Using real-world data from health systems to evaluate the safety and effectiveness of a catheter to treat ischemic ventricular tachycardia.

BACKGROUND: The ThermoCool STSF catheter is used for ablation of ischemic ventricular tachycardia (VT) in routine clinical practice, although outcomes have not been studied and the catheter does not have Food and Drug Administration (FDA) approval for this indication. We used real-world health system data to evaluate its safety and effectiveness for this indication. METHODS: Among patients undergoing ischemic VT ablation with the ThermoCool STSF catheter pooled across two health systems (Mercy Health and Mayo Clinic), the primary safety composite outcome of death, thromboembolic events, and procedural complications within 7 days was compared to a performance goal of 15%, which is twice the expected proportion of the primary composite safety outcome based on prior studies. The exploratory effectiveness outcome of rehospitalization for VT or heart failure or repeat VT ablation at up to 1 year was averaged across health systems among patients treated with the ThermoCool STSF vs. ST catheters. RESULTS: Seventy total patients received ablation for ischemic VT using the ThermoCool STSF catheter. The primary safety composite outcome occurred in 3/70 (4.3%; 90% CI, 1.2-10.7%) patients, meeting the pre-specified performance goal, p = 0.0045. At 1 year, the effectiveness outcome risk difference (STSF-ST) at Mercy was - 0.4% (90% CI: - 25.2%, 24.3%) and at Mayo Clinic was 12.6% (90% CI: - 13.0%, 38.4%); the average risk difference across both institutions was 5.8% (90% CI: - 12.0, 23.7). CONCLUSIONS: The ThermoCool STSF catheter was safe and appeared effective for ischemic VT ablation, supporting continued use of the catheter and informing possible FDA label expansion. Health system data hold promise for real-world safety and effectiveness evaluation of cardiovascular devices.

Integrating real-world data to assess cardiac ablation device outcomes in a multicenter study using the OMOP common data model for regulatory decisions: implementation and evaluation.

The objective of this study is to describe application of the Observational Medical Outcomes Partnership (OMOP) common data model (CDM) to support medical device real-world evaluation in a National Evaluation System for health Technology Coordinating Center (NESTcc) Test-Case involving 2 healthcare systems, Mercy Health and Mayo Clinic. CDM implementation was coordinated across 2 healthcare systems with multiple hospitals to aggregate both medical device data from supply chain databases and patient outcomes and covariates from electronic health record data. Several data quality assurance (QA) analyses were implemented on the OMOP CDM to validate the data extraction, transformation, and load (ETL) process. OMOP CDM-based data of relevant patient encounters were successfully established to support studies for FDA regulatory submissions. QA analyses verified that the data transformation was robust between data sources and OMOP CDM. Our efforts provided useful insights in real-world data integration using OMOP CDM for medical device evaluation coordinated across multiple healthcare systems.

Safety and Effectiveness of a Catheter With Contact Force and 6-Hole Irrigation for Ablation of Persistent Atrial Fibrillation in Routine Clinical Practice.

