Carbonate uranium isotopes record global expansion of marine anoxia during the Toarcian Oceanic Anoxic Event.

The Toarcian Oceanic Anoxic Event (T-OAE; ~183 Mya) was a globally significant carbon-cycle perturbation linked to widespread deposition of organic-rich sediments, massive volcanic CO2 release, marine faunal extinction, sea-level rise, a crisis in carbonate production related to ocean acidification, and elevated seawater temperatures. Despite recognition of the T-OAE as a potential analog for future ocean deoxygenation, current knowledge on the severity of global ocean anoxia is limited largely to studies of the trace element and isotopic composition of black shales, which are commonly affected by local processes. Here, we present the first carbonate-based uranium isotope (δ238U) record of the T-OAE from open marine platform limestones of the southeastern Tethys Ocean as a proxy for global seawater redox conditions. A significant negative δ238U excursion (~0.4‰) is recorded just prior to the onset of the negative carbon isotope excursion comprised within the T-OAE, followed by a long-lived recovery of δ238U values, thus confirming that the T-OAE represents a global expansion of marine anoxia. Using a Bayesian inverse isotopic mass balance model, we estimate that anoxic waters covered ~6 to 8% of the global seafloor during the peak of the T-OAE, which represents 28 to 38 times the extent of anoxia in the modern ocean. These data, combined with δ238U-based estimates of seafloor anoxic area for other CO2-driven Phanerozoic OAEs, suggest a common response of ocean anoxia to carbon release, thus improving prediction of future anthropogenically induced ocean deoxygenation.

Electrophysiological alterations during action semantic processing in Parkinson's disease.

Assessments of action semantics consistently reveal markers of Parkinson's disease (PD). However, neurophysiological signatures of the domain remain under-examined in this population, especially under conditions that allow patients to process stimuli without stringent time constraints. Here we assessed event-related potentials and time-frequency modulations in healthy individuals (HPs) and PD patients during a delayed-response semantic judgment task involving related and unrelated action-picture pairs. Both groups had shorter response times for related than for unrelated trials, but they exhibited discrepant electrophysiological patterns. HPs presented significantly greater N400 amplitudes as well as theta enhancement and mu desynchronization for unrelated relative to related trials. Conversely, N400 and theta modulations were abolished in the patients, who further exhibited a contralateralized cluster in the mu range. None of these patterns were associated with the participants' cognitive status. Our results suggest that PD involves multidimensional neurophysiological disruptions during action-concept processing, even under task conditions that elicit canonical behavioral effects. New constraints thus emerge for translational neurocognitive models of the disease.

Pileflebitis en pediatría: un desafío diagnóstico / Pylephlebitis in pediatrics: A diagnostic challenge

La pileflebitis es definida como la trombosis supurativa de la vena porta como complicación de infecciones abdominales. En pediatría, la etiología más frecuente es la apendicitis, generalmente de diagnóstico tardío, que se presenta como sepsis, con una elevada mortalidad. Para el diagnóstico son necesarios métodos de diagnóstico por imágenes; los más utilizados son la ecografía Doppler y la angiotomografía. El tratamiento se basa en la intervención quirúrgica, la antibioticoterapia y la anticoagulación. Esta última tiene indicación controvertida, pero podría mejorar el pronóstico y disminuir la morbimortalidad. Se presenta un caso clínico de pileflebitis secundaria a sepsis por Escherichia coli con punto de partida en una apendicitis aguda, en un paciente pediátrico que evoluciona a la transformación cavernomatosa de la vena porta. Es de importancia conocer el manejo de esta entidad, ya que, una vez superado el cuadro inicial, requerirá un minucioso seguimiento por la posibilidad de evolucionar a la insuficiencia hepática.

