Good machine learning practices: Learnings from the modern pharmaceutical discovery enterprise.

Machine Learning (ML) and Artificial Intelligence (AI) have become an integral part of the drug discovery and development value chain. Many teams in the pharmaceutical industry nevertheless report the challenges associated with the timely, cost effective and meaningful delivery of ML and AI powered solutions for their scientists. We sought to better understand what these challenges were and how to overcome them by performing an industry wide assessment of the practices in AI and Machine Learning. Here we report results of the systematic business analysis of the personas in the modern pharmaceutical discovery enterprise in relation to their work with the AI and ML technologies. We identify 23 common business problems that individuals in these roles face when they encounter AI and ML technologies at work, and describe best practices (Good Machine Learning Practices) that address these issues.

BioPrint meets the AI age: development of artificial intelligence-based ADMET models for the drug-discovery platform SAFIRE.

Background: To prioritize compounds with a higher likelihood of success, artificial intelligence models can be used to predict absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of molecules quickly and efficiently. Methods: Models were trained with BioPrint database proprietary data along with public datasets to predict various ADMET end points for the SAFIRE platform. Results: SAFIRE models performed at or above 75% accuracy and 0.4 Matthew's correlation coefficient with validation sets. Training with both proprietary and public data improved model performance and expanded the chemical space on which the models were trained. The platform features scoring functionality to guide user decision-making. Conclusion: High-quality datasets along with chemical space considerations yielded ADMET models performing favorably with utility in the drug discovery process.

A novel stochastic simulation approach enables exploration of mechanisms for regulating polarity site movement.

Cells polarize their movement or growth toward external directional cues in many different contexts. For example, budding yeast cells grow toward potential mating partners in response to pheromone gradients. Directed growth is controlled by polarity factors that assemble into clusters at the cell membrane. The clusters assemble, disassemble, and move between different regions of the membrane before eventually forming a stable polarity site directed toward the pheromone source. Pathways that regulate clustering have been identified but the molecular mechanisms that regulate cluster mobility are not well understood. To gain insight into the contribution of chemical noise to cluster behavior we simulated clustering using the reaction-diffusion master equation (RDME) framework to account for molecular-level fluctuations. RDME simulations are a computationally efficient approximation, but their results can diverge from the underlying microscopic dynamics. We implemented novel concentration-dependent rate constants that improved the accuracy of RDME-based simulations, allowing us to efficiently investigate how cluster dynamics might be regulated. Molecular noise was effective in relocating clusters when the clusters contained low numbers of limiting polarity factors, and when Cdc42, the central polarity regulator, exhibited short dwell times at the polarity site. Cluster stabilization occurred when abundances or binding rates were altered to either lengthen dwell times or increase the number of polarity molecules in the cluster. We validated key results using full 3D particle-based simulations. Understanding the mechanisms cells use to regulate the dynamics of polarity clusters should provide insights into how cells dynamically track external directional cues.

Chemotactic movement of a polarity site enables yeast cells to find their mates.

How small eukaryotic cells can interpret dynamic, noisy, and spatially complex chemical gradients to orient growth or movement is poorly understood. We address this question using Saccharomyces cerevisiae, where cells orient polarity up pheromone gradients during mating. Initial orientation is often incorrect, but polarity sites then move around the cortex in a search for partners. We find that this movement is biased by local pheromone gradients across the polarity site: that is, movement of the polarity site is chemotactic. A bottom-up computational model recapitulates this biased movement. The model reveals how even though pheromone-bound receptors do not mimic the shape of external pheromone gradients, nonlinear and stochastic effects combine to generate effective gradient tracking. This mechanism for gradient tracking may be applicable to any cell that searches for a target in a complex chemical landscape.

A Randomized Controlled Trial to Compare Analgesia and Functional Improvement After Continuous Neuroablative and Pulsed Neuromodulative Radiofrequency Treatment of the Genicular Nerves in Patients with Knee Osteoarthritis up to One Year After the Intervention.