Importance: The ThermoCool SmartTouch catheter (ablation catheter with contact force and 6-hole irrigation [CF-I6]) is approved by the US Food and Drug Administration (FDA) for paroxysmal atrial fibrillation (AF) ablation and used in routine clinical practice for persistent AF ablation, although clinical outcomes for this indication are unknown. There is a need to understand whether data from routine clinical practice can be used to conduct regulatory-grade evaluations and support label expansions. Objective: To use health system data to compare the safety and effectiveness of the CF-I6 catheter for persistent AF ablation with the ThermoCool SmartTouch SurroundFlow catheter (ablation catheter with contact force and 56-hole irrigation [CF-I56]), which is approved by the FDA for this indication. Design, Setting, and Participants: This retrospective, comparative-effectiveness cohort study included patients undergoing catheter ablation for persistent AF at Mercy Health or Mayo Clinic from January 1, 2014, to April 30, 2021, with up to a 1-year follow-up using electronic health record data. Exposures: Use of the CF-I6 or CF-I56 catheter. Main Outcomes and Measures: The primary safety outcome was a composite of death, thromboembolic events, and procedural complications within 7 to 90 days. The exploratory effectiveness outcome was a composite of AF-related hospitalization events after a 90-day blanking period. Propensity score weighting was used to balance baseline covariates. Risk differences were estimated between catheter groups and averaged across the 2 health care systems, testing for noninferiority of the CF-I6 vs the CF-I56 catheter with respect to the safety outcome using 2-sided 90% CIs. Results: Overall, 1450 patients (1034 [71.3%] male; 1397 [96.3%] White) underwent catheter ablation for persistent AF, including 949 at Mercy Health (186 CF-I6 and 763 CF-I56; mean [SD] age, 64.9 [9.2] years) and 501 at Mayo Clinic (337 CF-I6 and 164 CF-I56; mean [SD] age, 63.7 [9.5] years). A total of 798 (55.0%) had been treated with class I or III antiarrhythmic drugs before ablation. The safety outcome (CF-I6 - CF-I56) was similar at both Mercy Health (1.3%; 90% CI, -2.1% to 4.6%) and Mayo Clinic (-3.8%; 90% CI, -11.4% to 3.7%); the mean difference was noninferior, with a mean of 0.5% (90% CI, -2.6% to 3.5%; P < .001). The effectiveness was similar at 12 months between the 2 catheter groups (mean risk difference, -1.8%; 90% CI, -7.3% to 3.7%). Conclusions and Relevance: In this cohort study, the CF-I6 catheter met the prespecified noninferiority safety criterion for persistent AF ablation compared with the CF-I56 catheter, and effectiveness was similar. This study demonstrates the ability of electronic health care system data to enable safety and effectiveness evaluations of medical devices.

Feasibility of using real-world data in the evaluation of cardiac ablation catheters: a test-case of the National Evaluation System for Health Technology Coordinating Center.

OBJECTIVES: To determine the feasibility of using real-world data to assess the safety and effectiveness of two cardiac ablation catheters for the treatment of persistent atrial fibrillation and ischaemic ventricular tachycardia. DESIGN: Retrospective cohort. SETTING: Three health systems in the USA. PARTICIPANTS: Patients receiving ablation with the two ablation catheters of interest at any of the three health systems. MAIN OUTCOME MEASURES: Feasibility of identifying the medical devices and participant populations of interest as well as the duration of follow-up and positive predictive values (PPVs) for serious safety (ischaemic stroke, acute heart failure and cardiac tamponade) and effectiveness (arrhythmia-related hospitalisation) clinical outcomes of interest compared with manual chart validation by clinicians. RESULTS: Overall, the catheter of interest for treatment of persistent atrial fibrillation was used for 4280 ablations and the catheter of interest for ischaemic ventricular tachycardia was used 1516 times across the data available within the three health systems. The duration of patient follow-up in the three health systems ranged from 91% to 97% at ≥7 days, 89% to 96% at ≥30 days, 77% to 90% at ≥6 months and 66% to 84% at ≥1 year. PPVs were 63.4% for ischaemic stroke, 96.4% for acute heart failure, 100% at one health system for cardiac tamponade and 55.7% for arrhythmia-related hospitalisation. CONCLUSIONS: It is feasible to use real-world health system data to evaluate the safety and effectiveness of cardiac ablation catheters, though evaluations must consider the implications of variation in follow-up and endpoint ascertainment among health systems.

The avocado genome informs deep angiosperm phylogeny, highlights introgressive hybridization, and reveals pathogen-influenced gene space adaptation.

The avocado, Persea americana, is a fruit crop of immense importance to Mexican agriculture with an increasing demand worldwide. Avocado lies in the anciently diverged magnoliid clade of angiosperms, which has a controversial phylogenetic position relative to eudicots and monocots. We sequenced the nuclear genomes of the Mexican avocado race, P. americana var. drymifolia, and the most commercially popular hybrid cultivar, Hass, and anchored the latter to chromosomes using a genetic map. Resequencing of Guatemalan and West Indian varieties revealed that ∼39% of the Hass genome represents Guatemalan source regions introgressed into a Mexican race background. Some introgressed blocks are extremely large, consistent with the recent origin of the cultivar. The avocado lineage experienced 2 lineage-specific polyploidy events during its evolutionary history. Although gene-tree/species-tree phylogenomic results are inconclusive, syntenic ortholog distances to other species place avocado as sister to the enormous monocot and eudicot lineages combined. Duplicate genes descending from polyploidy augmented the transcription factor diversity of avocado, while tandem duplicates enhanced the secondary metabolism of the species. Phenylpropanoid biosynthesis, known to be elicited by Colletotrichum (anthracnose) pathogen infection in avocado, is one enriched function among tandems. Furthermore, transcriptome data show that tandem duplicates are significantly up- and down-regulated in response to anthracnose infection, whereas polyploid duplicates are not, supporting the general view that collections of tandem duplicates contribute evolutionarily recent "tuning knobs" in the genome adaptive landscapes of given species.