Pylephlebitis is defined as suppurative thrombosis of the portal vein as a complication of abdominal infections. In pediatrics, the most frequent etiology is appendicitis, generally of late diagnosis, presenting as sepsis, with a high mortality rate. Imaging methods are necessary for diagnosis; the most common are the Doppler ultrasound and computed tomography angiography. Treatment is based on surgery, antibiotic therapy, and anticoagulation. The indication for the latter is controversial, but it may improve prognosis and decrease morbidity and mortality. Here we describe a clinical case of pylephlebitis secondary to Escherichia coli sepsis, which started as acute appendicitis in a pediatric patient who progressed to cavernomatous transformation of the portal vein. It is important to know the management of this disease because, once the initial symptoms are overcome, it will require close follow-up due to a potential progression to liver failure.

Pylephlebitis in pediatrics: A diagnostic challenge. / Pileflebitis en pediatría: un desafío diagnóstico.

Pylephlebitis is defined as suppurative thrombosis of the portal vein as a complication of abdominal infections. In pediatrics, the most frequent etiology is appendicitis, generally of late diagnosis, presenting as sepsis, with a high mortality rate. Imaging methods are necessary for diagnosis; the most common are the Doppler ultrasound and computed tomography angiography. Treatment is based on surgery, antibiotic therapy, and anticoagulation. The indication for the latter is controversial, but it may improve prognosis and decrease morbidity and mortality. Here we describe a clinical case of pylephlebitis secondary to Escherichia coli sepsis, which started as acute appendicitis in a pediatric patient who progressed to cavernomatous transformation of the portal vein. It is important to know the management of this disease because, once the initial symptoms are overcome, it will require close follow-up due to a potential progression to liver failure.

La pileflebitis es definida como la trombosis supurativa de la vena porta como complicación de infecciones abdominales. En pediatría, la etiología más frecuente es la apendicitis, generalmente de diagnóstico tardío, que se presenta como sepsis, con una elevada mortalidad. Para el diagnóstico son necesarios métodos de diagnóstico por imágenes; los más utilizados son la ecografía Doppler y la angiotomografía. El tratamiento se basa en la intervención quirúrgica, la antibioticoterapia y la anticoagulación. Esta última tiene indicación controvertida, pero podría mejorar el pronóstico y disminuir la morbimortalidad. Se presenta un caso clínico de pileflebitis secundaria a sepsis por Escherichia coli con punto de partida en una apendicitis aguda, en un paciente pediátrico que evoluciona a la transformación cavernomatosa de la vena porta. Es de importancia conocer el manejo de esta entidad, ya que, una vez superado el cuadro inicial, requerirá un minucioso seguimiento por la posibilidad de evolucionar a la insuficiencia hepática.

Chronic kidney disease prevalence in asymptomatic patients with risk factors-usefulness of serum cystatin C: a cross-sectional study.

Background: Chronic kidney disease is recognized as a worldwide public health problem, particularly within an increasing prevalence of obesity, diabetes mellitus, and hypertension. This disease affects more than 13% of the world's population and is increasing. Further biochemical assessment with new biomarkers, such as serum cystatin C (CysC), would improve patient care and disease control. The aim of this study was to detect chronic kidney disease (CKD) in asymptomatic subjects with risk factors and evaluate CysC as early biomarker of renal damage and accurate test to estimation glomerular filtration (GF). Methods: This observational analytic and cross-sectional design included 195 patients of both sexes. A full clinical evaluation included height, weight, waist circumference, body mass index (BMI), blood pressure (BP), and family history of disease. Renal function was evaluated through serum creatinine (SCrea), serum CysC, urinary albumin, and urinary creatinine. GF was calculated using CKD-EPI creatinine (CKD-EPI Crea) and CKD-EPI creatinine-cystatin C equations (CKD-EPI Crea-CysC). Results: Renal injury showed 24% of patients with albuminuria; 18% of them were categorized as A2 and 6% as A3. Therefore, 73% had no progression risk (baseline risk), 20% moderate risk, and 7% high risk. Among analyzed groups, significant differences were found in BMI, BP, Screa, CysC, CKD-EPI Crea, and CKD-EPI Crea-CysC. Overweight population was analyzed by assessing CysC and calculating CKD-EPI Crea-CysC, showing an important change with respect to the general population. Conclusion: Combined CysC and Crea measurement provides incremental improvement in predicting measured GF.

