Delocalized, asynchronous, closed-loop discovery of organic laser emitters.

Contemporary materials discovery requires intricate sequences of synthesis, formulation, and characterization that often span multiple locations with specialized expertise or instrumentation. To accelerate these workflows, we present a cloud-based strategy that enabled delocalized and asynchronous design-make-test-analyze cycles. We showcased this approach through the exploration of molecular gain materials for organic solid-state lasers as a frontier application in molecular optoelectronics. Distributed robotic synthesis and in-line property characterization, orchestrated by a cloud-based artificial intelligence experiment planner, resulted in the discovery of 21 new state-of-the-art materials. Gram-scale synthesis ultimately allowed for the verification of best-in-class stimulated emission in a thin-film device. Demonstrating the asynchronous integration of five laboratories across the globe, this workflow provides a blueprint for delocalizing-and democratizing-scientific discovery.

A Modular Communicative Leadless Pacing-Defibrillator System.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (ICD) is associated with fewer lead-related complications than a transvenous ICD; however, the subcutaneous ICD cannot provide bradycardia and antitachycardia pacing. Whether a modular pacing-defibrillator system comprising a leadless pacemaker in wireless communication with a subcutaneous ICD to provide antitachycardia and bradycardia pacing is safe remains unknown. METHODS: We conducted a multinational, single-group study that enrolled patients at risk for sudden death from ventricular arrhythmias and followed them for 6 months after implantation of a modular pacemaker-defibrillator system. The safety end point was freedom from leadless pacemaker-related major complications, evaluated against a performance goal of 86%. The two primary performance end points were successful communication between the pacemaker and the ICD (performance goal, 88%) and a pacing threshold of up to 2.0 V at a 0.4-msec pulse width (performance goal, 80%). RESULTS: We enrolled 293 patients, 162 of whom were in the 6-month end-point cohort and 151 of whom completed the 6-month follow-up period. The mean age of the patients was 60 years, 16.7% were women, and the mean (±SD) left ventricular ejection fraction was 33.1±12.6%. The percentage of patients who were free from leadless pacemaker-related major complications was 97.5%, which exceeded the prespecified performance goal. Wireless-device communication was successful in 98.8% of communication tests, which exceeded the prespecified goal. Of 151 patients, 147 (97.4%) had pacing thresholds of 2.0 V or less, which exceeded the prespecified goal. The percentage of episodes of arrhythmia that were successfully terminated by antitachycardia pacing was 61.3%, and there were no episodes for which antitachycardia pacing was not delivered owing to communication failure. Of 162 patients, 8 died (4.9%); none of the deaths were deemed to be related to arrhythmias or the implantation procedure. CONCLUSIONS: The leadless pacemaker in wireless communication with a subcutaneous ICD exceeded performance goals for freedom from major complications related to the leadless pacemaker, for communication between the leadless pacemaker and subcutaneous ICD, and for the percentage of patients with a pacing threshold up to 2.0 V at a 0.4-msec pulse width at 6 months. (Funded by Boston Scientific; MODULAR ATP ClinicalTrials.gov NCT04798768.).

Minimizing higher-order aggregation maximizes iron mobilization by small molecules.

The natural product hinokitiol mobilizes iron across lipid bilayers at low concentrations and restores hemoglobinization in iron transporter protein-deficient systems. But hinokitiol fails to similarly mobilize iron at higher concentrations, limiting its uses in chemical biology and medicine. Here we show that at higher concentrations, hinokitiol3:Fe(III) complexes form large, higher-order aggregates, leading to loss of transmembrane iron mobilization. Guided by this understanding and systematic structure-function studies enabled by modular synthesis, we identified FeM-1269, which minimally aggregates and dose-dependently mobilizes iron across lipid bilayers even at very high concentrations. In contrast to hinokitiol, FeM-1269 is also well-tolerated in animals at high doses for extended periods of time. In a mouse model of anemia of inflammation, FeM-1269 increases serum iron, transferrin saturation, hemoglobin and hematocrit. This rationally developed iron-mobilizing small molecule has enhanced potential as a molecular prosthetic for understanding and potentially treating iron transporter deficiencies.