Altered Gene Regulatory Networks Are Associated With the Transition From C3 to Crassulacean Acid Metabolism in Erycina (Oncidiinae: Orchidaceae).

Crassulacean acid metabolism (CAM) photosynthesis is a modification of the core C3 photosynthetic pathway that improves the ability of plants to assimilate carbon in water-limited environments. CAM plants fix CO2 mostly at night, when transpiration rates are low. All of the CAM pathway genes exist in ancestral C3 species, but the timing and magnitude of expression are greatly altered between C3 and CAM species. Understanding these regulatory changes is key to elucidating the mechanism by which CAM evolved from C3. Here, we use two closely related species in the Orchidaceae, Erycina pusilla (CAM) and Erycina crista-galli (C3), to conduct comparative transcriptomic analyses across multiple time points. Clustering of genes with expression variation across the diel cycle revealed some canonical CAM pathway genes similarly expressed in both species, regardless of photosynthetic pathway. However, gene network construction indicated that 149 gene families had significant differences in network connectivity and were further explored for these functional enrichments. Genes involved in light sensing and ABA signaling were some of the most differently connected genes between the C3 and CAM Erycina species, in agreement with the contrasting diel patterns of stomatal conductance in C3 and CAM plants. Our results suggest changes to transcriptional cascades are important for the transition from C3 to CAM photosynthesis in Erycina.

Genome of the pitcher plant Cephalotus reveals genetic changes associated with carnivory.

Carnivorous plants exploit animals as a nutritional source and have inspired long-standing questions about the origin and evolution of carnivory-related traits. To investigate the molecular bases of carnivory, we sequenced the genome of the heterophyllous pitcher plant Cephalotus follicularis, in which we succeeded in regulating the developmental switch between carnivorous and non-carnivorous leaves. Transcriptome comparison of the two leaf types and gene repertoire analysis identified genetic changes associated with prey attraction, capture, digestion and nutrient absorption. Analysis of digestive fluid proteins from C. follicularis and three other carnivorous plants with independent carnivorous origins revealed repeated co-options of stress-responsive protein lineages coupled with convergent amino acid substitutions to acquire digestive physiology. These results imply constraints on the available routes to evolve plant carnivory.

Long-read sequencing uncovers the adaptive topography of a carnivorous plant genome.

Utricularia gibba, the humped bladderwort, is a carnivorous plant that retains a tiny nuclear genome despite at least two rounds of whole genome duplication (WGD) since common ancestry with grapevine and other species. We used a third-generation genome assembly with several complete chromosomes to reconstruct the two most recent lineage-specific ancestral genomes that led to the modern U. gibba genome structure. Patterns of subgenome dominance in the most recent WGD, both architectural and transcriptional, are suggestive of allopolyploidization, which may have generated genomic novelty and led to instantaneous speciation. Syntenic duplicates retained in polyploid blocks are enriched for transcription factor functions, whereas gene copies derived from ongoing tandem duplication events are enriched in metabolic functions potentially important for a carnivorous plant. Among these are tandem arrays of cysteine protease genes with trap-specific expression that evolved within a protein family known to be useful in the digestion of animal prey. Further enriched functions among tandem duplicates (also with trap-enhanced expression) include peptide transport (intercellular movement of broken-down prey proteins), ATPase activities (bladder-trap acidification and transmembrane nutrient transport), hydrolase and chitinase activities (breakdown of prey polysaccharides), and cell-wall dynamic components possibly associated with active bladder movements. Whereas independently polyploid Arabidopsis syntenic gene duplicates are similarly enriched for transcriptional regulatory activities, Arabidopsis tandems are distinct from those of U. gibba, while still metabolic and likely reflecting unique adaptations of that species. Taken together, these findings highlight the special importance of tandem duplications in the adaptive landscapes of a carnivorous plant genome.