[Transanal total mesorectal excision-a critical appraisal]. / Transanale totale mesorektale Exzision ­ eine kritische Standortbestimmung.

INTRODUCTION: Total mesorectal excision (TME) is the international standard for rectal cancer surgery. In addition to laparoscopic TME (lapTME), transanal TME (taTME) was developed in recent years to reduce the rate of incomplete TME, conversion to open surgery and postoperative functional impairment. Despite limited evidence, this technique is becoming increasingly more popular and is already routinely used by many hospitals for rectal cancer in varying tumor level locations. The aim of this review was to evaluate the taTME compared to anterior rectal resection with lapTME as the standard of care in rectal cancer surgery based on currently available evidence. METHOD: The databases PubMed and Medline were systematically searched for publications on transanal total mesorectal excision (taTME) and transanal minimally invasive surgery (TAMIS). Relevant studies were selected and further research based on the reference lists was undertaken. RESULTS: A total of 16 studies analyzing 3782 patients were identified. The taTME does not lead to a higher rate of complete TME-resected specimens compared to the standard procedure. So far, superiority could not be demonstrated for complication rates or for functional or oncological results. Serious complications secondary to dissection in incorrect planes were observed. The anastomotic level generally seems to be closer to the sphincter after taTME versus anterior lapTME. CONCLUSION: Considering current evidence, taTME failed to show superiority compared to conventional anterior lapTME. Although taTME has some potential advantages, it carries substantial risks. If performed outside of clinical trials, it should therefore only be used in carefully selected patients with a high possibility of conversion, following adequate patient informed consent and after intense and systematic training of the surgeon.

[LSD score. A new classification system for peristomal skin lesions]. / LSD-Score. Ein neues Klassifikationssystem für peristomale Hautläsionen.

BACKGROUND: Peristomal skin lesions are frequent complications of ostomy; however, there is no generally accepted nomenclature and classification system. OBJECTIVE: An interdisciplinary German expert panel (GESS) composed of ten members, developed an innovative semiquantitative classification system for peristomal skin lesions for further stratification of ostomy therapy. This score is based on criteria which can be assessed by stomal therapists and treating physicians. RESULTS: The new peristomal skin lesion score grades three categories: lesion (L), status of ostomy (S) and disease (D). The L category describes the integrity of the skin as normal (L0), lesion with sustained integrity of skin (L1), integrity destroyed (L2) and local infection (L3). The S category rates the complexity of ostomy therapy as normal (S0), increased (S1) and high but not sufficiently effective (S2). The additional letters for categorization O. R. P. H. E. US describe anatomical pathologies of the stoma itself: ostomy stenosis (O), retraction (R), prolapse (P), hernia (H), edema (E) and unfavorable site (US). A systemic disorder is either absent (D0), irrelevant (D1) or relevant (D2). The LSD score is the basis for a management algorithm. CONCLUSION: The LSD score is comprehensive, standardized and holistic. Its straightforward use by health professionals can improve the consistency of the description of skin lesions and enhance the quality of ostomy therapy.

Risk of fecal diversion in complicated perianal Crohn's disease.

The purpose of the study was to determine the overall risk of a permanent stoma in patients with complicated perianal Crohn's disease, and to identify risk factors predicting stoma carriage. A total of 102 consecutive patients presented with the first manifestation of complicated perianal Crohn's disease in our outpatient department between 1992 and 1995. Ninety-seven patients (95%) could be followed up at a median of 16 years after first diagnosis of Crohn's disease. Patients were sent a standardized questionnaire and patient charts were reviewed with respect to the recurrence of perianal abscesses or fistulas and surgical treatment, including fecal diversion. Factors predictive of permanent stoma carriage were determined by univariate and multivariate analysis. Thirty of 97 patients (31%) with complicated perianal Crohn's disease eventually required a permanent stoma. The median time from first diagnosis of Crohn's disease to permanent fecal diversion was 8.5 years (range 0-23 years). Temporary fecal diversion became necessary in 51 of 97 patients (53%), but could be successfully removed in 24 of 51 patients (47%). Increased rates of permanent fecal diversion were observed in 54% of patients with complex perianal fistulas and in 54% of patients with rectovaginal fistulas, as well as in patients that had undergone subtotal colon resection (60%), left-sided colon resection (83%), or rectal resection (92%). An increased risk for permanent stoma carriage was identified by multivariate analysis for complex perianal fistulas (odds ratio [OR] 5; 95% confidence interval [CI] 2-18), temporary fecal diversion (OR 8; 95% CI 2-35), fecal incontinence (OR 21, 95% CI 3-165), or rectal resection (OR 30; 95% CI 3-179). Local drainage, setons, and temporary stoma for deep and complicated fistulas in Crohn's disease, followed by a rectal advancement flap, may result in closing of the stoma in 47% of the time. The risk of permanent fecal diversion was substantial in patients with complicated perianal Crohn's disease, with patients requiring a colorectal resection or suffering from fecal incontinence carrying a particularly high risk for permanent fecal diversion. In contrast, patients with perianal Crohn's disease who required surgery for small bowel disease or a segmental colon resection carried no risk of a permanent stoma.