OBJECTIVES: To compare the analgesic and functional outcomes of continuous neuroablative radiofrequency (CNARF) and pulsed neuromodulative radiofrequency (PNMRF) treatment of genicular nerves up to 1 year after the intervention and to identify predictors associated with a successful outcome (defined as an at least 50% reduction in the pre-interventional visual analog scale [VAS] rating) after genicular radiofrequency treatment. DESIGN: A prospective randomized controlled trial. SETTING: The Pain Department of the Jerez de la Frontera University Hospital, Cadíz, Spain, from January 2018 until May 2019. SUBJECTS: Patients with grade 3-4 gonarthritis suffering from knee pain, with a VAS score ≥5 for >6 months. METHODS: Eligible participants were randomly assigned to receive either CNARF or PNMRF of the superior medial, superior lateral, and inferior medial genicular nerves. The VAS and Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scores were assessed before and at 1, 6, and 12 months after treatment. Medication use was quantified before and at 6 months after the intervention. Potential characteristics associated with the efficacy of radiofrequency intervention were explored by using multivariable statistical models. RESULTS: A total of 188 participants were included. The magnitude and duration of beneficial effect and reduction in analgesic use were significantly greater in the CNARF group. Success at 6 months after radiofrequency treatment decreased with grade 4 gonarthritis; higher pre-interventional VAS score; and concomitant depression, anxiety disorder, and diabetes mellitus. CONCLUSIONS: Therapeutic efficacy and reduction in analgesic consumption were superior after CNARF. Treatment success at 6 months after radiofrequency intervention decreased with more severe gonarthritis; higher pre-interventional pain intensity; and concomitant depression, anxiety disorder, and diabetes mellitus.

Perinatal exposure to octabromodiphenyl ether mixture, DE-79, alters the vasopressinergic system in adult rats.

Polybrominated diphenyl ethers (PBDEs) are persistent environmental pollutants considered as neurotoxicants and endocrine disruptors with important biological effects ranging from alterations in growth, reproduction, and effects on the hypothalamus-pituitary-adrenal axis. The vasopressinergic (AVPergic) system is a known target for pentaBDEs mixture (DE-71) and the structurally similar chemicals, polychlorinated biphenyls. However, the potential adverse effects of mixtures containing octaBDE compounds, like DE-79, on the AVPergic system are still unknown. The present study aims to examine the effects of perinatal DE-79 exposure on the AVPergic system. Dams were dosed from gestational day 6 to postnatal day 21 at doses of 0 (control), 1.7 (low) or 10.2 (high) mg/kg/day, and male offspring from all doses at 3-months-old were subjected to normosmotic and hyperosmotic challenge. Male offspring where later assessed for alterations in osmoregulation (i.e. serum osmolality and systemic vasopressin release), and both vasopressin immunoreactivity (AVP-IR) and gene expression in the hypothalamic paraventricular and supraoptic nuclei. Additionally, to elucidate a possible mechanism for the effects of DE-79 on the AVPergic system, both neuronal nitric oxide synthase immunoreactivity (nNOS-IR) and mRNA expression were investigated in the same hypothalamic nuclei. The results showed that perinatal DE-79 exposure AVP-IR, mRNA expression and systemic release in adulthood under normosmotic conditions and more evidently under hyperosmotic stimulation. nNOS-IR and mRNA expression were also affected in the same nuclei. Since NO is an AVP regulator, we propose that disturbances in NO could be a mechanism underlying the AVPergic system disruption following perinatal DE-79 exposure leading to osmoregulation deficits.

Effect of the Organization of Rhodopsin on the Association between Transducin and a Photoactivated Receptor.

After photoactivation, rhodopsin (R), a G-protein-coupled receptor, rapidly activates multiple transducin G-proteins (G) in an initial amplification step of phototransduction. G-protein activation requires diffusion-mediated association with an active rhodopsin (R*) at the rod disk membrane. Different organizations of R within the membrane have been revealded by several microscopy studies, including static and freely diffusing situations. However, it is unclear how such different scenarios influence the activation rate of G proteins. Through Monte Carlo simulations, we study the association reaction between a photoactivated rhodopsin and transducin under different reported receptor organizations including (a) R monomers diffusing freely, (b) R forming static dispersed crystalline domains made of rows of dimers, and (c) R arranged in static tracks formed by two adjacent rows of dimers. A key parameter in our simulations is the probability of binding following a collision ( p). For high p, the association rate between R* and G is higher in the freely diffusive system than in the static organizations, but for low collision efficiencies, the static organizations can result in faster association rates than the mobile system. We also observe that with low p, increasing the concentration of R increases the association rate significantly in the dispersed crystals configuration and just slightly in the free diffusive system. In summary, the lateral organization of rhodopsin influences the association rate between R* and G in a manner strongly dependent on the collision efficiency.

[Usefulness of cold ureteral biopsy during radical cystectomy as a predictor of recurrence risk: Review of our series.] / Utilidad de la biopsia fría ureteral durante la cistectomía radical como predictor de riesgo de recidiva: revisión de nuestra serie.

