Comparison of open and laparoscopic live donor nephrectomy.

OBJECTIVE: This study compares an initial group of patients undergoing laparoscopic live donor nephrectomy to a group of patients undergoing open donor nephrectomy to assess the efficacy, morbidity, and patient recovery after the laparoscopic technique. SUMMARY BACKGROUND DATA: Recent data have shown the technical feasibility of harvesting live renal allografts using a laparoscopic approach. However, comparison of donor recovery, morbidity, and short-term graft function to open donor nephrectomy has not been performed previously. METHODS: An initial series of patients undergoing laparoscopic live donor nephrectomy were compared to historic control subjects undergoing open donor nephrectomy. The groups were matched for age, gender, race, and comorbidity. Graft function, intraoperative variables, and clinical outcome of the two groups were compared. RESULTS: Laparoscopic donor nephrectomy was attempted in 70 patients and completed successfully in 94% of cases. Graft survival was 97% versus 98% (p = 0.6191), and immediate graft function occurred in 97% versus 100% in the laparoscopic and open groups, respectively (p = 0.4961). Blood loss, length of stay, parenteral narcotic requirements, resumption of diet, and return to normal activity were significantly less in the laparoscopic group. Mean warm ischemia time was 3 minutes after laparoscopic harvest. Morbidity was 14% in the laparoscopic group and 35% in the open group. There was no mortality in either group. CONCLUSIONS: Laparoscopic live donor nephrectomy can be performed with morbidity and mortality comparable to open donor nephrectomy, with substantial improvements in patient recovery after the laparoscopic approach. Initial graft survival and function rates are equal to those of open donor nephrectomy, but longer follow-up is necessary to confirm these observations.

Equivalent success of simultaneous pancreas kidney and solitary pancreas transplantation. A prospective trial of tacrolimus immunosuppression with percutaneous biopsy.

OBJECTIVE: This study was designed to evaluate the results of solitary pancreas transplantation in a protocol that uses the new immunosuppressant tacrolimus (FK) and liberally applies ultrasound-guided percutaneous pancreas biopsy to diagnose rejection. SUMMARY BACKGROUND DATA: Pancreas graft survival in patients who simultaneously receive a kidney transplant (SPK) historically has been 75% to 90% at 1 year, approaching that of cadaveric kidney transplantations. In sharp contrast, graft survival rates in patients who receive a pancreas atone (PA) have remained static over the past decade, with approximately 50% functional at 1 year. It was hypothesized that the results of PA transplantations would improve with newer maintenance immunosuppressants and biopsy techniques. METHODS: Twenty-seven PA recipients prospectively were treated with FK-based immunosuppression (PA-FK). Percutaneous biopsy was performed for hyperamylasemia, hyperlipasemia, hypoamylasuria, or unexplained fever. One year pancreas graft survival in these patients was compared to 15 cyclosporine treated PA cases (PA-CsA) and 113 SPK recipients. RESULTS: The 1-year pancreas graft survival rate of 90.1% in technically successful PA-FK patients was significantly better than the 53.4% rate in PA-CsA recipients (p = 0.002) and no different than the 87.4% rate in SPK recipients. The only graft lost to acute rejection in the PA-FK group was because of acknowledged patient noncompliance. Percutaneous biopsy substantially improved the diagnostic certainty in cases of suspected rejection and was associated with a low complication rate (3/178 = 1.5%). CONCLUSIONS: Modern immunosuppression and biopsy techniques have improved the success of solitary pancreas transplantations to the point where outcome is now equivalent to that of SPKs.

Laparoscopic splenectomy in patients with hematologic diseases.

