Association between proactive esophageal cooling and increased lab throughput.

INTRODUCTION: Proactive esophageal cooling has been FDA cleared to reduce the likelihood of ablation-related esophageal injury resulting from radiofrequency (RF) cardiac ablation procedures. Data suggest that procedure times for RF pulmonary vein isolation (PVI) also decrease when proactive esophageal cooling is employed instead of luminal esophageal temperature (LET) monitoring. Reduced procedure times may allow increased electrophysiology (EP) lab throughput. We aimed to quantify the change in EP lab throughput of PVI cases after the introduction of proactive esophageal cooling. METHODS: EP lab throughput data were obtained from three EP groups. We then compared EP lab throughput over equal time frames at each site before (pre-adoption) and after (post-adoption) the adoption of proactive esophageal cooling. RESULTS: Over the time frame of the study, a total of 2498 PVIs were performed over a combined 74 months, with cooling adopted in September 2021, November 2021, and March 2022 at each respective site. In the pre-adoption time frame, 1026 PVIs were performed using a combination of LET monitoring with the addition of esophageal deviation when deemed necessary by the operator. In the post-adoption time frame, 1472 PVIs were performed using exclusively proactive esophageal cooling, representing a mean 43% increase in throughput (p < .0001), despite the loss of two operators during the post-adoption time frame. CONCLUSION: Adoption of proactive esophageal cooling during PVI ablation procedures is associated with a significant increase in EP lab throughput, even after a reduction in total number of operating physicians in the post-adoption group.

Examining multi-objective deep reinforcement learning frameworks for molecular design.

Drug design and optimization are challenging tasks that call for strategic and efficient exploration of the extremely vast search space. Multiple fragmentation strategies have been proposed in the literature to mitigate the complexity of the molecular search space. From an optimization standpoint, drug design can be considered as a multi-objective optimization problem. Deep reinforcement learning (DRL) frameworks have demonstrated encouraging results in the field of drug design. However, the scalability of these frameworks is impeded by substantial training intervals and inefficient use of sample data. In this paper, we (1) examine the core principles of deep or multi-objective RL methods and their applications in molecular design, (2) analyze the performance of a recent multi-objective DRL-based and fragment-based drug design framework, named DeepFMPO, in a real-world application by incorporating optimization of protein-ligand docking affinity with varying numbers of other objectives, and (3) compare this method with a single-objective variant. Through trials, our results indicate that the DeepFMPO framework (with docking score) can achieve success, however, it suffers from training instability. Our findings encourage additional exploration and improvement of the framework. Potential sources of the framework's instability and suggestions of further modifications to stabilize the framework are discussed.

Adversarial deep evolutionary learning for drug design.

The design of a new therapeutic agent is a time-consuming and expensive process. The rise of machine intelligence provides a grand opportunity of expeditiously discovering novel drug candidates through smart search in the vast molecular structural space. In this paper, we propose a new approach called adversarial deep evolutionary learning (ADEL) to search for novel molecules in the latent space of an adversarial generative model and keep improving the latent representation space. In ADEL, a custom-made adversarial autoencoder (AAE) model is developed and trained under a deep evolutionary learning (DEL) process. This involves an initial training of the AAE model, followed by an integration of multi-objective evolutionary optimization in the continuous latent representation space of the AAE rather than the discrete structural space of molecules. By using the AAE, an arbitrary distribution can be provided to the training of AAE such that the latent representation space is set to that distribution. This allows for a starting latent space from which new samples can be produced. Throughout the process of learning, new samples of high quality are generated after each iteration of training and then added back into the full dataset, therefore, allowing for a more comprehensive procedure of understanding the data structure. This combination of evolving data and continuous learning not only enables improvement in the generative model, but the data as well. By comparing ADEL to the previous work in DEL, we see that ADEL can obtain better property distributions. We show that ADEL is able to design high-quality molecular structures which can be further used for virtual and experimental screenings.

Multi-Objective Drug Design Based on Graph-Fragment Molecular Representation and Deep Evolutionary Learning.

