Laparoscopic Versus Vaginal Uterosacral Ligament Suspension in Women With Pelvic Organ Prolapse: A Systematic Review and Meta-Analysis of the Literature.

OBJECTIVE: Uterosacral ligament suspension (USLS) is one of the most frequently used operations for the restoration of apical support in women with uterovaginal prolapse. However, existing studies are inconclusive as to whether and which surgical access route is superior. The aim of the present meta-analysis is tentatively to compare the efficiency and the postoperative complications of laparoscopic USLS (L-USLS) and vaginal USLS (V-USLS), highlighting that current evidence remains inconclusive regarding the superiority of either surgical access route. DATA SOURCES: We performed a systematic literature review of 5 major databases (Medline, Scopus, Google Scholar Cochrane Central Register of Controlled Trials and Clinicaltrials.gov) from inception till April 2023. METHODS OF STUDY SELECTION: No language restrictions were applied. All comparative studies that compared L-USLS and V-USLS for the management of women with uterovaginal prolapse were included. TABULATION, INTEGRATION, AND RESULTS: Data from 6 retrospective cohort studies on 856 patients were extracted and analyzed. The methodological quality of the included studies was assessed using the risk of bias in nonrandomized studies of interventions tool and ranged between moderate to serious. The pooled results suggest that L-USLS was associated with a potentially decreased incidence of ureteral compromise (odds ratio [OR], 0.19; 95% confidence interval [CI] 0.04-0.89; p = .04) and seemingly lower objective (OR 0.47; 95% CI 0.23-0.97; p = .04) and subjective recurrence rates (OR 0.46; 95% CI 0.23-0.92; p = .03). There were no significant differences between the rates of postoperative pain from USLS sutures, postoperative pelvic hematomas, the suture exposure/granulation tissue formation, and the prolapse recurrence retreatment among the 2 groups. CONCLUSION: The present meta-analysis indicates that L-USLS is possibly associated with significantly fewer ureteral compromise rates and decreased subjective and objective recurrences rates compared to V-USLS. Nevertheless, given the limitations in data quality and heterogeneity of the included studies, these findings should be interpreted with caution. Large-scale randomized studies are essential to more definitively determine the relative merits of the laparoscopic versus vaginal approach.

The Emerging Role on the Use of Platelet-Rich Plasma Products in the Management of Urogynaecological Disorders.

Background: The regenerative efficacy of platelet-derived products has been recently investigated in the treatment of pelvic floor disorders (PFDs). We aimed to synthesize the current evidence of platelet-rich plasma (PRP) products used in urogynaecological disorders including vaginal atrophy, pelvic organ prolapse (POP), urinary incontinence, vaginal fistulas and vaginal mesh exposure. Methods: A meticulous search of the currently available literature on the use of PRP for the management of PFDs was performed using 3 electronic databases. Results: PRP could be a feasible alternative modality for the management of vaginal atrophy with favourable outcomes in vaginal atrophy parameters and patients' satisfaction, especially when hormone therapy is contraindicated. In patients with POP, an increase in collagen concentration after PRP application was observed while the use of PRP resulted in improvement of stress urinary incontinence symptoms. A considerable proportion of vesicovaginal fistulas were treated after application of PRP-based injections. Conclusions: There is only limited evidence of the use of PRP for PFDs. Platelet-rich plasma appears to be a promising, easy to apply, cost-effective and feasible alternative therapeutic modality for the management of various urogynaecological disorders. Future randomized trials are needed to confirm the efficacy of PRP in the treatment of urogynaecological disorders.

Pelvic floor reconstructive surgery under local anesthesia: A systematic review and meta-analysis.

