

OBJECTIVES: To compare pre- and postoperative urodynamic findings in patients with a bulbourethral composite suspension and intraoperative urodynamically controlled sling tension adjustment. METHODS AND PATIENTS: All data were prospectively collected from 10 patients (mean age 66 years) who successfully underwent bulbourethral composite suspension for moderate to severe postprostatectomy incontinence. Patients were evaluated preoperatively and 3-6 months postoperatively by urodynamic measurements, including urethra pressure profiles (UPPs) and pressure flow studies (PFSs). Clinical outcome was evaluated by patient-reported pad use and questionnaires (ICIQ-UI SF and I-QOL). Intraoperatively sling tension was adjusted under repeated urodynamic measurements of abdominal leak point pressure. Data were evaluated using the Kruskal-Wallis Wilcoxon test. RESULTS: Sling implantation was successful in all patients. Pre- to postoperative pad use decreased significantly (P < .005). Five patients were pad-free, 3 used 1 pad, and 2 used 2 pads per day. Continence and quality of life improved significantly (ICIQ-UI SF: pre-op 17 vs post-op 4.9; I-QOL: pre-op 66 vs post-op 91; P < .05 for both). Urodynamic parameters during the filling phase remained unchanged. UPPs revealed a significant increase of the maximal urethral closure pressure (pre-op 40 cm H(2)O vs post-op 58 cm H(2)O) and functional length (pre-op 31 mm vs post-op 40 mm; P < .05 for both). Postoperatively, urodynamic maximal flow rates were slightly reduced from 16 mL/s to 12 mL/s (P = .4). PFSs revealed an unobstructed voiding in all patients. CONCLUSIONS: According to the present evaluation, a bulbourethral composite suspension with intraoperative urodynamically controlled sling tension adjustment improves continence without causing prolonged clinically or urodynamically significant voiding obstruction.