Drug discovery is a challenging process with a huge molecular space to be explored and numerous pharmacological properties to be appropriately considered. Among various drug design protocols, fragment-based drug design is an effective way of constraining the search space and better utilizing biologically active compounds. Motivated by fragment-based drug search for a given protein target and the emergence of artificial intelligence (AI) approaches in this field, this work advances the field of in silico drug design by (1) integrating a graph fragmentation-based deep generative model with a deep evolutionary learning process for large-scale multi-objective molecular optimization, and (2) applying protein-ligand binding affinity scores together with other desired physicochemical properties as objectives. Our experiments show that the proposed method can generate novel molecules with improved property values and binding affinities.

Comparing Age at Cancer Diagnosis between Hispanics and Non-Hispanic Whites in the United States.

BACKGROUND: Population age structure may confound the comparison of age at cancer diagnosis across racial/ethnic groups. We compared age at cancer diagnosis for U.S. Hispanics, a population that is younger on average, and non-Hispanic whites (NHW), before and after adjustment for the age structure of the source population. METHODS: We used Surveillance, Epidemiology, and End Results data from 18 U.S. regions in 2015 for 34 cancer sites to calculate crude and adjusted (using age- and sex-specific weights) mean ages at diagnosis. Differences in age at diagnosis comparing Hispanics to NHWs (δ) were assessed using independent sample t tests. RESULTS: Crude mean ages at diagnosis were lower among Hispanic males and females for all sites combined and for most cancer sites. After age-adjustment, Hispanic (vs. NHW) males remained younger on average at diagnosis of chronic myeloid leukemia [δ = -6.1; 95% confidence interval (CI), -8.1 to -4.1 years], testicular cancer (δ =-4.7; 95% CI, -5.4 to -4.0), Kaposi sarcoma (δ =-3.6; 95% CI,-6.3 to -0.8), mesothelioma (δ =-3.0; 95% CI,-4.3 to -1.7), and anal cancer (δ =-2.4; 95% CI, -3.9 to -0.8), and older at diagnosis of gallbladder cancer (δ = +3.8; 95% CI, 1.8 to 5.7) and Hodgkin's lymphoma (δ = +7.5; 95% CI, 5.7 to 9.4), and Hispanic (vs. NHW) females remained younger at diagnosis of mesothelioma (δ = -3.7; 95% CI, -6.7 to -0.7) and gallbladder cancer (δ = -3.0; 95% CI, -4.3 to -1.7) and older at diagnosis of skin cancer (δ = +3.8; 95% CI, 3.1 to 4.5), cervical cancer (δ = +4.1; 95% CI, 3.3 to 4.8), and Hodgkin's lymphoma (δ = +7.0; 95% CI, 5.0 to 9.1). CONCLUSIONS: On average, Hispanics are diagnosed with cancer at younger ages than NHWs; however, for many cancers these differences reflect the younger age structure in Hispanics. IMPACT: Population age structure should be considered when comparing age at cancer diagnosis across racial/ethnic groups.

Factors Predisposing to Survival After Resuscitation for Sudden Cardiac Arrest.

BACKGROUND: In the POST SCD study, the authors autopsied all World Health Organization (WHO)-defined sudden cardiac deaths (SCDs) and found that only 56% had an arrhythmic cause; resuscitated sudden cardiac arrests (SCAs) were excluded because they did not die suddenly. They hypothesized that causes underlying resuscitated SCAs would be similarly heterogeneous. OBJECTIVES: The aim of this study was to determine the causes and outcomes of resuscitated SCAs. METHODS: The authors identified all out-of-hospital cardiac arrests (OHCAs) from February 1, 2011, to January 1, 2015, of patients aged 18 to 90 years in San Francisco County. Resuscitated SCAs were OHCAs surviving to hospitalization and meeting WHO criteria for suddenness. Underlying cause was determined by comprehensive record review. RESULTS: The authors identified 734 OHCAs over 48 months; 239 met SCA criteria, 133 (55.6%) were resuscitated to hospitalization, and 47 (19.7%) survived to discharge. Arrhythmic causes accounted for significantly more resuscitated SCAs overall (92 of 133, 69.1%), particularly among survivors (43 of 47, 91.5%), than WHO-defined SCDs in POST SCD (293 of 525, 55.8%; p < 0.004 for both). Among resuscitated SCAs, arrhythmic cause, ventricular tachycardia/fibrillation initial rhythm, and white race were independent predictors of survival. None of the resuscitated SCAs due to neurologic causes survived. CONCLUSIONS: In this 4-year countywide study of OHCAs, only one-third were sudden, of which one-half were resuscitated to hospitalization and 1 in 5 survived to discharge. Arrhythmic cause predicted survival and nearly one-half of nonsurvivors had nonarrhythmic causes, suggesting that SCA survivors are not equivalent to SCDs. Early identification of nonarrhythmic SCAs, such as neurologic emergencies, may be a target to improve OHCA survival.

