Improved prediction of ligand-protein binding affinities by meta-modeling

The accurate screening of candidate drug ligands against target proteins through computational approaches is of prime interest to drug development efforts, as filtering potential candidates would save time and expenses for finding drugs. Such virtual screening depends in part on methods to predict the binding affinity between ligands and proteins. Given many computational models for binding affinity prediction with varying results across targets, we herein develop a meta-modeling framework by integrating published empirical structure-based docking and sequence-based deep learning models. In building this framework, we evaluate many combinations of individual models, training databases, and linear and nonlinear meta-modeling approaches. We show that many of our meta-models significantly improve affinity predictions over individual base models. Our best meta-models achieve comparable performance to state-of-the-art exclusively structure-based deep learning tools. Overall, we demonstrate that diverse modeling approaches can be ensembled together to gain substantial improvement in binding affinity prediction while allowing control over input features such as physicochemical properties or molecular descriptors.Comment: 61 pages, 3 main tables, 6 main figures, 6 supplementary figures, and supporting information. For 8 supplementary tables and code, see https://github.com/Lee1701/Lee2023

Characterizing peritoneal dialysis catheter use in pediatric patients after cardiac surgery

ObjectiveChildren who undergo cardiac surgery are at high risk for renal insufficiency and abdominal compartment syndrome. Peritoneal dialysis catheter (PDC) implantation is used in this population for abdominal decompression and access for dialysis. However, there is no consensus regarding PDC use, and the practice varies widely. This study was undertaken to assess associated factors, outcomes, and variability in the use of PDC in patients who have undergone cardiac surgery.MethodsThe cohort was obtained from the Kids' Inpatient Database, years 2006 and 2009. Patients who underwent cardiac surgery were included and the subset that underwent PDC implantation during the same hospitalization was identified. Univariable and multivariable analyses assessed factors associated with PDC and survival.ResultsA cohort of 28,259 patients underwent cardiac surgery, of whom 558 (2%) had PDCs placed. In the PDC group, 39.1% (n = 218) had acute renal failure whereas 3.5% or patients (n = 974) in the non-PDC group had acute renal failure. Among patients receiving PDC, mortality was 20.3% (n = 113; vs 3.4% overall mortality, n = 955). Excluding patients with acute renal failure, mortality remained 12% (n = 41) for the PDC group. Factors associated significantly with PDC placement in the overall cohort were younger age, greater surgical complexity, nonelective admission, hospital region, use of cardiopulmonary bypass, and acute renal failure.ConclusionsPatients receiving PDC after cardiac surgery had 20% mortality, which remained 12% after excluding patients with acute renal failure. Given the variability in PDC use and poor outcomes, further research is needed to assess the possible benefit of earlier intervention for peritoneal access in this high-risk cohort

PROTECCIÓN QUE EL ESTADO MEXICANO DEBE BRINDAR AL ADULTO MAYOR RESPECTO DE SU PATRIMONIO: LOS JUZGADORES DEL ESTADO DE MÉXICO

La reforma constitucional de 2011, colocó en el centro del sistema jurídico mexicano a los Derechos Humanos así, el artículo 1° constitucional señala: “Todas las autoridades, en el ámbito de sus competencias, tienen la obligación de promover, respetar, proteger y garantizar los derechos humanos de conformidad con los principios de universalidad, interdependencia, indivisibilidad y progresividad. En consecuencia, el Estado deberá prevenir, investigar, sancionar y reparar las violaciones a los derechos humanos, en los términos que establezca la ley.” Para efectos de que los adultos mayores estén en aptitud de dinamizar sus derechos y estos no queden sólo en el terreno de ideal normativo, el Estado mexicano, como garante de los derechos de los gobernados debe ir adaptando las normas protectoras conforme se presenten cambios sociales. El derecho debe ser tan dinámico como la propia sociedad, la normatividad debe revisarse en forma permanente y el legislador debe de realizar las adecuaciones pertinentes para que los derechos se dinamicen en términos de efectividad. Respecto de la protección del patrimonio de los adultos mayores es una prioridad revisar no sólo la armónica normatividad que ha de aplicar el juzgador, ya que en el diario quehacer jurisdiccional se perciben las más variadas acciones que ejercen fundamentalmente familiares para despojar de sus bienes a los adultos mayores, sin que ellos reciban beneficio directo alguno.La presente tesis muestra a través de su desarrollo el marco jurídico existente en cuanto a la protección del patrimonio del hombre de la tercera edad en el estado de México. En conjunto con la información del párrafo anterior se muestran datos estadísticos acerca de esta rama de la población (las personas de la tercera edad), así como del sistema judicial en materia civil que existe en el estado de México para la protección de sus patrimonio