AIMS: The decision on the appropriate type of anesthesia for pelvic floor repair depends on a variety of factors including patients' age, performance status, comorbidities, cost-effectiveness and personal preferences. We aim to review the literature on urogynecological procedures performed under local anesthesia (LA). METHODS: A systematic search of four electronic databases was conducted for articles published up to May 2020. Studies reporting outcomes of women who underwent pelvic floor reconstructive surgery under LA with or without sedation, were considered eligible. RESULTS: Nineteen studies (14 noncomparative and 5 comparative), including 1626 cases of urogynecological procedures under LA were recruited. Meta-analysis revealed significantly lower mean pain scores in LA group compared to general-regional anesthesia one (GA/RA) at both 4-6 h and 8-18 h postoperatively (160 patients; mean difference [MD], -1.70; 95% confidence interval [CI]: -3.12, -0.28; p = 0.02 and 160 patients; MD, -0.72; 95% CI: -1.17, 0.27; p = 0.002, respectively). Pain scores at >24 h did not differ among the two groups (160 patients; MD, -0.28; 95% CI: -0.60-0.05; p = 0.10). Intra- and postoperatively morphine use was not different among patients who received LA and GA during prolapse surgery while nausea rates were significantly lower in LA group compared to RA group 8 h postoperatively. CONCLUSIONS: LA with or without sedation represents a safe and efficient alternative anesthetic technique for urogynecological procedures with improved pain scores in up to 18 h postoperatively especially in patients who underwent surgery for SUI. LA is feasible and could be offered to patients undergoing pelvic floor surgery allowing a prompt postoperative recovery.

Total laparoscopic multi-compartment native tissue repair of pelvic organ prolapse and stress urinary incontinence.

AIM OF THE VIDEO: In this video we present the surgical management of a 59-year-old woman with stress urinary incontinece (SUI) and pelvic organ prolapse (POP) who had a history of rheumatoid arthritis and endometrial hyperplasia with atypia. METHODS: A concomitant laparoscopic hysterectomy with bilateral oophorectomy and a multi-compartment laparoscopic native tissue repair of the POP, combined with a Burch urethropexy, was performed to restore pelvic floor defects and treat the underlying endometrial pathology. CONCLUSION: Total laparoscopic multi-compartment repair of POP and/or SUI using native tissue appears to be a viable alternative to both laparoscopic procedures using synthetic meshes and vaginal native tissue repairs. Although not a routine option for the majority of patients with POP and SUI, this procedure may be offered in selected cases, where native tissue repair of the pelvic floor is preferred.

Extending the limits of vaginal hysterectomy under local anesthesia and conscious sedation.

INTRODUCTION AND HYPOTHESIS: In this video we present the surgical management of a 58-year-old woman presenting with a large prolapsed myomatous uterus treated with vaginal hysterectomy (VH) and pelvic floor repair (PFR) (uterosacral ligament suspension and posterior colporraphy) under local anesthesia and conscious sedation. METHODS: The patient underwent VH and PFR by using an infiltration of a local anesthetic solution of lidocaine, ropivacaine and adrenaline in combination with intravenous (iv) conscious sedation. Debulking techniques, such as intramyometrial coring, uterine bisection, myomectomy and wedge resection, were used to facilitate VH. The final weight of the removed uterus was 870 g. RESULTS: This video demonstrates that performing a surgically challenging VH under local anesthesia is feasible. CONCLUSIONS: Vaginal uterine morcellation can be performed to debulk the enlarged uterus so that hysterectomy can be accomplished under local anesthesia. The use of local anesthesia may safely be offered as an alternative to patients undergoing a complex vaginal hysterectomy and reconstructive surgery.

Women living with a midurethral sling in their 80s: long-term outcomes.

INTRODUCTION AND HYPOTHESIS: Surgical outcomes of elderly women who have been treated using midurethral slings could be influenced by confounding factors, such as age-related comorbidities. Aim of this study is to assess elderly patients (>75 years) who underwent a transobturator sling procedure with a follow-up of at least 13 years. METHODS: This is a prospective follow-up observational study including elderly women of current age ≥ 75 years old who underwent TVT-O placement at least 13 years prior to the study period. Main outcome measures were the objective and subjective cure rates at the follow-up visit. Secondary outcome measures included: patient-reported success rate, de novo urgency symptoms rate, evaluation of other subjective parameters related to the lower urinary tract function, and assessment of the health-related quality of life. RESULTS: Seventy-two out of 85 women (84.7%) meeting the inclusion and exclusion criteria were assessed at the follow-up visit. The mean follow-up period was 13.7 years (SD = 0.8). The overall objective and subjective cure rates were 80.5% (58 out of 72) and 84.7% (61 out of 72) respectively, whereas 9.7% of the patients (7 out of 72) reported being subjectively improved. The patient-reported success rate was 91.7% (66 out of 72). De novo urgency rate was 23.7% (9 out of 38), whereas 26.5% of the patients (9 out of 34) reported aggravation of preexisting urgency. CONCLUSIONS: In women of advanced age, the TVT-O procedure is a highly effective and long-lasting treatment. The safety profile of the TVT-O was not influenced by geriatric conditions, whereas the long-term presence of a polypropylene sling did not appear to trigger the onset of medical disorders.