OBJECTIVE: The authors review their initial experience with laparoscopic splenectomy in patients with hematologic diseases. Efficacy, morbidity, and mortality of the technique are presented, and other patient recovery parameters are discussed. SUMMARY BACKGROUND DATA: Laparoscopic splenectomy is performed infrequently and data regarding its safety and efficacy are scarce. Factors such as a high level of technical difficulty, the potential for sudden, severe hemorrhage, and slow accrual of operative experience due to a relatively limited number of procedures are responsible. The potential patient benefits from the development of a minimally invasive form of splenectomy are significant. METHODS: Clinical follow-up, a prospective longitudinal database, and review of medical records were analyzed for all patients referred for elective splenectomy for hematologic disease from March 1992 to March 1995. RESULTS: Laparoscopic splenectomy was attempted in 43 patients and successfully completed in 35 (81%). Therapeutic platelet response to splenectomy occurred in 82% of patients with immune thrombocytopenic purpura and hematocrit level increased in 60% of patients with autoimmune hemolytic anemia undergoing successful laparoscopic splenectomy. The morbidity rate was 11.6% (5 of 43 patients), and the mortality rate was 4.7% (2 of 43 patients). Return of gastrointestinal function occurred in patients 23.1 hours after laparoscopic splenectomy and 76 hours after conversion to open splenectomy (p < 0.05). Mean length of stay was 2.7 days after laparoscopic splenectomy and 6.8 days after conversion to open splenectomy (p < 0.05). CONCLUSION: Laparoscopic splenectomy may be performed with efficacy, morbidity, and mortality rates comparable to those of open splenectomy for hematologic diseases, and it appears to retain other patient benefits of laparoscopic surgery.

Flexible endoscopy for the diagnosis of esophageal trauma.

The role of flexible endoscopy in the diagnosis of esophageal trauma remains undefined. This study evaluates the use of immediate flexible fiberoptic esophagogastroduodenoscopy (EGD) as the primary diagnostic tool for detection of esophageal injury in trauma patients. Flexible EGD was performed on 31 patients for this purpose from August 1991 through January 1994. There were 28 males and 3 females with a mean age of 24.3 years (range, 16-54 years). Twenty-four of 31 patients (77%) were intubated at the time of the examination. Mechanism of injury was penetrating in 24 patients (20 gunshot wounds, four stab wounds) and blunt (motor vehicle crash) in seven patients. Penetrating injuries were located in the neck in 5 of 24 patients, in the chest in 15 of 24 patients, and in both the neck and chest in 4 of 24 patients. Upper gastrointestinal contrast studies were performed for 3 of 31 patients (10%), computed tomography was performed for eight patients (26%), bronchoscopy was performed for 13 patients (42%), angiography was performed for 17 patients (55%), and rigid esophagoscopy and laryngoscopy were each performed for one patient (3%). Evidence of esophageal trauma during EGD was seen in 5 of 31 patients. True-positive studies occurred for four patients, false-positive results occurred for one patient, true-negative results occurred for 26 patients (as demonstrated by exploration in five and clinical follow-up in 21), and no false-negative examinations occurred. Sensitivity of flexible EGD was 100%, specificity was 96%, and accuracy was 97%. No complications occurred related to the performance of EGD. Flexible fiberoptic endoscopy seems to be a safe and effective method for both detection and exclusion of esophageal trauma.

Opportunistic upper gastrointestinal infection in transplant recipients.

Opportunistic infection of the upper gastrointestinal tract by cytomegalovirus (CMV) or invasive fungal infection was studied in 219 consecutive kidney and kidney/pancreas transplant recipients with regard to incidence, presentation, and clinical outcome. Prompt upper endoscopy was done in all patients with these symptoms: dyspepsia, dysphagia, or bleeding. Multiple biopsies were obtained for fungal culture, CMV culture, CMV assay, and histologic examination for fungal invasion. Between April 1991 and July 1993, 57/219 (26%) transplant patients developed upper gastrointestinal symptoms. At endoscopy, gross mucosal abnormality was evident in 48/57 (84%). Opportunistic infection was found in 21/48 (44%); however, CMV infection was also detected in 2/9 (22%) who had a normal study. Overall, CMV was present in 15/57 (26%) and invasive fungal infection in 8/57 (14%). All 23 infections were successfully eradicated. Opportunistic infection occurred in 12/31 (39%) with dyspepsia, 9/14 (64%) with dysphagia, and 2/12 (17%) with bleeding. Graft loss occurred in 5/23 (22%) with opportunistic infection vs 23/196 (12%) other recipients. Upper gastrointestinal symptoms are indicative of serious opportunistic infection in a significant number of transplant recipients. As opportunistic infection may jeopardize allograft function, all patients with upper gastrointestinal tract symptoms require prompt endoscopy and biopsy to effect appropriate therapy. Random biopsy is also recommended in the face of a normal endoscopic examination.

The utility of prophylactic laparoscopic cholecystectomy in transplant candidates.