Predictive value of the PRAETORIAN score for defibrillation test success in patients with subcutaneous ICD: A subanalysis of the PRAETORIAN-DFT trial.

BACKGROUND: The PRAETORIAN score estimates the risk of failure of subcutaneous implantable cardioverter-defibrillator (S-ICD) therapy by using generator and lead positioning on bidirectional chest radiographs. The PRospective randomized compArative trial of subcutanEous implanTable cardiOverter-defibrillatoR ImplANtation with and without DeFibrillation Testing (PRAETORIAN-DFT) investigates whether PRAETORIAN score calculation is noninferior to defibrillation testing (DFT) with regard to first shock efficacy in spontaneous events. OBJECTIVE: This prespecified subanalysis assessed the predictive value of the PRAETORIAN score for defibrillation success in induced ventricular arrhythmias. METHODS: This multicenter investigator-initiated trial randomized 965 patients between DFT and PRAETORIAN score calculation after de novo S-ICD implantation. Successful DFT was defined as conversion of induced ventricular arrhythmia in <5 seconds from shock delivery within 2 attempts. Bidirectional chest radiographs were obtained after implantation. The predictive value of the PRAETORIAN score for DFT success was calculated for patients in the DFT arm. RESULTS: In total, 482 patients were randomized to undergo DFT. Of these patients, 457 (95%) underwent DFT according to protocol, of whom 445 (97%) had successful DFT and 12 (3%) had failed DFT. A PRAETORIAN score of ≥90 had a positive predictive value of 25% for failed DFT, and a PRAETORIAN score of <90 had a negative predictive value of 99% for successful DFT. A PRAETORIAN score of ≥90 was the strongest independent predictor for failed DFT (odds ratio 33.77; confidence interval 6.13-279.95; P < .001). CONCLUSION: A PRAETORIAN score of <90 serves as a reliable indicator for DFT success in patients with S-ICD, and a PRAETORIAN score of ≥90 is a strong predictor for DFT failure.

Intraoperative Neurophysiological Monitoring During Lead Placement for Dorsal Root Ganglion Stimulation: A Literature Review and Case Series.

INTRODUCTION: Dorsal root ganglion stimulation (DRG-S) is a viable interventional option for intractable pain management. Although systematic data are lacking regarding the immediate neurologic complications of this procedure, intraoperative neurophysiological monitoring (IONM) can be a valuable tool to detect real-time neurologic changes and prompt intervention(s) during DRG-S performed under general anesthesia and deep sedation. MATERIALS AND METHODS: In our single-center case series, we performed multimodal IONM, including peripheral nerve somatosensory evoked potentials (pnSSEPs) and dermatomal somatosensory evoked potentials (dSSEPs), spontaneous electromyography (EMG), transcranial motor evoked potentials (MEPs), and electroencephalogram (EEG) for some trials and all permanent DRG-S lead placement per surgeon preference. Alert criteria for each IONM modality were established before data acquisition and collection. An IONM alert was used to implement an immediate repositioning of the lead to reduce any possible postoperative neurologic deficits. We reviewed the literature and summarized the current IONM modalities commonly applied during DRG-S, including somatosensory evoked potentials and EMG. Because DRG-S targets the dorsal roots, we hypothesized that including dSSEP would allow more sensitivity as a proxy for potential sensory changes under generalized anesthesia than would including standard pnSSEPs. RESULTS: From our case series of 22 consecutive procedures with 45 lead placements, one case had an alert immediately after DRG-S lead positioning. In this case, dSSEP attenuation was seen, indicating changes in the S1 dermatome, which occurred despite ipsilateral pnSSEP from the posterior tibial nerve remaining at baselines. The dSSEP alert prompted the surgeon to reposition the S1 lead, resulting in immediate recovery of the dSSEP to baseline status. The rate of IONM alerts reported intraoperatively was 4.55% per procedure and 2.22% per lead (n = 1). No neurologic deficits were reported after the procedure, resulting in no postoperative neurologic complications or deficits. No other IONM changes or alerts were observed from pnSSEP, spontaneous EMG, MEPs, or EEG modalities. Reviewing the literature, we noted challenges and potential deficiencies when using current IONM modalities for DRG-S procedures. CONCLUSIONS: Our case series suggests dSSEPs offer greater reliability than do pnSSEPs in quickly detecting neurologic changes, and subsequent neural injury, during DRG-S cases. We encourage future studies to focus on adding dSSEP to standard pnSSEP to provide a comprehensive, real-time neurophysiological assessment during lead placement for DRG-S. More investigation, collaboration, and evidence are required to evaluate, compare, and standardize comprehensive IONM protocols for DRG-S.