Long-term outcome of conservative treatment in patients with diverticulitis of the sigmoid colon.

INTRODUCTION: The indication for surgery after conservative treatment of acute diverticulitis is still under debate. This is partly as a result of limited data on the outcome of conservative management in the long run. We therefore aimed to determine the long-term results of conservative treatment for acute diverticulitis. METHODS: The records of all patients treated at our institution for diverticulitis between 1985 and 1991 were reviewed (n=363, median age 64 years, range 29-93). Patients who received conservative treatment were interviewed in 1996 and 2002 [follow-up time 7 years 2 months (range 58-127 months) and 13 years 4 months (range 130-196 months). RESULTS: A total of 252 patients (69%) were treated conservatively, whereas 111 (31%) were operated on. At the first follow-up, 85 patients treated conservatively had died, one of them from bleeding diverticula. A recurrence of symptoms was reported by 78 of the remaining 167 patients, and 13 underwent surgery. At the second follow-up, one patient had died from sepsis after perforation during another episode of diverticulitis. Thirty-one of the 85 patients interviewed reported symptoms and 12 had been operated on. In summary, at the second follow-up interview, 34% of patients treated initially had had a recurrence and 10% had undergone surgery. No predictive factors for the recurrence of symptoms or later surgery could be determined. CONCLUSION: Despite a high rate of recurrences after conservative treatment of acute diverticulitis, lethal complications are rare. Surgery should thus mainly be undertaken to achieve relief of symptoms rather than to prevent death from complications.

Adjuvant chemoradiation using 5-fluorouracil/folinic acid/cisplatin with or without paclitaxel and radiation in patients with completely resected high-risk gastric cancer: two cooperative phase II studies of the AIO/ARO/ACO.

BACKGROUND: The current two studies evaluate the feasibility, toxicity and efficacy of an adjuvant combined modality treatment strategy containing a three to four-drug chemotherapy regimen plus 5-fluorouracil (FU)-based radiochemotherapy. PATIENTS AND METHODS: Between December 2000 and October 2003, a total of 86 patients were included in both studies. Patients with completely resected gastric adenocarcinoma including a D1 or D2 lymph node dissection (LND) were eligible. Treatment consisted of two cycles of folinic acid 500 mg/m2, 5-FU 2000 mg/m2 continuous infusion over 24 h once weekly for 6 consecutive weeks, paclitaxel 175 mg/m2 in weeks 1 and 4 and cisplatin 50 mg/m2 in weeks 2 and 5 (FLPP; n=41) or two cycles of the same 5-FU/folinic acid schedule but with cisplatin 50 mg/m2 only in weeks 1, 3 and 5 (FLP; n=45). Radiation with 45 Gy plus concomitantly applied 5-FU 225 mg/m2/24 h was scheduled in between the two cycles. RESULTS: Patients characteristics were: D1/D2 LND FLP group 53%/42%; FLPP group 27%/68%; stage distribution: UICC stages III/IV(M0) FLP group 63% and FLPP group 66%. Median follow-up was 10 months (3-25) for FLP and 18 months (2-51) for FLPP patients. CTC grade 3/4 toxicities during the first cycle/chemoradiation/second cycle of FLP: granulocytopenia 3%/0/27%, anorexia 6%/10%/8%; diarrhea 8%/0/4%, nausea 3%/0/4%; FLPP: granulocytopenia 0/0/37%, anorexia 5%/11%/6%; diarrhea 5%/0/3, nausea 3%/8%/0%; early death in one patient due to Pneumocystis carinii pneumonia. Projected 2-year progression-free survival was 64% (95% CI 56% to 68%) for the FLP and 61% (95% CI 42% to 78%) for the FLPP group. CONCLUSIONS: Both chemoradiation regimens appear feasible with an acceptable toxicity profile indicating that cisplatin can be added to 5-FU/FA and that even a four-drug regimen can be investigated further in prospective clinical trials in completely resected gastric cancer patients. Treatment should be given in experienced centres in order to avoid unnecessary toxicity.