BACKGROUND: This study addresses the impact of laparoscopic cholecystectomy prior to kidney or pancreas transplant. PATIENTS AND METHODS: Between January 1991 and July 1993, 551 patients were listed for transplant. Gallbladder ultrasound became part of the standard evaluation for all transplant candidates in October 1991. Pretransplant laparoscopic cholecystectomy was recommended for all patients found to have gallstones. To assess the benefit of this policy, patients transplanted prior to routine ultrasound (Group I; n = 88) were compared to those listed or transplanted after routine ultrasound (Group II; n = 406). RESULTS: In Group I, 18% developed gallstone complications requiring surgery. Surgical morbidity occurred in 14% and mortality in 7% of these operations. Graft loss occurred in 20% having biliary complications versus 7% among other recipients. In Group II, gallstones were detected in 10%, and 9% subsequently had laparoscopic cholecystectomy with no morbidity or mortality. CONCLUSIONS: Transplant recipients with unsuspected gallstones were found to have a high incidence of acute biliary complications. Urgent biliary surgery carried significant morbidity and mortality in these immunosuppressed patients and appeared to increase the risk of graft failure as well. A policy of screening gallbladder ultrasound and pretransplant laparoscopic cholecystectomy seems to reduce these concerns and is recommended for all transplant candidates.

Laparoscopic cholecystectomy and common bile duct stones. The utility of planned perioperative endoscopic retrograde cholangiography and sphincterotomy: experience with 63 patients.

OBJECTIVE: Planned perioperative endoscopic retrograde cholangiography (ERC) and sphincterotomy (ES) for suspected or proven common bile duct stones (CBDS) has been attempted in 63 of 540 consecutive patients undergoing laparoscopic cholecystectomy (LC). Experience with this intervention has been studied with respect to accuracy, efficacy, and safety. SUMMARY BACKGROUND DATA: The optimal management of CBDSs in the era of LC is not defined. Methods exist for the laparoscopic manipulation of the common bile duct; however, experience is limited. Until surgeons become comfortable with this more demanding technique, ERC and ES will have a prominent role in the perioperative management of CBDSs. METHODS: A preoperative group (n = 41) included all candidates for LC with historical, biochemical, or radiologic evidence of CBDSs. A postoperative LC group (n = 22) included patients with stones diagnosed by intraoperative cholangiogram (IOC) (n = 6) or with signs or symptoms of retained, but unproven, CBDSs (n = 16). RESULTS: Thirty-six (88%) of the preoperative attempts were successful. Stones were identified in 18 cases and ES and duct clearance were achieved in all 18. In the postoperative group, ERC was successful in 21 (95%) cases. Calculi were demonstrated in 5 of 6 patients with a positive IOC and 6 of 16 with clinically suspected retained stones. ES and duct clearance were achieved in all 11 patients with documented CBDSs. Overall, ERC was accomplished in 90% of cases. Stones were identified in 51% of cases and all stones were cleared by ES. Morbidity was confined to four cases of self-limited pancreatitis (6%). There were no deaths. CONCLUSIONS: The perioperative management of CBDSs is an appealing approach for patients anticipating the benefits of LC, at least until the laparoscopic manipulation of the common bile duct becomes a more widely accepted technique.

Laparoscopic management of acute cholecystitis.

The role of laparoscopic surgery in patients presenting with acute cholecystitis remains controversial. From September 1989 through August 1992, a total of 720 patients underwent cholecystectomy. Ninety-six were unplanned admissions with a clinical diagnosis of acute cholecystitis. Laparoscopic surgery was attempted in 83 patients. Thirteen individuals were not offered laparoscopy because of the surgeon's inexperience. Twenty-two (27%) patients required the laparoscopic procedure converted to an open laparotomy. The mean postoperative hospital stay for patients undergoing laparoscopic cholecystectomy was 3.3 days versus 6.8 days for the laparotomy group. There was no mortality and no bile duct or major vascular injuries in either group. The overall operative morbidity rate was 16.9%. Laparoscopic cholecystectomy appears to be a safe and beneficial option in selected patients with acute cholecystitis. A low threshold for conversion to laparotomy appeared to be an important factor in maintaining a low incidence of operative complications. Several modifications to the technique of laparoscopic cholecystectomy have evolved over the 3-year study period and are described.

Training for laparoscopic surgery.