Massively parallel reporter assays of melanoma risk variants identify MX2 as a gene promoting melanoma.

Genome-wide association studies (GWAS) have identified ~20 melanoma susceptibility loci, most of which are not functionally characterized. Here we report an approach integrating massively-parallel reporter assays (MPRA) with cell-type-specific epigenome and expression quantitative trait loci (eQTL) to identify susceptibility genes/variants from multiple GWAS loci. From 832 high-LD variants, we identify 39 candidate functional variants from 14 loci displaying allelic transcriptional activity, a subset of which corroborates four colocalizing melanocyte cis-eQTL genes. Among these, we further characterize the locus encompassing the HIV-1 restriction gene, MX2 (Chr21q22.3), and validate a functional intronic variant, rs398206. rs398206 mediates the binding of the transcription factor, YY1, to increase MX2 levels, consistent with the cis-eQTL of MX2 in primary human melanocytes. Melanocyte-specific expression of human MX2 in a zebrafish model demonstrates accelerated melanoma formation in a BRAFV600E background. Our integrative approach streamlines GWAS follow-up studies and highlights a pleiotropic function of MX2 in melanoma susceptibility.

State of Fluoroless Procedures in Cardiac Electrophysiology Practice.

In the past decade, the use of interventional electrophysiological (EP) procedures for the diagnosis and treatment of cardiac arrhythmias has exponentially increased. These procedures usually require fluoroscopy to guide the advancement and frequent repositioning of intracardiac catheters, resulting in both the patient and the operator being subjected to a considerable degree of radiation exposure. Although shielding options such as lead gowns, glasses, and pull-down shields are useful for protecting the operator, they do not lessen the patient's level of exposure. Furthermore, the prolonged use of lead gowns can exponentiate the onset of orthopedic problems among operators. Recent advancements in three-dimensional cardiac mapping systems and the use of radiation-free imaging technologies such as magnetic resonance imaging and intracardiac ultrasound allow operators to perform EP procedures with minimal or even no fluoroscopy. In this review, we sought to describe the state of fluoroless procedures in EP practice.

Designer aminoglycosides prevent cochlear hair cell loss and hearing loss.

Bacterial infections represent a rapidly growing challenge to human health. Aminoglycosides are widely used broad-spectrum antibiotics, but they inflict permanent hearing loss in up to ~50% of patients by causing selective sensory hair cell loss. Here, we hypothesized that reducing aminoglycoside entry into hair cells via mechanotransducer channels would reduce ototoxicity, and therefore we synthesized 9 aminoglycosides with modifications based on biophysical properties of the hair cell mechanotransducer channel and interactions between aminoglycosides and the bacterial ribosome. Compared with the parent aminoglycoside sisomicin, all 9 derivatives displayed no or reduced ototoxicity, with the lead compound N1MS 17 times less ototoxic and with reduced penetration of hair cell mechanotransducer channels in rat cochlear cultures. Both N1MS and sisomicin suppressed growth of E. coli and K. pneumoniae, with N1MS exhibiting superior activity against extended spectrum ß lactamase producers, despite diminished activity against P. aeruginosa and S. aureus. Moreover, systemic sisomicin treatment of mice resulted in 75% to 85% hair cell loss and profound hearing loss, whereas N1MS treatment preserved both hair cells and hearing. Finally, in mice with E. coli-infected bladders, systemic N1MS treatment eliminated bacteria from urinary tract tissues and serially collected urine samples, without compromising auditory and kidney functions. Together, our findings establish N1MS as a nonototoxic aminoglycoside and support targeted modification as a promising approach to generating nonototoxic antibiotics.

