Hemolytic Anemia Caused by Graft Kinking Following Ascending Aortic Replacement: Endovascular Treatment With a Palmaz XL Stent.

A 66-year-old man presented with hemolytic anemia, which required frequent blood transfusion, 6 months after surgical repair of an ascending aortic pseudoaneurysm. Hemolysis was attributed to luminal stenosis caused by graft kinking by laboratory test, CT and four-dimensional magnetic resonance imaging. First, an Excluder cuff was placed at the stenotic site under rapid pacing, but it migrated distally. Thereafter a Palmaz XL stent was placed at the stenotic site, which led to resolution of anemia. In this case, a Palmaz XL stent was successfully used to treat hemolytic anemia caused by graft kinking following ascending aortic surgery.

Impacts of an age-related hearing loss allele of cadherin 23 on severity of hearing loss in ICR and NOD/Shi mice.

The age-related hearing loss allele (Cdh23ahl) of the cadherin 23 gene leads to a more severe hearing loss phenotype through additive effects with risk alleles for hearing loss. In this study, we genome edited the Cdh23ahl allele to the wild-type Cdh23+ allele in outbred ICR mice and inbred NOD/Shi mice established from ICR mice and investigated their effects on hearing phenotypes. Several hearing tests confirmed that ICR mice developed early onset high-frequency hearing loss and exhibited individual differences in hearing loss onset times. Severe loss of cochlear hair cells was also detected in the high-frequency areas in ICR mice. These phenotypes were rescued by genome editing the Cdh23ahl allele to Cdh23+, suggesting that abnormal hearing phenotypes develop because of the interaction of the Cdh23ahl and risk alleles in the genetic background of ICR mice. NOD/Shi mice developed more severe hearing loss and hair cell degeneration than ICR mice. Hearing loss was detected at 1 month old. Hair cell loss, including degeneration of cell bodies and stereocilia, was observed in all regions of the cochlea in NOD/Shi mice. Although these phenotypes were partially rescued by genome editing to the Cdh23+ allele, the phenotypes associated with high-frequency hearing were mostly unrecovered in NOD/Shi mice. These results strongly suggest that the genetic background of NOD/Shi mice contain a potential risk allele for the acceleration of early onset high-frequency hearing loss.

Usefulness of 18F-FDG PET/computed tomography in differentiating between subacute and chronic aortic dissection: initial investigation.

OBJECTIVES: In the selection of thoracic endovascular repair for aortic dissection (AD), it is important to distinguish between the subacute and chronic phases, but there is no reliable way to distinguish between them in patients with unknown onset of AD. The purpose of this study was to assess the diagnostic performance of 2-[18F] fluoro-2-deoxy-d-glucose (18F-FDG)-PET/computed tomography (PET/CT) for discriminating subacute AD from chronic AD. METHODS: Thirteen patients with AD who were medically treated and followed up for 6 months were studied. 18F-FDG PET/CT images were obtained for each patient in the subacute phase (the first scan) and at 6 months (the second scan) after the onset. Target-to-background ratio (TBR) was measured as the maximum standardized uptake value (SUV) in the dissected aortic wall divided by blood pool SUV. RESULTS: TBR was significantly higher in the first scan (mean ± SD, 1.97 ± 0.32) than in the second scan (1.69 ± 0.29, P = 0.007). The area under the receiver operating characteristic curve of TBR for discriminating subacute AD from chronic AD was 0.76. With a threshold of 1.74, the TBR showed the sensitivity, specificity, and positive and negative predictive value of 85%, 69%, 73%, and 82%, respectively, for the discrimination of subacute AD from chronic AD. CONCLUSION: Metabolic assessment of dissected aortic wall by 18F-FDG PET/CT is useful in differentiating between subacute and chronic AD and can provide important information in determining the appropriate indication for treatment for patients with AD of unknown onset.

Utility of Psoas Muscle Area in Selecting Older Patients Feasible for Thoracic Endovascular Aortic Repair.

