International Pediatric ORL Group (IPOG) laryngomalacia consensus recommendations.

OBJECTIVE: To provide recommendations for the comprehensive management of young infants who present with signs or symptoms concerning for laryngomalacia. METHODS: Expert opinion by the members of the International Pediatric Otolaryngology Group (IPOG). RESULTS: Consensus recommendations include initial care and triage recommendations for health care providers who commonly evaluate young infants with noisy breathing. The consensus statement also provides comprehensive care recommendations for otolaryngologists who manage young infants with laryngomalacia including: evaluation and treatment considerations for commonly debated issues in laryngomalacia, initial work-up of infants presenting with inspiratory stridor, treatment recommendations based on disease severity, management of the infant with feeding difficulties, post-surgical treatment management recommendations, and suggestions for acid suppression therapy. CONCLUSION: Laryngomalacia care consensus recommendations are aimed at improving patient-centered care in infants with laryngomalacia.

Intraoperative acupuncture for posttonsillectomy pain: a randomized, double-blind, placebo-controlled trial.

OBJECTIVES/HYPOTHESIS: To evaluate the effect of intraoperative acupuncture on posttonsillectomy pain in the pediatric population. STUDY DESIGN: Prospective, double-blind, randomized, placebo-controlled trial. METHODS: Patients aged 3 to 12 years undergoing tonsillectomy were recruited at a tertiary children's hospital between February 2011 and May 2012. Participants were block-randomized to receive acupuncture or sham acupuncture during anesthesia for tonsillectomy. Surgeons, staff, and parents were blinded from treatment. Tonsillectomy was performed by one of two surgeons using a standard technique (monopolar cautery), and a single anesthetic protocol was followed. Study endpoints included time spent in the postanesthesia care unit, the amount of opioids administered in the perioperative period, and pain measures and presence of nausea/vomiting from postoperative home surveys. RESULTS: Fifty-nine children aged 3 to 12 years were randomized to receive acupuncture (n = 30) or sham acupuncture (n = 29). No significant demographic differences were noted between the two cohorts. Perioperative data were recorded for all patients; 73% of patients later returned home surveys. There were no significant differences in the amount of opioid medications administered or total postanesthesia care unit time between the two cohorts. Home surveys of patients but not of parents revealed significant improvements in pain control in the acupuncture treatment-group postoperatively (P = 0.0065 and 0.051, respectively), and oral intake improved significantly earlier in the acupuncture treatment group (P = 0.01). No adverse effects of acupuncture were reported. CONCLUSIONS: This study demonstrates that intraoperative acupuncture is feasible, well tolerated, and results in improved pain and earlier return of diet postoperatively. LEVEL OF EVIDENCE: 1b.

Designer aminoglycosides prevent cochlear hair cell loss and hearing loss.

Bacterial infections represent a rapidly growing challenge to human health. Aminoglycosides are widely used broad-spectrum antibiotics, but they inflict permanent hearing loss in up to ~50% of patients by causing selective sensory hair cell loss. Here, we hypothesized that reducing aminoglycoside entry into hair cells via mechanotransducer channels would reduce ototoxicity, and therefore we synthesized 9 aminoglycosides with modifications based on biophysical properties of the hair cell mechanotransducer channel and interactions between aminoglycosides and the bacterial ribosome. Compared with the parent aminoglycoside sisomicin, all 9 derivatives displayed no or reduced ototoxicity, with the lead compound N1MS 17 times less ototoxic and with reduced penetration of hair cell mechanotransducer channels in rat cochlear cultures. Both N1MS and sisomicin suppressed growth of E. coli and K. pneumoniae, with N1MS exhibiting superior activity against extended spectrum ß lactamase producers, despite diminished activity against P. aeruginosa and S. aureus. Moreover, systemic sisomicin treatment of mice resulted in 75% to 85% hair cell loss and profound hearing loss, whereas N1MS treatment preserved both hair cells and hearing. Finally, in mice with E. coli-infected bladders, systemic N1MS treatment eliminated bacteria from urinary tract tissues and serially collected urine samples, without compromising auditory and kidney functions. Together, our findings establish N1MS as a nonototoxic aminoglycoside and support targeted modification as a promising approach to generating nonototoxic antibiotics.

