Dynamic sampling in autonomous process optimization.

Autonomous process optimization (APO) is a technology that has recently found utility in a multitude of process optimization challenges. In contrast to most APO examples in microflow reactor systems, we recently presented a system capable of optimization in high-throughput batch reactor systems. The drawback of APO in a high-throughput batch reactor system is the reliance on reaction sampling at a predetermined static timepoint rather than a dynamic endpoint. Static timepoint sampling can lead to the inconsistent capture of the process performance under each process parameter permutation. This is important because critical process behaviors such as rate acceleration accompanied by decomposition could be missed entirely. To address this drawback, we implemented a dynamic reaction endpoint determination strategy to capture the product purity once the process stream stabilized. We accomplished this through the incorporation of a real-time plateau detection algorithm into the APO workflow to measure and report the product purity at the dynamically determined reaction endpoint. We then applied this strategy to the autonomous optimization of a photobromination reaction towards the synthesis of a pharmaceutically relevant intermediate. In doing so, we not only uncovered process conditions to access the desired monohalogenation product in 85 UPLC area % purity with minimal decomposition risk, but also measured the effect of each parameter on the process performance. Our results highlight the advantage of incorporating dynamic sampling in APO workflows to drive optimization toward a stable and high-performing process.

Ablation-induced left atrial mechanical dysfunction recovers in weeks after ablation.

BACKGROUND: The immediate impact of catheter ablation on left atrial mechanical function and the timeline for its recovery in patients undergoing ablation for atrial fibrillation (AF) remain uncertain. The mechanical function response to catheter ablation in patients with different AF types is poorly understood. METHODS: A total of 113 AF patients were included in this retrospective study. Each patient had three magnetic resonance imaging (MRI) studies in sinus rhythm: one pre-ablation, one immediate post-ablation (within 2 days after ablation), and one post-ablation follow-up MRI (≤ 3 months). We used feature tracking in the MRI cine images to determine peak longitudinal atrial strain (PLAS). We evaluated the change in strain from pre-ablation, immediately after ablation to post-ablation follow-up in a short-term study (< 50 days) and a 3-month study (3 months after ablation). RESULTS: The PLAS exhibited a notable reduction immediately after ablation, compared to both pre-ablation levels and those observed in follow-up studies conducted at short-term (11.1 ± 9.0 days) and 3-month (69.6 ± 39.6 days) intervals. However, there was no difference between follow-up and pre-ablation PLAS. The PLAS returned to 95% pre-ablation level within 10 days. Paroxysmal AF patients had significantly higher pre-ablation PLAS than persistent AF patients in pre-ablation MRIs. Both type AF patients had significantly lower immediate post-ablation PLAS compared with pre-ablation and post-ablation PLAS. CONCLUSION: The present study suggested a significant drop in PLAS immediately after ablation. Left atrial mechanical function recovered within 10 days after ablation. The drop in PLAS did not show a substantial difference between paroxysmal and persistent AF patients.

Total Synthesis of (+)-Discorhabdin V.

The discorhabdin natural products are a large subset of pyrroloiminoquinone alkaloids with a myriad of biological activities. Despite garnering much synthetic attention, few members have thus far been completed, particularly those featuring a bridging carbon-nitrogen bond that is found in numerous discorhabdins, including discorhabdin V. Herein we report the first total synthesis and full stereochemical assignment of (+)-discorhabdin V. To access the pyrroloiminoquinone we developed a convergent N-alkylation/oxidative aminocyclization/bromination cascade that joins two key components, which are both made on multigram scale. An intramolecular Heck reaction then forms the quaternary carbon center in an intermediate containing the carbon-nitrogen bridge, and a reductive N,O-acetal cyclization sequence introduces the final piperidine ring. Furthermore, we have established the relative configuration of (+)-discorhabdin V through experimental NOESY data and DP4 NMR probability calculations. The absolute configuration of the natural product has also been determined by circular dichroism and the use of an amino acid derived chiral starting material. Our work represents one of only two reports of a total synthesis of a nitrogen-bridged discorhabdin and paves the way for future biological evaluation of such compounds.

Contribution of atrial myofiber architecture to atrial fibrillation.

