Rare bird forecast: A combined approach using a long-term dataset of an Arctic seabird and a numerical weather prediction model.

Wildlife observation is a popular activity, and sightings of rare or difficult-to-find animals are often highly desired. However, predicting the sighting probabilities of these animals is a challenge for many observers, and it may only be possible by limited experts with intimate knowledge and skills. To tackle this difficulty, we developed user-friendly forecast systems of the daily observation probabilities of a rare Arctic seabird (Ross's Gull Rhodostethia rosea) in a coastal area in northern Japan. Using a dataset gathered during 16 successive winters, we applied a machine learning technique of self-organizing maps and explored how days with gull sightings were related to the meteorological pressure patterns over the Sea of Okhotsk (Method A). We also built a regression model that explains the relationship between gull sightings and local-scale environmental factors (Method B). We then applied these methods with the operational global numerical weather prediction model (a computer simulation application about the fluid dynamics of Earth's atmosphere) to forecast the daily observation probabilities of our target. Method A demonstrated a strong dependence of gull sightings on the 16 representative weather patterns and forecasted stepwise observation probabilities ranging from 0% to 85.7%. Method B also showed that the strength of the northerly wind and the advancement of the season explained gull sightings and forecasted continuous observation probabilities ranging from 0% to 95.5%. Applying these two methods with the operational global numerical weather prediction model successfully forecasted the varied observation probabilities of Ross's Gull from 1 to 5 days ahead from November to February. A 2-year follow-up observation also validated both forecast systems to be effective for successful observation, especially when both systems forecasted higher observation probabilities. The developed forecast systems would therefore allow cost-effective animal observation and may facilitate a better experience for a variety of wildlife observers.

Synthesis and Biological Evaluations of Novel Human Parathyroid Hormone 1 Receptor (hPTHR1) Agonists Bearing Bicyclic Aromatic Moiety.

We have previously shown that the small molecule hPTHR1 agonist PCO371 (1) orally and dose-dependently induces PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. Compound 2a, bearing a bicyclic aromatic ring, was identified as a novel hPTHR1 agonist during hit to lead modification. It showed moderate PTHR1 agonistic activity with an EC20 value of 15 µM, and its metabolic stability in human liver microsome (hLM) as well as its solubility in phosphate buffer (PPb) and Fasted state simulated intestinal fluid (FaSSIF) were found to be poor. As results of the initial derivatization of 2a, we identified the indole derivatives as another scaffold. In this article, we report on the structure-activity relationship (SAR), structure-metabolism relationship (SMR), and structure-solubility relationship (SSR) of bicyclic aromatic derivatives, and the in vivo efficacy of 2j.

Asymmetric epileptic spasms after corpus callosotomy in children with West syndrome may be a good indicator for unilateral epileptic focus and subsequent resective surgery.

OBJECTIVE: This retrospective study was designed to observe differences in ictal movements of epileptic spasm (ES) before and after corpus callosotomy (CC). We hypothesized that asymmetric expression of ES is more clarified after CC and would be a good indicator for the epileptic hemisphere. METHODS: We selected 16 patients with intractable ES in West syndrome who were seizure-free after CC and subsequent resection or disconnective surgery of the unilateral hemisphere. We retrospectively reviewed their behavioral ES recorded at video-electroencephalography monitoring before and after CC. Asymmetric neck flexion (NF) and involuntary muscular contraction of the upper and lower extremities (MCU and MCL, respectively) were primarily described correlating their laterality and the responsible hemisphere proved by surgical resection. RESULTS: Asymmetric NF, MCU, and MCL could be found both before and after CC. However, the percentage of those movements to the total number of ES increased after CC; asymmetric NF, 82.9% vs. 20.1%; unilaterally predominant MCU, 81% vs. 39.3%; and unilaterally predominant MCL, 77.6% vs. 29.9%. Regarding asymmetric NF, the direction in which the neck flexed or the head turned was significantly ipsilateral to the responsible hemisphere in 9 of 12 patients after CC (75%). The predominant side of MCU and MCL were significantly contralateral to the responsible hemisphere in 11 of 11 and 7 of 9 patients (100% and 77.8%, respectively). SIGNIFICANCE: Asymmetric NF, MCU, and MCL were clarified in patients with ES who were successfully treated with CC and subsequent surgery. Those changes in ictal behaviors after CC may indicate the lateralization of epileptic activity and encourage more curative surgical treatment.