BACKGROUND: The impact of psoas muscle area on overall survival is unknown for older patients undergoing elective thoracic endovascular aortic repair. METHODS: We retrospectively reviewed 105 patients aged 75 years or more who underwent elective thoracic endovascular aortic repair for descending thoracic aortic aneurysm between January 2010 and December 2019. Psoas muscle area was measured at the L3 level with preoperative computed tomography and adjusted by height squared to derive psoas muscle mass index. The patients were stratified into two groups, sarcopenia and nonsarcopenia. sarcopenia was defined as a psoas muscle mass index less than 5.40 cm2/m2 for men and less than 3.56 cm2/m2 for women. The overall survival was compared with the age- and sex-matched general population using the one-sample log rank test. The propensity score adjusted Cox proportional hazards model was applied to determine the hazard ratio for all-cause mortality. RESULTS: Twenty-three patients died during the follow-up period (median, 3 years). Thirty-eight patients (36%) were classified as sarcopenia. The 5-year overall survival rate was 46% (95% confidence interval, 29% to 73%) for sarcopenia and 84% (95% confidence interval, 74% to 94%) for nonsarcopenia. The overall survival was significantly lower in the sarcopenia group than in its matched general population (P = .004), whereas no statistically significant difference in overall survival was found between the nonsarcopenia group and its matched general population (P = .417). Sarcopenia was an independent risk factor for all-cause mortality (adjusted hazard ratio 2.64; 95% confidence interval, 1.02 to 6.82; P = .045). CONCLUSIONS: Psoas muscle mass index may be a good predictor of mortality among older patients undergoing elective thoracic endovascular aortic repair for descending thoracic aortic aneurysm.

Therapeutic window for obtaining favorable remodeling after thoracic endovascular aortic repair of type B aortic dissection.

OBJECTIVE: The purpose of the present study was to determine the most appropriate timing for thoracic endovascular aortic repair (TEVAR) of type B aortic dissection (TBAD) in terms of remodeling of the aorta. METHODS: A total of 41 patients who had undergone TEVAR for the treatment of aortic dissection were included in the present study. The patients were divided into two groups: those who had undergone TEVAR in the acute or subacute phase (group A) and those who had undergone TEVAR in the chronic phase (group B). The indications for TEVAR as the treatment of TBAD were the presence of aortic rupture or malperfusion of the aortic branches, a maximum aortic diameter of ≥40 mm on the initial diagnostic computed tomography scan, and/or expansion of the aorta of ≥5 mm within 3 months for acute and subacute TBAD. The indication was a maximum aortic diameter of ≥50 mm or expansion of the aorta of ≥5 mm within 1 year for chronic TBAD. The diameters of the aorta, true lumen, and false lumen were measured at the level of the most dilated part of the descending aorta (level M) and at the diaphragm (level D) on the computed tomography scan obtained before TEVAR and at the 2-year follow-up examination. RESULTS: The median interval between TEVAR and the onset of TBAD was 0.2 month (interquartile range, 0.03-0.7 month) in group A (n = 21) and 32 months (interquartile range, 4.7-35.2 months) in group B (n = 20). Except for the aortic diameter at level D in group B, favorable remodeling was obtained at both levels in both groups. The diameter change ratio of the aorta at level D was significantly greater in group A than in group B (P = .02). Receiver operating characteristic curve analysis of the interval for a significant decrease in the aortic diameter at level D yielded 4.2 months as the optimal threshold for performing TEVAR (area under the curve, 0.859; 95% confidence interval, 0.7-1.0). CONCLUSIONS: TEVAR for TBAD will result in favorable outcomes, irrespective of the timing of the procedure. However, it might be more effective to perform TEVAR within 4.2 months of the onset of TBAD, provided that the TEVAR procedure can be performed safely.

Myosin VI Haploinsufficiency Reduced Hearing Ability in Mice.

In human, myosin VI (MYO6) haploinsufficiency causes postlingual progressive hearing loss. Because the usefulness of mouse models remains unclear, we produced novel Myo6 null (-/-) mutant mice and analyzed the hearing phenotypes of Myo6+/- (+/-) heterozygous mutants. We first recorded and compared the auditory brainstem responses and distortion product otoacoustic emissions in control Myo6+/+ (+/+) wild-type and +/- mice. These hearing phenotypes of +/- mice were mild; however, we confirmed that +/- mice developed progressive hearing loss. In particular, the hearing loss of female +/- mice progressed faster than that of male +/- mice. The stereocilia bundles of +/- mice exhibited progressive taper loss in cochlear inner hair cells (IHCs) and outer hair cells (OHCs). The loss of OHCs in +/- heterozygotes occurred at an earlier age than in +/+ mice. In particular, the OHCs at the basal area of the cochlea were decreased in +/- mice. IHC ribbon synapses from the area at the base of the cochlea were significantly reduced in +/- mice. Thus, our study indicated that MYO6 haploinsufficiency affected the detection of sounds in mice, and we suggest that +/- mice with Myo6 null alleles are useful animal models for gene therapy and drug treatment in patients with progressive hearing loss due to MYO6 haploinsufficiency.