OBJECTIVES: To evaluate the association of positive margins in the intraoperative biopsy during radical cystectomy (RC) with the risk of recurrence in the uretero-ileal anastomosis or upper urinary tract (UUT), and identify potential risk factors for positive ureteral margins. METHODS: A retrospective, descriptive study was performed in patients treated with radical cystectomy due to transitional cell carcinoma (TCC), who underwent a cold biopsy of the ureteral margin at the time of cystectomy. A descriptive analysis and frequency distribution was performed. Fisher's test was used to calculate sensitivity and specificity and a survival analysis was performed. RESULTS: 230 patients were included. Prior to RC, transurethral resection of the bladder tumor and a CT scan were done. The percentage of positive margins was 4.81% for the right ureter and 4.27% for the left. Recurrence was detected in the anastomosis in 2.64% of the cases. In a 0.88% recurrence was found in the UUT (2 cases) at the level of left renal pelvis (1 case) and left kidney (1 case). In the multivariate analysis, neither recurrence in the anastomosis (p=1) or at the UUT (p=1) level during follow-up were significantly associated with the presence of positive margins. An association was found between the pathological biopsy of the right ureter and carcinoma in situ (CIS) of the bladder wall with UUT involvement. We found only association between the cold biopsy of the left ureter and tumor in left UTT. Reimplantation with positive margins was not statistically associated with neither ureteroileal anastomosis or UTT relapse. A relationship was found between the cold biopsy of both ureters and the definitive pathology. CONCLUSIONS: In our study, the presence of positive ureteral margins was not associated with an increased risk of recurrence in the anastomosis or UUT. Although it remains a topic for debate, a strategy to follow may be to adapt ureteral cold biopsies to individual risk, thus perform it in patients with bladder CIS.

Utilidad de la biopsia fría ureteral durante la cistectomía radical como predictor de riesgo de recidiva: revisión de nuestra serie / Usefulness of cold ureteral biopsy during radical cystectomy as a predictor of recurrence risk: Review of our series

OBJETIVOS: Evaluar la asociación de márgenes positivos en la biopsia intra-operatoria al tiempo de la cistectomía radical (CR) con el riesgo de recidiva en la anastomosis urétero-ileal o a nivel del tracto urinario superior (TUS), y estudiar posibles factores de riesgo preoperatorios asociados con el margen ureteral positivo. MÉTODO: Estudio descriptivo retrospectivo de pacientes tratados mediante CR debido a carcinoma de células transicionales (CCT), a los que se les realizó al tiempo de la CR una biopsia fría del margen ureteral. Se realizó un análisis descriptivo y distribuciones de frecuencias. Se empleó el test de Fisher, se calcularon los valores de sensibilidad (Se) y especificidad (Sp) de la prueba, y se realizó un análisis de supervivencia. RESULTADOS: Se incluyeron 230 pacientes que fueron sometidos a CR. Previamente a la CR se les realizó resección transuretral (RTU) de vejiga y tomografía axial computarizada (TC). El porcentaje de márgenes positivos fue de 4,8% para el uréter derecho y de 4,7% para el izquierdo. Se detectó recidiva en la anastomosis en el 2,6% de los casos. En un 0,8% se encontró recidiva en el TUS (2 casos) a nivel de pelvis renal izquierda (1 caso) y riñón izquierdo (1 caso). En el análisis multivariante, ni la recidiva en la anastomosis (p=1) ni a nivel del TUS (p=1) a lo largo del seguimiento, se asociaron de forma significativa con la presencia de márgenes positivos. De forma secundaria se estudiaron los posibles factores anatomopatológicos preoperatorios asociados con el riesgo de margen positivo, encontrando asociación entre la anatomía patológica (A-P) intraoperatoria del uréter derecho y CIS en la RTU vesical y con tumor del TUS asociado. La reimplantación con margen positivo no se asoció estadísticamente con recidiva en la anastomosis ni con recidiva en el TUS. Hubo relación entre A-P intraoperatoria de ambos uréteres y la definitiva. CONCLUSIONES: En nuestro estudio, la presencia de márgenes ureterales positivos no se asociaron con mayor riesgo de recidiva en la anastomosis o en el TUS. Aunque sigue siendo un tema a debate, una estrategia a seguir puede ser adaptar la biopsia fría ureteral al riesgo individual y realizarla a pacientes con CIS vesical