BACKGROUND: The role of fiber orientation on a global chamber level in sustaining atrial fibrillation (AF) is unknown. The goal of this study was to correlate the fiber direction derived from Diffusion Tensor Imaging (DTI) with AF inducibility. METHODS: Transgenic goats with cardiac-specific overexpression of constitutively active TGF-ß1 (n = 14) underwent AF inducibility testing by rapid pacing in the left atrium. We chose a minimum of 10 minutes of sustained AF as a cut-off for AF inducibility. Explanted hearts underwent DTI to determine the fiber direction. Using tractography data, we clustered, visualized, and quantified the fiber helix angles in 8 different regions of the left atrial wall using two reference vectors defined based on anatomical landmarks. RESULTS: Sustained AF was induced in 7 out of 14 goats. The mean helix fiber angles in 7 out of 8 selected regions were statistically different (P-Value < 0.05) in the AF inducible group. The average fractional anisotropy (FA) and the mean diffusivity (MD) were similar in the two groups with FA of 0.32±0.08 and MD of 8.54±1.72 mm2/s in the non-inducible group and FA of 0.31±0.05 (P-value = 0.90) and MD of 8.68±1.60 mm2/s (P-value = 0.88) in the inducible group. CONCLUSIONS: DTI based fiber direction shows significant variability across subjects with a significant difference between animals that are AF inducible versus animals that are not inducible. Fiber direction might be contributing to the initiation and sustaining of AF, and its role needs to be investigated further.

Effects of Biventricular Pacing Locations on Anti-Tachycardia Pacing Success in a Patient-Specific Model.

Patients with drug-refractory ventricular tachycardia (VT) often undergo implantation of a cardiac defibrillator (ICD). While life-saving, shock from an ICD can be traumatic. To combat the need for defibrillation, ICDs come equipped with low-energy pacing protocols. These anti-tachycardia pacing (ATP) methods are conventionally delivered from a lead inserted at the apex of the right ventricle (RV) with limited success. Recent studies have shown the promise of biventricular leads placed in the left ventricle (LV) for ATP delivery. This study tested the hypothesis that stimulating ATP from multiple biventricular locations will improve termination rates in a patient-specific computational model. VT was first induced in the model, followed by ATP delivery from 1-4 biventricular stimulus sites. We found that combining stimulation sites does not alter termination success so long as a critical stimulus site is included. Combining the RV stimulus site with any combination of LV sites did not affect ATP success except for one case. Including the RV site may allow biventricular ATP to be a robust approach across different scar distributions without affecting the efficacy of other stimulation sites. Combining sites may increase the likelihood of including a critical stimulus site when such information cannot be ascertained.

Transfer Learning for Improved Classification of Drivers in Atrial Fibrillation.

"Drivers" are theorized mechanisms for persistent atrial fibrillation. Machine learning algorithms have been used to identify drivers, but the small size of current driver datasets limits their performance. We hypothesized that pretraining with unsupervised learning on a large dataset of unlabeled electrograms would improve classifier accuracy on a smaller driver dataset. In this study, we used a SimCLR-based framework to pretrain a residual neural network on a dataset of 113K unlabeled 64-electrode measurements and found weighted testing accuracy to improve over a non-pretrained network (78.6±3.9% vs 71.9±3.3%). This lays ground for development of superior driver detection algorithms and supports use of transfer learning for other datasets of endocardial electrograms.

Case report: Personalized computational model guided ablation for left atrial flutter.

Atypical atrial flutter is seen post-ablation in patients, and it can be challenging to map. These flutters are typically set up around areas of scar in the left atrium. MRI can reliably identify left atrial scar. We propose a personalized computational model using patient specific scar information, to generate a monodomain model. In the model conductivities are adjusted for different tissue regions and flutter was induced with a premature pacing protocol. The model was tested prospectively in patients undergoing atypical flutter ablation. The simulation-predicted flutters were visualized and presented to clinicians. Validation of the computational model was motivated by recording from electroanatomical mapping. These personalized models successfully predicted clinically observed atypical flutter circuits and at times even better than invasive maps leading to flutter termination at isthmus sites predicted by the model.

Screening for generality in asymmetric catalysis.

Research in the field of asymmetric catalysis over the past half century has resulted in landmark advances, enabling the efficient synthesis of chiral building blocks, pharmaceuticals and natural products1-3. A small number of asymmetric catalytic reactions have been identified that display high selectivity across a broad scope of substrates; not coincidentally, these are the reactions that have the greatest impact on how enantioenriched compounds are synthesized4-8. We postulate that substrate generality in asymmetric catalysis is rare not simply because it is intrinsically difficult to achieve, but also because of the way chiral catalysts are identified and optimized9. Typical discovery campaigns rely on a single model substrate, and thus select for high performance in a narrow region of chemical space. Here we put forth a practical approach for using multiple model substrates to select simultaneously for both enantioselectivity and generality in asymmetric catalytic reactions from the outset10,11. Multisubstrate screening is achieved by conducting high-throughput chiral analyses by supercritical fluid chromatography-mass spectrometry with pooled samples. When applied to Pictet-Spengler reactions, the multisubstrate screening approach revealed a promising and unexpected lead for the general enantioselective catalysis of this important transformation, which even displayed high enantioselectivity for substrate combinations outside of the screening set.