Relevance of Aortic Dissection Chronicity to the Development of Stent Graft-induced New Entry.

BACKGROUND: The relevance of aortic dissection chronicity to the development of stent graft-induced new entry (SINE) is unknown. METHODS: This study enrolled 69 patients who underwent thoracic endovascular aortic repair (TEVAR) for chronic aortic dissection from January 2006 to December 2017 and were followed up for ≥6 months. Their medical records were reviewed retrospectively. Patients were stratified according to TEVAR timing into an early group (≤6 months from the onset of aortic dissection) and a late group (>6 months after the onset). The incidence of SINE as well as the interval between TEVAR and the development of SINE was compared between these groups. RESULTS: During the follow-up period, SINE occurred in 12% (3/26) and 35% (15/43) of patients in the early and late groups, respectively (P = .029). The interval between TEVAR and SINE development was significantly longer in the late group than the early group (median, 92 days vs 1144 days, respectively; P = .002). According to the multivariate analysis results, the late group (hazard ratio, 3.667; 95% confidence interval, 1.037-12.968; P = .044) and the distal oversizing ratio (hazard ratio, 1.492; 95% confidence interval, 1.071-2.080; P = .018) were the independent predictors for SINE development. CONCLUSIONS: TEVAR should be performed in the early period of the chronic phase to prevent SINE. Close and lifelong follow-up is mandatory for patients who undergo TEVAR >6 months after onset because SINE can develop several years after TEVAR in those patients.

Parallel Placement of Excluder Legs for the Treatment of a Type IIIb Endoleak Using AFX2.

Endoleak is a major complication of endovascular aneurysm repair (EVAR). Type IIIb endoleaks, which are caused by endograft fabric disruption, are relatively rare. Although relining of the previously placed endograft with another main endograft is considered an ideal approach, it is sometimes difficult. The efficacy of parallel placement of Excluder legs has been reported in various settings. Here, we report the successful treatment of a type IIIb endoleak with parallel placement of Excluder legs during EVAR by using an AFX2 device.

18F-FDG uptake as a predictive factor for progressive aortic enlargement in aortic dissection.

OBJECTIVE: Progressive aortic enlargement (PAE) is a critical adverse event in patients with medically treated aortic dissection (AD). However, no reliable predictor of the PAE has been established. The purpose of this study was to evaluate the value of 18F-FDG PET/CT for the prediction of PAE in patients with medically treated AD. METHODS: Sixteen patients with AD who underwent optimal medical therapy were enrolled. 18F-FDG PET/CT examinations were performed in subacute phase (2 weeks-3 months) after the onset of AD. Target-to-background ratio (TBR) was measured as the maximum standardized uptake value (SUV) in the dissected aortic wall divided by blood pool SUV. The relation between TBR and occurrence of PAE (> 10 mm/year) was evaluated. RESULTS: PAE was observed in four patients during the median follow-up period of 24 months. The TBR measured in the 4 patients showing PAE was significantly higher than that in the remaining 12 patients without PAE (2.44 ± 0.56 vs 1.87 ± 0.33, P = 0.025). The area under the receiver operating characteristic curve of TBR for predicting PAE was 0.82. With a threshold of 2.34, the TBR showed the sensitivity, specificity, and positive and negative predictive value of 75%, 92%, 75%, and 92%, respectively, for the prediction of PAE. CONCLUSIONS: Higher 18F-FDG uptake in the dissected aortic wall as determined by TBR is associated with increased risk of PAE in patients with medically treated AD. TBR shows good specificity and negative predictive value for predicting PAE.

Parallel Placement of Excluder Legs to Treat Abdominal Aortic Aneurysms with Aortoiliac Occlusive Lesion.

The effectiveness of endovascular aneurysm repair (EVAR) has been proven, but anatomical limitations, including narrow access route, may obstruct procedure of EVAR and cause serious complications. Parallel placement of Excluder legs (W. L. Gore & Associates, Inc., Newark, DE, USA) was established to treat patients with type IIIb endoleak or those with a narrow aorta, who could not be treated using a standard main body. In this report, we applied this technique in two patients with aortoiliac aneurysms with occlusive lesion.

Thoracic endovascular aortic repair for the treatment of ruptured acute type B aortic dissection.

