MolScore: a scoring, evaluation and benchmarking framework for generative models in de novo drug design.

Generative models are undergoing rapid research and application to de novo drug design. To facilitate their application and evaluation, we present MolScore. MolScore already contains many drug-design-relevant scoring functions commonly used in benchmarks such as, molecular similarity, molecular docking, predictive models, synthesizability, and more. In addition, providing performance metrics to evaluate generative model performance based on the chemistry generated. With this unification of functionality, MolScore re-implements commonly used benchmarks in the field (such as GuacaMol, MOSES, and MolOpt). Moreover, new benchmarks can be created trivially. We demonstrate this by testing a chemical language model with reinforcement learning on three new tasks of increasing complexity related to the design of 5-HT2a ligands that utilise either molecular descriptors, 266 pre-trained QSAR models, or dual molecular docking. Lastly, MolScore can be integrated into an existing Python script with just three lines of code. This framework is a step towards unifying generative model application and evaluation as applied to drug design for both practitioners and researchers. The framework can be found on GitHub and downloaded directly from the Python Package Index.Scientific ContributionMolScore is an open-source platform to facilitate generative molecular design and evaluation thereof for application in drug design. This platform takes important steps towards unifying existing benchmarks, providing a platform to share new benchmarks, and improves customisation, flexibility and usability for practitioners over existing solutions.

Cryothermal energy demonstrates shorter ablation time and lower complication rates compared with radiofrequency in surgical hybrid ablation for recurrent ventricular tachycardia.

BACKGROUND: Recurrent ventricular tachycardia (VT) after prior endocardial catheter ablation(s) presents challenges in the setting of prior cardiac surgery where percutaneous epicardial access may not be feasible. OBJECTIVE: The purpose of this study was to compare the outcomes of cryothermal vs radiofrequency ablation in direct surgical epicardial access procedures. METHODS: We performed a retrospective study of consecutive surgical epicardial VT ablation cases. Surgical cases using cryothermal vs radiofrequency ablation were analyzed and outcomes were compared. RESULTS: Between 2009 and 2022, 43 patients underwent either a cryothermal (n = 17) or a radiofrequency (n = 26) hybrid epicardial ablation procedure with direct surgical access. Both groups were similarly matched for age, sex, etiology of VT, and comorbidities with a high burden of refractory VT despite previous endocardial and/or percutaneous epicardial ablation procedures. The surgical access site was lateral thoracotomy (76.5%) in the cryothermal ablation group compared with lateral thoracotomy (42.3%) and subxiphoid approach (38.5%) in the radiofrequency group, with the remainder in both groups performed via median sternotomy. The ablation time was significantly shorter in those undergoing cryothermal ablation vs radiofrequency ablation (11.54 ± 15.5 minutes vs 48.48 ± 23.6 minutes; P < .001). There were no complications in the cryothermal ablation group compared with 6 patients with complications in the radiofrequency group. Recurrent VT episodes and all-cause mortality were similar in both groups. CONCLUSION: Hybrid surgical VT ablation with cryothermal or radiofrequency energy demonstrated similar efficacy outcomes. Cryothermal ablation was more efficient and safer than radiofrequency in a surgical setting and should be considered when surgical access is required.

Ventricular Parasystole in Cardiomyopathy Patients: A Link Between His-Purkinje System Damage and Ventricular Fibrillation.