Laparoscopic cholecystectomy has rapidly become the procedure of choice for most patients with symptomatic gallbladder disease. Laparoscopic surgery, however, has not been a required component of most general surgery training programs. The demonstrated efficacy of laparoscopic surgery dictates that this discipline be rapidly incorporated into residency programs. Laparoscopic cholecystectomy and other surgical endoscopic procedures have been an integral part of the training program at the University of Maryland since 1989. Currently, residents who are completing their training have performed on average 50 to 75 laparoscopic procedures as the primary surgeon and 25 to 30 as the first assistant. In addition to training future community and academic physicians, those surgeons currently in practice must receive appropriate instruction in laparoscopic surgery. Most practicing surgeons attend a 2- to 3-day intensive course offering both didactic and hands-on experience. Additional exposure to clinical cases is achieved by working with other surgeons with laparoscopic expertise. Full credentialing in laparoscopic cholecystectomy generally requires proctoring by a surgeon from the local community. Since 1990 faculty from the University of Maryland have been active in the local community serving as proctors to surgeons in 14 hospitals.

Laparoscopic general surgery: current status and future prospects.

The capability of performing major abdominal surgery while avoiding a large abdominal incision has clear benefits for patient care. Laparoscopic cholecystectomy can reduce hospital stays and the length of the recovery period, as well as decrease postoperative pain, diminish scarring, and provide significant cost savings.

Laparoscopic cholangiography. Results and indications.

One hundred sixty-five operative cholangiograms were attempted in 364 patients who underwent laparoscopic cholecystectomy (45%). Laparoscopic cholangiography was successful in 150 of 165 attempts (91%). Eighty-nine per cent of studies were normal (134/150) and 11% were abnormal (16/150). All 134 patients with normal cholangiograms remained asymptomatic (false-negative rate, 0%). False-positive studies occurred in 3 of 150 (2%) total cholangiograms and 3 of 12 (25%) abnormal cholangiograms consistent with choledocholithiasis. A total of 16 of 364 patients had proven common bile duct stones (4.4%). Eight of the sixteen stones were removed by preoperative endoscopic retrograde cholangiopancreatography/sphincterotomy. Five of sixteen stones were found at cholangiography, four of which were unsuspected (4/150, 2.6%). Retained common duct stones were found in 3 of 214 patients not undergoing cholangiography (1.4%). No complications or deaths occurred that were due to cholangiography. One biliary injury occurred (1/364, 0.3%), in a patient with aberrant anatomy who did not undergo cholangiography. Laparoscopic cholangiography is a safe technique with a success rate greater than 90%. Routine cholangiography is presently recommended for prevention of biliary injury, detection of stones in the cystic and common ducts, and for training purposes, especially during the learning phase of laparoscopic cholecystectomy.

Laparoscopic cholecystectomy. Experience with 375 consecutive patients.

Three hundred seventy-five consecutive patients underwent laparoscopic cholecystectomy from September 1989 to January 1991. Three hundred forty-one (91%) presented on an elective basis, and the remaining 34 patients (9%) were admitted for acute cholecystitis (24), gallstone pancreatitis (9), and cholangitis (1). Of the 375 patients, 20 were converted to laparotomy and cholecystectomy, for an overall success rate of 95% for patients undergoing laparoscopic cholecystectomy. Three hundred nineteen patients (90%) were discharged within 24 hours of surgery. Operative cholangiography was completed in 141 patients, showing choledocholithiasis in five (managed by postoperative endoscopic retrograde cholangiopancreatography [ERCP] in 4, common bile duct exploration [CBDE] in 1). Two retained stones (0.9%) were detected in 214 patients not undergoing cholangiography. Three patients (0.8%) were reoperated on because of perioperative complications. Overall morbidity for patients undergoing laparoscopic cholecystectomy was 3.5%. Major complications (0.6%) included a single common hepatic duct injury and a delayed cystic duct leak at 10 days. Minor complications occurred in 11 patients (2.9%). The single perioperative death (0.3%) was due to a myocardial infarction on postoperative day 3, after an otherwise uncomplicated laparoscopic procedure. Laparoscopic cholecystectomy appears to offer significant advantages to patient recovery, and these data suggest that it can be performed with an efficacy, morbidity rate, and mortality rate similar to those of open cholecystectomy.

Establishment of a laparoscopic cholecystectomy training program.