OBJECTIVES: To evaluate the association of positive margins in the intraoperative biopsy during radical cystectomy (RC) with the risk of recurrence in the uretero-ileal anastomosis or upper urinary tract (UUT), and identify potential risk factors for positive ureteral margins. METHODS: A retrospective, descriptive study was performed in patients treated with radical cystectomy due to transitional cell carcinoma (TCC), who underwent a cold biopsy of the ureteral margin at the time of cystectomy. A descriptive analysis and frequency distribution was performed. Fisher's test was used to calculate sensitivity and specificity and a survival analysis was performed. RESULTS: 230 patients were included. Prior to RC, transurethral resection of the bladder tumor and a CT scan were done. The percentage of positive margins was 4.81% for the right ureter and 4.27% for the left. Recurrence was detected in the anastomosis in 2.64% of the cases. In a 0.88% recurrence was found in the UUT (2 cases) at the level of left renal pelvis (1 case) and left kidney (1 case). In the multivariate analysis, neither recurrence in the anastomosis (p=1) or at the UUT (p=1) level during follow-up were significantly associated with the presence of positive margins. An association was found between the pathological biopsy of the right ureter and carcinoma in situ (CIS) of the bladder wall with UUT involvement. We found only association between the cold biopsy of the left ureter and tumor in left UTT. Reimplantation with positive margins was not statistically associated with neither ureteroileal anastomosis or UTT relapse. A relationship was found between the cold biopsy of both ureters and the definitive pathology. CONCLUSIONS: In our study, the presence of positive ureteral margins was not associated with an increased risk of recurrence in the anastomosis or UUT. Although it remains a topic for debate, a strategy to follow may be to adapt ureteral cold biopsies to individual risk, thus perform it in patients with bladder CIS

Principles that govern competition or co-existence in Rho-GTPase driven polarization.

Rho-GTPases are master regulators of polarity establishment and cell morphology. Positive feedback enables concentration of Rho-GTPases into clusters at the cell cortex, from where they regulate the cytoskeleton. Different cell types reproducibly generate either one (e.g. the front of a migrating cell) or several clusters (e.g. the multiple dendrites of a neuron), but the mechanistic basis for unipolar or multipolar outcomes is unclear. The design principles of Rho-GTPase circuits are captured by two-component reaction-diffusion models based on conserved aspects of Rho-GTPase biochemistry. Some such models display rapid winner-takes-all competition between clusters, yielding a unipolar outcome. Other models allow prolonged co-existence of clusters. We investigate the behavior of a simple class of models and show that while the timescale of competition varies enormously depending on model parameters, a single factor explains a large majority of this variation. The dominant factor concerns the degree to which the maximal active GTPase concentration in a cluster approaches a "saturation point" determined by model parameters. We suggest that both saturation and the effect of saturation on competition reflect fundamental properties of the Rho-GTPase polarity machinery, regardless of the specific feedback mechanism, which predict whether the system will generate unipolar or multipolar outcomes.

Particle-based simulations of polarity establishment reveal stochastic promotion of Turing pattern formation.

Polarity establishment, the spontaneous generation of asymmetric molecular distributions, is a crucial component of many cellular functions. Saccharomyces cerevisiae (yeast) undergoes directed growth during budding and mating, and is an ideal model organism for studying polarization. In yeast and many other cell types, the Rho GTPase Cdc42 is the key molecular player in polarity establishment. During yeast polarization, multiple patches of Cdc42 initially form, then resolve into a single front. Because polarization relies on strong positive feedback, it is likely that the amplification of molecular-level fluctuations underlies the generation of multiple nascent patches. In the absence of spatial cues, these fluctuations may be key to driving polarization. Here we used particle-based simulations to investigate the role of stochastic effects in a Turing-type model of yeast polarity establishment. In the model, reactions take place either between two molecules on the membrane, or between a cytosolic and a membrane-bound molecule. Thus, we developed a computational platform that explicitly simulates molecules at and near the cell membrane, and implicitly handles molecules away from the membrane. To evaluate stochastic effects, we compared particle simulations to deterministic reaction-diffusion equation simulations. Defining macroscopic rate constants that are consistent with the microscopic parameters for this system is challenging, because diffusion occurs in two dimensions and particles exchange between the membrane and cytoplasm. We address this problem by empirically estimating macroscopic rate constants from appropriately designed particle-based simulations. Ultimately, we find that stochastic fluctuations speed polarity establishment and permit polarization in parameter regions predicted to be Turing stable. These effects can operate at Cdc42 abundances expected of yeast cells, and promote polarization on timescales consistent with experimental results. To our knowledge, our work represents the first particle-based simulations of a model for yeast polarization that is based on a Turing mechanism.

Safety of the Transcranial Focal Electrical Stimulation via Tripolar Concentric Ring Electrodes for Hippocampal CA3 Subregion Neurons in Rats.

Epilepsy is a neurological disorder that affects approximately one percent of the world population. Noninvasive electrical brain stimulation via tripolar concentric ring electrodes has been proposed as an alternative/complementary therapy for seizure control. Previous results suggest its efficacy attenuating acute seizures in penicillin, pilocarpine-induced status epilepticus, and pentylenetetrazole-induced rat seizure models and its safety for the rat scalp, cortical integrity, and memory formation. In this study, neuronal counting was used to assess possible tissue damage in rats (n = 36) due to the single dose or five doses (given every 24 hours) of stimulation on hippocampal CA3 subregion neurons 24 hours, one week, and one month after the last stimulation dose. Full factorial analysis of variance showed no statistically significant difference in the number of neurons between control and stimulation-treated animals (p = 0.71). Moreover, it showed no statistically significant differences due to the number of stimulation doses (p = 0.71) nor due to the delay after the last stimulation dose (p = 0.96). Obtained results suggest that stimulation at current parameters (50 mA, 200 µs, 300 Hz, biphasic, charge-balanced pulses for 2 minutes) does not induce neuronal damage in the hippocampal CA3 subregion of the brain.