A randomized trial of exercise training in abdominal aortic aneurysm disease.

PURPOSE: Screening programs and greater public awareness have increased the recognition of early abdominal aortic aneurysm (AAA) disease. No medical therapy has proven effective in limiting AAA progression, and little is known regarding the safety and efficacy of exercise training in these patients. We evaluated the safety and efficacy of up to 3 yr of training in patients with early (≤5.5 cm) AAA disease. METHODS: One hundred and forty patients with small AAAs (72 ± 8 yr) were randomized to exercise training (n = 72) or usual care (n = 68). Exercise subjects participated in a combination of in-house and home training for up to 3 yr. Cardiopulmonary exercise testing (CPX) was performed at baseline and 3, 12, 24, and 36 months. Comparisons were made for AAA expansion, safety, CPX responses, and weekly energy expenditure. RESULTS: The average duration of participation was 23.4 ± 9.6 months; 81% of subjects completed ≥1 year. No adverse clinical events or excessive AAA growth rates related to training occurred. Exercise subjects expended a mean 1999 ± 1030 kcal·wk. Increases in peak exercise time and estimated METs occurred at the 3-month and 1-, 2-, and 3-yr evaluations (P < 0.01 between groups). A significant between-group interaction occurred for V˙O2 at the ventilatory threshold (P = 0.02), and submaximal heart rate was significantly reduced among exercise subjects. Neither exercise status nor level of fitness significantly influenced rate of AAA enlargement. CONCLUSIONS: These results support the safety and efficacy of training in patients with small AAA, a population for which few previous data are available. Despite advanced age and comorbidities, training up to 3 yr was well tolerated and sustainable in AAA patients. Training did not influence rate of AAA enlargement.

Agreement between activity-monitoring devices during home rehabilitation: a substudy of the AAA STOP trial.

As part of a home-based rehabilitation program, 24 older adult patients (71 ± 3 years) with abdominal aortic aneurysm (AAA) disease underwent 3 days (12 awake hr/day) of activity monitoring using an accelerometer (ACC), a pedometer, and a heart rate (HR) monitor, and recorded hourly activity logs. Subjects then underwent an interview to complete a 3-day activity recall questionnaire (3-DR). Mean energy expenditure (EE) in kcals/ day for HR, ACC, and 3-DR were 1,687 ± 458, 2,068 ± 529, and 1,974 ± 491, respectively. Differences in EE were not significant between 3-DR and ACC, but HR differed from both ACC (p < .001) and 3-DR (p < .01). ACC and 3-DR had the highest agreement, with a coefficient of variation of 7.9% and r = .86. Thus, ACC provided a reasonably accurate reflection of EE based the criterion measure, an activity recall questionnaire. ACC can be effectively used to monitor EE to achieve an appropriate training stimulus during home-based cardiac rehabilitation.

Integrity and regeneration of mechanotransduction machinery regulate aminoglycoside entry and sensory cell death.

Sound perception requires functional hair cell mechanotransduction (MET) machinery, including the MET channels and tip-link proteins. Prior work showed that uptake of ototoxic aminoglycosides (AG) into hair cells requires functional MET channels. In this study, we examined whether tip-link proteins, including Cadherin 23 (Cdh23), regulate AG entry into hair cells. Using time-lapse microscopy on cochlear explants, we found rapid uptake of gentamicin-conjugated Texas Red (GTTR) into hair cells from three-day-old Cdh23(+/+) and Cdh23(v2J/+) mice, but failed to detect GTTR uptake in Cdh23(v2J/v2J) hair cells. Pre-treatment of wildtype cochleae with the calcium chelator 1,2-bis(o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA) to disrupt tip-links also effectively reduced GTTR uptake into hair cells. Both Cdh23(v2J/v2J) and BAPTA-treated hair cells were protected from degeneration caused by gentamicin. Six hours after BAPTA treatment, GTTR uptake remained reduced in comparison to controls; by 24 hours, drug uptake was comparable between untreated and BAPTA-treated hair cells, which again became susceptible to cell death induced by gentamicin. Together, these results provide genetic and pharmacologic evidence that tip-links are required for AG uptake and toxicity in hair cells. Because tip-links can spontaneously regenerate, their temporary breakage offers a limited time window when hair cells are protected from AG toxicity.