Treatment of advanced rectal cancer in a patient after combined pancreas-kidney transplantation.

BACKGROUND: Organ transplantation is a standard procedure today. Due to immunosuppressive drugs and increasing survival after organ transplantation, patients with transplanted organs carry an increased risk of developing malignant tumours. Accordingly, more patients with malignant tumours after transplantation will be faced by general or oncology surgeons. We report the case of a 48-year-old patient with advanced rectal cancer 6.5 years after pancreas-kidney-transplantation for type I diabetes. METHOD: The patient was treated with neo-adjuvant radio-chemotherapy, followed by low anterior rectal resection with total mesorectal excision. Consecutively, a solitary hepatic metastasis, a solitary pulmonary metastasis and a chest wall metastasis were resected over the course of 13 months. RESULT: The patient eventually died of metastasized cancer 32 months after therapy had been initiated, his organ grafts functioning well until his death. CONCLUSION: Our case report provides evidence that transplantation patients should receive standard oncology treatment, including neo-adjuvant treatment, so long as their general condition and organ graft functions allow us to do so, although a higher degree of morbidity might be encountered.

[Crohn disease--surgical standards]. / Morbus Crohn--Chirurgische Standards.

Surgery for Crohn's disease is restricted to the treatment of complications. Even then, nearly all patients with Crohn's disease must be operated on at least once in lifetime. Surgical concepts base on the right timing for the operation, interventional drainage of abscesses, accurate pre-operative work-up to determine the extent of inflammation, and bowel conserving operation techniques. Respecting these principles, surgery for Crohn's disease can be performed with low complication rates restoring in most cases patients' quality of life.

[Postoperative ileus: part I (Experimental results)]. / Postoperativer Ileus: Teil I (Experimentelle Therapieansätze).

Postoperative gastro-intestinal motility disorders are of major importance for patient management following abdominal surgery both for clinical and economic reasons. In recent years, new pathophysiological links have been identified that contribute to postoperative ileus. The activation of sympathetic efferent neurons by visceral afferent nerve fibers, catecholamines, the stimulation of beta 3 -receptors in the gut wall, an inflammatory response of the gut wall with the consecutive release of nitric oxide, and opioids given for postoperative analgesia seem to be of major importance regarding the development of postoperative ileus. The pharmacological reduction of visceral afferent nerve fiber activity, non-steroidal anti-inflammatory drugs (NSAIDs) instead of opioids for postoperative pain, peripheral opioid receptor antagonists together with opioids for postoperative analgesia, motilides and 5-HT4 receptor agonists as prokinetic drugs are strategies that are currently evaluated to treat postoperative ileus. Our review summarizes the present knowledge on the pathophysiology of postoperative ileus and new experimental treatments that might be of importance in the future.

[Postoperative ileus: part II (Clinical therapy)]. / Postoperativer Ileus: Teil II (Klinische Therapie).

To avoid or reduce postoperative ileus, the operative trauma should be minimized and epidural anesthesia for spinal inhibition of the sympathetic nervous system or i. v. lidocaine should be used, all of which probably act by reducing visceral afferent nerve fiber activity. Recent data suggest that perioperative fluid restriction might reduce postoperative ileus. Epidural anesthesia with local anesthetics and replacing opioids by non-steroidal anti-inflammatory drugs (NSAIDs) for postoperative pain treatment improve the recovery of gastrointestinal motility disturbances. Prior to the operation, the patient should be informed regarding postoperative motility disorders, its length and the presumed resumption of oral food intake, which has been shown to shorten hospital stay. Early postoperative food intake stimulates small and large bowel motility via interenteric reflex arches, avoids i. v. lines and renders discharge acceptable for the patient. Treatment of postoperative ileus includes osmotic laxatives and prokinetic drugs like erythromycine and acetylcholinesterase inhibitors. By combining epidural anesthesia and the sparse use of i. v. opioids with early food intake and, if necessary, laxatives or prokinetics, postoperative ileus should be coped adequately. Nevertheless, the development of new specific prokinetic drugs with minimal or no side effects should remain a target for drug companies to further improve treatment of postoperative ileus.