A recently developed alternative to traditional laparotomy and cholecystectomy is laparoscopic-guided cholecystectomy. This procedure has the advantages of reduced hospital stay, early return to work, diminished abdominal wall scarring, and less patient discomfort. The complex nature of this procedure and the current lack of extensive clinical experience preclude the traditional "hands-on" training normally practiced in surgical residency programs. At the University of Maryland, we have developed a program to instruct both surgeons and surgical residents in the techniques of laparoscopic surgery. Technical competence is achieved under the close supervision and guidance of an experienced laparoscopic surgeon. Training of residents in this procedure, therefore, is not very different than that for other general surgical procedures. Surgeons already in clinical practice, however, gain experience under somewhat different circumstances. Initial training involves didactic instruction through laparoscopic surgical atlases and educational videotapes. Further training uses a simulation device which enables the trainee to practice techniques of laparoscopic suturing, knot-tying, and clip application. Actual operative experience is acquired primarily in experimental animal preparations. Laparoscopic-guided removal of the gallbladder is performed in young swine (20-25 kg) under conditions that mimic those in the operating room. Further clinical experience can be acquired by assisting on several laparoscopic operations, usually involving diagnostic or pelvic procedures. Actual operative experience with laparoscopic cholecystectomy, of course, comprises the final phase of the educational program. The introduction of clinical laparoscopic training into general surgery residency programs should influence the widespread adoption of this new procedure.

Laparoscopic guided cholecystectomy.

Cholecystectomy remains the most effective form of therapy for patients with symptomatic cholelithiasis. An alternative method of gallbladder removal, laparoscopic guided cholecystectomy, was attempted in 100 patients. Five patients required conversion of the laparoscopic procedure to an open laparotomy for the following reasons: discovery of a pancreatic malignancy in one patient, extensive adhesions in one, presence of an aberrant accessory right hepatic duct in one, common hepatic duct injury in one, and avulsion of the cystic duct in one. Both ductal injuries occurred during the early phase of the clinical program. In those patients undergoing laparoscopic cholecystectomy, 93 were discharged within 24 hours of surgery and 94 returned to normal activity within 1 week. Laparoscopic guided cholecystectomy appears to offer a number of advantages in patient care as well as a significant reduction in health care expenses for gallbladder disease. Appropriate training in laparoscopic surgery is necessary in order to avoid operative complications.

Outpatient management of partial-thickness burns: Biobrane versus 1% silver sulfadiazine.

A randomized, prospective study comparing the use of Biobrane (group 1) with the use of 1% silver sulfadiazine (group 2) in treating 56 partial-thickness burn wounds was carried out in 52 outpatients with burns that comprised less than 10% of their total body surface area. The two groups were similar in age, gender, race, and extent of burn. Wounds of patients in group 1 (30) were compared with those of group 2 (26) for healing time, pain, compliance with scheduled visits, and costs. Infected and skin-grafted wounds were excluded from healing time analysis. Infection rates of the two groups were similar (three of 30 vs two of 26). One patient in each group underwent skin grafting. Healing times of group 1 wounds were significantly less than those of group 2 (10.6 +/- 0.8 vs 15.0 +/- 1.2 days, P less than .01). Using a pain scale of 1 to 5, Biobrane-treated patients averaged lower pain scores at 24 hours after the burn (1.6 +/- 0.8 vs 3.6 +/- 1.3 P less than .001) and used less pain medication. Compliance with scheduled outpatient visits was also improved in the Biobrane-treated group (88.6% vs 63.2% attendance, P less than .001). Idealized total treatment costs averaged $434 for patients in group 1 compared with $504 for patients in group 2. We conclude that when used on properly selected wounds, Biobrane therapy can significantly decrease pain and total healing time without increasing the cost of outpatient burn care. Improved patient compliance may be an added benefit.

Urinary interleukins in patients receiving intravesical Bacillus Calmette-Guerin therapy for superficial bladder cancer.

