Reagent Engineering for Group Transfer Biocatalysis.

Biocatalysis has become a major driver in the innovation of preparative chemistry. Enzyme discovery, engineering and computational design have matured to reliable strategies in the development of biocatalytic processes. By comparison, substrate engineering has received much less attention. In this Minireview, we highlight the idea that the design of synthetic reagents may be an equally fruitful and complementary approach to develop novel enzyme-catalysed group transfer chemistry. This Minireview discusses key examples from the literature that illustrate how synthetic substrates can be devised to improve the efficiency, scalability and sustainability, as well as the scope of such reactions. We also provide an opinion as to how this concept might be further developed in the future, aspiring to replicate the evolutionary success story of natural group transfer reagents, such as adenosine triphosphate (ATP) and S-adenosyl methionine (SAM).

A 1,3,2-Diazaphospholene-Catalyzed Reductive Claisen Rearrangement.

1,3,2-Diazaphospholenes (DAPs) are an emerging class of organic hydrides. In this work, we exploited them as efficient catalysts for very mild reductive Claisen rearrangements. The method is tolerant towards a wide variety of functional groups and operates at ambient temperature. Besides being enantiospecific for substrates with existing stereogenic centers, the diastereoselectivity can be switched by varying solvents and DAP catalysts. The reaction kinetics show direct rearrangements of O-bound phospholene enolates and provide a proof-of-principle for catalytic enantioselective reactions.

Chiral 1,3,2-Diazaphospholenes as Catalytic Molecular Hydrides for Enantioselective Conjugate Reductions.

Secondary 1,3,2-diazaphospholenes have a polarized P-H bond and are emerging as molecular hydrides. Herein, a class of chiral, conformationally restricted methoxy-1,3,2-diazaphospholene catalysts is reported. We demonstrate their catalytic potential in asymmetric 1,4-reductions of α,ß-unsaturated carbonyl derivatives, including enones, acyl pyrroles, and amides, which proceeded in enantioselectivities of up to 95.5:4.5 e.r.

Adenosine mapping for adenosine-dependent accessory pathway ablation.

BACKGROUND: This study describes the use of adenosine during ablation procedures to allow conduction through adenosine-dependent accessory pathways (APs), which are inactive at the time of the procedure. The technique allows for successful mapping and ablation of these pathways. METHODS: Retrospective review of all patients undergoing AP ablation from 1998 to 2008 to identify patients with absent or intermittent AP conduction during electrophysiology study. Adenosine boluses were used to activate the AP for the purpose of mapping in each case. RESULTS: Adenosine mapping was utilized in seven patients. One patient had a concealed AP at baseline and six patients had manifest preexcitation at baseline but lost AP conduction during the case. Alternative methods of enhancing AP conduction were attempted in five patients, but failed. Acute ablation results included: four patients with complete elimination of AP conduction, two patients with AP conduction only with adenosine, and one patient with return of baseline preexcitation. Patients with residual antegrade conduction had right superior (anterior) septal APs considered too close to the atrioventricular conduction system for safe ablation. At median follow-up of 2 years, all three patients with residual AP conduction had recurrence of supraventricular tachycardia; the remainder remained free of preexcitation and SVT. CONCLUSION: Adenosine mapping is a useful technique for facilitating AP ablation when pathway conduction is absent or inconsistent, and may enhance conduction in mechanically inhibited or previously ablated APs. Recurrence of AP conduction only during adenosine administration is predictive of late recurrence.

1-O-Benzyl-2,3-O-iso-propyl-idene-6-O-tosyl-α-l-sorbo-furan-ose.

