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Introduction Point-by-point 3-dimensional (3D) electroanatomic mapping (EAM) is used to guide catheter ablation of premature ventricular complexes (PVCs). Due to the differences in the spatial excursion of the cardiac chambers during cardiac cycles in PVCs vs sinus rhythm, the 3D location registration during PVCs is shifted relative to sinus rhythm. In this study, we describe our strategy to adjust for this displacement in real-time during PVC mapping. Methods and results We report 21 patients who underwent catheter ablation of 23 unique PVCs using Carto 3. After mapping the earliest site for each PVC, we reregistered its 3D location to a sinus rhythm beat in real-time, and used this to guide ablation lesion delivery. The PVC earliest location was spatially displaced from the successful ablation lesion in sinus rhythm by average 6.7 (range 3.3-13.0) mm. Offline, we subsequently analyzed 25 unique chamber maps and 606 PVC points. For each point, we reregistered the 3D location to a preceding sinus beat. The PVC points were displaced from sinus rhythm location by average 4.4 (0.3-13.7) mm. The maximally displaced point for each chamber was 7.7 (4.7-13.7) mm. The general direction of shift during PVC was leftward and inferior relative to sinus rhythm. Conclusions During electroanatomic mapping of PVCs using the Carto 3 system, points mapped during PVCs are spatially displaced relative to their location in sinus rhythm. Electrophysiologists should recognize this phenomenon and account for the shift to guide accurate delivery of ablation lesions.

Aim To determine whether home-use icterometry improves parental recognition of neonatal jaundice, early care seeking and treatment to minimize risks of bilirubin encephalopathy. Methods Cluster-randomised controlled trial of community-level icterometry used at home by mothers in Chi Linh, Vietnam. Rural health-care workers identified and enrolled term newborns. Post-partum mothers received jaundice education and icterometry instructions and were cluster-randomised by commune. Cases received icterometers (icterometer group (IG)) and controls did not (control group (CG)). Subjects received mobile telephone calls from post-natal days 2–7 to determine maternal recognition by visual inspection and icterometer detection of jaundice (≥3.0 on five-point scale). Mothers without telephones, premature newborns ( 5 days were excluded. Results Three hundred fifty-two subjects were enrolled (183 IG and 169 CG), of whom 11 (3.4%) were lost to telephone follow-up. Jaundice was recognised and/or detected in 94 (27%) of all newborns. Icterometry helped 11 mothers (6%) detect neonatal jaundice that was not visually recognised by IG mothers. Detection by IG mothers was not statistically greater than CG mothers (P = 0.09). Follow-up care seeking was 8% in both groups (P = 0.2), and 11% of jaundiced newborns received treatment (9% IG vs. 16% CG, P = 0.3). Newborns who received care had bilirubin measurements that averaged 257 μmol/L IG vs. 322 μmol/L CG (P = 0.3). There were no deaths. Conclusions In this pilot study, home-use icterometry may help improve parental detection of jaundice in rural Vietnam. However, larger studies are necessary to determine the changes in recognition, care seeking and treatment.

Debates over the proper theory of, or approach to, constitutional interpretation rage through many Western constitutional democracies. Although the number of distinct theories, if finely individuated, might match the number of theorists who have entered the fray, it has become customary to group the competing accounts into two broad camps, commonly labeled ‘originalism’ and ‘non-originalism’. This article presents an overview of non-originalist approaches to constitutional interpretation. However, because non-originalism is defined as the negation of originalism – that is, diverse theories are grouped together as ‘non-originalist,’ not so much by what they commonly affirm, as by what they commonly deny – the project naturally focuses as well on originalist theories of interpretation. After specifying what originalism maintains, and what objections it encounters, the essay sketches some of the more prominent non-originalist approaches to constitutional interpretation and identifies some of the criticisms they face and worries they provoke. Preliminarily, it explains why ‘theories of constitutional interpretation’ constitute only a subset of ‘theories of judicial review.’