Computational prediction of complex cationic rearrangement outcomes.

Recent years have seen revived interest in computer-assisted organic synthesis1,2. The use of reaction- and neural-network algorithms that can plan multistep synthetic pathways have revolutionized this field1,3-7, including examples leading to advanced natural products6,7. Such methods typically operate on full, literature-derived 'substrate(s)-to-product' reaction rules and cannot be easily extended to the analysis of reaction mechanisms. Here we show that computers equipped with a comprehensive knowledge-base of mechanistic steps augmented by physical-organic chemistry rules, as well as quantum mechanical and kinetic calculations, can use a reaction-network approach to analyse the mechanisms of some of the most complex organic transformations: namely, cationic rearrangements. Such rearrangements are a cornerstone of organic chemistry textbooks and entail notable changes in the molecule's carbon skeleton8-12. The algorithm we describe and deploy at https://HopCat.allchemy.net/ generates, within minutes, networks of possible mechanistic steps, traces plausible step sequences and calculates expected product distributions. We validate this algorithm by three sets of experiments whose analysis would probably prove challenging even to highly trained chemists: (1) predicting the outcomes of tail-to-head terpene (THT) cyclizations in which substantially different outcomes are encoded in modular precursors differing in minute structural details; (2) comparing the outcome of THT cyclizations in solution or in a supramolecular capsule; and (3) analysing complex reaction mixtures. Our results support a vision in which computers no longer just manipulate known reaction types1-7 but will help rationalize and discover new, mechanistically complex transformations.

Tuning sterol extraction kinetics yields a renal-sparing polyene antifungal.

Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model1. Recently, the clinically vital but also highly renal-toxic small-molecule natural product amphotericin B was instead found to kill fungi primarily by forming extramembraneous sponge-like aggregates that extract ergosterol from lipid bilayers2-6. Here we show that rapid and selective extraction of fungal ergosterol can yield potent and renal-sparing polyene antifungals. Cholesterol extraction was found to drive the toxicity of amphotericin B to human renal cells. Our examination of high-resolution structures of amphotericin B sponges in sterol-free and sterol-bound states guided us to a promising structural derivative that does not bind cholesterol and is thus renal sparing. This derivative was also less potent because it extracts ergosterol more slowly. Selective acceleration of ergosterol extraction with a second structural modification yielded a new polyene, AM-2-19, that is renal sparing in mice and primary human renal cells, potent against hundreds of pathogenic fungal strains, resistance evasive following serial passage in vitro and highly efficacious in animal models of invasive fungal infections. Thus, rational tuning of the dynamics of interactions between small molecules may lead to better treatments for fungal infections that still kill millions of people annually7,8 and potentially other resistance-evasive antimicrobials, including those that have recently been shown to operate through supramolecular structures that target specific lipids9.

Impact of Age on Subcutaneous Implantable Cardioverter-Defibrillator in a Large Patient Cohort: Mid-Term Follow-Up.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) is an accepted alternative to transvenous (TV) ICD to provide defibrillation therapy to treat life-threatening ventricular tachyarrhythmias in high-risk patients. S-ICD outcomes by age group have not been reported. OBJECTIVES: In this study, the authors sought to report S-ICD outcomes in different age groups in a multicenter S-ICD post-approval study (PAS) involving the largest cohort of patients ever reported. METHODS: Patients were prospectively enrolled in the S-ICD PAS and stratified based on age: young, aged 15-34 years; adult, aged 35-69 years; and elderly, aged ≥70 years. Patient characteristics and clinical outcomes through 3 years of follow up after implantation were compared. RESULTS: The S-ICD PAS enrolled 1,637 patients. Elderly patients were more likely to receive an S-ICD as a replacement of a TV-ICD (15.1% elderly vs 12.3% adult vs 7.4% young). Secondary prevention indication decreased with age (32.7% young vs 22.2% adult vs 20.5% elderly). Mortality rate was significantly higher in the elderly group (24.0% elderly vs 13.0% adult vs 7.4% young; P < 0.0001), whereas the complication rate did not differ significantly (12.3% young vs 11.3% adult vs 8.1% elderly). Rates of appropriate shock (12.7% young vs 13.0% adult vs 13.8% elderly) and inappropriate shock (7.8% young vs 9.1% adult vs 8.8% elderly) rates did not differ between groups (P = 0.96 and P = 0.98, respectively). CONCLUSIONS: Implant complications and appropriate and inappropriate shock rates were similar among age groups. S-ICD for secondary prevention was more common in the young group. Replacing a TV-ICD for an S-ICD increases with age. (S-ICD System Post-Approval Study; NCT01736618).

