Interventions for treating people with symptoms of bladder pain syndrome: a network meta-analysis.

BACKGROUND: Bladder pain syndrome (BPS), which includes the condition of interstitial cystitis, is a poorly understood clinical condition for which patients present with varying symptoms. Management of BPS is challenging for both patients and practitioners. At present, there is no universally accepted diagnosis and diverse causes have been proposed. This is reflected in wide-ranging treatment options, used alone or in combination, with limited evidence. A network meta-analysis (NMA) simultaneously comparing multiple treatments may help to determine the best treatment options for patients with BPS. OBJECTIVES: To conduct a network meta-analysis to assess the effects of interventions for treating people with symptoms of bladder pain syndrome (BPS). SEARCH METHODS: We searched the Cochrane Incontinence Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL, in the Cochrane Library), MEDLINE, MEDLINE In-Process, MEDLINE Epub Ahead of Print, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and handsearched journals and conference proceedings (searched 11 May 2018) and the reference lists of relevant articles. We conducted a further search on 5 June 2019, which yielded four small studies that were screened for eligibility but were not incorporated into the review. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs of interventions for treating adults with BPS. All types of interventions (including conservative, pharmacological and surgical) were eligible. DATA COLLECTION AND ANALYSIS: We assessed the risk of bias of included studies using Cochrane's 'Risk of bias' tool. Primary outcomes were the number of people cured or improved, pain, frequency and nocturia. For each outcome, random-effects NMA models were fitted using WinBUGS 1.4. We monitored median odds ratios (ORs) for binary outcomes and mean differences (MDs) for continuous outcomes with 95% credible intervals (Crls). We compared results of the NMA with direct evidence from pairwise meta-analysis of head-to-head trials. We used the CINeMA tool to assess the certainty of evidence for selected treatment categories. MAIN RESULTS: We included 81 RCTs involving 4674 people with a median of 38 participants (range 10 to 369) per RCT. Most trials compared treatment against control; few trials compared two active treatments. There were 65 different active treatments, and some comparisons were informed by direct evidence from only one trial. To simplify, treatments were grouped into 31 treatment categories by mode of action. Most studies were judged to have unclear or high risk of bias for most domains, particularly for selection and detection bias. Overall, the NMA suggested that six (proportion cured/improved), one (pain), one (frequency) and zero (nocturia) treatment categories were effective compared with control, but there was great uncertainty around estimates of effect. Due to the large number of intervention comparisons in this review, we focus on three interventions: antidepressants, pentosan polysulfate (PPS) and neuromuscular blockade. We selected these interventions on the basis that they are given 'strong recommendations' in the EAU Guidelines for management of BPS (EAU Guidelines 2019). We found very low-certainty evidence suggesting that antidepressants were associated with greater likelihood of cure or improvement compared with control (OR 5.91, 95% CrI 1.12 to 37.56), but it was uncertain whether they reduced pain (MD -1.27, 95% CrI -3.25 to 0.71; low-certainty evidence), daytime frequency (MD -2.41, 95% CrI -6.85 to 2.05; very low-certainty evidence) or nocturia (MD 0.01, 95% CrI -2.53 to 2.50; very low-certainty evidence). There was no evidence that PPS had improved cure/improvement rates (OR 0.14, 95% CrI 0.40 to 3.35; very low-certainty evidence) or reduced pain (MD 0.42, 95% CrI -1.04 to 1.91; low-certainty evidence), frequency (MD -0.37, 95% CrI -5.00 to 3.44; very low-certainty evidence) or nocturia (MD -1.20, 95% CrI -3.62 to 1.28; very low-certainty evidence). There was evidence that neuromuscular blockade resulted in greater cure or improvement (OR 5.80, 95% CrI 2.08 to 18.30) but no evidence that it improved pain (MD -0.33, 95% CrI -1.71 to 1.03), frequency (MD -0.91, 95% CrI -3.24, 1.29) or nocturia (MD -0.04, 95% CrI -1.35 to 1.27). The certainty of this evidence was always very low. AUTHORS' CONCLUSIONS: We are uncertain whether some treatments may be effective in treating patients with BPS because the certainty of evidence was generally low or very low. Data were available for a relatively large number of trials, but most had small sample sizes and effects of treatments often could not be estimated with precision. An NMA was successfully conducted, but limited numbers of small trials for each treatment category hampered our ability to fully exploit the advantages of this analysis. Larger, more focused trials are needed to improve the current evidence base.