Shorter distance between the esophagus and the left atrium is associated with higher rates of esophageal thermal injury after radiofrequency ablation.

BACKGROUND: Esophageal thermal injury (ETI) is a known and potentially serious complication of catheter ablation for atrial fibrillation. We intended to evaluate the distance between the esophagus and the left atrium posterior wall (LAPW) and its association with esophageal thermal injury. METHODS: A retrospective analysis of 73 patients who underwent esophagogastroduodenoscopy (EGD) after LA radiofrequency catheter ablation for symptomatic atrial fibrillation and pre-ablation magnetic resonance imaging (MRI) was used to identify the minimum distance between the inner lumen of the esophagus and the ablated atrial endocardium (pre-ablation atrial esophageal distance; pre-AED) and occurrence of ETI. Parameters of ablation index (AI, Visitag Surpoint) were collected in 30 patients from the CARTO3 system and compared with assess if ablation strategies and AI further impacted risk of ETI. RESULTS: Pre-AED was significantly larger in patients without ETI than those with ETI (5.23 ± 0.96 mm vs. 4.31 ± 0.75 mm, p < .001). Pre-AED showed high accuracy for predicting ETI with the best cutoff value of 4.37 mm. AI was statistically comparable between Visitag lesion markers with and without associated esophageal late gadolinium enhancement (LGE) detected by postablation MRI in the low-power long-duration ablation group (LPLD, 25-40 W for 10-30 s, 393.16 [308.62-408.86] vs. 406.58 [364.38-451.22], p = .16) and high-power short-duration group (HPSD, 50 W for 5-10 s, 336.14 [299.66-380.11] vs. 330.54 [286.21-384.71], p = .53), respectively. CONCLUSION: Measuring the distance between the LA and the esophagus in pre-ablation LGE-MRI could be helpful in predicting ETI after LAPW ablation.

Short-term natural course of esophageal thermal injury after ablation for atrial fibrillation.

INTRODUCTION: Esophageal injury is rare but potentially a devastating complication of atrial fibrillation (AF) ablation. The goal here was to provide insight into the short-term natural history of esophageal thermal injury (ETI) after radiofrequency catheter ablation (RFCA) for AFby esophagogastroduodenoscopy (EGD). METHODS: We screened patients who underwent RFCA for AF and EGD based on esophageal late gadolinium enhancement (LGE) in postablation magnetic resonance imaging. Patients with ETI diagnosed with EGD were included. We defined severity of ETI according to Kansas City classification: type 1: erythema; type 2: ulcers (2a: superficial; 2b deep); type 3 perforation (3a: perforation; 3b: perforation with atrioesophageal fistula [AEF]). Repeated EGD was performed within 1-14 days after the last EGD if recommended and possible until any certain healing signs (visible reduction in size without deepening of ETI or complete resolution) were observed. RESULTS: ETI was observed in 62 of 378 patients who underwent EGD after RFCA. Out of these 62 patients with ETI, 21% (13) were type 1, 50% (31) were type 2a and 29% (18) were type 2b at the initial EGD. All esophageal lesions, but one type 2b lesion that developed into an AEF, showed signs of healing in repeated EGD studies within 14 days after the procedure. The one type 2b lesion developing into an AEF showed an increase in size and ulcer deepening in repeat EGD 8 days after the procedure. CONCLUSION: We found that all ETI which did not progress to AEF presented healing signs within 14 days after the procedure and that worsening ETI might be an early signal for developing esophageal perforation.

Enantioselective Aryl-Iodide-Catalyzed Wagner-Meerwein Rearrangements.

We report a strategy for effecting catalytic, enantioselective carbocationic rearrangements through the intermediacy of alkyl iodanes as stereodefined carbocation equivalents. Asymmetric Wagner-Meerwein rearrangements of ß-substituted styrenes are catalyzed by the C2-symmetric aryl iodide 1 to provide access to enantioenriched 1,3-difluorinated molecules possessing interesting and well-defined conformational properties. Hammett and kinetic isotope effect studies, in combination with computational investigations, reveal that two different mechanisms are operative in these rearrangement reactions, with the pathway depending on the identity of the migrating group. In reactions involving alkyl-group migration, intermolecular fluoride attack is product- and enantio-determining. In contrast, reactions in which aryl rearrangement occurs proceed through an enantiodetermining intramolecular 1,2-migration prior to fluorination. The fact that both pathways are promoted by the same chiral aryl iodide catalyst with high enantioselectivity provides a compelling illustration of generality across reaction mechanisms in asymmetric catalysis.