The impact of the atrial wall thickness in normal/mild late-gadolinium enhancement areas on atrial fibrillation rotors in persistent atrial fibrillation patients.

Background: Some of atrial fibrillation (AF) drivers are found in normal/mild late-gadolinium enhancement (LGE) areas, as well as moderate ones. The atrial wall thickness (AWT) has been reported to be important as a possible AF substrate. However, the AWT and degree of LGEs as an AF substrate has not been fully validated in humans. Objective: The purpose of this study was to evaluate the impact of the AWT in normal/mild LGE areas on AF drivers. Methods: A total of 287 segments in 15 persistent AF patients were assessed. AF drivers were defined as non-passively activated areas (NPAs), where rotational activation was frequently observed, and were detected by the novel real-time phase mapping (ExTRa Mapping), mild LGE areas were defined as areas with a volume ratio of the enhancement voxel of 0% to <10%. The AWT was defined as the minimum distance from the manually determined endocardium to the epicardial border on the LGE-MRI. Results: NPAs were found in 20 (18.0%) of 131 normal/mild LGE areas where AWT was significantly thicker than that in the passively activated areas (PAs) (2.5 ± 0.3 vs. 2.2 ± 0.3 mm, p < .001). However, NPAs were found in 41 (26.3%) of 156 moderate LGE areas where AWT was thinner than that of PAs (2.1 ± 0.2 mm vs. 2.23 ± 0.3 mm, p = .02). An ROC curve analysis yielded an optimal cutoff value of 2.2 mm for predicting the presence of an NPA in normal/mild LGE areas. Conclusion: The location of AF drivers in normal/mild LGE areas might be more accurately identified by evaluating AWT.

Two High-Precision Proximity Capacitance CMOS Image Sensors with Large Format and High Resolution.

This paper presents newly developed two high-precision CMOS proximity capacitance image sensors: Chip A with 12 µm pitch pixels with a large detection area of 1.68 cm2; Chip B with 2.8 µm pitch 1.8 M pixels for a higher resolution. Both fabricated chips achieved a capacitance detection precision of less than 100 zF (10-19 F) at an input voltage of 20 V and less than 10 zF (10-20 F) at 300 V due to the noise cancelling technique. Furthermore, by using multiple input pulse amplitudes, a capacitance detection dynamic range of up to 123 dB was achieved. The spatial resolution improvement was confirmed by the experimentally obtained modulation transfer function for Chip B with various line and space pattens. The examples of capacitance imaging using the fabricated chips were also demonstrated.

Diversity and determinants of the sigmoid septum and its impact on morphology of the outflow tract as revealed using cardiac computed tomography.

BACKGROUND: The sigmoid septum has been generally evaluated subjectively and qualitatively, without detailed examination of its diversity, impact on the morphology of the left ventricular outflow tract (LVOT), and anatomical background. METHODS: We enrolled 100 patients without any background cardiac diseases (67.5 ± 12.8 years old; 43% women) who underwent cardiac computed tomography. Basal septal morphology was evaluated using antero-superior and medial bulging angles (bidirectional angulation of the basal septum relative to the LVOT). The eccentricity index of the LVOT, area narrowing ratio (LVOT/virtual basal ring area), aortic-to-left ventricular axial angle (angulation of the aortic root relative to the left ventricle), and wedged height (non-coronary aortic sinus to inferior epicardium distance) were also quantified. RESULTS: The antero-superior bulging, medial bulging, aortic-to-left ventricular axial angles, LVOT eccentricity index, area narrowing ratio, and wedged height were 76° ± 17°, 166° ± 27°, 127° ± 9°, 1.8 ± 0.5, 1.0 ± 0.2, and 41.2 ± 9.1 mm, respectively. Both bulging angles were correlated with each other and contributed to the narrowing and deformation of the LVOT. Angulated aortic root was not correlated with either bidirectional septal bulge or LVOT narrowing. Clockwise rotation of the aortic root rotation was an independent predictor of prominent antero-superior septal bulge. Deeper aortic wedging was a common independent predictor of bidirectional septal bulge. CONCLUSIONS: The extent of septal bulge varies in normal hearts. Along with deep aortic wedging, the bidirectional bulge of the basal septum deforms and narrows the LVOT without affecting the virtual basal ring morphology.