Midurethral slings for treatment of stress urinary incontinence review.

PURPOSE: The midurethral sling (MUS) has largely been regarded as the "gold standard" in treatment of stress urinary incontinence (SUI). Recently the safety and use of the MUS has come under scrutiny following concerns about the use of mesh implants. The aim of this review was to detail the background to SUI which has led to the development of MUS, to highlight the issues surrounding the use of mesh under the current climate of mesh controversies and to provide an update on current evidence on the use of MUS. MATERIALS AND METHODS: We conducted a review of the literature looking at the efficacy and safety of MUS. RESULTS: MUS has good rates of subjective cure in the short and into the longer term. The overall rates of complications are low including those associated with the use of mesh implants. When compared to other continence procedures, MUS is equally effective in regard to cure but has lower rates of complications and more favorable operative outcomes. The use of mesh has been supported by major Urogynaecological Societies along with the reports from government driven enquiries into the use of mesh. CONCLUSIONS: Overall, MUS have been shown to be an effective and safe surgical treatment for management of stress urinary incontinence.

Is the microbiome influencing patient care in lower urinary tract dysfunction? Report from the ICI-RS 2017.

AIMS: This report sets out to consider the role of the microbiome within the bladder to provide clinicians with knowledge on this specific area of research and recommend potential topics for further studies. METHODS: This is a report from the Plenary 6: Is the microbiome influencing patient care in lower urinary tract dysfunction (LUTD)? RESULTS: There appear to be complex associations between microbial presence in the bladder and lower urinary tract symptoms. There appears to be a greater role of bacteria in the development of overactive bladder symptoms than previously thought with bacteria such as Gardnerella highlighted to be more prevalent in women with urgency urinary incontinence. Some species of Lactobacillus have also been found to play a protective role in both overactive bladder syndrome and bladder pain syndrome. CONCLUSIONS: The bladder is a reservoir for bacterial colonization and what was previously thought to be a sterile environment now seems to be a complex interaction of both multiple protective and pathogenic bacterial species than can give rise to lower urinary tract symptoms. While most clinicians use antibacterial agents as part of treatment regimens, and evidence does suggest a role of antibacterial therapies in treatment of LUTS, this remains a far from an ideal solution.

Mid-urethral sling operations for stress urinary incontinence in women.