A novel approach for in vivo measurement of mouse red cell redox status.

Maintenance of a reducing redox balance is a critical physiologic function of red cells (RBC) that can be perturbed in variety of RBC pathologies. Here we describe a new approach to evaluate in vivo RBC redox status using a redox sensitive GFP (roGFP2) sensor under control of a ß-globin mini-promoter, directing expression specifically to erythroid cells. RoGFP2 expressing RBCs demonstrate ratiometric and reversible shifts in fluorescence on exposure to oxidants and reductants. We demonstrate that roGFP2 expressing RBC can be used to monitor thiol redox status during in vitro phenylhydrazine treatment and over the course of in vivo RBC aging, where a shift to a more oxidized state is observed in older cells. Thus, roGFP2 transgenic mice are a new and versatile tool that can be used to probe how RBC redox status responds in the context of drug therapy, physiologic stressors and pathologic states.

Renal dysfunction in chronic hepatitis B patients treated with adefovir dipivoxil.

UNLABELLED: Renal dysfunction has been reported in patients treated with adefovir dipivoxil (ADV); however, its incidence and clinical importance may be underappreciated given the lack of long-term follow-up and data outside of a clinical trial setting. Our goal was to examine the severity and incidence of renal dysfunction in a real-life setting for patients treated with ADV and whose baseline estimated glomerular filtration rate (eGFR) was >50 mL/minute. We performed a cohort study of 290 chronic hepatitis B patients: 145 patients treated with 10 mg ADV and 145 patients unexposed to ADV at two community clinics, who were matched for age (+/-10 years), sex, and baseline eGFR. The exposed and unexposed populations were well-matched with a similar mean age (46-47 years), proportion of male patients (76.5%), baseline serum creatinine (0.97-0.99 mg/dL), and baseline creatinine clearance (85.0-85.4 mL/minute). The incidence density for renal dysfunction defined by treatment termination and/or development of eGFR < or =50 mL/minute was five cases per 100 patient-years in the exposed group compared with 1.36 cases per 100 patient-years in the unexposed group (P = 0.02). The relative risk of exposed to unexposed was 3.68 (95% confidence interval 1.1-19.3). On Cox proportional hazard analysis also inclusive of sex, ADV was a significant predictor of significant renal dysfunction (hazard ratio [HR] 3.94, P = 0.03). There were also significant trends for age >50 years (HR 3.49, P = 0.087), mild renal impairment at baseline (HR 4.49, P = 0.073), and hypertension and/or diabetes mellitus (HR 2.36, P = 0.074). CONCLUSION: ADV is an independent predictor for significant deterioration of renal function. Patients on ADV should be monitored, especially patients who are older, have baseline renal insufficiency, or have hypertension and/or diabetes mellitus.

Fluorescence enhancement of warfarin induced by interaction with beta-cyclodextrin.

Warfarin is the most common agent used for control and prevention of venous as well as arterial thromboembolism (blood clots). In aqueous media, warfarin forms inclusion complexes with a family of cyclic oligosaccharides, alpha, beta, gamma-cyclodextrins (CD). The formation of these complexes results in enhancement of the fluorescence of warfarin. Such spectroscopic changes offer a venue for the development of bioanalytical methodologies for warfarin quantification in biological liquids. We characterized the photophysical properties of warfarin in solvents with varying polarity and viscosity. The fluorescence quantum yield of warfarin correlated: (1) strongly with the solvent viscosity (R = 0.979) and (2) weakly with the solvent polarity (R = 0.118). These findings indicate that it is the change of the viscosity, rather than polarity, of the microenvironment that causes the fluorescence enhancement of warfarin upon binding to beta-CD. Utilizing the observed fluorescence enhancement in fluorescence titration measurements, the binding constants of warfarin to beta-CD were obtained (2.6 x 10(2) M(-1)-3.7 x 10(2) M(-1)). Using multivariable linear analysis, we extracted the stoichiometry of warfarin-beta-CD interaction (1:1).