PURPOSE: To evaluate the efficacy of thoracic endovascular aortic repair (TEVAR) for ruptured acute type B aortic dissection (r-ATBAD). MATERIALS AND METHODS: The study included 18 patients (15 men and 3 women) who underwent TEVAR for r-ATBAD in two institutions between 1997 and 2017. The mean patient age was 74 ± 10 years. The false lumen was patent in 13 patients (72%) and was mostly thrombosed in 5 patients (28%). Three patients had malperfusion of aortic branches. Eight patients (44%) were in circulatory shock. RESULTS: Eleven patients (61%) died during or following TEVAR during admission. The causes of death were aortic rupture (n = 6), sepsis (n = 2), cerebral hypoxia (n = 1), pneumonia (n = 1), and renal failure (n = 1). Statistical analysis showed that dissection extending to the infrarenal level was significantly related to death from aortic rupture (P = 0.013). Early adverse events were observed in 12 patients (67%). One patient died from a non-aorta-related cause (sepsis) after discharge. The overall survival rate at 1 year was 39%. After discharge, an aorta-related adverse event (intimal injury) was observed in one patient. The adverse event-free survival rate at 1 year was 17%. CONCLUSIONS: Our results indicate that TEVAR for r-ATBAD is associated with high mortality and morbidity. More advanced strategies may be required to improve the outcome.

Thoracic endovascular aortic repair for retrograde type A aortic dissection.

OBJECTIVE: The efficacy of thoracic endovascular aortic repair (TEVAR) for retrograde type A aortic dissection (r-TAAD) with the entry tear in the descending aorta has not been clarified. METHODS: The medical records of 31 patients who underwent TEVAR for r-TAAD at three institutions between May 1997 and January 2016 were retrospectively reviewed. RESULTS: The mean age of the patients (30 men and 1 woman) was 64 ± 11 years. The entry tear was located in the descending thoracic aorta in all patients. Seven patients (23%) had dissection-related complications. The false lumen of the ascending aorta was patent in 13 patients (42%) and thrombosed in 18 (58%). The maximum diameter of the ascending aorta was 45 ± 4 mm. TEVAR was performed in the acute phase in 24 patients (77%) and in the subacute phase in 7 (23%). Only one patient (3%) died of aortic rupture within 30 days after TEVAR. Early aorta-related adverse events were observed in eight patients (26%), of whom five underwent additional interventions. The mean follow-up period was 99 ± 69 months. There were no late aorta-related deaths, although five patients died of other causes during follow-up. Overall survival rates at 1 year, 5 years, and 10 years were 97%, 93%, and 80%, respectively. Late aorta-related adverse events were observed in seven patients (23%), of whom five underwent additional interventions. Aorta-related event-free survival rates at 1 year, 5 years, and 10 years were 58%, 58%, and 51%, respectively. CONCLUSIONS: TEVAR for r-TAAD seems promising in terms of survival. However, the incidence of postoperative aorta-related adverse events is not negligible, so careful selection of patients is important. In addition, close follow-up is mandatory after TEVAR to avoid catastrophic consequences.

Splenic Artery Aneurysm Treated With Endovascular Stent Grafting: A Case Report and Review of Literature.

INTRODUCTION:: Although endovascular therapy is becoming an alternative to open surgical repair of splenic artery aneurysms (SAAs), reports on the use of stent grafts for SAA repair are limited. We present our experience of endovascular therapy using a stent graft for the treatment of an SAA that had ruptured into the gastric lumen. We also reviewed 18 cases of stent graft repair for SAAs, including the present case. CASE REPORT:: A 43-year-old man was admitted due to hematemesis. Endoscopic examination and contrast-enhanced computed tomography (CT) revealed a dissecting SAA that had ruptured into the stomach. Two 10 × 100 mm Viabahn (W.L. Gore, Flagstaff, Arizona) stent grafts were used to exclude the aneurysm. No complications occurred during the procedure. Although postoperative CT showed complete exclusion of the aneurysm, endoscopic examination showed a discharge of purulent matter from the aneurysm. Therefore, surgical debridement and omental implantation were added to avoid stent graft infection. Follow-up CT obtained 1 year later showed the residual aneurysm almost disappeared without any evidence of infection. LITERATURE REVIEW:: A literature search in the PubMed database returned 17 cases with sufficient data. Review of these cases, together with the present case, revealed a 100% technical success rate, 11% splenic infarction rate, 94% graft patency rate, and 0% reintervention rate. CONCLUSION:: Endovascular repair of SAAs using stent grafts appears to be safe and effective. In terms of preserving the blood flow and avoiding splenic infarction, it may be superior to coil embolization. Even in a case with aneurysm infection, stent graft repair may be an acceptable method to minimize invasion of concomitant surgical intervention.