Background:Conventional insertion of implantable cardioverter-defibrillator (ICD) includes an evaluation of the defibrillation threshold (DFT). Implanting an ancillary defibrillation lead in the azygos vein has been introduced as a therapeutic option in patients with “high” DFT. This study reports the efficacy and stability of azygos defibrillation coils implanted for elevated DFTs. Methods:This is a retrospective review of seven consecutive patients with right and left pectoral, single- and dual-chamber, and biventricular ICDs and elevated DFTs, in whom an azygos defibrillation coil was introduced. Results:Addition of an azygos defibrillator lead achieved a satisfactory safety margin during single energy defibrillation efficacy testing in four out of seven patients, with success at maximum device output in two patients. No satisfactory safety margin was achieved in the remaining patient, despite the further addition of a subcutaneous defibrillation coil. No change in lead position was observed over a mean radiographic follow-up of 8 months. No complications were noted during a mean follow-up of 14 months, including no deaths, and no ICD shocks. Conclusion:Implanting a defibrillation coil into the azygos vein is feasible and safe. In a majority of patients with failed defibrillation efficacy testing, adding an azygos coil achieves success on repeat testing. Therefore, this technique is one option for lowering the defibrillation threshold in patients who fail DFT testing of their ICD.

Background: Patients with ischemic cardiomyopathy (ICM) who have monomorphic ventricular tachycardia (VT) induced by programmed ventricular stimulation (PVS) are at increased risk of sudden cardiac death (SCD). Among a primary prevention population, the prognostic significance of induced polymorphic ventricular arrhythmias is unknown. Methods:A total of 105 consecutive patients who received an implantable cardioverter-defibrillator (ICD) for primary prevention of SCD in the setting of ICM and non-sustained VT were retrospectively evaluated. Seventy-five patients (group I) had induction of monomorphic VT and 30 patients (group II) had a sustained ventricular arrhythmia other than monomorphic VT (ventricular flutter, ventricular fibrillation, and polymorphic VT) induced during PVS. Results:Baseline characteristics were similar between group I and group II except for ejection fraction (25% vs. 31%, P = 0.0001) and QRS duration (123 milliseconds vs. 109 milliseconds, P = 0.04). Sixteen of 75 (21.3%) patients in group I and 6 of 30 (20%) patients in group II received appropriate ICD therapy (P = 0.88). Survival free from ICD therapy was similar between groups (P = 0.54). There was a trend toward increased all-cause mortality among patients in group I by Kaplan-Meier analysis (P = 0.08). However, when adjusted for age, EF, and QRS duration mortality was similar (P = 0.45). Conclusions:There is no difference in rates of appropriate ICD discharge or mortality between patients dichotomized by type of rhythm induced during PVS. These results suggest that patients in this population who have inducible VF or sustained polymorphic VT have similar rates of subsequent clinical ventricular tachyarrhythmias as those with inducible monomorphic VT.

Defibrillation Energy Requirements of CRT-D Patients. Objectives: While defibrillation energy requirements (DERs) have been extensively studied in patients receiving conventional defibrillators, the DERs of patients receiving cardiac resynchronization therapy with defibrillation capability (CRT-D) devices have not been well described. The purpose of this analysis was to characterize DERs (defined as true threshold or the presence of appropriate safety margins) in patients undergoing implant of a CRT-D and to determine whether DERs in this population were similar to those reported for patients undergoing implantation of conventional defibrillators. Methods: Data were analyzed retrospectively from the VENTAK CHF/CONTAK CD biventricular pacing study. An appropriate safety margin of at least 10 J was verified with at least two successful conversions with 21 J or less. Multivariate logistic regression was performed to determine baseline predictors of failed DER testing. Results: Of 501 patients enrolled, 444 (89%) had successful DER test outcomes. Of the remaining 57 patients, 34 converted with energies >21J, and 23 had their testing terminated prematurely or were not tested, primarily due to patient condition. Larger left ventricular internal dimension in diastole (P = 0.003) and prolonged procedure time (P = 0.01) were significant predictors of higher energy requirements. Few significant complications arose from DER testing. Conclusions: DER testing can be accomplished safely and successfully in the majority of CRT-D patients. However, safety margins cannot be ascertained in a significant number of these patients. Left ventricular inner diameter in diastole (LVIDd) and prolonged procedure time may predict higher DERs, and could be used to anticipate the need for a high-energy device or inclusion of a subcutaneous array.