Impact of nonischemic scar features on local ventricular electrograms and scar-related ventricular tachycardia circuits in patients with nonischemic cardiomyopathy.

BACKGROUND: The association of local electrogram features with scar morphology and distribution in nonischemic cardiomyopathy has not been investigated. We aimed to quantify the association of scar on late gadolinium-enhanced cardiac magnetic resonance with local electrograms and ventricular tachycardia circuit sites in patients with nonischemic cardiomyopathy. METHODS AND RESULTS: Fifteen patients with nonischemic cardiomyopathy underwent late gadolinium-enhanced cardiac magnetic resonance before ventricular tachycardia ablation. The transmural extent and intramural types (endocardial, midwall, epicardial, patchy, transmural) of scar were measured in late gadolinium-enhanced cardiac magnetic resonance short-axis planes. Electroanatomic map points were registered to late gadolinium-enhanced cardiac magnetic resonance images. Myocardial wall thickness, scar transmurality, and intramural scar types were independently associated with electrogram amplitude, duration, and deflections in linear mixed-effects multivariable models, clustered by patient. Fractionated and isolated potentials were more likely to be observed in regions with higher scar transmurality (P<0.0001 by ANOVA) and in regions with patchy scar (versus endocardial, midwall, epicardial scar; P<0.05 by ANOVA). Most ventricular tachycardia circuit sites were located in scar with >25% scar transmurality. CONCLUSIONS: Electrogram features are associated with scar morphology and distribution in patients with nonischemic cardiomyopathy. Previous knowledge of electrogram image associations may optimize procedural strategies including the decision to obtain epicardial access.

Phrenic nerve injury: An underrecognized and potentially preventable complication of pulmonary vein isolation using a wide-area circumferential ablation approach.

INTRODUCTION: Phrenic nerve injury (PNI) is a well-known, although uncommon, complication of pulmonary vein isolation (PVI) using radiofrequency energy. Currently, there is no consensus about how to avoid or minimize this injury. The purpose of this study was to determine how often the phrenic nerve, as identified using a high-output pacing, lies along the ablation trajectory of a wide-area circumferential lesion set. We also sought to determine if PVI can be achieved without phrenic nerve injury by modifying the ablation lesion set so as to avoid those areas where phrenic nerve capture (PNC) is observed. METHODS AND RESULTS: We prospectively enrolled 100 consecutive patients (age 61.7 ± 9.2 years old, 75 men) who underwent RF PVI using a wide-area circumferential ablation approach. A high-output (20 mA at 2 milliseconds) endocardial pacing protocol was performed around the right pulmonary veins and the carina where a usual ablation lesion set would be made. A total of 30% of patients had PNC and required modification of ablation lines. In the group of patients with PNC, the carina was the most common site of capture (85%) followed by anterior right superior pulmonary vein (RSPV) (70%) and anterior right inferior pulmonary vein (RIPV) (30%). A total of 25% of PNC group had capture in all 3 (RSPV, RIPV, and carina) regions. There was no difference in the clinical characteristics between the groups with and without PNC. RF PVI caused no PNI in either group. CONCLUSION: High output pacing around the right pulmonary veins and the carina reveals that the phrenic nerve lies along a wide-area circumferential ablation trajectory in 30% of patients. Modification of ablation lines to avoid these sites may prevent phrenic nerve injury during RF PVI.

The effect of antiarrhythmic medication management on atrial fibrillation ablation outcomes.