BACKGROUND: Urinary incontinence is a very common and debilitating problem affecting about 50% of women at some point in their lives. Stress urinary incontinence (SUI) is a predominant cause in 30% to 80% of these women imposing significant health and economic burden on society and the women affected. Mid-urethral sling (MUS) operations are a recognised minimally invasive surgical treatment for SUI. MUS involves the passage of a small strip of tape through either the retropubic or obturator space, with entry or exit points at the lower abdomen or groin, respectively. This review does not include single-incision slings. OBJECTIVES: To assess the clinical effects of mid-urethral sling (MUS) operations for the treatment of SUI, urodynamic stress incontinence (USI) or mixed urinary incontinence (MUI) in women. SEARCH METHODS: We searched: Cochrane Incontinence Specialised Register (including: CENTRAL, MEDLINE, MEDLINE In-Process, ClinicalTrials.gov) (searched 26 June 2014); Embase Classic (January 1947 to Week 25 2014); WHO ICTRP (searched 30 June 2014); reference lists. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials amongst women with SUI, USI or MUI, in which both trial arms involve a MUS operation. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the methodological quality of potentially eligible studies and extracted data from included trials. MAIN RESULTS: We included 81 trials that evaluated 12,113 women. We assessed the quality of evidence for outcomes using the GRADE assessment tool; the quality of most outcomes was moderate, mainly due to risk of bias or imprecision.Fifty-five trials with data contributed by 8652 women compared the use of the transobturator route (TOR) and retropubic route (RPR). There is moderate quality evidence that in the short term (up to one year) the rate of subjective cure of TOR and RPR are similar (RR 0.98, 95% CI 0.96 to 1.00; 36 trials, 5514 women; moderate quality evidence) ranging from 62% to 98% in the TOR group, and from 71% to 97% in the RPR group. Short-term objective cure was similar in the TOR and RPR groups (RR 0.98, 95% CI 0.96 to 1.00; 40 trials, 6145 women). Fewer trials reported medium-term (one to five years) and longer-term (over five years) data, but subjective cure was similar between the groups (RR 0.97, 95% CI 0.87 to 1.09; 5 trials, 683 women; low quality evidence; and RR 0.95, 95% CI 0.80 to 1.12; 4 trials, 714 women; moderate quality evidence, respectively). In the long term, subjective cure rates ranged from 43% to 92% in the TOR group, and from 51% to 88% in the RPR group.MUS procedures performed using the RPR had higher morbidity when compared to TOR, though the overall rate of adverse events remained low. The rate of bladder perforation was lower after TOR (0.6% versus 4.5%; RR 0.13, 95% CI 0.08 to 0.20; 40 trials, 6372 women; moderate quality evidence). Major vascular/visceral injury, mean operating time, operative blood loss and length of hospital stay were lower with TOR.Postoperative voiding dysfunction was less frequent following TOR (RR 0.53, 95% CI 0.43 to 0.65; 37 trials, 6200 women; moderate quality evidence). Overall rates of groin pain were higher in the TOR group (6.4% versus 1.3%; RR 4.12, 95% CI 2.71 to 6.27; 18 trials, 3221 women; moderate quality evidence) whereas suprapubic pain was lower in the TOR group (0.8% versus 2.9%; RR 0.29, 95% CI 0.11 to 0.78); both being of short duration. The overall rate of vaginal tape erosion/exposure/extrusion was low in both groups: 24/1000 instances with TOR compared with 21/1000 for RPR (RR 1.13, 95% CI 0.78 to 1.65; 31 trials, 4743 women; moderate quality evidence). There were only limited data to inform the need for repeat incontinence surgery in the long term, but it was more likely in the TOR group than in the RPR group (RR 8.79, 95% CI 3.36 to 23.00; 4 trials, 695 women; low quality evidence).A retropubic bottom-to-top route was more effective than top-to-bottom route for subjective cure (RR 1.10, 95% CI 1.01 to 1.19; 3 trials, 477 women; moderate quality evidence). It incurred significantly less voiding dysfunction, and led to fewer bladder perforations and vaginal tape erosions.Short-and medium-term subjective cure rates between transobturator tapes passed using a medial-to-lateral as opposed to a lateral-to-medial approach were similar (RR 1.00, 95% CI 0.96 to 1.06; 6 trials, 759 women; moderate quality evidence, and RR 1.06, 95% CI 0.91 to 1.23; 2 trials, 235 women; moderate quality evidence). There was moderate quality evidence that voiding dysfunction was more frequent in the medial-to-lateral group (RR 1.74, 95% CI 1.06 to 2.88; 8 trials, 1121 women; moderate quality evidence), but vaginal perforation was less frequent in the medial-to-lateral route (RR 0.25, 95% CI 0.12 to 0.53; 3 trials, 541 women). Due to the very low quality of the evidence, it is unclear whether the lower rates of vaginal epithelial perforation affected vaginal tape erosion (RR 0.42, 95% CI 0.16 to 1.09; 7 trials, 1087 women; very low quality evidence). AUTHORS' CONCLUSIONS: Mid-urethral sling operations have been the most extensively researched surgical treatment for stress urinary incontinence (SUI) in women and have a good safety profile. Irrespective of the routes traversed, they are highly effective in the short and medium term, and accruing evidence demonstrates their effectiveness in the long term. This review illustrates their positive impact on improving the quality of life of women with SUI. However, a brief economic commentary (BEC) identified three studies suggesting that transobturator may be more cost-effective compared with retropubic. Fewer adverse events occur with employment of a transobturator approach with the exception of groin pain. When comparing transobturator techniques of a medial-to-lateral versus a lateral-to-medial insertion, there is no evidence to support the use of one approach over the other. However, a bottom-to-top route was more effective than top-to-bottom route for retropubic tapes.A salient point illustrated throughout this review is the need for reporting of longer-term outcome data from the numerous existing trials. This would substantially increase the evidence base and provide clarification regarding uncertainties about long-term effectiveness and adverse event profile.