BACKGROUND: The clinical relevance and prognostic implications of ventricular parasystole are unknown. OBJECTIVES: This study sought to assess the prevalence of ventricular parasystole in patients with implantable cardioverter-defibrillators (ICDs) and ventricular parasystole's association with ventricular arrhythmias and conduction system abnormalities. METHODS: This study retrospectively evaluated patients who underwent ICD interrogation at a single center between June 1, 2019, and August 31, 2020, and reviewed all available ICD and electrocardiogram data. This study identified patients with ventricular parasystole and compared the prevalence of ventricular fibrillation (VF), ventricular tachycardia (VT), and new conduction system abnormalities in those with ≥5 years of intrinsic QRS-complex electrocardiograms to those without parasystole. RESULTS: This study included 374 patients (age 57 ± 21 years, 72% male, 45% nonischemic, 32% ischemic cardiomyopathy), of which, 104 (28%) had VT only, 39 (10%) VF only, and 10 (3%) both VT/VF. Ventricular parasystole was identified in 33 patients (9%); parasystolic foci were predominantly from the His-Purkinje system. Compared with those without parasystole, patients with parasystole had a significantly higher rate of VF (36% vs 11%; P < 0.01), but not VT (42% vs 29%; P = 0.12). Patients with parasystole, compared with those without parasystole, had a higher prevalence of new conduction abnormalities, particularly progressive intraventricular conduction delay (11 of 18 [61%] vs 12 of 83 [14%]; P < 0.01) and new right bundle branch block (4 of 18 [22%] vs 1 of 83 [1%]; P < 0.01). CONCLUSIONS: Ventricular parasystole was strongly associated with new conduction system abnormalities and VF in patients who have cardiomyopathy with ICDs, suggesting a potential link between VF and His-Purkinje damage in this patient population.

Sudden cardiac arrest in athletes and strategies to optimize preparedness.

Sudden cardiac arrest (SCA) is the leading cause of death in young athletes. Despite efforts to improve preparedness for cardiac emergencies, the incidence of out-of-hospital cardiac arrests in athletes remains high, and bystander awareness and readiness for SCA support are inadequate. Initiatives such as designing an emergency action plan (EAP) and mandating training in cardiopulmonary resuscitation (CPR) and automated external defibrillator use (AED) for team members and personnel can contribute to improved survival rates in SCA cases. This review provides an overview of SCA in athletes, focusing on identifying populations at the highest risk and evaluating the effectiveness of different screening practices in detecting conditions that may lead to SCA. We summarize current practices and recommendations for improving the response to SCA events, and we highlight the need for ongoing efforts to optimize preparedness through the implementation of EAPs and the training of individuals in CPR and AED use. Additionally, we propose a call to action to increase awareness and training in EAP development, CPR, and AED use for team members and personnel. To improve outcomes of SCA cases in athletes, it is crucial to enhance bystander awareness and preparedness for cardiac emergencies. Implementing EAPs and providing training in CPR and AED use for team members and personnel are essential steps toward improving survival rates in SCA cases.

Magnetic resonance imaging is safe in patients with left bundle branch pacing.

BACKGROUND: The use of left bundle branch pacing (LBBP) has dramatically increased since it was first described in 2016, but to date there are no published data on the safety of performing magnetic resonance imaging (MRI) in these patients. METHODS: Patients with LBBP who underwent MRI between January 2016 and October 2022 were retrospectively studied in our clinical center, which has a special program for imaging patients with cardiac devices. All patients underwent close cardiac monitoring throughout the MRI scans. Occurrence of arrhythmias or other adverse effects during MRI were assessed. LBBP lead parameters immediately pre- and post-MRI and at an outpatient follow-up were compared. RESULTS: Fifteen patients with LBBP underwent a total of 19 MRI sessions during the study period. Lead parameters did not significantly change after the MRI or on follow-up, which took place at a median of 91 days after the MRI. No patient developed arrhythmias during the MRI sessions, and no adverse effects such as lead dislodgement were reported. CONCLUSION: Although larger studies are necessary to verify our findings, MRI in patients with LBBP appears safe based on this initial case series.

Outcomes in orthotopic heart transplantation following pacemaker implantation.