BACKGROUND: Patients commonly present for atrial fibrillation (AF) ablation while taking antiarrhythmic (AA) medications. It is unknown if AA use at the time of ablation affects procedural outcome. This study compares the AF ablation outcomes of patients who underwent ablation while on AA medications to those who were not on AA medications. METHODS AND RESULTS: A total of 180 consecutive patients who underwent their first catheter ablation of AF were identified from the Johns Hopkins Hospital AF registry and divided into 2 cohorts: those On AA at the time of ablation (127 patients, mean follow-up 24.6 months) and those Off AA at the time of ablation (53 patients, mean follow-up 20.3 months). Follow-up was performed to identify recurrent AF. There was no statistically significant difference in the percentage of patients without a recurrence of symptomatic AF (single procedure success rate) in the On and Off AA groups at 6 months postablation (53.5% vs 50.1%, P = 0.75), or by the end of follow-up (37.8% vs 41.5%, P = 0.64). For those patients who had symptomatic AF recurrence, the average time to recurrence was 6.2 ± 9.0 months in the On AA group and 4.2 ± 7.2 months in the Off AA group (P = 0.27). CONCLUSIONS: There was no statistically significant difference in the rate of symptomatic AF recurrence between the On AA and Off AA groups in this study. The use of AA medications at the time of ablation does not appear to affect procedural outcomes in this population.

Myocardial structural associations with local electrograms: a study of postinfarct ventricular tachycardia pathophysiology and magnetic resonance-based noninvasive mapping.

BACKGROUND: The association of scar on late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) with local electrograms on electroanatomic mapping has been investigated. We aimed to quantify these associations to gain insights regarding LGE-CMR image characteristics of tissues and critical sites that support postinfarct ventricular tachycardia (VT). METHODS AND RESULTS: LGE-CMR was performed in 23 patients with ischemic cardiomyopathy before VT ablation. Left ventricular wall thickness and postinfarct scar thickness were measured in each of 20 sectors per LGE-CMR short-axis plane. Electroanatomic mapping points were retrospectively registered to the corresponding LGE-CMR images. Multivariable regression analysis, clustered by patient, revealed significant associations among left ventricular wall thickness, postinfarct scar thickness, and intramural scar location on LGE-CMR, and local endocardial electrogram bipolar/unipolar voltage, duration, and deflections on electroanatomic mapping. Anteroposterior and septal/lateral scar localization was also associated with bipolar and unipolar voltage. Antiarrhythmic drug use was associated with electrogram duration. Critical sites of postinfarct VT were associated with >25% scar transmurality, and slow conduction sites with >40 ms stimulus-QRS time were associated with >75% scar transmurality. CONCLUSIONS: Critical sites for maintenance of postinfarct VT are confined to areas with >25% scar transmurality. Our data provide insights into the structural substrates for delayed conduction and VT and may reduce procedural time devoted to substrate mapping, overcome limitations of invasive mapping because of sampling density, and enhance magnetic resonance-based ablation by feature extraction from complex images.

Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors.

mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series.

Electrophysiology studies in patients undergoing ICD implantation: findings from the NCDR®.

BACKGROUND: Electrophysiology studies (EPS) have historically played a role in sudden death risk stratification. More recent studies point to the left ventricular ejection fraction (EF) as a guide to implantable cardioverter defibrillators (ICD) implantation. The extent of EPS use in patients undergoing ICD implantation in the current era remains unknown. METHODS: Patients undergoing de novo ICD implantation in the ICD Registry between September 2006 and March 2009 who also underwent EPS within 30 days before implant were compared to the remaining cohort to identify clinical characteristics that correlated with EPS performance. Multivariate models were generated using hierarchical logistic regression analysis. RESULTS: EPS were performed in 33,786 of 275,273 patients. Those undergoing EPS were more likely to have had a history of syncope, family history of sudden death, lack of congestive heart failure, narrower QRS intervals, and higher EF. Overall, 63.9% of EPS were performed in patients receiving primary prevention ICDs. Ventricular tachyarrhythmias were induced in 46.1% of primary prevention and 54.2% of secondary prevention ICD recipients. Monomorphic ventricular tachycardia was the most common type of arrhythmia induced in both groups. Complication rates were not higher in those undergoing EPS. CONCLUSIONS: EPS were performed predominantly in patients with borderline or less well-defined risk factors for sudden death. Ventricular arrhythmias induced from EPS were not uncommon and may help identify individuals at higher risk for future ICD therapies. Efforts to better define the role of EPS in patients undergoing ICD implantation should be considered.