Retropubic or transobturator mid-urethral slings for intrinsic sphincter deficiency-related stress urinary incontinence in women: a systematic review and meta-analysis.

INTRODUCTION AND HYPOTHESIS: Stress urinary incontinence is a common problem affecting 12-46% of women. A cohort of women have a more severe form of stress urinary incontinence usually due to intrinsic urethral sphincter deficiency that has traditionally resulted in lower success rates with standard treatment modalities. We aim to address the question of whether transobturator sling insertion is more effective than retropubic sling insertion in the treatment of intrinsic sphincter deficiency-related stress urinary incontinence in women. METHODS: We searched MEDLINE, CINAHL, CENTRAL, journals, and major conferences (up to 30 June 2014). All randomised controlled trials in women with stress urinary incontinence or mixed urinary incontinence with associated intrinsic sphincter deficiency who underwent a retropubic or transobturator mid-urethral sling operation were included in this meta-analysis. The Cochrane risk of bias tool and the GRADE system were used to assess the quality of evidence. RESULTS: Fifty-five randomised controlled trials compared transobturator and retropubic mid-urethral slings. Twelve trials included women with intrinsic sphincter deficiency, but only 8 trials (399 women) reported data specifically for this cohort. There was a statistically significant difference in short- and medium-term (≤5 years) subjective cure rates, with the number of women reporting a cure in the transobturator group at 150 out of 199 and the retropubic group at 171 out of 200. This gives a 12% relative risk reduction in achieving cure with the transobturator route (RR 0.88, 95% CI 0.80 to 0.96, I(2) = 0%, moderate quality evidence [GRADE]). Objective cure was reported by five trials of 324 women and showed no statistically significant difference between the two groups, with a rate of 110 out of 159 in the transobturator group and 126 out of 165 in the retropubic group (RR 0.90, 95% CI 0.79 to 1.03). Post-operative voiding dysfunction and de novo urgency or urgency urinary incontinence in the two treatment groups showed no significant difference. The need to undergo repeat incontinence surgery in the long term (≥5 years) was higher with the transobturator route (RR 14.4, 95% CI 1.95 to 106, 147 women). CONCLUSIONS: Mid-urethral slings are effective in treating women with intrinsic sphincter deficiency-associated stress urinary incontinence. The retropubic route resulted in higher subjective cure rates compared with transobturator routes. Both routes improved the overall quality of life.

Mid-urethral sling operations for stress urinary incontinence in women.