IN THE TITLE COMPOUND (SYSTEMATIC NAME: {(3aS,5S,6R,6aS)-3a-[(benz-yloxy)meth-yl]-6-hy-droxy-2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxol-5-yl}methyl 4-methyl-benzene-sulfonate), C23H28O8S, the absolute structure and relative stereochemistry of the four chiral centres have been established by X-ray crystallography, with the absolute configuration inferred from the use of l-sorbose as the starting material. The central furan-ose ring adopts a slightly twisted envelope conformation (with the C atom bearing the methyl-benzene-sulfonate substituent as the flap) from which three substituents depart pseudo-axially (-CH2-O-benzyl, -OH and one acetonide O atom) and two substituents pseudo-equatorially (-CH2-O-tosyl and second acetonide O atom). The dioxalane ring is in a flattened envelope conformation with the fused CH C atom as the flap. In the crystal, mol-ecules pack in columns along [010] linked by O-H⋯O hydrogen bonds involving the furan-ose hy-droxy group and furan-ose ether O atom.

Safety and Glycemic Outcomes During the MiniMed™ Advanced Hybrid Closed-Loop System Pivotal Trial in Adolescents and Adults with Type 1 Diabetes.

Introduction: This trial assessed safety and effectiveness of an advanced hybrid closed-loop (AHCL) system with automated basal (Auto Basal) and automated bolus correction (Auto Correction) in adolescents and adults with type 1 diabetes (T1D). Materials and Methods: This multicenter single-arm study involved an intent-to-treat population of 157 individuals (39 adolescents aged 14-21 years and 118 adults aged ≥22-75 years) with T1D. Study participants used the MiniMed™ AHCL system during a baseline run-in period in which sensor-augmented pump +/- predictive low glucose management or Auto Basal was enabled for ∼14 days. Thereafter, Auto Basal and Auto Correction were enabled for a study phase (∼90 days), with glucose target set to 100 or 120 mg/dL for ∼45 days, followed by the other target for ∼45 days. Study endpoints included safety events and change in mean A1C, time in range (TIR, 70-180 mg/dL) and time below range (TBR, <70 mg/dL). Run-in and study phase values were compared using Wilcoxon signed-rank test or paired t-test. Results: Overall group time spent in closed loop averaged 94.9% ± 5.4% and involved only 1.2 ± 0.8 exits per week. Compared with run-in, AHCL reduced A1C from 7.5% ± 0.8% to 7.0% ± 0.5% (<0.001, Wilcoxon signed-rank test, n = 155), TIR increased from 68.8% ± 10.5% to 74.5% ± 6.9% (<0.001, Wilcoxon signed-rank test), and TBR reduced from 3.3% ± 2.9% to 2.3% ± 1.7% (<0.001, Wilcoxon signed-rank test). Similar benefits to glycemia were observed for each age group and were more pronounced for the nighttime (12 AM-6 AM). The 100 mg/dL target increased TIR to 75.4% (n = 155), which was further optimized at a lower active insulin time (AIT) setting (i.e., 2 h), without increasing TBR. There were no severe hypoglycemic or diabetic ketoacidosis events during the study phase. Conclusions: These findings show that the MiniMed AHCL system is safe and allows for achievement of recommended glycemic targets in adolescents and adults with T1D. Adjustments in target and AIT settings may further optimize glycemia and improve user experience. Clinical Trial Registration number: NCT03959423.

Is cardiology evaluation necessary in children with electrocardiogram abnormalities noted on polysomnogram?

OBJECTIVES: (1) To determine the prevalence of cardiac disease in children with electrocardiogram (ECG) abnormalities on polysomnogram (PSG). (2) To assess whether factors such as family history of heart disease and severity of sleep apnea are associated with cardiac disease. STUDY DESIGN: Case series with chart review from 2002 to 2012. SETTING: Tertiary children's hospital. SUBJECTS AND METHODS: Children between 1 and 16 years of age with ECG abnormalities on PSG who were referred to cardiology for evaluation were included. Children with a known history of cardiac disease were excluded. RESULTS: Sixty-one children had ECG abnormalities on PSG and were subsequently referred to cardiology. The mean age was 6.5 years (SD, 4.5), and 64% (n = 39) of subjects were African American. The mean obstructive apnea hypopnea index (AHI) was 8.8 (SD, 13.3), and 26% of the children had severe obstructive sleep apnea (AHI >10). The most common ECG abnormality (n = 52) recorded on PSG was premature ventricular contractions. Thirty percent (n = 18) of children had marked arrhythmias noted on their PSG ECG. Most children referred to cardiology underwent echocardiogram (45/61) and 24-hour arrhythmia monitoring (42/61). Five children (8%) had cardiac pathology, including atrial and ventricular ectopy, tuberous sclerosis, mitral regurgitation, and aortic insufficiency. Factors such as family history of heart disease (P = .40) and severe OSA (P = .74) were not associated with cardiac pathology. CONCLUSION: Cardiac pathology in children with abnormal ECGs on PSG is common. Cardiology referral in such patients should be considered. Further research is needed to determine the appropriate cardiac workup.