Anorectal functional disorders in the absence of anorectal inflammation in patients with Crohn's disease.

BACKGROUND: Histological alterations in the enteric nervous system (ENS) have been described in patients suffering from Crohn's disease (CD). The aim of this study was to investigate whether patients with CD without rectal inflammation have abnormal anorectal function compared with healthy volunteers. METHODS: Fifty-four patients with CD and 26 healthy volunteers were examined by anorectal manometry and answered a standardized questionnaire. No patient had active CD in the rectum as determined by endoscopy. RESULTS: Maximum anal resting and squeeze pressures did not differ between patients and healthy volunteers. The rectoanal inhibitory reflex was absent in 24 of 54 patients and two of 26 healthy volunteers (P < 0.05). The first sensation to distension of the rectal balloon was reported at mean(s.e.m.) 57.9(4.4) ml by patients and 37.5(2.2) ml by healthy volunteers (P < 0.01). The standardized interview revealed additional disorders of anorectal function in patients with CD. CONCLUSION: Anorectal function appears to be altered in many patients with CD even in the absence of macroscopic anorectal disease. This may be due to a disorder of the ENS.

Evaluation of the barostat for recordings of gastrointestinal motility.

BACKGROUND: The barostat has been used to investigate gastrointestinal motility. No detailed technical evaluation to characterize the properties of this device for motility recordings has been reported. We, therefore, aimed to test the barostat in vitro under standardized conditions. METHODS: Barostat and manometry recordings were performed using a combined catheter in a pressure chamber. Some of the experiments were made in pig sigmoid colon in order to mimic recordings in a hollow organ. Data are mean +/- SD. RESULTS: Baseline changes of the bag volume under constant conditions were 3.9 +/- 2.0%. The bag volume increased by 4.5 +/- 1.1% with a temperature increase from 22 to 37 degrees C (p < 0.05). At external pressures above the bag operating pressure, the barostat bag collapsed, while only minimal volume reductions occurred at external pressures below the bag pressure. Barostat recordings of pressure events were delayed when compared with manometry and not linearly related to the pressure increases. CONCLUSION: The influence of temperature changes on barostat recordings is small. The volume decrease in the barostat bag is not linearly related to the external pressure increase and influenced by the operating pressure in the bag. This experimental study provides insight and caveats for those planning to use the barostat device for motility recordings of the gastrointestinal tract.

Neostigmine increases postoperative colonic motility in patients undergoing colorectal surgery.

BACKGROUND: Gastrointestinal motility is frequently impaired after abdominal surgery. We investigated the effects of neostigmine on colonic motility in patients after colorectal surgery and in healthy volunteers. METHODS: Colonic motility was recorded by a manometry/barostat system in 12 patients after left colonic or rectal resection during baseline and after the intravenous administration of increasing doses of neostigmine on postoperative days 1, 2, and 3. In addition, colonic motility was recorded in 7 healthy volunteers. RESULTS: Neostigmine increased the colonic motility index. This increase was from 135 +/- 28 mm Hg/min at baseline to 574 +/- 219 mm Hg/min after administration of 5 microg/kg neostigmine on day 3 after surgery (mean +/- SEM, P <.05). In healthy volunteers, neostigmine at a dose of 5 microg/kg increased the colonic motility index from 184 +/- 73 to 446 +/- 114 mm Hg/min (P <.05). Barostat bag volumes decreased dose-dependently after neostigmine administration in patients as well as in volunteers, indicating an increase in colonic tone. CONCLUSIONS: Colonic motility and tone increased after neostigmine administration at a dose of 5 microg/kg in postoperative patients and in healthy volunteers. Neostigmine can be used to stimulate colonic motility after colorectal surgery and has a similar effect postoperatively as in healthy volunteers.

Neurotransmitter coding of enteric neurones in the submucous plexus is changed in non-inflamed rectum of patients with Crohn's disease.