Radical excision of a complicated transobturator tape.

AIM OF THE VIDEO: In this video, we present the case of a late-detected sinus formation 4 years after a TOT placement. METHOD: A combined surgical approach (transvaginal and transcutaneous routes) performed by a urogynecologist and an orthopaedic surgeon was chosen to carry out a radical en bloc excision of the sinus tract with the right half of the tape. This combined approach has the advantage of completely removing the biofilm adhered to the surface of the tape and the surrounding tissues, thus making antibiotic therapy more effective. CONCLUSION: Surgical removal of these microbial commmunities is very important for the resolution of device-related infections. Severe infectious complications of transobturator slings should be managed by a tertiary multidisciplinary team to optimize patient care.

Vaginal hysterectomy with anterior and posterior repair for pelvic organ prolapse under local anesthesia: results of a pilot study.

INTRODUCTION AND HYPOTHESIS: Vaginal hysterectomy (VH) and pelvic floor repair (PFR) for the surgical management of pelvic organ prolapse (POP) are usually performed under regional anesthesia. The aim of this study is to evaluate the feasibility of performing VH and PFR under local anesthesia and to compare postoperative pain and patient recovery parameters with patients undergoing the same surgical procedure under regional anesthesia. METHODS: This was a single-center prospective cohort study of women with advanced POP. The standard care group consisted of 20 patients who underwent VH and PFR under a combined spinal-epidural (CSE) block, whereas the local anesthesia group consisted of 20 patients who underwent VH and PFR under local anesthesia and intravenous sedation. Primary outcomes included the intensity of postoperative pain and the percentage of patients with moderate/severe pain. Secondary outcomes included percentage of patients who used opioids, incidence of nausea/vomiting, level of sedation, and patient satisfaction rate. RESULTS: The median pain intensity at rest was significantly lower in the local anesthesia group at 2 h, 4 h, and 8 h postoperatively (median values: 0 vs 1.9, 0 vs 4.1, and 1 vs 2.7 respectively). The percentage of patients needing opioids was significantly lower for the local anesthesia group (35% vs 95%, p = 0.002). The proportion of patients presenting nausea and vomiting symptoms in the two groups was similar. CONCLUSIONS: Local anesthesia for patients undergoing VH and PFR has been shown to be a viable alternative to regional anesthesia, offering reduced postoperative pain and less opioid use for the first 8 h.

Misoprostol vs vasopressin as a single hemostatic agent in laparoscopic myomectomy: Comparable, or just better than nothing?

AIM: Laparoscopic myomectomy may be associated with considerable blood loss, especially in patients in whom no specific hemostatic measures are used. We conducted this retrospective comparative study to investigate whether misoprosol is an effective and safe alternative to vasopressin when used as single hemostatic agent in laparoscopic myomectomy. METHODS: Two hundred cases undergoing laparoscopic myomectomy (-ies), were included. Of these, 50 pre-treated with vaginal misoprostol 400mcg 1 h before surgery (group 1), were compared with two historic consecutive groups: 100 patients treated with intraoperative intra-myometrial injection of dilute vasopressin (20 IU/100 mL normal saline) (group 2), and 50 treated without use of any hemostatic agent (group3). RESULTS: Mean procedure length did not differ significantly between the three groups (127.9 vs 100.6 vs 130.8 min). Mean estimated blood loss (EBL) was 179.7 ± 200.0 mL in group 1, compared with 147.8 ± 171.8 mL in group 2 (P = 0.793) and 321.8 ± 246.0 mL in group 3, respectively (P < 0.001). EBL was lower in group 2 in most of the study's subgroups of patients stratified according to size and number of fibroids compared with group 1, with the exception of patients with ≥4 fibroids, and ≥7 cm in size. In these subgroups, misoprostol appeared more effective. Neither agent was associated with serious adverse events. CONCLUSION: Vaginal misoprostol can be effective in reducing blood loss during laparoscopic myomectomy. Although rates of EBL are, in general, higher compared with those obtained with vasopressin, they are significantly reduced compared with those observed when no hemostatic agent is used. In extended procedures, vaginal misoprostol, due to its prolonged uterotonic action, may be associated with reduced blood loss compared with vasopressin.