Intravesical administration of Bacillus Calmette-Guerin (BCG) causes a localized cell-mediated immune response. The intensity of this inflammatory response may be gauged by measuring the levels of both interleukin-2 (IL-2) and an inhibitor of interleukin-2 (IL-2-IN) activity in the urine during the hours after a BCG instillation. The levels of urinary IL-2 and IL-2-IN in the sixth week of BCG therapy predicted the subsequent clinical course in a group of 25 patients (P less than 0.01). Measurement of urinary IL-2 and IL-2-IN activity may be used to identify accurately those patients likely to develop a tumor recurrence, thereby sparing them the risk associated with inadequately treated bladder cancer. Since IL-2 and IL-2-IN are competitive with respect to biologic activity, and since relatively high urinary levels of either IL-2 or IL-2-IN activity correlated with a favorable clinical course, the authors conclude that the presence of bioactive IL-2 in urine is not required for the prevention of recurrent superficial bladder cancer.

The role of pre-resectional laser recanalization for obstructing carcinomas of the colon and rectum.

The Nd:YAG laser has proved its efficacy for recanalizing obstructing lesions throughout the gastrointestinal tract. In a preliminary report using the Nd:YAG laser as a pre-resectional treatment for functionally obstructing colorectal carcinoma we showed that this modality accomplished good decompression, allowing for formal bowel preparation, a definitive one-stage operation with no increased mortality or morbidity, and that the use of the Nd:YAG laser was significantly cost-effective. Our cumulative experience from 1985 to 1988 includes 11 patients; nine underwent pre-resection laser therapy followed by primary resection and anastomosis, and two underwent abdominoperineal resection. Tumors were located above the peritoneal reflection in nine patients and below in two patients. All patients had orthograde bowel preparation with Golytley the day after laser therapy and underwent definitive surgery. There were no wound or intra-abdominal infections or postoperative fatalities. These 11 laser-treated patients were compared with age-matched controls who had undergone earlier colonic diversion. No significant differences were noted for age, sex, tumor location or differentiation, stage, or overall survival. Comparisons between laser-treated patients and controls for the preoperative length of stay and total length of stay were significantly different (p = 0.002 and p = 0.001, respectively). When comparing laser-treated patients and controls, preoperative and total hospital costs were significantly different (p = 0.003 and p = 0.01). We have found that pre-resectional laser recanalization has allowed for primary resection and anastomosis in patients who have obstructing left colon and rectal carcinomas without compromising patient safety.

The effect of estrogen on low-density lipoprotein binding kinetics in aortic endothelial cells.

The inhibition of atherosclerosis by estrogen has been shown clinically and experimentally, but the mechanism by which this occurs is unknown. Previous studies have shown that estrogen enhances the uptake of low-density lipoprotein (LDL) by bovine aortic endothelial cells (BAEC) while not altering membrane binding at saturating levels of LDL. In this study the effect of estrogen on LDL binding kinetics has been investigated. Computer-assisted Scatchard analysis of binding data suggests a single-site binding model. Estrogen-treated BAEC showed a lower binding affinity (Ka = 2.47 +/- 0.74 E7 M-1) than control cells (1.95 +/- 0.21 E7 M-1) (p = 0.0012). Estrogen-treated cells, however, had a greater binding capacity (Bmax = 1.26 +/- 0.07 E-10M) than control cells (Bmax = 8.49 +/- 0.44 E-11M) (p = 0.0004). The latter was due primarily to a difference in LDL binding at higher concentrations of LDL (greater than 40 micrograms/ml). These findings are consistent with an estrogen-stimulated increase in low-affinity binding of LDL to BAEC, which may not be directly receptor mediated and which appears to enhance the uptake of LDL at higher lipoprotein concentrations. Such alterations in LDL uptake by endothelial cells could influence the formation of atherosclerotic plaque.

Urinary interleukin-2 inhibition in patients with cystitis.

An inhibitor of interleukin-2 activity (IL-2-IN) is present in the urine of most patients during the acute phase of untreated bacterial cystitis (UTI). We measured urinary IL-2-IN activity in 30 adults with uncomplicated UTIs and followed the patients for an additional 6 months. Urinary IL-2-IN activity ranged between 0 and 1.97 units/mg urine creatinine (U/mg u.c.). Relatively low levels of IL-2-IN (less than 0.5 U/mg u.c.) correlated with a prior history of recurrent UTIs (p less than 0.01), and also were predictive of a subsequent UTI during the 6 month follow-up, regardless of the prior medical history (p less than 0.01). Measurement of urinary IL-2-IN during the untreated phase of a UTI may prove helpful for directing antibiotic prophylaxis against subsequent UTIs.