Primary left ventricular rehabilitation is effective in maintaining two-ventricle physiology in the borderline left heart

ObjectiveBorderline left heart disease is characterized by left heart obstructive lesions (coarctation, aortic and mitral stenoses, left ventricular hypoplasia) and endocardial fibroelastosis. The multilevel obstruction and impaired left ventricular systolic and diastolic function contribute to failure of biventricular circulation. We studied the effects of left ventricular rehabilitation—endocardial fibroelastosis resection with mitral or aortic valvuloplasty—on left ventricular function and clinical outcomes.MethodsAll patients with borderline left heart structures and endocardial fibroelastosis who underwent a primary left ventricular rehabilitation procedure were retrospectively analyzed to determine operative mortality, reintervention rates, and hemodynamic status. Left heart dimensions and hemodynamics were recorded from preoperative and postoperative echocardiogram and cardiac catheterization. Postoperative left atrial pressure was obtained from the intracardiac line early after left ventricular rehabilitation. Preoperative and postoperative values were compared by paired t test.ResultsBetween 1999 and 2008, 9 patients with endocardial fibroelastosis and borderline left heart disease underwent left ventricular rehabilitation at a median age of 5.6 months (range, 1–38 months). There was no operative mortality, and at a median follow-up of 25 months (6 months to 10 years) there was 1 death from noncardiac causes and 2 patients required reoperations. Significant increases in ejection fraction and left ventricular end-diastolic volume were observed, whereas left atrial pressure and right ventricular/left ventricular pressure ratios decreased postoperatively.ConclusionIn patients with borderline left hearts, primary left ventricular rehabilitation with endocardial fibroelastosis resection and mitral and aortic valvuloplasty results in improved left ventricular systolic and diastolic performance and decreased right ventricular pressures. This approach may provide an alternative to single-ventricle management in this difficult patient group

Staged Left Ventricular Recruitment After Single-Ventricle Palliation in Patients With Borderline Left Heart Hypoplasia

ObjectivesThe goal of this study was to review results of a novel management strategy intended to rehabilitate the left heart (LH) in patients with LH hypoplasia who have undergone single-ventricle palliation (SVP).BackgroundManagement of patients with hypoplastic LH syndrome and borderline left ventricle (LV) involves 2 options: SVP or biventricular repair. We hypothesized that staged LV recruitment and biventricular conversion may be achieved after SVP by using a strategy consisting of relief of inflow and outflow tract obstructions, resection of endocardial fibroelastosis, and promotion of flow through the LV.MethodsPatients with hypoplastic LH and borderline LV who underwent traditional SVP (n = 34) or staged LV recruitment (n = 34) between 1995 and 2010 were retrospectively analyzed and compared with a control SVP group.ResultsMean initial z-scores for LH structures before stage 1 SVP were not significantly different between groups. Mortality occurred in 4 of 34 patients after LV recruitment and in 7 of 34 after traditional SVP. LH dimension z-scores increased significantly over time after LV recruitment, whereas they declined after traditional SVP, with significant interaction between stage of palliation and treatment group. Restriction of the atrial septum (conducted in 19 of 34 patients) was the only predictor of increase in left ventricular end-diastolic volume (p < 0.001). Native biventricular circulation was achieved in 12 patients after staged LV recruitment; all of these patients had restriction at the atrial septum.ConclusionsIn these patients with borderline LH disease who underwent SVP, it is possible to increase LH dimensions by using an LV recruitment strategy. In a subset of patients, this strategy allowed establishment of biventricular circulation

Resonant Visible Light Modulation with Graphene

Fast modulation and switching of light at visible and near-infrared (vis-NIR) frequencies is of utmost importance for optical signal processing and sensing technologies. No fundamental limit appears to prevent us from designing wavelength-sized devices capable of controlling the light phase and intensity at gigaherts (and even terahertz) speeds in those spectral ranges. However, this problem remains largely unsolved, despite recent advances in the use of quantum wells and phase-change materials for that purpose. Here, we explore an alternative solution based upon the remarkable electro-optical properties of graphene. In particular, we predict unity-order changes in the transmission and absorption of vis-NIR light produced upon electrical doping of graphene sheets coupled to realistically engineered optical cavities. The light intensity is enhanced at the graphene plane, and so is its absorption, which can be switched and modulated via Pauli blocking through varying the level of doping. Specifically, we explore dielectric planar cavities operating under either tunneling or Fabry-Perot resonant transmission conditions, as well as Mie modes in silicon nanospheres and lattice resonances in metal particle arrays. Our simulations reveal absolute variations in transmission exceeding 90% as well as an extinction ratio >15 dB with small insertion losses using feasible material parameters, thus supporting the application of graphene in fast electro-optics at vis-NIR frequencies.Comment: 17 pages, 13 figures, 54 reference