Treatment of Infected Aneurysm with Combined Endovascular Aneurysm Repair and Abscess Drainage.

PURPOSE: To evaluate the clinical utility of combination therapy with endovascular aneurysm repair (EVAR) and abscess drainage for the treatment of infected aneurysms. MATERIALS AND METHODS: Between July 2009 and May 2015, 8 patients underwent combination therapy with EVAR and abscess drainage. There were 5 men and 3 women, with a mean age of 75 years ± 7. Aneurysms were of the thoracic aorta in 5 patients, the abdominal aorta in 2, and the internal iliac artery in 1. Four patients had concurrent infection, including pyelonephritis in 2, pelvic abscess in 1, and suppurative knee arthritis in 1. Three patients had ruptured aneurysms. Abscess drainage was performed percutaneously under computed tomographic guidance in 5 patients, thoracoscopic guidance in 2, and both in 1. RESULTS: Six patients (75%) were discharged without additional intervention except for antibiotic therapy, and the other 2 patients (25%) underwent open repair to control infection and to repair endoleak, respectively. There were no in-hospital deaths. During the mean follow-up period of 48 months ± 22, all patients were alive except for 1 patient who died of recurrence of rectal cancer at 51 months. There were no aorta- or artery-related adverse events. Overall survival rates at 1 and 5 years were 100% and 80%, respectively. Aneurysm-related event-free rates at 1 and 5 years were 75%. CONCLUSIONS: Combination therapy with EVAR and abscess drainage for the treatment of infected aneurysms seems to be a promising strategy as an alternative or "bridge" to open surgery.

Ocular Hypotensive Effect of ONO-9054, an EP3/FP Receptor Agonist: Results of a Randomized, Placebo-controlled, Dose Escalation Study.

PURPOSE: To assess pharmacodynamic and safety profiles of ONO-9054 following single and multiple day dosing in subjects with ocular hypertension or open-angle glaucoma. MATERIALS AND METHODS: This was a phase I, single-center, randomized, double-masked, placebo-controlled dose-escalation study. Nine subjects were randomized to each of ONO-9054 3, 10, 20, 30 µg/mL and 12 to placebo. Subjects received a single drop to each eye at 07:00±30 minutes (single dose). Following a 4-day no-treatment period, subjects were dosed once daily for 14 consecutive days (multiple day dosing). Intraocular pressure (IOP) was measured regularly and compared with baseline measurements. Ocular examinations assessed safety and tolerability. RESULTS: Mean IOP decreased dose dependently. Following single dosing, IOP decreased from 22.9±4.0 to 15.9±2.3 mm Hg (ONO-9054, 30 µg/mL) at peak effect 9 hours postdose; the reduction in placebo-treated subjects was from 22.3±2.4 to 21.5±3.3 mm Hg. Following multiple day dosing, the greatest reduction in IOP occurred 1 hour postdose on day 18, from 23.3±0.6 to 15.1±2.4 mm Hg (ONO-9054, 10 µg/mL); the smallest reduction at this time was from 23.9±0.8 to 18.6±2.0 mm Hg (ONO-9054, 3 µg/mL). Pressures remained reduced on day 19, 25 hours after the last dose, when the lowest measurement was 15.8±2.1 mm Hg (ONO-9054, 10 µg/mL). Anterior uveitis and vitreous detachment were each reported in 2 subjects and considered moderate by the Investigator. Ocular hyperemia and tolerability symptoms were generally mild and transient. CONCLUSIONS: ONO-9054 was well-tolerated and elicited dose-dependent reductions in IOP, which were sustained for at least 24 hours following 2 weeks of consecutive daily dosing.

EP3/FP dual receptor agonist ONO-9054 administered morning or evening to patients with open-angle glaucoma or ocular hypertension: results of a randomised crossover study.