The first indoleamine-2,3-dioxygenase-1 (IDO1) inhibitors containing carborane.

Indoleamine-2,3-dioxygenase-1 (IDO1) is a critical immunoregulatory enzyme responsible for the metabolism of tryptophan during inflammation and disease. Based upon a pyranonaphthoquinone framework, the first examples of indoleamine-2,3-dioxygenase-1 (IDO1) inhibitors containing a carborane cage are reported. The novel closo-1,2-carboranyl-N-pyranonaphthoquinone derivatives display low µM binding affinity for the human recombinant enzyme, with IC50 values ranging from 0.78 to 1.77 µM.

Comparison of Fontan survivors with and without pacemakers: a report from the Pediatric Heart Network Fontan Cross-Sectional Study.

OBJECTIVE: Although many Fontan patients undergo pacemaker placement, there are few studies characterizing this population. Our purpose was to compare clinical characteristics, functional status and measures of ventricular performance in Fontan patients with and without a pacemaker. PATIENTS AND DESIGN: The National Heart, Lung, and Blood Institute funded Pediatric Heart Network Fontan Cross-Sectional Study characterized 546 Fontan survivors. Clinical characteristics, medical history and study outcomes (Child Health Questionnaire [CHQ]), echocardiographic evaluation of ventricular function, and exercise testing) were compared between subjects with and without pacemakers. RESULTS: Of 71 subjects with pacemakers (13%), 43/71 (61%) were in a paced rhythm at the time of study enrollment (age 11.9 ± 3.4 years). Pacemaker subjects were older at study enrollment, more likely to have single left ventricles, and taking more medications. There were no differences in age at Fontan or Fontan type between the pacemaker and no pacemaker groups. There were no differences in exercise performance between groups. CHQ physical summary scores were lower in the pacemaker subjects (39.7 ± 14.3 vs. 46.1 ± 11.2, P =.001). Ventricular ejection fraction z-score was also lower (-1.4 ± 1.9 vs. -0.8 ± 2.0, P =.05) in pacemaker subjects. CONCLUSIONS: In our cohort of Fontan survivors, those with a pacemaker have poorer functional status and evidence of decreased ventricular systolic function compared to Fontan survivors without a pacemaker.

The study of antiarrhythmic medications in infancy (SAMIS): a multicenter, randomized controlled trial comparing the efficacy and safety of digoxin versus propranolol for prophylaxis of supraventricular tachycardia in infants.

BACKGROUND: Supraventricular tachycardia (SVT) is one of the most common conditions requiring emergent cardiac care in children, yet its management has never been subjected to a randomized controlled clinical trial. The purpose of this study was to compare the efficacy and safety of the 2 most commonly used medications for antiarrhythmic prophylaxis of SVT in infants: digoxin and propranolol. METHODS AND RESULTS: This was a randomized, double-blind, multicenter study of infants <4 months with SVT (atrioventricular reciprocating tachycardia or atrioventricular nodal reentrant tachycardia), excluding Wolff-Parkinson-White, comparing digoxin with propranolol. The primary end point was recurrence of SVT requiring medical intervention. Time to recurrence and adverse events were secondary outcomes. Sixty-one patients completed the study, 27 randomized to digoxin and 34 to propranolol. SVT recurred in 19% of patients on digoxin and 31% of patients on propranolol (P=0.25). No first recurrence occurred after 110 days of treatment. The 6-month recurrence-free status was 79% for patients on digoxin and 67% for patients on propranolol (P=0.34), and there were no first recurrences in either group between 6 and 12 months. There were no deaths and no serious adverse events related to study medication. CONCLUSIONS: There was no difference in SVT recurrence in infants treated with digoxin versus propranolol. The current standard practice may be treating infants longer than required and indicates the need for a placebo-controlled trial. Clinical Trial Registration Information- http://clinicaltrials.gov; NCT-00390546.