PREVENtion of HeartMate II Pump Thrombosis Through Clinical Management: The PREVENT multi-center study

BACKGROUND: Recommended structured clinical practices including implant technique, anti-coagulation strategy, and pump speed management (PREVENT [PREVENtion of HeartMate II Pump Thrombosis Through Clinical Management] recommendations) were developed to address risk of early (<3 months) pump thrombosis (PT) risk with HeartMate II (HMII; St. Jude Medical, Inc. [Thoratec Corporation], Pleasanton, CA). We prospectively assessed the HMII PT rate in the current era when participating centers adhered to the PREVENT recommendations. METHODS: PREVENT was a prospective, multi-center, single-arm, non-randomized study of 300 patients implanted with HMII at 24 participating sites. Confirmed PT (any suspected PT confirmed visually and/or adjudicated by an independent assessor) was evaluated at 3 months (primary end-point) and at 6 months after implantation. RESULTS: The population included 83% men (age 57 years ± 13), 78% destination therapy, and 83% Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Profile 1-3. Primary end-point analysis showed a confirmed PT of 2.9% at 3 months and 4.8% at 6 months. Adherence to key recommendations included 78% to surgical recommendations, 95% to heparin bridging, and 79% to pump speeds ≥9,000 RPMs (92% >8,600 RPMs). Full adherence to implant techniques, heparin bridging, and pump speeds ≥9,000 RPMs resulted in a significantly lower risk of PT (1.9% vs 8.9%; p < 0.01) and lower composite risk of suspected thrombosis, hemolysis, and ischemic stroke (5.7% vs 17.7%; p < 0.01) at 6 months. CONCLUSIONS: Adoption of all components of a structured surgical implant technique and clinical management strategy (PREVENT recommendations) is associated with low rates of confirmed PT

Database NewSQL performance evaluation for big data in the public cloud

For very years, relational databases have been the leading model for data storage, retrieval and management. However, due to increasing needs for scalability and performance, alternative systems have emerged, namely NewSQL technology. NewSQL is a class of modern relational database management systems (RDBMS) that provide the same scalable performance of NoSQL systems for online transaction processing (OLTP) read-write workloads, while still maintaining the ACID guarantees of a traditional database system. In this research paper, the performance of a NewSQL database is evaluated, compared to a MySQL database, both running in the cloud, in order to measure the response time against different configurations of workloads.Instituto de Investigación en Informátic

3D Real-Time Echocardiography Combined with Mini Pressure Wire Generate Reliable Pressure-Volume Loops in Small Hearts

BACKGROUND: Pressure-volume loops (PVL) provide vital information regarding ventricular performance and pathophysiology in cardiac disease. Unfortunately, acquisition of PVL by conductance technology is not feasible in neonates and small children due to the available human catheter size and resulting invasiveness. The aim of the study was to validate the accuracy of PVL in small hearts using volume data obtained by real-time three-dimensional echocardiography (3DE) and simultaneously acquired pressure data. METHODS: In 17 piglets (weight range: 3.6–8.0 kg) left ventricular PVL were generated by 3DE and simultaneous recordings of ventricular pressure using a mini pressure wire (PVL3D). PVL3D were compared to conductance catheter measurements (PVLCond) under various hemodynamic conditions (baseline, alpha-adrenergic stimulation with phenylephrine, beta-adrenoreceptor-blockage using esmolol). In order to validate the accuracy of 3D volumetric data, cardiac magnetic resonance imaging (CMR) was performed in another 8 piglets. RESULTS: Correlation between CMR- and 3DE-derived volumes was good (enddiastolic volume: mean bias -0.03ml ±1.34ml). Computation of PVL3D in small hearts was feasible and comparable to results obtained by conductance technology. Bland-Altman analysis showed a low bias between PVL3D and PVLCond. Systolic and diastolic parameters were closely associated (Intraclass-Correlation Coefficient for: systolic myocardial elastance 0.95, arterial elastance 0.93, diastolic relaxation constant tau 0.90, indexed end-diastolic volume 0.98). Hemodynamic changes under different conditions were well detected by both methods (ICC 0.82 to 0.98). Inter- and intra-observer coefficients of variation were below 5% for all parameters. CONCLUSIONS: PVL3D generated from 3DE combined with mini pressure wire represent a novel, feasible and reliable method to assess different hemodynamic conditions of cardiac function in hearts comparable to neonate and infant size. This methodology may be integrated into clinical practice and cardiac catheterization programs and has the capability to contribute to clinical decision making even in small hearts