Direct comparison of a novel antitachycardia pacing algorithm against present methods using virtual patient modeling.

BACKGROUND: Antitachycardia pacing (ATP) success rates as low as 50% for fast ventricular tachycardias (VTs) have been reported providing an opportunity for improved ATP to decrease shocks. OBJECTIVE: The purpose of this study was to determine how a new automated antitachycardia pacing (AATP) therapy would perform compared with traditional burst ATP using computer modeling to conduct a virtual study. METHODS: Virtual patient scenarios were constructed from magnetic resonance imaging and electrophysiological (EP) data. Cardiac EP simulation software (CARPEntry) was used to generate reentrant VT. Simulated VT exit sites were physician adjudicated against corresponding clinical 12-lead electrocardiograms. Burst ATP comprised 3 sequences of 8 pulses at 88% of VT cycle length, with each sequence decremented by 10 ms. AATP was limited to 3 sequences, with each sequence learning from the previous sequences. RESULTS: Two hundred fifty-nine unique ATP scenarios were generated from 7 unique scarred hearts. Burst ATP terminated 145 of 259 VTs (56%) and accelerated 2.0%. AATP terminated 189 of 259 VTs (73%) with the same acceleration rate. The 2 dominant ATP failure mechanisms were identified as (1) insufficient prematurity to close the excitable gap; and (2) failure to reach the critical isthmus of the VT. AATP reduced failures in these categories from 101 to 63 (44% reduction) without increasing acceleration. CONCLUSION: AATP successfully adapted ATP sequences to terminate VT episodes that burst ATP failed to terminate. AATP was successful with complex scar geometries and EP heterogeneity as seen in the real world.

Effective Ablation Settings That Predict Chronic Scar After Left Atrial Ablation.

OBJECTIVES: The goal of this study was to find effective parameters that can be used in real-time that result in chronic scar verified by left atrial (LA) late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). BACKGROUND: Automated annotation can be a useful tool while ablating in tagging areas that will result in scar, but the effective settings that best predict chronic scar are still unknown. METHODS: Patients underwent pulmonary vein isolation using a CARTO3 mapping system with a VISITAG Module and 3-month post-ablation LGE-CMR. The electroanatomical map (EAM) was used to retrospectively tag ablated areas with 5 different parameters: catheter stability; stability duration; force over time; minimum contact force; and impedance drop. The ablation tags in EAM were projected to the 3-month post-ablation LGE-CMR. Tags were divided into 2 groups depending on if they correlated with CMR-based scar tags (STAGs) or nonscar tags (NTAGs); the effective parameters were estimated for the 2 groups at different power levels. RESULTS: This study assessed 70 consecutive patients and 28,939 ablation tags. Ablation time and force time integral (FTI) were significantly larger in the STAG group. Mean contact force, change of catheter tip temperature, and impedance were not significantly different between STAGs and NTAGs. The minimum ablation time and FTI to make durable scar lesions were 17.6, 13.6, and 11.0 s and 226.1, 187.4, and 161.4 g at 25, 35, and 50 W, respectively. CONCLUSIONS: Minimum ablation time and FTI values are critical parameters that determine durable atrial scar creation and their minimum values vary with the ablation power setting.

Blanking period after radiofrequency ablation for atrial fibrillation guided by ablation lesion maturation based on serial MR imaging.

BACKGROUND: Recent guidelines recommend a 3-month blanking period after atrial fibrillation (AF) ablations, which are based on clinical observation. Our goal was to quantify the timeline of the radiofrequency ablation lesion maturation using serial late gadolinium enhancement-magnetic resonance imaging (LGE-MRI) and to develop a blanking period estimate based on visible lesion maturation. METHODS: Inclusion criteria targeted patients who underwent AF ablation and at least four MRI scans: at baseline before ablation, within 24 hours after (acute), between 24 hours and 90 days after (subacute), and more than 90 days after ablation (chronic). Central nonenhanced (NE) and surrounding hyperenhanced (HE) area volumes were measured and normalized to chronic lesion volume. RESULTS: This study assessed 75 patients with 309 MRIs. The acute lesion was heterogeneous with a HE region surrounding a central NE region in LGE-MRI; the acute volume of the total (HE + NE) lesion was 2.62 ± 0.46 times larger than that of the chronic lesion. Acute T2-weighted imaging also showed a relatively large area of edema. Both NE and HE areas gradually receded over time and NE was not observed after 30 days. Larger initial NE volume was associated with a significantly greater chronic scar volume and this total lesion volume receded to equal the chronic lesion size at approximately 72.5 days (95% prediction interval: 57.4-92.2). CONCLUSION: On the basis of serial MRI, atrial ablation lesions are often fully mature before the typical 90-day blanking period, which could support more timely clinical decision making for arrhythmia recurrence.