Safety and results of cryoablation in patients <5 years old and/or <15 kilograms.

Current recommendations discourage elective radiofrequency ablation in patients <5 years old and/or weighing <15 kg, primarily because of the greater complication rate. To describe the current use, complications, and immediate outcomes of cryoablation in this patient population, a multicenter retrospective review of all patients <5 years old and/or weighing <15 kg who were treated with cryoablation for arrhythmia was performed. Eleven centers contributed data for 68 procedures on 61 patients. Of those, 34% were elective and 24% (n = 16) were both cryoablation and radiofrequency ablation. The median age and weight at ablation was 3.5 years (range 8 days to 9.9 years) and 15.2 kg (range 2.3 to 23), respectively. Congenital heart disease was present in 23% of the patients. The immediate success rate of cryoablation alone was 74%. No major complications occurred with cryoablation only; however, 2 of the 16 patients who underwent cryoablation and radiofrequency ablation had major complications. Of the 50 patients receiving cryoablation, 8 (16%) had variable degrees of transient atrioventricular block. The recurrence rate was 20% after cryoablation and 30% after cryoablation plus radiofrequency ablation. In conclusion, cryoablation appears to have a high safety profile in these patients. Compared to older and larger patients, the efficacy of cryoablation in this small, young population was lower and the recurrence rates were higher. Cryoablation's effect on the coronary arteries has not been fully elucidated and requires additional research.

Long-term outcomes for cryoablation of pediatric patients with atrioventricular nodal reentrant tachycardia.

The long-term efficacy and complications of cryoablation for pediatric atrioventricular nodal reentrant tachycardia (AVNRT) have not been completely defined. We performed a retrospective review of pediatric patients diagnosed with AVNRT and treated with cryoablation therapy. A total of 73 patients underwent cryoablation for AVNRT from 2003 to 2008. Of the 73 patients, 61 were included in the present study. The mean interval from initial successful ablation was 3 + or - 1 years. Of the 61 patients, 4 had documented recurrence of AVNRT after the initially successful ablation, 3 with late recurrence 1 to 2 years after ablation. Procedural complications consisting of transient atrioventricular block developed in 10 patients, and 2 patients were diagnosed with new arrhythmias after AVNRT ablation (1 with junctional ectopic tachycardia and 1 with left ventricular outflow tract tachycardia originating near the region of the atrioventricular node 3 months after ablation). In conclusion, cryoablation is a safe and effective therapy for AVNRT. Recurrences can develop late, up to 2 years after initially successful ablation.

Arrhythmias in a contemporary fontan cohort: prevalence and clinical associations in a multicenter cross-sectional study.