Perinatal exposure to organohalogen pollutants decreases vasopressin content and its mRNA expression in magnocellular neuroendocrine cells activated by osmotic stress in adult rats.

Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are environmental pollutants that produce neurotoxicity and neuroendocrine disruption. They affect the vasopressinergic system but their disruptive mechanisms are not well understood. Our group reported that rats perinatally exposed to Aroclor-1254 (A1254) and DE-71 (commercial mixtures of PCBs and PBDEs) decrease somatodendritic vasopressin (AVP) release while increasing plasma AVP responses to osmotic activation, potentially emptying AVP reserves required for body-water balance. The aim of this research was to evaluate the effects of perinatal exposure to A1254 or DE-71 (30mgkg/day) on AVP transcription and protein content in the paraventricular and supraoptic hypothalamic nuclei, of male and female rats, by in situ hybridization and immunohistochemistry. cFOS mRNA expression was evaluated in order to determine neuroendocrine cells activation due to osmotic stimulation. Animal groups were: vehicle (control); exposed to either A1254 or DE-71; both, control and exposed, subjected to osmotic challenge. The results confirmed a physiological increase in AVP-immunoreactivity (AVP-IR) and gene expression in response to osmotic challenge as reported elsewhere. In contrast, the exposed groups did not show this response to osmotic activation, they showed significant reduction in AVP-IR neurons, and AVP mRNA expression as compared to the hyperosmotic controls. cFOS mRNA expression increased in A1254 dehydrated groups, suggesting that the AVP-IR decrease was not due to a lack of the response to the osmotic activation. Therefore, A1254 may interfere with the activation of AVP mRNA transcript levels and protein, causing a central dysfunction of vasopressinergic system.

Dendritic spine geometry can localize GTPase signaling in neurons.

Dendritic spines are the postsynaptic terminals of most excitatory synapses in the mammalian brain. Learning and memory are associated with long-lasting structural remodeling of dendritic spines through an actin-mediated process regulated by the Rho-family GTPases RhoA, Rac, and Cdc42. These GTPases undergo sustained activation after synaptic stimulation, but whereas Rho activity can spread from the stimulated spine, Cdc42 activity remains localized to the stimulated spine. Because Cdc42 itself diffuses rapidly in and out of the spine, the basis for the retention of Cdc42 activity in the stimulated spine long after synaptic stimulation has ceased is unclear. Here we model the spread of Cdc42 activation at dendritic spines by means of reaction-diffusion equations solved on spine-like geometries. Excitable behavior arising from positive feedback in Cdc42 activation leads to spreading waves of Cdc42 activity. However, because of the very narrow neck of the dendritic spine, wave propagation is halted through a phenomenon we term geometrical wave-pinning. We show that this can account for the localization of Cdc42 activity in the stimulated spine, and, of interest, retention is enhanced by high diffusivity of Cdc42. Our findings are broadly applicable to other instances of signaling in extreme geometries, including filopodia and primary cilia.

Permanently compromised NADPH-diaphorase activity within the osmotically activated supraoptic nucleus after in utero but not adult exposure to Aroclor 1254.

Stimulated vasopressin (VP) release from magnocellular neuroendocrine cells in the supraoptic nucleus (SON) of hyperosmotic rats is inhibited by treatment with the industrial polychlorinated biphenyl (PCB) mixture, Aroclor 1254. Because VP responses to hyperosmotic stimulation are regulated by nitric oxide (NO) signaling, we studied NO synthase (NOS) activity in the SON of hyperosmotic rats as potential target of PCB-induced disruption of neuroendocrine processes necessary for osmoregulation. To examine PCB-induced changes in NOS activity under normosmotic and hyperosmotic conditions, male Sprague-Dawley rats were exposed to Aroclor 1254 (30mg/kg/day) in utero and NADPH-diaphorase (NADPH-d) activity was assessed in SON sections at three ages: postnatal day 10, early adult (3-5 months) or late adult (14-16 months). Hyperosmotic treatment increased mean NADPH-d staining density of oil hyperosmotic controls by 19.9% in early adults and 58% in late adulthood vs normosmotic controls. In utero exposure to PCBs reduced hyperosmotic-induced upregulation of NADPH-d activity to control levels in early adults and by 28% in late adults. Basal NADPH-d was reduced in postnatal rats. Rats receiving PCB exposure as early adults orally for 14 days displayed normal responses. Our findings show that developmental but not adult exposure to PCBs significantly reduces NOS responses to hyperosmolality in neuroendocrine cells. Moreover, reduced NADPH-d activity produced by in utero exposure persisted in stimulated late adult rats concomitant with reduced osmoregulatory capacity vs oil controls (375±9 vs 349±5mOsm/L). These findings suggest that developmental PCBs permanently compromise NOS signaling in the activated neuroendocrine hypothalamus with potential osmoregulatory consequences.