The impact of computed tomography-derived aortic atheroma volume on prognosis after transcatheter aortic valve replacement.

BACKGROUND: The impact of the extent of aortic atheroma on patients' prognosis after transcatheter aortic valve replacement (TAVR) has not been completely evaluated. This study aimed to evaluate the prognostic value of the aortic atheroma volume (AAV) derived from computed tomography, and the effect of its differences among the segments of the aorta, in patients undergoing TAVR. METHODS: In total, 143 patients with symptomatic severe aortic stenosis who underwent pre-procedural computed tomography before TAVR procedure indication were evaluated. AAV was calculated by measuring the aortic lumen and vessel volume using every 1-mm axial image and was further divided into thoracic (TAAV) and abdominal segments (AbAAV). RESULTS: During a median follow-up of 651 days, 24 all-cause and 14 cardiac deaths occurred. In the Kaplan-Meier analysis, the high AAV group had significantly higher all-cause and cardiac mortalities than the low AAV group (p = 0.016 and 0.023, respectively). Regarding segmental AAV, all-cause and cardiac mortalities did not have significant differences between the high and low TAAV groups. Moreover, all-cause and cardiac mortalities were significantly higher in the high AbAAV group than in the low AbAAV group (p = 0.0043 and 0.023, respectively). The multivariable analysis showed that only AbAAV was an independent predictor for all-cause mortality (hazard ratio: 1.06, p = 0.046). CONCLUSION: AAV was significantly associated with the mortality after TAVR. The current study suggests the pre-procedural assessment of AAV is valuable in predicting prognosis after TAVR. However, further investigation with a larger sample size is needed to validate our findings.

Varied Extent of Mitral Annular Disjunction Among Cases With Different Phenotypes of Mitral Valve Prolapse.

Detailed 3-dimensional analysis of mitral annular disjunction was undertaken in 3 comparative cases of mitral valve prolapse. A case of Barlow disease showed extensive disjunction, whereas cases of fibroelastic deficiency and forme fruste demonstrated less extensive disjunction. Considering the current controversies surrounding disjunction, these observations call for detailed research in the future. (Level of Difficulty: Advanced.).

Prognostic Impact of Myocardial Extracellular Volume Fraction Assessment Using Dual-Energy Computed Tomography in Patients Treated With Aortic Valve Replacement for Severe Aortic Stenosis.

Background Myocardial extracellular volume fraction (ECV), measured by cardiac magnetic resonance imaging, is a useful prognostic marker for patients who have undergone aortic valve replacement (AVR) for aortic stenosis. However, the prognostic significance of ECV measurements based on computed tomography (CT) is unclear. This study evaluated the association between ECV measured with dual-energy CT and clinical outcomes in patients with aortic stenosis who underwent transcatheter or surgical AVR. Methods and Results We retrospectively enrolled 95 consecutive patients (age, 84.0±5.0 years; 75% women) with severe aortic stenosis who underwent preprocedural CT for transcatheter AVR planning. ECV was measured using iodine density images obtained by delayed enhancement dual-energy CT. The primary end point was a composite outcome of all-cause death and hospitalization for heart failure after AVR. The mean ECV measured with CT was 28.1±3.8%. During a median follow-up of 2.6 years, 22 composite outcomes were observed, including 15 all-cause deaths and 11 hospitalizations for heart failure. In Kaplan-Meier analysis, the high ECV group (≥27.8% [median value]) had significantly higher rates of composite outcomes than the low ECV group (<27.8%) (log-rank test, P=0.012). ECV was the only independent predictor of adverse outcomes on multivariable Cox regression analysis (hazards ratio, 1.25; 95% CI, 1.10‒1.41; P<0.001). Conclusions Myocardial ECV measured with dual-energy CT in patients who underwent aortic valve intervention was an independent predictor of adverse outcomes after AVR.