BACKGROUND: Bradyarrhythmias including sinus node dysfunction (SND) and atrioventricular block (AVB) can necessitate pacemaker (PPM) implantation in orthotopic heart transplant (OHT) recipients. Prior studies have shown conflicting findings regarding the effect of PPM implantation on survival. We evaluated the effect of PPM indication on long-term re-transplant-free survival in OHT patients. METHODS: We conducted a retrospective cohort study of OHT patients at UCLA Medical Center from 1985 to 2018. Indication for PPM (SND, AVB) was identified. Cox proportional hazards model with pacemaker implantation as a time-varying covariate was used to evaluate its effect on the primary endpoint of retransplant or death. We included 1609 OHTs in 1511 adult patients with median follow-up of 12 years. RESULTS: At transplant, patients were aged 53 ± 13 years and 1125 (74.5%) were male. Pacemakers were implanted in 109 (7.2%) patients; 65 for SND (4.3%) and 43 for AVB (2.8%). Repeat OHT was performed in 103 (6.4%) cases and 798 (52.8%) patients died during the follow-up period. The risk of the primary endpoint was significantly higher in patients requiring PPM for AVB (HR 3.0, 95% CI 2.1-4.2, p < .01) after controlling for age at OHT, gender, hypertension, diabetes, renal disease, history of repeat OHT, acute rejection, transplant coronary vasculopathy, and atrial fibrillation, but not PPM for SND (HR 1.0, 95% CI 0.70-1.4, p = 1.0). CONCLUSIONS: Patients who required PPM for AVB, but not SND, were at significantly higher risk of death or retransplant compared to patients who did not require PPM.

A Case of Bradycardia With Irregular Rhythm and Varying QRS Morphology.

We describe the case of a 92-year-old male patient presenting with shortness of breath and an electrocardiogram showing bradycardia with irregular rhythm and varying QRS morphology. A differential diagnosis is discussed. (Level of Difficulty: Advanced.).

Clinical predictors and implications of cardiac inflammation detected on positron emission tomography (PET) in patients referred for premature ventricular complex (PVC) ablation.

BACKGROUND: Positron emission tomography computed tomography (PET-CT) is not routinely used for premature ventricular complexes (PVCs). Whether specific clinical factors are associated with abnormal PET-CT results is not clear. METHODS: The treatment courses and baseline characteristics of consecutive patients in a single center between 2012 and 2021, age > 18 years old, and who received 18F-fluorodeoxyglucose (FDG) PET-CT imaging for evaluation of PVCs were retrospectively analyzed. RESULTS: A total of 102 patients was included. Of these, 27 patients (26.4%) had abnormal PET-CT and 61 (59.8%) had normal imaging. Abnormal PET-CT findings were associated with non-sustained ventricular tachycardia (NSVT) (95.2% vs. 52.6%, p = 0.001), higher number of PVC morphologies (2.29 ± 0.7 vs. 1.31 ± 0.6, p < 0.001), greater PVC coupling interval dispersion (72.47 ± 66.4 ms vs. 13.42 ± 17.9 ms, p < 0.001), and greater likelihood of fast heart rate dependent PVCs (78.5% vs. 38.2%, p = 0.017). Fourteen (51.8%) patients had an abnormal PET-CT and abnormal late gadolinium enhancement (LGE). Patients with abnormal PET-CT were more frequently treated with immunosuppression (81.4% vs. 3.2%, p < .0001) than with catheter ablation (11.1% vs. 45.9%, p = 0.002) compared to the normal PET-CT group. Over a median follow-up of 862 days (IQR 134, 1407), PVC burden decreased in both groups [from 23 ± 16% to 9 ± 10% (p < 0.001) in abnormal PET-CT group and from 21 ± 15% to 7 ± 10% (p < 0.001) in normal PET-CT group]. CONCLUSIONS: Abnormal PET-CT findings were more commonly associated with NSVT, multiform PVCs, greater PVC coupling interval dispersion, and fast heart rate dependent PVCs. LGE was not sensitive for detecting inflammation. Immunosuppression was effective in managing PVCs with abnormal PET-CT.

Augmented Hill-Climb increases reinforcement learning efficiency for language-based de novo molecule generation.