BACKGROUND/AIMS: The novel prostaglandin E (EP) 3 and prostaglandin F (FP) receptor agonist ONO-9054 is effective in lowering intraocular pressure (IOP) in patients with ocular hypertension and open-angle glaucoma when administered once daily. This study compares the effects of morning (AM) versus evening (PM) dosing of ONO-9054 on tolerability and IOP lowering. METHODS: This was a single-centre, randomised, double-masked, two-sequence, placebo-controlled crossover study in 12 subjects with bilateral primary open-angle glaucoma or ocular hypertension. Two 14-day crossover regimens were separated by a 2-week washout: ONO-9054 (1 drop to each eye) in the morning (07:00) and vehicle in the evening (19:00) and vice versa. IOP was measured multiple times during select days. Ocular examinations also evaluated safety and tolerability. RESULTS: Mild ocular hyperaemia, reported by six subjects with PM dosing, was the most frequent adverse event. Mild to moderate dryness was also slightly more frequent after PM dosing. Maximum IOP reduction from baseline occurred on day 2 with decreases from baseline of -7.4 mm Hg (-30.8%) for AM dosing and -9.1 mm Hg, (-38.0%) for PM dosing; after 14 days, mean reduction in IOP was -6.8 mm Hg (-28.6%) for AM dosing and -7.5 mm Hg (-31.0%) for PM dosing. CONCLUSIONS: PM dosing of ONO-0954 was associated with a slightly increased frequency of mild hyperaemia and mild to moderate dryness. Both dosing schedules provided sustained reduction in IOP. TRIAL REGISTRATION NUMBER: NCT01670266.

A Novel Dual Agonist of EP3 and FP Receptors for OAG and OHT: Safety, Pharmacokinetics, and Pharmacodynamics of ONO-9054 in Healthy Volunteers.

PURPOSE: The use of a dual prostaglandin E3 (EP3) and prostaglandin F (FP) receptor agonist is a novel approach for the reduction of intraocular pressure (IOP) in open angle glaucoma and ocular hypertension and, as such, ONO-9054 may have benefits over existing therapies. The objectives of this phase I study were to assess the safety, tolerability, systemic pharmacokinetics (PK), and pharmacodynamics (PD) profiles of ONO-9054 (Sepetoprost), the prodrug of ONO-AG-367, in healthy, normotensive adults. METHODS: In this randomized, double-masked, placebo-controlled, single-dose escalating study, 48 male and female healthy volunteers each received a single drop of ONO-9054 0.3, 1.0, 3.0, 10.0, 20.0, or 30.0 µg/mL, or matching placebo in each eye. Blood samples of PK were taken up to 24 hours post dose; ocular and systemic safety, tolerability, and PD assessments were conducted up to approximately 72 hours post dose, and on day 7 at the follow-up visit. RESULTS: We found ONO-9054 was safe and well tolerated and ONO-AG-367 exhibited dose-dependent systemic PK with rapid elimination. The effect of PD was assessed by reduction in IOP, with the maximum change from baseline in IOP in these normotensive individuals of -28.23% achieved at the 30.0 µg/mL dose at 9 hours post administration. CONCLUSIONS: A single dose of the novel EP3 and FP receptor agonist ONO-9054 was safe and well tolerated in healthy volunteers at doses between 0.3 and 30.0 µg/mL and resulted in a significant reduction in intraocular IOP with maximum reduction at 9 hours post dose. This supports further evaluation of ONO-9054 for the treatment of ocular hypertension and open angle glaucoma. (ClinicalTrials.gov number, NCT01508988.).

Population pharmacokinetics and exposure-response relationship of a muscarinic receptor antagonist, imidafenacin.

This study was designed to update the population pharmacokinetic model and investigate the exposure-response (efficacy and safety) and concentration-QT relationships for imidafenacin, a synthetic orally active muscarinic receptor antagonist. The population pharmacokinetic model was updated using data from 90 healthy subjects and 852 patients with an overactive bladder. Plasma concentration data from nine clinical studies were used, including new data from a long-term dose escalation study. The updated population pharmacokinetic model for imidafenacin adequately described the plasma concentration profile. The results were generally consistent with those obtained from the previous population pharmacokinetic analysis, indicating that no new covariates were found to influence the pharmacokinetics of imidafenacin. Exposure-response relationships in the long-term dose escalation study were investigated using a regression analysis with efficacy and safety endpoints as dependent variables. There was no clear relationship between exposure and any endpoint. The concentration-QT relationship was also evaluated to assess whether imidafenacin prolonged the concentration-dependent QT interval. There was no clear relationship between the plasma concentration of imidafenacin and QTc, indicating that concentration-dependent QTc interval prolongation was not observed.