Analysis of kinase inhibitor selectivity using a thermodynamics-based partition index.

In the quest for safe, efficacious kinase inhibitors as drugs, selectivity is often assessed early using kinase profiling panels. Here we present a selectivity index based on thermodynamics principles that can help in analysis of the resulting data. The "partition" selectivity index is easy to calculate and is applicable in certain situations where other widely used indices are not. It is uniquely useful in analysis of small, focused selectivity panel data frequently encountered in medicinal chemistry hit-to-lead and lead optimization. For larger "kinome" panels, the partition index allows assessment of selectivity relative to a kinase or multiple kinases of interest.

Automated detection and characterization of complex fractionated atrial electrograms in human left atrium during atrial fibrillation.

BACKGROUND: Complex fractionated atrial electrograms (CFAEs) have been reported as ablative targets for the treatment of atrial fibrillation (AF). However, the process of CFAE identification is highly dependent on the operator's judgment. OBJECTIVE: It is the aim of the study to report our initial experience with a novel software algorithm designed to automatically detect CFAEs. METHODS: Nineteen patients (6 female, 58 +/- 8 years) who underwent catheter ablation of paroxysmal (n = 11) or persistent (n = 8) AF were included in the study. During ongoing AF, 100 +/- 15 left atrial (LA) endocardial locations were sampled under the guidance of integrated electroanatomical mapping with computed tomographic images. Bipolar electrograms recorded throughout the LA were analyzed using custom software that allows for automated detection of CFAEs. Interval confidence level (ICL), defined as the number of intervals between consecutive CFAE complexes during 2.5-second recordings, was used to characterize CFAEs. The CFAE sites with an ICL >/=5 were considered as sites with highly repetitive CFAEs, which are thought to be potential ablation targets. For purposes of analysis, the LA was divided into 6 areas: pulmonary vein (PV) ostia, posterior wall, interatrial septum, roof, mitral annulus area, and appendage. RESULTS: Among a total of 1,904 LA locations sampled in 19 patients, 1,644 (86%) were categorized as CFAE sites, whereas 260 (14%) were categorized as as non-CFAE sites. Thirty-four percent of all CFAE sites were identified as sites with highly repetitive CFAEs. Of these, 24% were located at the interatrial septum, 22% on the posterior wall, 20% at the PV ostia, 18% at the mitral annulus area, 14% on the roof, and 2.7% at the LA appendage. In all patients, highly repetitive CFAE sites were distributed in 4 or more areas of the LA. Persistent AF patients had more highly repetitive CFAE sites on the posterior wall than paroxysmal AF patients (30% +/- 7.3% vs 14% +/- 8.2%, P < .001). There was a strong trend toward more highly repetitive CFAE sites located at the PV ostia in patients with paroxysmal AF compared with persistent AF patients (24% +/- 13% vs 13% +/- 7.7%, P = .05). CONCLUSION: With the use of custom software, CFAE complexes were identified in more than 80% of the LA endocardial locations. LA sites with highly repetitive CFAE sites were located predominately in the septum, posterior wall, and PV ostia. Patients with persistent AF had a different anatomical distribution pattern of highly repetitive CFAE sites from those with paroxysmal AF, with a greater prevalence of highly repetitive CFAEs located on the posterior wall. Further studies are warranted to determine the clinical significance of these findings.

Infarct tissue heterogeneity by magnetic resonance imaging identifies enhanced cardiac arrhythmia susceptibility in patients with left ventricular dysfunction.