Aims To evaluate whether ketoconazole or cimetidine alter the pharmacokinetics of loratadine, or its major metabolite, desloratadine (DCL), or alter the effects of loratadine or DCL on electrocardiographic repolarization in healthy adult volunteers. Methods Two randomized, evaluator-blind, multiple-dose, three-way crossover drug interaction studies were performed. In each study, subjects received three 10 day treatments in random sequence, separated by a 14 day washout period. The treatments were loratadine alone, cimetidine or ketoconazole alone, or loratadine plus cimetidine or ketoconazole. The primary study endpoint was the difference in mean QTc intervals from baseline to day 10. In addition, plasma concentrations of loratadine, DCL, and ketoconazole or cimetidine were obtained on day 10. Results Concomitant administration of loratadine and ketoconazole significantly increased the loratadine plasma concentrations (307%; 90% CI 205-428%) and DCL concentrations (73%; 62-85%) compared with administration of loratadine alone. Concomitant administration of loratadine and cimetidine significantly increased the loratadine plasma concentrations (103% increase; 70-142%) but not DCL concentrations (6% increase; 1-11%) compared with administration of loratadine alone. Cimetidine or ketoconazole plasma concentrations were unaffected by coadministration with loratadine. Despite increased concentrations of loratadine and DCL, there were no statistically significant differences for the primary electrocardiographic repolarization parameter (QTc) among any of the treatment groups. No other clinically relevant changes in the safety profile of loratadine were observed as assessed by electrocardiographic parameters (mean (90% CI) QTc changes: loratadine vs loratadine + ketoconazole = 3.6 ms (-2.2, 9.4); loratadine vs loratadine + cimetidine = 3.2 ms (-1.6, 7.9)), clinical laboratory tests, vital signs, and adverse events. Conclusions Loratadine 10 mg daily was devoid of any effects on electrocardiographic parameters when coadministered for 10 days with therapeutic doses of ketoconazole or cimetidine in healthy volunteers. It is concluded that, although there was a significant pharmacokinetic drug interaction between ketoconazole or cimetidine and loratadine, this effect was not accompanied by a change in the QTc interval in healthy adult volunteers.

These studies were conducted to assess the systemic bioavailability of mometasone furoate (MF) administered by both the dry-powder inhaler (DPI) and the metered-dose inhaler with an alternate propellant (MDI-AP). The pharmacokinetics of single doses (400 micrograms) of MF administered by intravenous (i.v.) and inhalation routes was assessed in a randomized, three-way crossover study involving 24 healthy volunteers. In a separate study, 6 healthy subjects were administered a single dose of tritiated (3H-) MF by DPI, and the radioactivity in blood, urine, feces, and expired air was determined. Following i.v. administration, MF was detected in all subjects for at least 8 hours postdose. The half-life (t1/2) following i.v. administration was 4.5 hours. In contrast, following DPI administration, plasma MF concentrations were below the limit of quantification (LOQ, 50 pg/mL) for many subjects (10 of 24), and the systemic bioavailability by this route was estimated to be less than 1%. Only two plasma samples following MDI-AP administration had plasma concentrations of MF above the LOQ indicating no detectable systemic bioavailability in 92% of the subjects. A separate study with 6 healthy male subjects administered a single dose of 3H-MF (200 microCi) by DPI revealed that much of the dose (approximately 41%) was excreted unchanged in the feces (0-72 hours), while that which was absorbed was extensively metabolized. These results indicate that inhaled MF has negligible systemic bioavailability and is extensively metabolized and should therefore be well tolerated in the chronic treatment of asthma.

The metabolism of SCH 40120, which is the clinically effective antipsoriatic drug 10-(3-chlorophenyl)-6,8,9,10-tetrahydrobenzol[b][1,8]naphthyrid in-5(7H)-one, was determined in vitro. Rat, dog, cynomolgus monkey, and human liver slices hydroxylated the aliphatic, cyclohexenyl ring of the drug and conjugated the resulting carbinol. The identified metabolites comprised the corresponding 6-, 7-, and 9-carbinols, the glucuronide of the 6-carbinol, and the 6-ketone derived from the parent drug. Although the three carbinols appeared in the liver isolates of all species studied, the relative amounts of these metabolites varied across species. With a high, non-physiological ratio of substrate to liver, the 6-carbinol and its glucuronide were the major metabolites in human and monkey, whereas the 6-ketone was a minor metabolite in dog. Containing a stereogenic axis and center, the 6-carbinol existed as diastereomeric atropisomers. Its structure was established by 13C and 1H NMR spectroscopy, mass spectrometry, and comparison to an authentic sample.