Severe pelvic organ prolapse. Is there a long-term cure?

INTRODUCTION AND HYPOTHESIS: Vaginally assisted laparoscopic sacrocolpopexy (VALS) is a combined vaginal and laparoscopic surgical approach that has been described for the treatment of women with a uterus who suffer from severe multicompartmental pelvic organ prolapse (POP). The aim of this study is to evaluate the long-term anatomical and functional outcomes and report the long-term mesh-related complications. METHODS: This was a single-center prospective study of women with advanced POP who underwent VALS with at least 3 years of follow-up. The primary outcome was "composite surgical success" defined as: (1) no descent of the vaginal apex (point C) more than one-third into the vaginal canal and no anterior or posterior vaginal wall beyond the hymen (Ba and Bp < 0) (anatomical success), (2) no vaginal bulge symptoms and (3) no re-treatment for prolapse recurrence. RESULTS: The median follow-up was 7 years (range 3-10 years) with a composite surgical success rate of 95.7% (90/94). Failures (4.3%) included one (1.1%) case of anatomical recurrence (Bp: +1), one woman (1.1%) reporting vaginal bulge symptoms and two women (2.1%) who underwent a posterior colporrhaphy 6 and 12 months after primary surgery (reoperation rate: 2.1%). Two of 94 patients (2.1%) had been treated for mesh extrusion of the vaginal cuff prior to the follow-up visit. CONCLUSIONS: The combined VALS technique can be considered a safe and effective procedure for the treatment of severe POP allowing a long-term anatomical restoration of all compartments with excellent functional outcomes.

Pre- and postoperative magnetic resonance imaging (MRI) findings in patients treated with laparoscopic sacrocolpopexy. Is it a safe procedure for all patients?

INTRODUCTION: Laparoscopic sacrocolpopexy (LSCP) is a reference operation for apical compartment prolapse repair. Aim of this study is to describe the early and midterm postoperative MRI findings of the lumbosacral region (LSR) in patients undergoing LSCP and to detect any imaging changes that the presence of the mesh may cause on patients with preexisting degenerative disease of the LSR. METHODS: Patients with POP-Q grade III and IV uterovaginal or vaginal vault prolapse who were considered eligible for LSCP were invited to participate. An MRI of the LSR was performed preoperatively and then 3 and 12 months postoperatively. Patients with vaginal vault prolapse underwent LSCP, while women with uterovaginal prolapse were treated with the vaginally assisted laparoscopic sacrocolpopexy (VALS). RESULTS: A total of 30 patients were included in the study; 18 (60%) underwent LSCP and 12 (40%) VALS. On preoperative MRIs, 83.3% (25/30) of patients had degenerative changes and 70% (21/30) reported having low back pain (LBP). Postoperative MRIs did not reveal any imaging changes compared to the preoperative MRI findings both for patients with or without preexisting degenerative abnormalities of the LSR. No significant changes in the LBP score were observed postoperatively. CONCLUSIONS: Any bone marrow or soft-tissue changes at MRIs of the LSR early after the insertion of a synthetic mesh, does not constitute an expected postoperative finding and should raise the suspicion of an ongoing inflammatory or infectious spinal process (spondylodiscitis). Additionally, LSCP seems to be a safe surgical approach for women with preexisting degenerative disease of the LSR.

Assessment of overactive bladder symptoms among women with successful pessary placement.