BACKGROUND: The extent of the peri-infarct zone by magnetic resonance imaging (MRI) has been related to all-cause mortality in patients with coronary artery disease. This relationship may result from arrhythmogenesis in the infarct border. However, the relationship between tissue heterogeneity in the infarct periphery and arrhythmic substrate has not been investigated. In the present study, we quantify myocardial infarct heterogeneity by contrast-enhanced MRI and relate it to an electrophysiological marker of arrhythmic substrate in patients with left ventricular (LV) systolic dysfunction undergoing prophylactic implantable cardioverter defibrillator placement. METHODS AND RESULTS: Before implantable cardioverter defibrillator implantation for primary prevention of sudden cardiac death, 47 patients underwent cine and contrast-enhanced MRI to measure LV function, volumes, mass, and infarct size. A method for quantifying the heterogeneous infarct periphery and the denser infarct core is described. MRI indices were related to inducibility of sustained monomorphic ventricular tachycardia during electrophysiological or device testing. For the noninducible versus inducible patients, LV ejection fraction (30+/-10% versus 29+/-7%, P=0.79), LV end-diastolic volume (220+/-70 versus 228+/-57 mL, P=0.68), and infarct size by standard contrast-enhanced MRI definitions (P=NS) were similar. Quantification of tissue heterogeneity at the infarct periphery was strongly associated with inducibility for monomorphic ventricular tachycardia (noninducible versus inducible: 13+/-9 versus 19+/-8 g, P=0.015) and was the single significant factor in a stepwise logistic regression. CONCLUSIONS: Tissue heterogeneity is present and quantifiable within human infarcts. More extensive tissue heterogeneity correlates with increased ventricular irritability by programmed electrical stimulation. These findings support the hypothesis that anatomic tissue heterogeneity increases susceptibility to ventricular arrhythmias in patients with prior myocardial infarction and LV dysfunction.

Recognition of nucleic acid bases and base-pairs by hydrogen bonding to amino acid side-chains.

Sequence-specific protein-nucleic acid recognition is determined, in part, by hydrogen bonding interactions between amino acid side-chains and nucleotide bases. To examine the repertoire of possible interactions, we have calculated geometrically plausible arrangements in which amino acids hydrogen bond to unpaired bases, such as those found in RNA bulges and loops, or to the 53 possible RNA base-pairs. We find 32 possible interactions that involve two or more hydrogen bonds to the six unpaired bases (including protonated A and C), 17 of which have been observed. We find 186 "spanning" interactions to base-pairs in which the amino acid hydrogen bonds to both bases, in principle allowing particular base-pairs to be selectively targeted, and nine of these have been observed. Four calculated interactions span the Watson-Crick pairs and 15 span the G:U wobble pair, including two interesting arrangements with three hydrogen bonds to the Arg guanidinum group that have not yet been observed. The inherent donor-acceptor arrangements of the bases support many possible interactions to Asn (or Gln) and Ser (or Thr or Tyr), few interactions to Asp (or Glu) even though several already have been observed, and interactions to U (or T) only if the base is in an unpaired context, as also observed in several cases. This study highlights how complementary arrangements of donors and acceptors can contribute to base-specific recognition of RNA, predicts interactions not yet observed, and provides tools to analyze proposed contacts or design novel interactions.

Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B.

Common obesity is primarily characterized by resistance to the actions of the hormone leptin. Mice deficient in protein tyrosine phosphatase 1B (PTP1B) are resistant to diabetes and diet-induced obesity, prompting us to further define the relationship between PTP1B and leptin in modulating obesity. Leptin-deficient (Lep(ob/ob)) mice lacking PTP1B exhibit an attenuated weight gain, a decrease in adipose tissue, and an increase in resting metabolic rate. Furthermore, PTP1B-deficient mice show an enhanced response toward leptin-mediated weight loss and suppression of feeding. Hypothalami from these mice also display markedly increased leptin-induced Stat3 phosphorylation. Finally, substrate-trapping experiments demonstrate that leptin-activated Jak2, but not Stat3 or the leptin receptor, is a substrate of PTP1B. These results suggest that PTP1B negatively regulates leptin signaling, and provide one mechanism by which it may regulate obesity.