Initial Experience With Intercostal Insertion of an Extravascular ICD Lead Compatible With Existing Pulse Generators.

BACKGROUND: This study assessed safety and feasibility of a novel extravascular implantable cardioverter defibrillator (ICD) lead when inserted anteriorly through a rib space and connected to various commercially available ICD pulse generators (PGs) placed in either a left mid-axillary or left pectoral pocket. Currently available or investigational, extravascular-ICDs include a subcutaneous or subxiphoid lead connected to customized extravascular-ICD PGs. METHODS: This novel extravascular-ICD (AtaCor Medical Inc, San Clemente, CA) employs a unique intercostal implant technique and is designed to function with commercial DF-4 ICD PGs. In this nonrandomized, single-center, acute study, 36 de novo or replacement ICD (transvenous ICD) patients enrolled to receive a concomitant extravascular-ICD lead inserted through an intercostal space along the left parasternal margin. extravascular-ICD leads were connected to DF-4 compatible ICD PGs positioned in either a left mid-axillary or pectoral pocket for acute sensing and defibrillation testing. Defibrillation testing started at 30 Joules (J) and stepped up or down in 5 to 10 joule increments depending on the success and limitations of the generator used. RESULTS: Successful acute defibrillation using ≤35 J was noted in 100% of left mid-axillary PG subjects (n=27, mean 16.3±8.6 J) and 83% of left pectoral PG subjects (n=6, mean 21.0±8.4 J). Furthermore, 24 of 27 (89%) of patients tested with a left, mid-axillary intermuscular PG had successful VF conversion with defibrillation energies at least 10 J below the maximum delivered output of the device. All evaluable episodes (n=93) were automatically sensed, detected, and shocked. No serious device-related intraoperative adverse events were observed. CONCLUSIONS: This first-in-human study documented the safe and reliable placement of a novel extravascular ICD lead with effective sensing and defibrillation of induced ventricular fibrillation using commercial DF-4 ICD PGs.

MIDA- and TIDA-Boronates Stabilize α-Radicals Through B-N Hyperconjugation.

Multifunctional organoboron compounds increasingly enable the simple generation of complex, Csp3 -rich small molecules. The ability of boron-containing functional groups to modify the reactivity of α-radicals has also enabled a myriad of chemical reactions. Boronic esters with vacant p-orbitals have a significant stabilizing effect on α-radicals due to delocalization of spin density into the empty orbital. The effect of coordinatively saturated derivatives, such as N-methyliminodiacetic acid (MIDA) boronates and counterparts, remains less clear. Herein, we demonstrate that coordinatively saturated MIDA and TIDA boronates stabilize secondary alkyl α-radicals via σB-N hyperconjugation in a manner that allows site-selective C-H bromination. DFT calculated radical stabilization energies and spin density maps as well as LED NMR kinetic analysis of photochemical bromination rates of different boronic esters further these findings. This work clarifies that the α-radical stabilizing effect of boronic esters does not only proceed via delocalization of radical character into vacant boron p-orbitals, but that hyperconjugation of tetrahedral boron-containing functional groups and their ligand electron delocalizing ability also play a critical role. These findings establish boron ligands as a useful dial for tuning reactivity at the α-carbon.

Segmental Dynamics of Membranous Cholesterol are Coupled.