OBJECTIVES: Our aim was to examine the prevalence of arrhythmias and identify independent associations of time to arrhythmia development. BACKGROUND: Since introduction of the Fontan operation in 1971, long-term results have steadily improved with newer modifications. However, atrial arrhythmias are frequent and contribute to ongoing morbidity and mortality. Data are lacking regarding the prevalence of arrhythmias and risk factors for their development in the current era. METHODS: The Pediatric Heart Network Fontan Cross-Sectional study evaluated data from 7 centers, with 520 patients age 6 to 18 years (mean 8.6 +/- 3.4 years after the Fontan operation), including echocardiograms, electrocardiograms, exercise testing, parent-reported Child Health Questionnaire (CHQ) results, and medical history. RESULTS: Supraventricular tachycardias were present in 9.4% of patients. Intra-atrial re-entrant tachycardia (IART) was present in 7.3% (32 of 520). The hazard of IART decreased until 4 to 6 years post-Fontan, and then increased with age thereafter. Cardiac anatomy and resting heart rate (including marked bradycardia) were not associated with IART. We identified 3 independent associations of time to occurrence of IART: lower CHQ physical summary score (p < 0.001); predominant rhythm (p = 0.002; highest risk with paced rhythm), and type of Fontan operation (p = 0.037; highest risk with atriopulmonary connection). Time to IART did not differ between patients with lateral tunnel and extracardiac conduit types of Fontan repair. Ventricular tachycardia was noted in 3.5% of patients. CONCLUSIONS: Overall prevalence of IART was lower in this cohort (7.3%) than previously reported. Lower functional status, an atriopulmonary connection, and paced rhythm were determined to be independently associated with development of IART after Fontan. (Relationship Between Functional Health Status and Ventricular Performance After Fontan-Pediatric Heart Network; NCT00132782).

Novel minimally invasive, intrapericardial implantable cardioverter defibrillator coil system: a useful approach to arrhythmia therapy in children.

BACKGROUND: Current approaches to implantable cardioverter defibrillator (ICD) implantation in children remain challenging. Transvenous access may be limited due to patient size or anatomy, while epicardial patches require sternotomy or thoracotomy. We present an alternative approach; minimally invasive placement of a transvenous ICD coil within the pericardial space with active fixation. METHODS: Between August 2005 and October 2008, 7 children meeting indications for ICD therapy for ventricular tachyarrhythmias underwent intrapericardial placement of an ICD coil system. Median age was 5 years (range, 1 to 17), weight was 14 kg (range, 8 to 46), and 4 patients weighed less than 20 kg. The ICD system was composed of a single or dual defibrillation coil, an active can, and either ventricular or dual chamber epicardial sense-pace leads. All implantations were performed through a small subxiphoid incision and pericardial window without sternotomy. The coil lead was actively fixated in the transverse sinus under fluoroscopic guidance, and the generator placed in a subrectus pocket in the upper abdomen through the same incision. RESULTS: There were no perioperative complications, and no early or late deaths. All implants had acceptable defibrillation energies (range, 5 to 15 J) that were successfully tested intraoperatively, and none required energy increase or lead revision during follow-up (range, 1 to 39 months; median, 20 months). Impedance between the active can and the defibrillation coil remained stable in all. There were no inappropriate discharges. Thirty-six successful ICD discharges in 4 patients were recorded. Two patients underwent subsequent orthotopic heart transplantation and ICD system removal. CONCLUSIONS: Intrapericardial placement of an ICD coil system can be safely and successfully carried out through a minimally invasive subxiphoid approach in small infants and children. This novel ICD configuration demonstrates excellent performance, and provides a particularly efficacious approach to ventricular tachyarrhythmia therapy in pediatric patients.

A tangled affair: pacemaker malfunction and syncope in a child due to Twiddler's syndrome.

Manipulation of an implanted pacemaker by the patient is a rare cause of malfunction, especially in children. We describe a child who inadvertently rotated his pacemaker under the skin, knotting the leads and dislodging them from the heart, leading to syncope and heart block. Our experience with this case underscores the need to consider this diagnosis in children as well as in adults if this problem is to be averted.

Surgical correction of mitral valve prolapse : a cure for recurrent ventricular tachycardia in Marfan syndrome?

We describe the case of a 3-year-old child with neonatal Marfan syndrome complicated by mitral valve prolapse with regurgitation, marked aortic root dilatation, and ventricular tachycardia. The patient had resolution of ventricular tachycardia following surgical intervention consisting of a valve-sparing aortic root replacement and mitral valve annuloplasty.