Physiological skin FDG uptake: A quantitative and regional distribution assessment using PET/MRI.

PURPOSE: To retrospectively assess the repeatability of physiological F-18 labeled fluorodeoxyglucose (FDG) uptake in the skin on positron emission tomography/magnetic resonance imaging (PET/MRI) and explore its regional distribution and relationship with sex and age. METHODS: Out of 562 examinations with normal FDG distribution on whole-body PET/MRI, 74 repeated examinations were evaluated to assess the repeatability and regional distribution of physiological skin uptake. Furthermore, 224 examinations were evaluated to compare differences in the uptake due to sex and age. Skin segmentation on PET was performed as body-surface contouring on an MR-based attenuation correction map using an off-line reconstruction software. Bland-Altman plots were created for the repeatability assessment. Kruskal-Wallis test was performed to compare the maximum standardized uptake value (SUVmax) with regional distribution, age, and sex. RESULTS: The limits of agreement for the difference in SUVmean and SUVmax of the skin were less than 30%. The highest SUVmax was observed in the face (3.09±1.04), followed by the scalp (2.07±0.53). The SUVmax in the face of boys aged 0-9 years and 10-20 years (1.33±0.64 and 2.05±1.00, respectively) and girls aged 0-9 years (0.98±0.38) was significantly lower than that of men aged ≥20 years and girls aged ≥10 years (p<0.001). In women, the SUVmax of the face (2.31±0.71) of ≥70-year-olds was significantly lower than that of 30-39-year-olds (3.83±0.82) (p<0.05). CONCLUSION: PET/MRI enabled the quantitative analysis of skin FDG uptake with repeatability. The degree of physiological FDG uptake in the skin was the highest in the face and varied between sexes. Although attention to differences in body habitus between age groups is needed, skin FDG uptake also depended on age.

Visualization of intensive atrial inflammation and fibrosis after cryoballoon ablation: PET/MRI and LGE-MRI analysis.

BACKGROUND: Atrial inflammation plays an important role in initiating atrial fibrosis, which could perpetuate atrial fibrillation (AF). However, the method of visualization of atrial inflammation has not been established. We sought to investigate whether the intensive atrial inflammation caused by cryoballoon ablation (CBA) could be detected by positron emission tomography/ magnetic resonance imaging (PET/MRI) and whether the atrial inflammation could be associated with consequent fibrosis. METHODS: A total of 10 paroxysmal atrial fibrillation patients after CBA were enrolled. To detect and quantify intensive atrial inflammation, PET/MRI was performed to assess regional 18F-fluorodeoxyglucose (18F-FDG) uptake one day after the CBA, and the standardized uptake values (SUV) max were compared between the pulmonary vein (PV) antrum where CBA could be applied and the healthy left atrial (LA) wall where CBA could not be applied. Furthermore, the atrial inflammation one day after the procedure and atrial fibrosis areas one month after the procedure were three-dimensionally quantified by PET/MRI and late-gadolinium enhancement magnetic resonance imaging (LGE-MRI), respectively. RESULTS: The mean SUV max at the PV antrum was significantly higher than that on the healthy LA wall (2.12 ± 0.35 vs 1.73 ± 0.30, P = .00021). The volume of the atrial inflammation strongly correlated with that of the atrial fibrosis (r = .94 [.76-.99], P = .00006). CONCLUSIONS: The atrial inflammation after CBA could be detected by PET/MRI. CBA-induced atrial inflammation was strongly associated with consequent lesion maturation.

Prevalence and extent of mitral annular disjunction in structurally normal hearts: comprehensive 3D analysis using cardiac computed tomography.