BACKGROUND: Urinary incontinence is a very common and debilitating problem affecting about 50% of women at some point in their lives. Stress urinary incontinence (SUI) is a contributory or predominant cause in 30% to 80% of these women. Mid-urethral sling (MUS) operations are a recognised minimally invasive surgical treatment for SUI. MUS involves the passage of a small strip of tape through either the retropubic or obturator space, with entry or exit points at the lower abdomen or groin, respectively. This review does not include single incision slings. OBJECTIVES: To assess the clinical effects of mid-urethral sling (MUS) operations for the treatment of stress urinary incontinence (SUI), urodynamic stress incontinence (USI) or mixed urinary incontinence (MUI) in women. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from CENTRAL, MEDLINE, MEDLINE in process, ClinicalTrials.gov and handsearching of journals and conference proceedings (searched 26 June 2014), Embase and Embase Classic (January 1947 to Week 25 2014), WHO ICTRP (searched on 30 June 2014) and the reference lists of relevant articles. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials amongst women with SUI, USI or MUI, in which both trial arms involve a MUS operation. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the methodological quality of potentially eligible studies and extracted data from the included trials. MAIN RESULTS: We included 81 trials that evaluated 12,113 women. We assessed the quality of evidence for outcomes using the GRADE assessment tool; the quality of most outcomes was moderate, mainly due to risk of bias or imprecision.Fifty-five trials with data contributed by 8652 women compared the use of the transobturator route (TOR) and retropubic route (RPR). There is moderate quality evidence that in the short term (up to one year) the rate of subjective cure of TOR and RPR are similar (RR 0.98, 95% CI 0.96 to 1.00; 36 trials, 5514 women; moderate quality evidence) ranging from 62% to 98% in the TOR group, and from 71% to 97% in the RPR group. Short-term objective cure was similar in the TOR and RPR groups (RR 0.98, 95% CI 0.96 to 1.00; 40 trials, 6145 women). Fewer trials reported medium-term (one to five years) and longer-term (over five years) data, but subjective cure was similar between the groups (RR 0.97, 95% CI 0.87 to 1.09; 5 trials, 683 women; low quality evidence; and RR 0.95, 95% CI 0.80 to 1.12; 4 trials, 714 women; moderate quality evidence, respectively). In the long term, subjective cure rates ranged from 43% to 92% in the TOR group, and from 51% to 88% in the RPR group.MUS procedures performed using the RPR had higher morbidity when compared to TOR, though the overall rate of adverse events remained low. The rate of bladder perforation was lower after TOR (0.6% versus 4.5%; RR 0.13, 95% CI 0.08 to 0.20; 40 trials, 6372 women; moderate quality evidence). Major vascular/visceral injury, mean operating time, operative blood loss and length of hospital stay were lower with TOR.Postoperative voiding dysfunction was less frequent following TOR (RR 0.53, 95% CI 0.43 to 0.65; 37 trials, 6200 women; moderate quality evidence). Overall rates of groin pain were higher in the TOR group (6.4% versus 1.3%; RR 4.12, 95% CI 2.71 to 6.27; 18 trials, 3221 women; moderate quality evidence) whereas suprapubic pain was lower in the TOR group (0.8% versus 2.9%; RR 0.29, 95% CI 0.11 to 0.78); both being of short duration. The overall rate of vaginal tape erosion/exposure/extrusion was low in both groups: 24/1000 instances with TOR compared with 21/1000 for RPR (RR 1.13, 95% CI 0.78 to 1.65; 31 trials, 4743 women; moderate quality evidence). There were only limited data to inform the need for repeat incontinence surgery in the long term, but it was more likely in the TOR group than in the RPR group (RR 8.79, 95% CI 3.36 to 23.00; 4 trials, 695 women; low quality evidence).A retropubic bottom-to-top route was more effective than top-to-bottom route for subjective cure (RR 1.10, 95% CI 1.01 to 1.19; 3 trials, 477 women; moderate quality evidence). It incurred significantly less voiding dysfunction, and led to fewer bladder perforations and vaginal tape erosions.Short-and medium-term subjective cure rates between transobturator tapes passed using a medial-to-lateral as opposed to a lateral-to-medial approach were similar (RR 1.00, 95% CI 0.96 to 1.06; 6 trials, 759 women; moderate quality evidence, and RR 1.06, 95% CI 0.91 to 1.23; 2 trials, 235 women; moderate quality evidence). There was moderate quality evidence that voiding dysfunction was more frequent in the medial-to-lateral group (RR 1.74, 95% CI 1.06 to 2.88; 8 trials, 1121 women; moderate quality evidence), but vaginal perforation was less frequent in the medial-to-lateral route (RR 0.25, 95% CI 0.12 to 0.53; 3 trials, 541 women). Due to the very low quality of the evidence, it is unclear whether the lower rates of vaginal epithelial perforation affected vaginal tape erosion (RR 0.42, 95% CI 0.16 to 1.09; 7 trials, 1087 women; very low quality evidence). AUTHORS' CONCLUSIONS: Mid-urethral sling operations have been the most extensively researched surgical treatment for stress urinary incontinence (SUI) in women and have a good safety profile. Irrespective of the routes traversed, they are highly effective in the short and medium term, and accruing evidence demonstrates their effectiveness in the long term. This review illustrates their positive impact on improving the quality of life of women with SUI. With the exception of groin pain, fewer adverse events occur with employment of a transobturator approach. When comparing transobturator techniques of a medial-to-lateral versus a lateral-to-medial insertion, there is no evidence to support the use of one approach over the other. However, a bottom-to-top route was more effective than top-to-bottom route for retropubic tapes.A salient point illustrated throughout this review is the need for reporting of longer-term outcome data from the numerous existing trials. This would substantially increase the evidence base and provide clarification regarding uncertainties about long-term effectiveness and adverse event profile.

Maternal congenital cardiac disease: outcomes of pregnancy in a single tertiary care center.