A plethora of AI-based techniques now exists to conduct de novo molecule generation that can devise molecules conditioned towards a particular endpoint in the context of drug design. One popular approach is using reinforcement learning to update a recurrent neural network or language-based de novo molecule generator. However, reinforcement learning can be inefficient, sometimes requiring up to 105 molecules to be sampled to optimize more complex objectives, which poses a limitation when using computationally expensive scoring functions like docking or computer-aided synthesis planning models. In this work, we propose a reinforcement learning strategy called Augmented Hill-Climb based on a simple, hypothesis-driven hybrid between REINVENT and Hill-Climb that improves sample-efficiency by addressing the limitations of both currently used strategies. We compare its ability to optimize several docking tasks with REINVENT and benchmark this strategy against other commonly used reinforcement learning strategies including REINFORCE, REINVENT (version 1 and 2), Hill-Climb and best agent reminder. We find that optimization ability is improved ~ 1.5-fold and sample-efficiency is improved ~ 45-fold compared to REINVENT while still delivering appealing chemistry as output. Diversity filters were used, and their parameters were tuned to overcome observed failure modes that take advantage of certain diversity filter configurations. We find that Augmented Hill-Climb outperforms the other reinforcement learning strategies used on six tasks, especially in the early stages of training or for more difficult objectives. Lastly, we show improved performance not only on recurrent neural networks but also on a reinforcement learning stabilized transformer architecture. Overall, we show that Augmented Hill-Climb improves sample-efficiency for language-based de novo molecule generation conditioning via reinforcement learning, compared to the current state-of-the-art. This makes more computationally expensive scoring functions, such as docking, more accessible on a relevant timescale.

Structure-Based Discovery of Negative Allosteric Modulators of the Metabotropic Glutamate Receptor 5.

Recently determined structures of class C G protein-coupled receptors (GPCRs) revealed the location of allosteric binding sites and opened new opportunities for the discovery of novel modulators. In this work, molecular docking screens for allosteric modulators targeting the metabotropic glutamate receptor 5 (mGlu5) were performed. The mGlu5 receptor is activated by the main excitatory neurotransmitter of the nervous central system, L-glutamate, and mGlu5 receptor activity can be allosterically modulated by negative or positive allosteric modulators. The mGlu5 receptor is a promising target for the treatment of psychiatric and neurodegenerative diseases, and several allosteric modulators of this GPCR have been evaluated in clinical trials. Chemical libraries containing fragment- (1.6 million molecules) and lead-like (4.6 million molecules) compounds were docked to an allosteric binding site of mGlu5 identified in X-ray crystal structures. Among the top-ranked compounds, 59 fragments and 59 lead-like compounds were selected for experimental evaluation. Of these, four fragment- and seven lead-like compounds were confirmed to bind to the allosteric site with affinities ranging from 0.43 to 8.6 µM, corresponding to a hit rate of 9%. The four compounds with the highest affinities were demonstrated to be negative allosteric modulators of mGlu5 signaling in functional assays. The results demonstrate that virtual screens of fragment- and lead-like chemical libraries have complementary advantages and illustrate how access to high-resolution structures of GPCRs in complex with allosteric modulators can accelerate lead discovery.

Detection of inflammation using cardiac positron emission tomography for evaluation of ventricular arrhythmias: An institutional experience.