AIMS: Mitral annular disjunction is fibrous separation between the attachment of the posterior mitral leaflet and the basal left ventricular myocardium initially described in dissected hearts. Currently, it is commonly evaluated by echocardiography, and potential relationships with mitral valve prolapse and ventricular arrhythmia have been suggested. However, controversy remains as its prevalence and extent have not been fully elucidated in normal living subjects. METHODS AND RESULTS: Systolic datasets of cardiac computed tomography obtained from 98 patients (mean age, 69.1 ± 12.6 years; 81% men) with structurally normal hearts were assessed retrospectively. Circumferential extent of both mitral leaflets and disjunction was determined by rotating orthogonal multiplanar reconstruction images around the central axis of the mitral valvar orifice. Distribution angle within the circumference of the mitral valvar attachment and maximal height of disjunction were quantified. In total, 96.0% of patients demonstrated disjunction. Average distribution angles of the anterior and posterior mitral leaflets were 91.3 ± 9.4° and 269.8 ± 9.7°, respectively. Average distribution angle of the disjunction was 105.1 ± 49.2°, corresponding to 39.0 ± 18.2% of the entire posterior mitral valvar attachment. Median value of the maximal height of disjunction was 3.0 (1.5-7.0) mm. Distribution prevalence map of the disjunction revealed characteristic double peaks, with frequent sites of the disjunction located at the anterior to antero-lateral and inferior to infero-septal regions. CONCLUSION: Mitral annular disjunction is a rather common finding in the normal adult heart with bimodal distribution predominantly observed involving the P1 and P3 scallops of the posterior mitral leaflet.

Circulating intermediate monocytes and atrial structural remodeling associated with atrial fibrillation recurrence after catheter ablation.

BACKGROUND: Inflammation, such as that associated with intermediate CD14++ CD16+ monocytes and atrial structural remodeling (SRM), may be important in the recurrence of atrial fibrillation (AF) after catheter ablation. However, the relationship between the intermediate CD14++ CD16+ monocytes, SRM, and AF recurrence is unclear. METHODS: Twenty-four patients with AF were enrolled. The proportion of intermediate monocytes (PIM) was assessed before ablation by flow cytometry. As a surrogate marker of SRM, the volume ratio (VR) of signal intensity greater than 1 standard deviation on late-gadolinium enhancement magnetic resonance imaging (LGE-MRI) was calculated. We investigated whether PIM correlated with SRM on LGE-MRI and determined the optimal cutoff value for predicting AF recurrence. RESULTS: Univariate analysis revealed positive correlations between PIM and BNP with SRM (PIM: r = .593, p = .002; BNP: r = .567, p = .004). Multivariable analysis revealed that PIM was independently associated with VR on LGE-MRI (ß = .522; p = .033). The finding of an area under the receiver operating characteristic curve of 0.750 revealed that a VR ≥ 13.3% on LGE-MRI as the optimal cutoff value to predict AF recurrence with 80% sensitivity and 71% specificity, which was associated with PIM ≥ 10.0%. CONCLUSION: Intermediate monocytes were significantly positively correlated with SRM. PIM ≥ 10% was associated with a VR ≥ 13.3% on LGE-MRI, which predicted AF recurrence after catheter ablation.

Feasibility of catheter ablation in patients with persistent atrial fibrillation guided by fragmented late-gadolinium enhancement areas.

BACKGROUND: A computer simulation model has demonstrated that atrial fibrillation (AF) driver can be attached to heterogeneous fibrosis assessed by late gadolinium enhancement magnetic resonance imaging (LGE-MRI). However, it has not been well elucidated in patients with persistent AF. The aim of this study was to investigate whether radiofrequency (RF) applications in the fragmented LGE area (FLA) could terminate AF or convert it to atrial tachycardia (AT) and improve the rhythm outcome. METHODS: A total of 31 consecutive persistent AF patients with FLAs were enrolled (FLA ablation group, mean age: 69 ± 8 years, mean left atrial diameter: 42 ± 6 mm). A favorable response was defined as direct AF termination or AT conversion during RF applications at the FLA. The rhythm outcome was compared between the FLA ablation group and FLA burden-matched pulmonary vein isolation (PVI) group. RESULTS: Favorable responses were found in 15 (48%) of 31 patients in the FLA group (AF termination in seven, AT conversion in eight patients), but not in the PVI group. AF recurrence at 12 months follow-up was significantly less in the FLA ablation group than in the PVI group (4 [13%] vs. 12 [39%] of 31 patients, log-rank p = .023). In patients with a favorable response, AT recurred in 1 (7%) of 15 patients, but AF did not. CONCLUSIONS: FLA ablation could terminate AF or convert it to AT in half of the patients. No AF recurrence was documented in patients with a favorable response.