Knowledge of the neurochemical coding of submucosal neurones in the human gut is important to assess neuronal changes under pathological conditions. We therefore investigated transmitter colocalization patterns in rectal submucosal neurones in normal tissue (n=11) and in noninflamed tissue of Crohn's disease (CD) patients (n=17). Neurone-specific enolase (NSE), choline acetyltransferase (ChAT), vasoactive intestinal polypeptide (VIP), substance P (SP), nitric oxide synthase (NOS) and calcitonin gene-related peptide (CGRP) were detected immunohistochemically in whole-mount preparations from rectal biopsies. The neuronal marker NSE revealed no differences in the number of cells per ganglion (controls 5.0; CD 5.1). Four cell populations with distinct neurochemical codes were identified. The sizes of the populations ChAT/VIP (58% vs. 55%), ChAT/SP (8% vs. 8%), and ChAT/- (22% vs. 22%) were similar in control and CD. The population VIP/- was significantly increased in CD (12% vs. 2% in controls). Unlike in controls, all NOS neurones colocalized ChAT in CD. Thickened CGRP-fibres occurred in CD. We identified neurochemically distinct populations in the human submucous plexus. The increase in the VIP/- population, extensive colocalization of ChAT and NOS and hypertrophied CGRP fibres indicated adaptive changes in the enteric nervous system in noninflamed rectum of CD patients.

Intraperitoneal capsaicin treatment reduces postoperative gastric ileus in awake rats.

INTRODUCTION: Postoperative gastric ileus interferes with postoperative recovery of the patients. Previous studies suggest that capsaicin-sensitive afferent neurons are involved in the mediation of postoperative gastric ileus. METHODS: A group of rats were equipped with a strain gauge transducer sutured to the gastric wall. Gastric motility was recorded after intraperitoneal injection of capsaicin (0.1 micromol/kg and 1 micromol/kg) or vehicle. The rats were given 2 days of recovery before gastric motility was investigated in a postoperative ileus model. RESULTS: Pretreatment with capsaicin 2 days prior to abdominal surgery significantly increased postoperative gastric motility, with complete recovery of gastric motility at 30 min postoperatively (with the baseline motility index set at 100+/-4%, the gastric motility index 30-45 min postoperatively was 64+/-4% for the vehicle, 138+/-20% for capsaicin 0.1 micromol/kg, and 110+/-12% for capsaicin 1 micromol/kg: P=0.0008 vehicle vs capsaicin). In contrast, capsaicin treatment 2 h prior to abdominal surgery did not increase postoperative gastric motility (gastric motility index 30-45 min postoperatively was 64+/-4% for the vehicle and 51+/-8% for capsaicin 0.1 micromol/kg). The acute intraperitoneal injection of capsaicin decreased gastric motility by about 50-60%, the response lasting for 15-30 min. CONCLUSIONS: Intraperitoneal capsaicin treatment 2 days prior to abdominal surgery resulted in immediate recovery of postoperative gastric motility, indicating an important role for serosal visceral afferent nerve fibers in the mediation of postoperative gastric ileus. Possibly, capsaicin or vanilloid (capsaicin) receptor agonists can be used to treat postoperative ileus in the future.

Preoperative intraluminal application of capsaicin increases postoperative gastric and colonic motility in rats.

In a model to investigate postoperative gastrointestinal motility with strain gauge transducers in awake rats, we tested the effects of intraluminal capsaicin infusion into the cecum 2 days or 14 days prior to abdominal surgery. Acute infusion of capsaicin into the cecum for 30 minutes increased the gastric, small intestinal, and colonic motility index by up to 115%, 34%, and 59%, respectively, compared to vehicle infusion. Intraluminal capsaicin infusion 2 days prior to abdominal surgery significantly increased the intraoperative gastric and colonic motility index by 166% and 100%, respectively, compared to vehicle, but had no effect on small intestinal motility. The postoperative decrease in gastric or colonic motility was completely prevented by capsaicin pretreatment, representing a 73% and a 72% increase in the motility index during the first postoperative hour and a 40% and a 29% increase in the motility index during the second postoperative hour compared to vehicle, whereas the postoperative decrease in small intestinal motility was not altered by capsaicin pretreatment. In contrast, intraluminal capsaicin infusion 14 days prior to abdominal surgery had no effect on postoperative inhibition of gastrointestinal motility. Our results suggest that capsaicin-sensitive visceral afferent C-fibers, presumably of the submucosa, play an important role in mediating postoperative ileus. Intraluminal capsaicin does probably ablate these nerve fibers temporarily, with no systemic side effects observed with the use of the tail flick test as a measure of skin nociception.