Terapia de revascularización percutánea en pacientes portadores de estenosis crítica carotídea-coronaria: resultados en un hospital y a largo plazo / Percutaneous revascularization therapy in patients of critical carotid-coronary stenosis: results in hospital and long term

Objetivo: Analizar la morbimortalidad a 30 días y 6 meses en pacientes sometidos a una intervención percutánea (IP) por estenosis critíca carotídea (EAC)-coronaria (EACo) en un centro hospitalario de alto volumen, experto en el tratamiento de la enfermedad multivascular. Antecedentes: El tratamiento óptimo de los pacientes con EAC y EACo concomitante sigue siendo controvertido. Ha sido reportada una variedad de estrategias terapéuticas, incluyendo a la cirugía de revascularización coronaria (BACo), sola o en combinación con la revascularización percutánea o quirúrgica de la arteria carótida. Material y métodos: Entre enero de 1998 y junio de 2013 fueron tratados 118 (149 lesiones) pacientes consecutivos con EAC (estenosis carotídea sintomática en el 37.6%) y EACo en forma estadiada o simultánea a IP carotídeo-coronario con stent. El objetivo primario (PP) fue evaluar la incidencia de los eventos cardiacos y cerebro-vasculares mayores (ECVM) (muerte, infarto al miocardio y accidente vascular cerebral mayor) en los 30 días posteriores, tanto al primero como segundo procedimiento. Con un EuroSCORE (ES) promedio de 2.75 ± 1.5. Resultados: A 30 días, la incidencia de PP fue de 4.02%; la muerte global infarto agudo al miocardio (IAM) y accidente vascular cerebral mayor (AVCM) ocurrieron en el 2.01, 1.34 y 0.67% respectivamente; no observamos diferencia en AVC mayor y muerte en el grupo Sx versus Asx, 2.14% versus 2.14%, p = 0.809; ambos grupos, sin embargo, en el infarto fue mayor en Asx versus Sx 4.3% versus 0%, p = 0.053. Se hizo un seguimiento a seis meses de 140 lesiones tratadas; cuatro pacientes se sometieron a revascularización coronaria, uno falleció, tres de ellos presentaron IAM y muerte cardiovascular, 0% de AVC ipsilaterales; 1.4% presentó reestenosis in stent carotídeo tratándose con angioplastia balón (ATP). Conclusiones: En los pacientes con EAC y EACo concomitante, un tratamiento percutáneo combinado se compara muy favorablemente con las experiencias quirúrgicas o híbridos con evidente menor ECVM. Tal estrategia puede ser especialmente más adecuada a pacientes complejos con alto riesgo quirúrgico.

Objectives: To analyze the morbidity and mortality at 30 days and 6 months in patients taken to a Percutaneous Intervention (PI) for critical Carotid and coronary stenosis in a center of high volume expert in the treatment of multivessel disease. Background: The optimal treatment of patients with Carotid and Coronary disease concomitant remains controversial. A variety of therapeutic strategies, including coronary artery bypass surgery (CABG), alone or in combination with percutaneous or surgical revascularization of the carotid artery have been reported. Material and methods: Between January 1998 and June 2013, 118 patients with (149 lesions) carriers of Coronary and Carotid disease (symptomatic carotid stenosis in 37.6%) were treated as staged or simultaneous PI Carotid-Coronary stenting. The primary endpoint (EP) to assess the incidence of major cerebrovascular and cardiac events (MACE) (death, myocardial infarction, cerebral vascular accident major) within 30 days after the first and second proceedings, with EuroSCORE (ES) 2.75 ± 1.5 avg. Results: The incidence of EP was 4.02%, global death, acute myocardial infarction (AMI) and cerebral vascular accident major (CVAM) occurred in 2.01, 1.34 and 0.67% respectively. In group Asx versus Sx we not observed a greater difference in the CVAM and death 2.14% versus 2.14%, p = 0.809 both groups, however in AMI was higher in Asx versus Sx group 4.3% versus 0%, p = 0.053. At 6 month follow up 4 patients underwent CABG one dies, 3 patients more presented AMI and death, 0% ipsilateral CVA, 1.4% had carotid stent restenosis with being treated PTA. Conclusions: In patients with carotid and coronary stenosis concomitant, combined percutaneous treatment compares very favorably to previous surgical or hybrid experiences less obvious MACE. This strategy may be particularly suited to more complex patients with high surgical risk.