Late-gadolinium enhancement properties associated with atrial fibrillation rotors in patients with persistent atrial fibrillation.

BACKGROUND: A computational model demonstrated that atrial fibrillation (AF) rotors could be distributed in patchy late-gadolinium enhancement (LGE) areas and play an important role in AF drivers. However, this was not validated in humans. OBJECTIVE: The purpose of this study was to evaluate the LGE properties of AF rotors in patients with persistent AF. METHODS: A total of 287 segments in 15 patients with persistent AF (long-standing persistent AF in 9 patients) that underwent AF ablation were assessed. Non-passively activated areas (NPAs), where rotational activation (AF rotor) was frequently observed, were detected by the novel real-time phase mapping (ExTRa Mapping). The properties of the LGE areas were assessed using the LGE heterogeneity and the density which was evaluated by the entropy (LGE-entropy) and the volume ratio of the enhancement voxel (LGE-volume ratio), respectively. RESULTS: NPAs were found in 61 (21%) of 287 segments and were mostly found around the pulmonary vein antrum. A receiver operating characteristic curve analysis yielded an optimal cutoff value of 5.7% and 10% for the LGE-entropy and LGE-volume ratio, respectively. The incidence of NPAs was significantly higher at segments with an LGE-entropy of >5.7 and LGE-volume ratio of >10% than at the other segments (38 [30%] of 126 vs. 23 [14%] of 161 segments; p = .001). No NPAs were found at segments with an LGE-volume ratio of >50% regardless of the LGE-entropy. Of five patients with AF recurrence, NPAs outside the PV antrum were not ablated in three patients and the remaining NPAs were ablated, but their LGE-entropy and LGE-volume ratio were low. CONCLUSION: AF rotors are mostly distributed in relatively weak and much more heterogenous LGE areas.

A complete dietary review of Japanese birds with special focus on molluscs.

Birds often hold important positions in the food webs of ecosystems. As a result, interactions between birds and their prey have attracted attention not only in ecology, but also in fields like agriculture and conservation. Avian food resources are well researched in Japan, however there is no database critically reviewing molluscs as a food resource for birds. Here, we present a new database reviewing dietary information for all Japanese bird species. In addition to addressing general diet categories and specific food habits for each bird, we include detailed data on the molluscan prey observed for all species that consume them. The information within this database was collected through intense literary review to provide a complete look at bird species historically present around the country. We also include new information on snail species found in the upper digestive tract of harvested wild birds. This database is publicly available in the Zenodo repository. The information should aid research around the Japanese archipelago, especially projects involving birds or molluscs.

Normative Aortic Valvar Measurements in Adults Using Cardiac Computed Tomography　- A Potential Guide to Further Sophisticate Aortic Valve-Sparing Surgery.

BACKGROUND: A thorough understanding of the anatomy of the aortic valve is necessary for aortic valve-sparing surgery. Normal valvar dimensions and their relationships in the living heart, however, have yet to be fully investigated in a 3-dimensional fashion.Methods and Results:In total, 123 consecutive patients (66±12 years, Men 63%) who underwent coronary computed tomographic angiography were enrolled. Mid-diastolic morphology of the aortic roots, including height of the interleaflet triangles, geometric height, free margin length of each leaflet, effective height, and coaptation length were measured using multiplanar reconstruction images. Average height of the interleaflet triangle, geometric height, free margin length, effective height, and the coaptation length were 17.3±1.8, 14.7±1.3, 32.6±3.6, 8.6±1.4, and 3.2±0.8 mm, respectively. The right coronary aortic leaflet displayed the longest free margin length and shortest geometric height. Geometric height, free margin length, and effective height showed positive correlations with aortic root dimensions. Coaptation length, however, remained constant regardless of aortic root dimensions. CONCLUSIONS: Diversities, as well as characteristic relationships among each value involving the aortic root, were identified using living-heart datasets. The aortic leaflets demonstrated compensatory elongation along with aortic root dilatation to maintain constant coaptation length. These measurements will serve as the standard value for revealing the underlying mechanism of aortic regurgitation to plan optimal aortic valve-sparing surgery.