INTRODUCTION AND HYPOTHESIS: The causal association between pelvic organ prolapse (POP) and overactive bladder (OAB) symptoms is supported by several theories. The aim of this study is to assess any changes in OAB symptoms among women with POP and OAB after successful pessary placement. METHODS: During the study period, all women with symptomatic POP stage II or greater and OAB symptoms were offered the solution of either a ring or a Gellhorn pessary. All patients were asked to complete a 3-day micturition/incontinence diary. Objective evaluation endpoints at baseline and at 6 weeks included: change in the mean number of micturitions/24 h, change in the mean volume voided per micturition/24 h, and change in the number of urinary incontinence episodes. Subjective evaluation of the urgency, frequency, and nocturia symptoms was carried out using the score change of the questions 3, 5, and 2 of the International Consultation on Incontinence Questionnaire for Evaluating Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) respectively. RESULTS: Seventy-four women were included in the study. A statistically significant decrease (-28.3%; p < 0.001) of the mean number of micturitions/24 h with a significant increase (37%; p < 0.001) in the mean voided volume per micturition/24 h was observed. The total urine volume/24 h remained unchanged. The number of urinary incontinence episodes was significantly increased 6 weeks after pessary placement (p < 0.001). De novo stress urinary incontinence (SUI) was reported by 16.7% of the initially stress continent women. CONCLUSIONS: Women with coexisting POP and OAB symptoms may experience a significant improvement in micturition frequency and in urgency and frequency symptoms after successful pessary fitting.

Safety and efficacy of the cervical pessary combined with vaginal progesterone for the prevention of spontaneous preterm birth.

INTRODUCTION: The aim of this study was to evaluate the safety and efficacy of the combined treatment of cervical pessary and endovaginal progesterone for the prevention of spontaneous preterm birth (SPB) in women with a short cervical length (CL) between 20 and 24 weeks of gestation. MATERIALS AND METHODS: This is a prospective study of women with a singleton pregnancy and a sonographically detected mid-trimester CL ≤25 mm. The primary outcome measure was spontaneous delivery before 34 weeks (238 days) of gestation. RESULTS: The study sample consisted of 90 women with a mean CL of 14.2 mm (SD=6.5 mm). Of the women, 34.4% had at least one risk factor for SPB; 7.8% delivered preterm before 34 weeks of gestation, and 25.6%, before 37 weeks. Neonatal death occurred in two (2.2%) cases due to respiratory distress syndrome. Lower body mass index values, history of preterm delivery and number of second trimester miscarriages were independently associated with delivery before 34 weeks. CONCLUSION: The combination of vaginal progesterone and cervical pessary for the prevention of SPB in women with a short cervix is safe and well tolerated. This therapy was associated with pregnancy prolongation, reduced prematurity rate and a low rate of perinatal complications.

Vaginal hysterectomy for uterovaginal prolapse: what is the incidence of concurrent gynecological malignancy?

INTRODUCTION AND HYPOTHESIS: Vaginal hysterectomy (VH) is a commonly performed procedure for the operative treatment of uterovaginal prolapse (UVP). The reported incidence of unexpected gynecological cancer in cases of VH for UVP ranges between 0.3 and 0.8 %. Aim of the study is to assess the incidence of malignant and premalignant gynecological histopathological findings among women who underwent a VH for UVP and had a normal preoperative workup. METHODS: The histopathology reports of women who underwent VH for the treatment of UVP were retrospectively assessed. All women had a history of normal cervical smear tests and a normal preoperative transvaginal scan. Patients with a history of a premalignant or malignant gynecological pathological condition and women with abnormal uterine bleeding were excluded. RESULTS: Overall, 14 out of 333 women who underwent VH (4.2 %) were found to have abnormal histopathological findings of the uterus. Among them, there were 9 cases of endometrial hyperplasia of any type (2.7 %), 1 case of cervical cancer (0.3 %), 1 case of cervical intraepithelial neoplasia (CIN) III (0.3 %), and 3 cases of CINI (0.9 %). No cases of endometrial cancer were detected. Among women who underwent salpingo-oophorectomy (n = 86) three simple serous cysts (3.5 %) were found, with no cases of ovarian cancer. CONCLUSIONS: The incidence of unexpected premalignant or malignant gynecological pathological conditions among asymptomatic women who underwent VH, with a history of normal cervical smear tests and normal preoperative TVS, was low but not negligible. This information should be included in the preoperative counseling of women planning to undergo surgery for UVP.

Seven years of objective and subjective outcomes of transobturator (TVT-O) vaginal tape: why do tapes fail?