Cierre percutáneo primario del defecto del tabique interventricular postinfarto con el dispositivo de Amplatzer: resultados inmediatos y seguimiento a largo plazo / Primary percutaneous closure of postinfarction septal defect with Amplatzer device: immediate results and long-term follow-up

Introducción: La reparación quirúrgica inmediata de una comunicación interventricular que complica el infarto agudo del miocardio (CIV post-IAM) se asocia con la alta mortalidad. El cierre con dispositivo percutáneo parece ser seguro y efectivo en pacientes con CIV post-IAM; reportamos los resultados inmediatos y a largo plazo en la utilización del dispositivo Amplatzer en el cierre primario de una CIV post-IAM. Material y métodos: De junio del 2006 a enero del 2014, 17 pacientes portadores de una CIV post-IAM se sometieron a un cierre percutáneo con Amplatzer a una edad promedio de 66.8 ± 5.5, 82.4% en shock cardiogénico (ShC), el 35.3% recibieron tratamiento trombolítico (TT) en ventana, el tiempo promedio del diagnóstico de CIV al cierre percutáneo (IP) fue de 8.7 ± 5.8 días. Resultados: Con un seguimiento actual de 13.25 ± 12.6 meses, el éxito del procedimiento fue del 100%, el shunt (QP:QS) se redujo de 2.9 ± 0.95 a 1.5 ± 0.40 L/min p = 0.0001, 12 pacientes (70.6%) se sometieron a una Angioplastía Coronaria Transluminal Percutánea (ACTP) del vaso culpable posterior al cierre de la CIV. La mortalidad a 30 días fue de 52.9%, siendo más alta en el paciente con ShC versus no-ShC 64.3 versus 0% p = 0.043 OR 2.8 (IC 95% 1.38-5.6). Conclusión: El cierre primario de CIV post-IAM es una técnica muy promisoria que puede ser realizada con una alta tasa de éxito y mínimas complicaciones y puede ser tomado como una alternativa a la cirugía. Sin embargo, a pesar de ser una técnica menos invasiva, la mortalidad permanece alta y muy evidente en el paciente en ShC.

Introduction: The immediate surgical repair of a ventricular septal defect complicating acute myocardial infarction (VSD post-AMI) is associated with high mortality. The percutaneous closure device is safe and effective in patients with post-infarction VSD; we report the immediate and long term results in the use of the Amplatzer device in the primary closure of post infarction VSD. Material and methods: From June 2006 to January 2014, 17 patients carriers of post-infarction VSD underwent percutaneous Amplatzer closure with a mean age 66.8 ± 5.5, 82.4% in cardiogenic shock (CS), 35.3% were thrombolyzed (TT) in window, the average time to percutaneous closure of VSD 8.7 ± 5.8 days. Results: With a current monitoring of 13.25 ± 12.6 months procedural success were in 100% shunt (QP:QS) was reduced from 2.9 to 1.5 ± 0.40 ± 0.95 L/min p = 0.0001, 12 patients (70.6%) undergoing PTCA the culprit vessel post-closure of the VSD. Global mortality at 30 days was 52.9%, being higher in patients with CS versus 64.3 versus 0% no-CS p = 0.043 OR 2.8 (CI 95% 1.38-5.6). Conclusion: The primary closure of postinfarction VSD is a very promising technique that can be performed with a high success rate and minimal complications and may be taken as an alternative to surgery. However despite being a less invasive technique remains high mortality very evident in patients in CS.

Ablación septal con alcohol en la miocardiopatía hipertrófica: Experiencia de 10 años de un centro de cardiología. Resultados inmediatos y seguimiento a 12 meses / Septal ablation with alcohol in hipertrophic miocardiopathy: Ten years experience in a cardiologic center. Immediate and long term results