Cholesterol promotes the structural integrity of the fluid cell membrane and interacts dynamically with many membrane proteins to regulate function. Understanding site-resolved cholesterol structural dynamics is thus important. This long-standing challenge has thus far been addressed, in part, by selective isotopic labeling approaches. Here we present a new 3D solid-state NMR (SSNMR) experiment utilizing scalar 13C-13C polarization transfer and recoupling of the 1H-13C interactions in order to determine average dipolar couplings for all 1H-13C vectors in uniformly 13C-enriched cholesterol. The experimentally determined order parameters (OP) agree exceptionally well with molecular dynamics (MD) trajectories and reveal coupling among several conformational degrees of freedom in cholesterol molecules. Quantum chemistry shielding calculations further support this conclusion and specifically demonstrate that ring tilt and rotation are coupled to changes in tail conformation and that these coupled segmental dynamics dictate the orientation of cholesterol. These findings advance our understanding of physiologically relevant dynamics of cholesterol, and the methods that revealed them have broader potential to characterize how structural dynamics of other small molecules impact their biological functions.

Design and rationale of the MODULAR ATP global clinical trial: A novel intercommunicative leadless pacing system and the subcutaneous implantable cardioverter-defibrillator.

Background: The subcutaneous implantable cardioverter-defibrillator (S-ICD) has demonstrated safety and efficacy for the treatment of malignant ventricular arrhythmias. However, a limitation of the S-ICD lies in the inability to either pace-terminate ventricular tachycardia or provide prolonged bradycardia pacing support. Objective: The rationale and design of a prospective, single-arm, multinational trial of an intercommunicative leadless pacing system integrated with the S-ICD will be presented. Methods: A technical description of the modular cardiac rhythm management (mCRM) system (EMPOWER leadless pacemaker and EMBLEM S-ICD) and the implantation procedure is provided. MODULAR ATP (Effectiveness of the EMPOWER™ Modular Pacing System and EMBLEM™ Subcutaneous ICD to Communicate Antitachycardia Pacing) is a multicenter, international trial enrolling up to 300 patients at risk of sudden cardiac death at up to 60 centers trial design. The safety endpoint of freedom from major complications related to the mCRM system or implantation procedure at 6 months and 2 years are significantly higher than 86% and 81%, respectively, and all-cause survival is significantly >85% at 2 years. Results: Efficacy endpoints are that at 6 months mCRM communication success is significantly higher than 88% and the percentage of subjects with low and stable thresholds is significantly higher than 80%. Substudies to evaluate rate-responsive features and performance of the pacing module are also described. Conclusion: The MODULAR ATP global clinical trial will prospectively test the safety and efficacy of the first intercommunicating leadless pacing system with the S-ICD. This trial will allow for robust validation of device-device communication, pacing performance, rate responsiveness, and system safety.

Postapproval Study of a Subcutaneous Implantable Cardioverter-Defibrillator System.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) was developed to avoid complications related to transvenous implantable cardioverter-defibrillator (TV-ICD) leads. Device safety and efficacy were demonstrated previously with atypical clinical patients or limited follow-up. OBJECTIVES: The S-ICD PAS (Subcutaneous Implantable Cardioverter-Defibrillator System Post Approval Study) is a real-world, multicenter, registry of U.S. centers that was designed to assess long-term S-ICD safety and efficacy in a diverse group of patients and implantation centers. METHODS: Patients were enrolled in 86 U.S. centers with standard S-ICD indications and were observed for up to 5 years. Efficacy endpoints were first and final shock efficacy. Safety endpoints were complications directly related to the S-ICD system or implantation procedure. Endpoints were assessed using prespecified performance goals. RESULTS: A total of 1,643 patients were prospectively enrolled, with a median follow-up of 4.2 years. All prespecified safety and efficacy endpoint goals were met. Shock efficacy rates for discrete episodes of ventricular tachycardia or ventricular fibrillation were 98.4%, and they did not differ significantly across follow-up years (P = 0.68). S-ICD-related and electrode-related complication-free rates were 93.4% and 99.3%, respectively. Only 1.6% of patients had their devices replaced by a TV-ICD for a pacing need. Cumulative all-cause mortality was 21.7%. CONCLUSIONS: In the largest prospective study of the S-ICD to date, all study endpoints were met, despite a cohort with more comorbidities than in most previous trials. Complication rates were low and shock efficacy was high. These results demonstrate the 5-year S-ICD safety and efficacy for a large, diverse cohort of S-ICD recipients. (Subcutaneous Implantable Cardioverter-Defibrillator [S-ICD] System Post Approval Study [PAS]; NCT01736618).