BACKGROUND: The use of cardiac positron emission tomography-computed tomography (PET-CT) is increasingly used for the detection of underlying inflammation in patients with ventricular arrhythmias (ventricular tachycardia/ventricular fibrillation [VT/VF]), but the role of PET-CT remains undefined, particularly for patients who do not meet Task Force criteria for sarcoidosis. OBJECTIVE: The purpose of this study was to determine the utility of PET-CT for clinical evaluation of VT/VF in patients with nonischemic cardiomyopathy. METHODS: Consecutive patients with nonischemic cardiomyopathy and VT/VF who underwent cardiac PET-CT to detect inflammation between 2012 and 2019 were analyzed for baseline demographic characteristics, imaging results, and outcomes. Patients with known sarcoidosis or other conditions requiring immunosuppressive therapy were excluded. RESULTS: PET-CT was performed in 133 patients with mean age 56.3 ± 13.5 years and left ventricular ejection fraction 43% ± 16.1%, with evidence of myocardial inflammation detected in 32 (23.5%). Patients with myocardial inflammation were managed conservatively with medical therapy including immunosuppressive agents. Ten patients with myocardial inflammation ultimately required catheter ablation for ongoing arrhythmias. There was no significant difference in arrhythmia recurrence between PET-positive and PET-negative groups (37.5% vs 32.4%; P = .43) or in time to recurrence (P = .26), in spite of the disparate management strategies. Gadolinium-enhanced cardiac magnetic resonance imaging was performed in 96 patients (72%); however, magnetic resonance imaging did not detect 31% of cases with active inflammation that were otherwise detected on PET-CT. CONCLUSION: The use of PET-CT significantly improves the detection of underlying myocardial inflammation contributing to ventricular arrhythmias. Management of these patients with immunosuppressive medical therapy is effective for arrhythmia control and may obviate the need for invasive ablation procedures in some patients.

Development of a Care Pathway for Atrial Fibrillation Patients in the Emergency Department.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and its prevalence is continuously increasing in the United States, leading to a progressive rise in the number of disease-related emergency department (ED) visits and hospitalizations. Although optimal long-term outpatient management for AF is well defined, the guidelines for optimal ED management of acute AF episodes is less clear. Studies have demonstrated that discharging patients with AF from the ED after acute stabilization is both safe and cost effective; however, the majority of these patients in the United States and in our institution are admitted to the hospital. To improve care of these patients, we established a multidisciplinary collaboration to develop an evidence-based systematic approach for the treatment and management of AF in the ED, that led to the creation of the University of California-Cardioversion, Anticoagulation, Rate Control, Expedited Follow-up/Education Atrial Fibrillation Pathway. Our pathway focuses on the acute stabilization of AF, adherence to best practices for anticoagulation, and reduction in unnecessary admissions through discharge from the ED with expedited outpatient follow-up whenever safe. A novel aspect of our pathway is that it is primarily driven by the ED physicians, while other published protocols primarily involve consulting cardiologists to guide management in the ED. Our protocol is very pertinent considering the current trend toward increased AF prevalence in the United States, coupled with a need for widespread implementation of strategies aimed at improving management of these patients while safely reducing hospital admissions and the economic burden of AF.

Identification of anti-schistosomal, anthelmintic and anti-parasitic compounds curated and text-mined from the scientific literature.

More than a billion people are infected with parasitic worms, including nematodes, such as hookworms, and flatworms, such as blood flukes. Few drugs are available to treat worm infections, but high-throughput screening approaches hold promise to identify novel drug candidates. One problem for researchers who find an interesting 'hit' from a high-throughput screen is to identify whether that compound, or a similar compound has previously been published as having anthelmintic or anti-parasitic activity. Here, we present (i) data sets of 2,828 anthelmintic compounds, and 1,269 specific anti-schistosomal compounds, manually curated from scientific papers and books, and (ii) a data set of 24,335 potential anthelmintic and anti-parasitic compounds identified by text-mining PubMed abstracts. We provide their structures in simplified molecular-input line-entry system (SMILES) format so that researchers can easily compare 'hits' from their screens to these anthelmintic compounds and anti-parasitic compounds and find previous literature on them to support/halt their progression in drug discovery pipelines.

Forensic cardiac device analysis at the Los Angeles County Department of the Coroner: A 20-year experience.