[Penetrating injuries of the rectum and anus: primary management, reconstruction, rehabilitation]. / Pfählungsverletzungen des Rektums und des Anus: Primärversorgung, Rekonstruktion, Rehabilitation.

In adults direct trauma to the anus and rectum originates mostly from gun shots, road traffic accidents, autoeroticism or sexual abuse. Real "impalement" injuries have been frequently seen only in children. As in any polytraumatized patient primary diagnostic procedure--after adequate resuscitation of the patient--consists of X-ray and ultrasound. The patient should be examined in the OR under general anaesthesia and placed in lithotomy position. Treatment often requires a multidisciplinary approach. Primary surgical therapy consists of 4 D's: debridement, drainage, diversion and distal irrigation. No primary reconstructive surgery should be tried. After recovery of the patient dedicated functional testing has do be done prior to reconstructive measures which include sphincter reconstruction. With this concept mortality is low, but functional outcome is variable.

Postoperative colonic motility and tone in patients after colorectal surgery.

PURPOSE: Colonic motility is crucial for the resolution of postoperative ileus. However, few data are available on postoperative colonic motility and no data on postoperative colonic tone. We aimed to characterize postoperative colonic tone and motility in patients. METHODS: Nineteen patients were investigated with combined barostat and manometry recordings after left colonic surgery. During surgery a combined recording catheter was placed in the colon with two barostat bags and four manometry channels cephalad to the anastomosis. Recordings were performed twice daily from Day 1 to Day 3 after surgery. RESULTS: Manometry showed an increasing colonic motility index, which was a mean (+/- standard error of the mean) of 37 +/- 5 mmHg/minute on Day 1, 87 +/- 19 mmHg/minute on Day 2, and 102 +/- 13 mmHg/minute on Day 3 (P < 0.05 for Day 1 vs. Day 2 and Day 2 vs. Day 3). Low barostat bag volumes indicating a high colonic tone were observed on Day 1 after surgery and increased subsequently (barostat bag I was 19 +/- 4, 32 +/- 6, and 32 +/- 6 ml; barostat bag II was 13 +/- 1, 19 +/- 3, and 22 +/- 5 ml on Days 1, 2, and 3, respectively; for both barostat bags P < 0.05 for Day 1 vs. Day 2 but not Day 2 vs. Day 3). CONCLUSIONS: Colonic motility increased during the postoperative course. The low barostat bag volumes indicated a high colonic tone postoperatively which would correspond to a contracted rather than to a distended colon. High colonic tone postoperatively may be relevant for pharmacologic treatment of postoperative ileus.

Surgical management of peptic ulcer disease today--indication, technique and outcome.

AIMS: The current surgical management of peptic ulcer disease and its outcome have been reviewed. RESULTS: Today, surgery for peptic ulcer disease is largely restricted to the treatment of complications. In peptic ulcer perforation, a conservative treatment trial can be given in selected cases. If laparotomy is necessary, simple closure is sufficient in the large majority of cases, and definitive ulcer surgery to reduce gastric acid secretion is no longer justified in these patients. Laparoscopic surgery for perforated peptic ulcer has failed to prove to be a significant advantage over open surgery. In bleeding peptic ulcers, definitive hemostasis can be achieved by endoscopic treatment in more than 90% of cases. In 1-2% of cases, immediate emergency surgery is necessary. Some ulcers have a high risk of re-bleeding, and early elective surgery might be advisable. Surgical bleeding control can be achieved by direct suture and extraluminal ligation of the gastroduodenal artery or by gastric resection. Benign gastric outlet obstruction can be controlled by endoscopic balloon dilatation in 70% of cases, but gastrojejunostomy or gastric resection are necessary in about 30% of cases. CONCLUSIONS: Elective surgery for peptic ulcer disease has been largely abandoned, and bleeding or obstructing ulcers can be managed safely by endoscopic treatment in most cases. However, surgeons will continue to encounter patients with peptic ulcer disease for emergency surgery. Currently, laparoscopic surgery has no proven advantage in peptic ulcer surgery.