A Materials Acceleration Platform for Organic Laser Discovery.

Conventional materials discovery is a laborious and time-consuming process that can take decades from initial conception of the material to commercialization. Recent developments in materials acceleration platforms promise to accelerate materials discovery using automation of experiments coupled with machine learning. However, most of the automation efforts in chemistry focus on synthesis and compound identification, with integrated target property characterization receiving less attention. In this work, an automated platform is introduced for the discovery of molecules as gain mediums for organic semiconductor lasers, a problem that has been challenging for conventional approaches. This platform encompasses automated lego-like synthesis, product identification, and optical characterization that can be executed in a fully integrated end-to-end fashion. Using this workflow to screen organic laser candidates, discovered eight potential candidates for organic lasers is discovered. The lasing threshold of four molecules in thin-film devices and find two molecules with state-of-the-art performance is tested. These promising results show the potential of automated synthesis and screening for accelerated materials development.

Closed-loop optimization of general reaction conditions for heteroaryl Suzuki-Miyaura coupling.

General conditions for organic reactions are important but rare, and efforts to identify them usually consider only narrow regions of chemical space. Discovering more general reaction conditions requires considering vast regions of chemical space derived from a large matrix of substrates crossed with a high-dimensional matrix of reaction conditions, rendering exhaustive experimentation impractical. Here, we report a simple closed-loop workflow that leverages data-guided matrix down-selection, uncertainty-minimizing machine learning, and robotic experimentation to discover general reaction conditions. Application to the challenging and consequential problem of heteroaryl Suzuki-Miyaura cross-coupling identified conditions that double the average yield relative to a widely used benchmark that was previously developed using traditional approaches. This study provides a practical road map for solving multidimensional chemical optimization problems with large search spaces.

Outcomes and challenges of the provisional stenting technique: Insights from the PROGRESS-BIFURCATION registry.

BACKGROUND: Provisional stenting is the most commonly used coronary bifurcation stenting strategy. METHODS: We examined the clinical and angiographic characteristics, challenges encountered, and procedural outcomes with the provisional bifurcation stenting strategy in the Prospective Global Registry of Percutaneous Coronary Intervention (PCI) in Bifurcation Lesions (PROGRESS-BIFURCATION, NCT05100992). RESULTS: Provisional stenting was used in 334 of 430 bifurcation interventions (78%). Technical success was lower (95% vs. 100%, p = 0.017) in provisional, but procedural success (90% vs. 95%, p = 0.095) and incidence of in-hospital major adverse cardiovascular events were similar (5% vs. 5%, p = 0.945) compared with two-stent strategies. Provisional was less often preferred in left main/left anterior descending involvement (47% vs. 73%, p < 0.001). Provisional stenting cases had smaller side branch (SB) diameter (2.4 ± 0.5 vs. 2.7 ± 0.6 mm, p < 0.001), shorter SB lesion length (5 [3-8] vs. 10 [5-10] mm, p < 0.001), less SB diameter stenosis (46 ± 35 vs. 81 ± 20%, p < 0.001), and were less likely to be Medina 1,1,1 (34% vs. 73%, p < 0.001). PCI challenges were less common (30% vs. 58%, p < 0.001) with provisional stenting: (1) rewiring difficulty (43%) that was overcome with use of a different wire (74%) or microcatheter (46%); (2) inability to deliver a stent (22%) or balloon (9%) that was overcome with use of a smaller balloon (88%), rewiring (25%), or increased support/microcatheter (25%). CONCLUSIONS: Provisional bifurcation stenting was more often performed in distal lesions with less SB involvement and had lower technical success, but similar procedural success and complications compared with two-stent strategies.

FAIR data pipeline: provenance-driven data management for traceable scientific workflows.