Cardiac implantable electronic devices (CIEDs) store information continuously; however, the log of these devices is rarely analyzed in forensic practice. We retrospectively reviewed all cases referred for CIED interrogation by the Los Angeles County Department of Medical Examiner-Coroner between 2001 and 2020. According to the Department's practice, CIED interrogation may be requested for decedents in which details or cause of death are not clear from autopsy and clinical history. The CIED analysis was considered informative for the coroner's investigation either if it detected an arrhythmia or malfunction likely related to decedent's terminal event or if it was essential to determine time of death or identity of decedent. A total of 57 CIEDs were evaluated during the 20-year period. In almost half of cases (26/57: 45.6%), device analysis was informative for coroner's investigation. Arrhythmias likely related to terminal event were commonly detected (21/57: 36.8%). Device malfunction was identified as the likely cause of death in almost 10% of decedents (5/57: 8.8%), including three cases of battery depletion (3/57: 5.3%), one case of misclassification of ventricular tachycardia as supraventricular tachycardia with failure to deliver therapy (1/57: 1.7%), and one case of lead failure due to a broken pacing wire (1/57: 1.7%). Not infrequently, CIED interrogation was essential for determination of time of death (9/57: 15.8%), and there was one case (1/57: 1.7%) in which interrogation was essential for identifying the decedent. Our study shows that postmortem CIED interrogation can provide unique information regarding mechanism and time of death, and decedent's identity.

Continuous heart rate dynamics preceding in-hospital pulseless electrical activity or asystolic cardiac arrest of respiratory etiology.

INTRODUCTION: Respiratory failure is a common cause of pulseless electrical activity (PEA) and asystolic cardiac arrest, but the changes in heart rate (HR) pre-arrest are not well described. We describe HR dynamics prior to in-hospital cardiac arrest (IHCA) among PEA/asystole arrest patients with respiratory etiology. METHODS: In this retrospective study, we evaluated 139 patients with 3-24 hours of continuous electrocardiogram data recorded preceding PEA/asystole IHCA from 2010-2017. We identified respiratory failure cases by chart review and evaluated electrocardiogram data to identify patterns of HR changes, sinus bradycardia or sinus arrest, escape rhythms, and development right ventricular strain prior to IHCA. RESULTS: A higher proportion of respiratory cases (58/73, 79 %) fit a model of HR response characterized by tachycardia followed by rapid HR decrease prior to arrest, compared to non-respiratory cases (30/66, 45 %, p < 0.001). Among the 58 respiratory cases fitting this model, 36 (62 %) had abrupt increase in HR occurring 64 (IQR 23-191) minutes prior to arrest, while 22 (38 %) had stable tachycardia until time of HR decrease. Mean peak HR was 123 ± 21 bpm. HR decrease occurred 3.0 (IQR 2.0-7.0) minutes prior to arrest. Sinus arrest occurred during the bradycardic phase in 42/58 of cases; escape rhythms were present in all but 2/42 (5 %) cases. Right ventricular strain ECG pattern, when present, occurred at a median of 2.2 (IQR -0.05-17) minutes prior to onset of HR decrease. CONCLUSION: IHCAs of respiratory etiology follow a model of HR increase from physiologic compensation to hypoxia, followed by rapid HR decrease prior to arrest.

Late-Onset Infection in a Leadless Pacemaker.

Infection of leadless pacemakers (LPM) is rare, even in patients at high risk for infections. Only 3 cases of LPM infection have been documented in the literature, all occurring within 1 month of device implantation. We report the first case, to our knowledge, of late-onset LPM infection, developing almost 2 years after implantation. (Level of Difficulty: Beginner.).

Massive Air Embolism During Atrial Fibrillation Ablation: Averting Disaster in a Time of Crisis.

A 62-year-old male with symptomatic persistent atrial fibrillation underwent radiofrequency catheter ablation. During exchange of the saline irrigation bag, the patient developed sudden hypotension and bradycardia and was found to have a massive air embolism. Air was successfully aspirated with catheters, and the patient did not suffer any permanent sequelae. (Level of Difficulty: Intermediate.).