INTRODUCTION AND HYPOTHESIS: This study reports long-term outcomes of the transvaginal tension-free vaginal tape-obturator (TVT-O) procedure for treating stress urinary incontinence (SUI), including possible risk factors for failure. METHODS: This was a retrospective study of women who underwent TVT-O with or without concomitant prolapse surgery. Procedures were performed at a tertiary referral urogynecology unit. Participants presented with SUI and had urodynamic stress incontinence (USI). Women with a history of previous anti-incontinence procedures, radical pelvic surgery, and detrusor overactivity (DO) were excluded. Objective cure was defined as absence of urine leakage during a cough stress test (CST). Subjective outcome was based on the International Consultation on Incontinence Questionnaire for Evaluating Female Lower Urinary Tract Symptoms (ICIQ-FLUTS). Quality of life was assessed using the King's Health Questionnaire (KHQ). Univariate and multivariate analyses were used to identify risk factors for subjective failure. RESULTS: One hundred twenty-four consecutive women were assessed, with a median follow-up of 90.3 (range 80-103) months. Overall objective and subjective cure rates were 81.5 % (101/124) and 83.5 % (103/124), respectively. A significant improvement was observed in all KHQ domains. Concomitant vaginal hysterectomy [odds ratio (OR) = 2.98, 95 % confidence interval (CI) 1.10-8.05, p = 0.03] and increasing point C (OR = 1.17, 95 % CI 1.05-1.30, p = 0.006] were associated with a higher risk for subjective failure. De novo urgency rate was 7 %. CONCLUSIONS: The TVT-O procedure provides high objective and subjective long-term efficacy, a clinically meaningful improvement in patient quality of life, and an excellent safety profile. Concomitant vaginal hysterectomy and apical compartment prolapse were associated with a higher risk for objective and subjective failure.

Gynecologic oncology patients in the surgical high dependency unit: an analysis of indications.

PURPOSE: The establishment of high dependency units (HDUs) has been an undoubted advance in the management of patients undergoing major oncological procedures. The aim of this study was to examine the impact of various preoperative and perioperative patients' characteristics on the prolonged HDU stay. METHODS: We conducted a retrospective study including all gynecologic oncology patients who underwent surgical management and were admitted postoperatively to our hospitals' HDU from 2006 to 2010. RESULTS: A total of 1,014 patients were transferred to the HDU and divided into two groups according to the length of HDU stay. Group A consisted of 840 (82.8 %) patients who stayed in the HDU for ≤24 h and Group B included 174 (17.2 %) patients who remained in the HDU under close observation for >24 h. Older age was the only preoperative characteristic that remained significantly associated with HDU prolonged stay. In addition, three intraoperative factors such as use of invasive hemodynamic monitoring, bowel resection and estimated blood loss were proved to be independently associated with prolonged HDU stay. CONCLUSION: Certain characteristics could identify those patients who are more likely to benefit most from HDU admission.

Platelet-Rich Plasma for the Treatment of Stress Urinary Incontinence-A Randomized Trial.

IMPORTANCE: Urinary incontinence affects millions of women worldwide. OBJECTIVE: The aim of the current study was to evaluate the efficacy and safety of periurethral platelet-rich plasma (PRP) injections in women with stress urinary incontinence (SUI). STUDY DESIGN: This was a single-center, double-blind, randomized sham-controlled trial. Fifty participants with SUI and urodynamic stress incontinence were randomized in 2 equally sized groups. Women in the PRP group received 2 PRP injections at 3 levels of the urethra at 4- to 6-week intervals. Women in the sham group were injected with sodium chloride 0.9%. At baseline, participants underwent urodynamic studies and a 1-hour pad test and completed the International Consultation on Incontinence Questionnaire-Female Lower Urinary Tract Symptoms (ICIQ-FLUTS), the Patient Global Impression Scale of Improvement, and the King's Health Questionnaire. At follow-up visits (1, 3, and 6 months), women underwent the 1-hour pad test and completed the King's Health Questionnaire and the ICIQ-FLUTS. Primary outcome was the subjective evaluation as indicated by the response to question 11a of the ICIQ-FLUTS questionnaire. Secondary outcomes included scores of questionnaires and urine loss assessed on the 1-hour pad test. The level of discomfort during injections and any adverse events were also evaluated. RESULTS: During follow-up, the mean score of the 11a question decreased significantly in the PRP group compared with sham. Subjective cure was significantly higher in the PRP group (32% vs 4%, P < 0.001). A significant reduction of urine loss assessed on the 1-hour pad test was observed in the PRP group compared with the sham group at 6-month follow-up. No adverse events were observed. CONCLUSIONS: Periurethral PRP injections were superior to sham injections in improving SUI symptoms with an excellent safety profile.