OBJECTIVE: To evaluate contemporary perinatal and cardiac outcomes of pregnancies in women with major structural congenital heart disease. METHODS: Obstetric, neonatal, and cardiac outcomes were abstracted retrospectively from medical records of all women with congenital cardiac disease delivering at our institution from 2000-2007 and compared by type of structural defect. Predictors of adverse cardiac or obstetric events were identified. RESULTS: Over the 7-year study period, 74 deliveries occurred in 69 women with congenital heart disease, median age 28 years. There were three right-obstructive defects, 14 left-obstructive defects, four right-regurgitant defects, 19 conotruncal defects, 19 shunts, and four miscellaneous lesions. There were 21 adverse cardiac events in 15 pregnancies (20.2%); these were defined as maternal death, congestive heart failure, myocardial infarction, stroke, the need for urgent cardiac intervention, or arrhythmia requiring treatment. There were 44 adverse obstetric events in 34 pregnancies (45.9%), defined as preterm delivery, stillbirth, preeclampsia, small for gestational age, or neonatal intensive care unit admission. Patients with shunt morphology were more likely to experience adverse obstetric and cardiac outcomes. CONCLUSION: Pregnancy in women with underlying major congenital heart defects poses increased risks to both mother and fetus. Nonetheless, favorable maternal and neonatal outcomes occur in the majority of patients.

Vaginal birth after cesarean delivery in twin gestations: a large, nationwide sample of deliveries.

OBJECTIVE: The purpose of this study was to assess the maternal morbidity associated with attempted vaginal birth after cesarean (VBAC) in twin gestations using a large, nationwide sample of deliveries. STUDY DESIGN: Data for this study were obtained from an administrative dataset, the Nationwide Inpatient Sample, a representative sample of discharges from non-Federal hospitals, for the years 1993 to 2002. Patients admitted nonemergently for the delivery of twin gestations who had a history of previous cesarean delivery were selected. Patients that either delivered vaginally or who had discharge codes that indicated labor before cesarean delivery were defined as the trial of labor group, while patients who had a cesarean delivery without discharge codes that indicated labor were defined as the elective cesarean group. Various complications of delivery were analyzed for each group. RESULTS: We identified 4705 women who underwent an elective cesarean delivery and 1850 women who underwent a trial of labor. For women who had a trial of labor, 836 (45.2%) delivered vaginally. The rate of uterine rupture was higher in the trial of labor group than in the elective cesarean group (0.9% vs 0.1%, P < .001), and the rate of wound complications was lower (0.6% vs 1.3%, P < .02). The rates of other complications including hysterectomy, transfusion, major postpartum infection, thromboembolism, uterine dehiscence, and pelvic hematoma were not significantly different between the 2 groups. CONCLUSION: Our study showed a significantly higher rate of uterine rupture in the trial of labor group that is similar to the rates reported for trial of labor after cesarean in singleton pregnancies.

Short-term and long-term survival of new neurons in the rat dentate gyrus.

New neurons continue to be generated in the dentate gyrus throughout adulthood. Previous studies have shown that a significant proportion of new granule cells labeled with the thymidine analogue bromodeoxyuridine (BrdU) are lost from the adult dentate gyrus within 2 weeks. How long this loss continues and the extent to which it represents cell death, as opposed to dilution of label, is unclear. To address these questions, adult rats were injected with BrdU, and BrdU labeling in the dentate gyrus was compared at several survival time points. Double labeling with BrdU and the cell cycle marker Ki-67 showed that BrdU is detectable for up to 4 days in some cells that continue to divide, indicating that any decrease in the number of BrdU-labeled cells after 4 days is likely to reflect cell death rather than BrdU dilution. Death of new cells in the granule cell layer occurred at a steady rate between 6 and 28 days after labeling, resulting in loss of 50% of BrdU-labeled cells over this 22-day period. New granule cells that survived this first month lived for at least 5 additional months. In contrast, 26% of the granule cells labeled with BrdU at the peak of dentate gyrus development on postnatal day (P) 6 died between 1 and 6 months after labeling. These findings suggest that granule cells born during adulthood that become integrated into circuits and survive to maturity are very stable and may permanently replace granule cells born during development.