Objetivo: Conocer las características demográficas, clínicas, hemodinámicas y su evolución intrahospitalaria a mediano plazo en la miocardiopatía hipertrófica septal obstructiva. Material y métodos: Estudio observacional, longitudinal con dirección retrospectiva, descriptivo y no comparativo (serie de casos) que incluye 21 pacientes con diagnóstico de miocardiopatía hipertrófica septal obstructiva con los siguientes criterios: clase funcional III-IV de la New York Heart Association refractarios a tratamiento y/o con gradiente ≥ 30 mmHg en reposo o ≥ 60 mmHg provocado y además con movimiento sistólico anterior o insuficiencia mitral > GII esto, por ecocardiografía. Resultados: Variables demográficas: edad promedio de la cohorte fue de 50 ± 16; distribución por género: hombres n = 8 (38.1%), mujeres n = 13 (61.9%); síntomas: angor n = 9 (42.9%), disnea n = 18 (85.7), síncope n = 5 (23.8); clases funcionales (New York Heart Association) (preablación): clase funcional 3 n = 12 (57.1%), clase funcional 4 n = 1 (4.8%); uso de fármacos: BB n =15 (71.4%), Verapamil n = 13 (61.9%), IECA n = 3 (14.3%), ECG: HVI n = 17 (81%), FA n = 1 (4.8%), BCRIHH n = 3 (14.3%); ecocardiográficas: eco basal PPVI 14.9 ± 4.4 mm, SIV 22.7 ± 4.9 mm, FE 65.5 + 7%, Gte.TSVI 106.9 ± 29.9 mmHg, grado IM-3 n = 7 (33.3%), grado IM-4 n = 10 (47.6%); postintervención Eco Gte TVSI 44.6 ± 24.3 mm, grado IM-3 n = 3 (14.3%), grado IM-4 n = 1 (4.8%), alcohol 3.4 ± 0.9 mL; estancia intrahospitalaria 5.9 ± 3 días, CPK-total 1466 ± 924, CK-MB 215 ± 128; complicaciones eléctricas BAV transitorio n = 11(52.9%), MCPD n = 1 (4.8), hemodinámicas-FE basal 65.5 + 16, FE post 62.2 ± 6.5, gte basal 106.33 ± 37 mmHg, Gte-post 44 ± 34 mmhg; evolución: 1 año CF-NYHA, CF1: n = 19 (90.5%), CF2: n = 2 (9.5%), eco Gte TSVI 22.0 ± 5.7 mmHg, SIV 20.7 ± 3.1 mm, FE (68.7 ± 6.2%), IM-0 n = 11 (52.4%), IM-1 n = 6 (28.6%), IM-2 n = 4 (19%); mortalidad intrahospitalaria del 0%. Conclusión: La ablación septal con alcohol es un método que tiene una alta tasa de éxito con una mejoría en cuanto a la calidad de vida del paciente y con un índice de complicaciones baja.

Objective: To know the demographic, clinical, hemodynamic, and hospital course, and medium term septal obstructive hypertrophic cardiomyopathy. Material and methods: Observational, longitudinal direction retrospective, descriptive and comparative (case series), including 21 patients with septal obstructive hypertrophic cardiomyopathy with the following criteria: functional class III-IV New York Heart Association refractory to treatment and/or ≥ 30 mmHg gradient at rest or ≥ 60 mm Hg provoked, and others have systolic anterior motion or mitral insufficiency > GII this by echocardiography. Results: Demographic variables: population-average age of the cohort was 50 ± 16 years, distribution by gender: men n = 8 (38.1%), women n = 13 (61.9%) symptoms: angor n = 9 (42.9%), dyspnea n = 18 (85.7), syncope n = 5 (23.8) CF-NYHA (pre-ablation): CF3 n = 12 (57.1%), CF4 n = 1 (4.8%); drug use: BB n = 15 (71.4%), verapamil n = 13 (61.9%), ACE inhibitors n = 3 (14.3%), ECG LVH n = 17 (81%), FA n = 1 (4.8%), LBHH n = 3 (14.3%); ecocardiogaphic-eco baseline: 14.9 ± 4.4 mm WPLV, IVS 22.7 ± 4.9 mm, EF: 65.5 ± 7%, Gte.TVG: 106.9 ± 29.9 mmHg, MI-3 grade n = 7 (33.3%), grade MI-4 n = 10 (47.6%) Post-intervention-eco gte TVG 44.6 ± 24.3 mm, grade MI-3 n = 3 (14.3%), grade MI-4 n = 1 (4.8%) 3.4 ± 0.9 ml alcohol, hospital stay 5.9 ± 3 days, CPK-total 1466 ± 924; CK-MB 215 ± 128, LVB transient electrical complications n = 11 (52.9%), permanent cardiac pacemaker n = 1 (4.8)-FE hemodynamic baseline: 65.5% ± 16, post-FE 62.2% ± 6.5; Gte Basal: 106.33 ± 37 mmhg GTE-post 44 ± 34 mmHg, evolution: 1 year follow-up CF-NYHA, CF1: n = 19 (90.5%), CF2: n = 2 (9.5%); Eco Gte 22.0 ± 5.7 mm Hg LVOT, 20.7 ± 3.1 mm SIV, FE (68.7 ± 6.2%), IM-0 n = 11 (52.4%), IM-1 n = 6 (28.6%), IM-2 n = 4 (19%), hospital mortality of 0%. Conclusion: The alcohol septal ablation is a method that has a high success rate, with an improvement in the quality of life of patients with a low complication rate.