Modern epidemiological analyses to understand and combat the spread of disease depend critically on access to, and use of, data. Rapidly evolving data, such as data streams changing during a disease outbreak, are particularly challenging. Data management is further complicated by data being imprecisely identified when used. Public trust in policy decisions resulting from such analyses is easily damaged and is often low, with cynicism arising where claims of 'following the science' are made without accompanying evidence. Tracing the provenance of such decisions back through open software to primary data would clarify this evidence, enhancing the transparency of the decision-making process. Here, we demonstrate a Findable, Accessible, Interoperable and Reusable (FAIR) data pipeline. Although developed during the COVID-19 pandemic, it allows easy annotation of any data as they are consumed by analyses, or conversely traces the provenance of scientific outputs back through the analytical or modelling source code to primary data. Such a tool provides a mechanism for the public, and fellow scientists, to better assess scientific evidence by inspecting its provenance, while allowing scientists to support policymakers in openly justifying their decisions. We believe that such tools should be promoted for use across all areas of policy-facing research. This article is part of the theme issue 'Technical challenges of modelling real-life epidemics and examples of overcoming these'.

Device-related complications in subcutaneous versus transvenous ICD: a secondary analysis of the PRAETORIAN trial.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) is developed to overcome lead-related complications and systemic infections, inherent to transvenous ICD (TV-ICD) therapy. The PRAETORIAN trial demonstrated that the S-ICD is non-inferior to the TV-ICD with regard to the combined primary endpoint of inappropriate shocks and complications. This prespecified secondary analysis evaluates all complications in the PRAETORIAN trial. METHODS AND RESULTS: The PRAETORIAN trial is an international, multicentre, randomized trial in which 849 patients with an indication for ICD therapy were randomized to receive an S- ICD (N = 426) or TV-ICD (N = 423) and followed for a median of 49 months. Endpoints were device-related complications, lead-related complications, systemic infections, and the need for invasive interventions. Thirty-six device-related complications occurred in 31 patients in the S-ICD group of which bleedings were the most frequent. In the TV-ICD group, 49 complications occurred in 44 patients of which lead dysfunction was most frequent (HR: 0.69; P = 0.11). In both groups, half of all complications were within 30 days after implantation. Lead-related complications and systemic infections occurred significantly less in the S-ICD group compared with the TV-ICD group (P < 0.001, P = 0.03, respectively). Significantly more complications required invasive interventions in the TV-ICD group compared with the S-ICD group (8.3% vs. 4.3%, HR: 0.59; P = 0.047). CONCLUSION: This secondary analysis shows that lead-related complications and systemic infections are more prevalent in the TV-ICD group compared with the S-ICD group. In addition, complications in the TV-ICD group were more severe as they required significantly more invasive interventions. This data contributes to shared decision-making in clinical practice.

Infection in patients with subcutaneous implantable cardioverter-defibrillator: Results of the S-ICD Post Approval Study.

BACKGROUND: Early subcutaneous implantable cardioverter-defibrillator (S-ICD) studies included atypical cohorts of patients who were younger with fewer comorbidities. Recent S-ICD studies included patient populations with more comorbidities. OBJECTIVES: The goals of this study were to determine the incidence and predictors of S-ICD-related infection over a 3-year follow-up period and to use these results to develop an infection risk score. METHODS: The S-ICD Post Approval Study is a US prospective registry of 1637 patients. Baseline demographic characteristics and outcomes with 3-year postimplantation follow-up were compared between patients with and without device-related infection. A risk score was derived from multivariable proportional hazards analysis of 22 variables. RESULTS: Infection was observed in 55 patients (3.3%), with 69% of infections occurring within 90 days and a vast majority (92.7%) within 1 year of implantation. Late infections more likely involved device erosion; no infections occurred after year 2. The annual mortality rate postinfection was 0.6%/y. No lead extraction complications or bacteremia related to infection were observed. An infection risk score was created with diabetes, age, prior transvenous ICD implant, and ejection fraction as predictors. Patients with a risk score of ≥3 had an 8.8 hazard ratio (95% confidence interval 2.8-16.3) of infection compared with a 0 risk score. CONCLUSION: Infection rates in the S-ICD Post Approval Study were similar to other S-ICD populations and not associated with systemic blood-borne infections. Late infection (>1 year) is uncommon and associated with system erosion. A high-risk infection cohort can be identified that may facilitate preventive measures.