Lesion characteristics between cryoballoon ablation and radiofrequency ablation with a contact force-sensing catheter: Late-gadolinium enhancement magnetic resonance imaging assessment.

BACKGROUND: Pulmonary vein isolation (PVI) lesions after cryoballoon ablation (CBA) are characterized as a wider and more continuous than that after conventional radiofrequency catheter ablation (RFCA) without the contact force (CF)-sensing technology. However, the impact on the lesion characteristics of ablation with a CF-sensing catheter has not been well discussed. We sought to assess the lesions using late-gadolinium enhancement magnetic resonance imaging (LGE-MRI) and to compare the differences between the two groups (CB group vs. RF group). METHODS: A total of 30 consecutive patients who underwent PVI were enrolled (CB group, 18; RF group, 12). The RF applications were delivered with a target lesion size index (LSI) of 5. The PVI lesions were assessed by LGE-MRI 3 months after the PVI. The region around the PV was divided into eight segments: roof, anterior-superior, anterior carina, anterior inferior, bottom, posterior inferior, posterior carina, and posterior superior segment. The lesion width and visual gap of each segment were compared between the two groups. The visual gaps were defined as no-enhancement site of >4 mm. RESULTS: The mean LSI was 4.7 ± 0.7. The lesion width was significantly wider but the visual gaps were more frequently documented at the bottom segment of right PV in the CBA group (lesion width: 8.1 ± 2.2 vs. 6.3 ± 2.2 mm; p = .032; visual gap at the bottom segment or right PV: 39% vs. 0%; p = .016). CONCLUSIONS: The PVI lesion was wider after CBA, while the visual gaps were fewer after RFCA with a CF-sensing catheter.

Evaluation of the Role of P-glycoprotein (P-gp)-Mediated Efflux in the Intestinal Absorption of Common Substrates with Elacridar, a P-gp Inhibitor, in Rats.

BACKGROUND AND OBJECTIVES: P-glycoprotein (P-gp) has been shown previously to contribute to the intestinal absorption of verapamil, diltiazem, tacrolimus, colchicine and indinavir in situ; however, its contribution in vivo is unknown. The present study aimed to evaluate the in vivo involvement of P-gp using elacridar as its inhibitor to distinguish the contribution of P-gp from cytochrome P450 (CYP) 3A. METHODS: Fexofenadine (5 mg/kg) and buspirone (1 mg/kg) were used as probe substrates of P-gp and CYP3A, respectively. Each dual substrate (1 or 2 mg/kg) was orally administered to rats after elacridar pre-treatment (3 mg/kg). Additionally, verapamil, diltiazem or tacrolimus was orally co-administered with fexofenadine. RESULTS: Elacridar drastically increased the area under the plasma concentration-time curve (AUC0-t) of oral fexofenadine by 8.6-fold; however, it did not affect the AUC0-t of oral buspirone. Therefore, elacridar inhibited P-gp without affecting CYP3A. The absorption of oral verapamil, diltiazem and tacrolimus was not influenced by elacridar pre-treatment, and the increase in the AUC0-t of fexofenadine was approximately 3-fold when co-administered with each substrate; the minimal effect of elacridar was attributable to the limited contribution of P-gp but not to their self-inhibition against the transporter. Conversely, elacridar significantly increased the AUC0-t of colchicine (5.3-fold) and indinavir (2.0-fold), indicating that P-gp contributes to their absorption. CONCLUSIONS: Elacridar is useful for distinguishing the contribution of P-gp from CYP3A to the absorption of drugs in rats. The in vivo contribution of P-gp is minimal for high permeable compounds owing to their fraction absorbed of nearly 1.0.

Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist.

We have previously shown that the oral administration of the small molecule hPTHR1 agonist PCO371 and its lead compound, 1 (CH5447240) results in PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. However, 1 was converted to a reactive metabolite in a human liver microsome assay. In this article, we report on the modification path that led to an enhancement of PTHR1 agonistic activity and reduction in the formation of a reactive metabolite to result in a potent, selective, and orally active PTHR1 agonist 1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione (PCO371, 16c). This compound is currently being evaluated in a phase 1 clinical study for the treatment of hypoparathyroidism.