Deep Learning Based Prediction of Atrial Fibrillation Disease Progression with Endocardial Electrograms in a Canine Model.

OBJECTIVE: We sought to determine whether electrical patterns in endocardial wavefronts contained elements specific to atrial fibrillation (AF) disease progression. METHODS: A canine paced model (n=7, female mongrel, 29±2 kg) of persistent AF was endocardially mapped with a 64-electrode basket catheter during periods of AF at 1 month, 3 month, and 6 months post-implant of stimulator. A 50-layer residual network was then trained to map half-second electrogram samples to their source timepoint. RESULTS: The trained network achieved final validation and testing accuracies of 51.6 and 48.5% respectively. Per class F1 scores were 24%, 59%, and 53% for 1 month, 3 month, and 6 month inputs from the testing dataset. CONCLUSION: Differentiation of AF based on its time progression was shown to be feasible with a deep learning method. This is promising for differentiating treatment based on disease progression though low accuracy with earlier timepoints may be an obstacle to identifying nascent AF.

Matching Glycosyl Donor Reactivity to Sulfonate Leaving Group Ability Permits SN2 Glycosylations.

Here we demonstrate that highly ß-selective glycosylation reactions can be achieved when the electronics of a sulfonyl chloride activator and the reactivity of a glycosyl donor hemiacetal are matched. While these reactions are compatible with the acid- and base-sensitive protecting groups that are commonly used in oligosaccharide synthesis, these protecting groups are not relied upon to control selectivity. Instead, ß-selectivity arises from the stereoinversion of an α-glycosyl arylsulfonate in an SN2-like mechanism. Our mechanistic proposal is supported by NMR studies, kinetic isotope effect (KIE) measurements, and DFT calculations.

Passenger hotspot mutations in cancer driven by APOBEC3A and mesoscale genomic features.

Cancer drivers require statistical modeling to distinguish them from passenger events, which accumulate during tumorigenesis but provide no fitness advantage to cancer cells. The discovery of driver genes and mutations relies on the assumption that exact positional recurrence is unlikely by chance; thus, the precise sharing of mutations across patients identifies drivers. Examining the mutation landscape in cancer genomes, we found that many recurrent cancer mutations previously designated as drivers are likely passengers. Our integrated bioinformatic and biochemical analyses revealed that these passenger hotspot mutations arise from the preference of APOBEC3A, a cytidine deaminase, for DNA stem-loops. Conversely, recurrent APOBEC-signature mutations not in stem-loops are enriched in well-characterized driver genes and may predict new drivers. This demonstrates that mesoscale genomic features need to be integrated into computational models aimed at identifying mutations linked to diseases.

Changes in atrial electrophysiological and structural substrate and their relationship to histology in a long-term chronic canine atrial fibrillation model.

BACKGROUND: Atrial fibrillation (AF) is related to numerous electrophysiological changes; however, the extent of structural and electrophysiological remodeling with long-term AF is not well characterized. METHODS: Dogs (n = 6) were implanted with a neurostimulator in the right atrium (AF group). No implantation was done in the Control group (n = 3). Electroanatomical mapping was done prior to and following more than 6 months of AF. Magnetic resonance imaging was also done to assess structural remodeling. Animals were euthanized and tissue samples were acquired for histological analysis. RESULTS: A significant increase was seen in the left atrial (LA) volume among all AF animals (22.25 ± 12.60 cm3 vs 34.00 ± 12.23 cm3 , P = .01). Also, mean bipolar amplitude in the LA significantly decreased from 5.96 ± 2.17 mV at baseline to 3.23 ± 1.51 mV (P < .01) after chronic AF. Those significant changes occurred in each anterior, lateral, posterior, septal, and roof regions as well. Additionally, the dominant frequency (DF) in the LA increased from 7.02 ± 0.37 Hz to 10.12 ± 0.28 Hz at chronic AF (P < .01). Moreover, the percentage of fibrosis in chronic AF animals was significantly larger than that of control animals in each location (P < .01). CONCLUSIONS: Canine chronic AF is accompanied by a significant decrease in intracardiac bipolar amplitudes. These decreased electrogram amplitude values are still higher than traditional cut-off values used for diseased myocardial tissue. Despite these "normal" bipolar amplitudes, there is a significant increase in DF and tissue fibrosis.