Absceso de Brodie en la clavícula: una forma poco frecuente de presentación / Brodie abscess in the clavicle: an uncommon presentation

La osteomielitis (OM) se define como la inflamación ósea de origen infeccioso. La forma aguda es frecuente en la edad pediátrica. El absceso de Brodie es un tipo de osteomielitis subaguda, históricamente con baja incidencia, pero que actualmente se presenta un aumento de la misma. De poca repercusión clínica, con pruebas de laboratorio inespecíficas y estudios radiológicos de difícil interpretación, es crucial la sospecha diagnóstica. Se asemeja a procesos neoplásicos, benignos o malignos. Recae en la experiencia del profesional realizar el diagnóstico adecuado. El tratamiento consiste en antibioticoterapia, tanto parenteral como por vía oral, y eventualmente drenaje quirúrgico. Presentamos una paciente sana que consultó por una tumoración en topografía de clavícula izquierda de 3 meses de evolución. Se realizó diagnóstico de absceso de Brodie, inició tratamiento y se obtuvo una buena respuesta. Resulta imprescindible tener un alto índice de sospecha de esta entidad para no someter al paciente a estudios, pruebas invasivas o tratamientos erróneos, y evitar secuelas a futuro.

Osteomyelitis is defined as an inflammation of the bone caused by infection. Acute osteomyelitis is common in pediatrics. A Brodie abscess is a type of subacute osteomyelitis, with a historically low incidence; however, its incidence is currently increasing. Given its little clinical impact, with non-specific laboratory tests and radiological studies of difficult interpretation, diagnostic suspicion is crucial. It resembles neoplasms, either benign or malignant. An adequate diagnosis falls on the health care provider's experience. Treatment consists of antibiotics, both parenteral and oral, with potential surgical drainage. Here we describe the case of a healthy female patient with a tumor found in the topography of the left clavicle 3 months before. She was diagnosed with Brodie abscess; treatment was started with a good response. A high index of suspicion of Brodie abscess is critical to avoid invasive tests and studies or inadequate treatments, and to prevent future sequelae.

Multimodal Imaging of Dental Pulp Healing Patterns Following Tooth Autotransplantation and Regenerative Endodontic Treatment.

INTRODUCTION: Understanding the healing process of dental pulp after tooth autotransplantation (TAT) and regenerative endodontic treatment (RET) of immature teeth is important both clinically and scientifically. This study aimed to characterize the pattern of dental pulp healing in human teeth that underwent TAT and RET using state-of-the-art imaging techniques. MATERIALS AND METHODS: This study examined 4 human teeth, 2 premolars that underwent TAT, and 2 central incisors that received RET. The premolars were extracted after 1 year (case 1) and 2 years (case 2) due to ankylosis, while the central incisors were extracted after 3 years (cases 3 and 4) for orthodontic reasons. Nanofocus x-ray computed tomography was used to image the samples before being processed for histological and immunohistochemical analysis. Laser scanning confocal second harmonic generation imaging (SHG) was used to examine the patterns of collagen deposition. A maturity-matched premolar was included as a negative control for the histological and SHG analysis. RESULTS: Analysis of the 4 cases revealed different patterns of dental pulp healing. Similarities were observed in the progressive obliteration of the root canal space. However, a striking loss of typical pulpal architecture was observed in the TAT cases, while a pulp-like tissue was observed in one of the RET cases. Odontoblast-like cells were observed in cases 1 and 3. CONCLUSIONS: This study provided insights into the patterns of dental pulp healing after TAT and RET. The SHG imaging sheds light on the patterns of collagen deposition during reparative dentin formation.

Telemonitoreo y sistema de alerta en tiempo real en insuficiencia cardiaca: estudio piloto de factibilidad, aceptabilidad y eficacia / Telemonitoring and a real-time alert system in heart failure: a preliminary pilot study of feasibility, acceptability and efficacy

Resumen Introducción: Existe creciente evidencia que el telemonitoreo (TM) de pacientes con insuficiencia cardíaca (IC) parece mejorar su evolución. No se han diseñado y evaluado plataformas de TM en Argentina. El objetivo fue evaluar la factibilidad, aceptabilidad, usabilidad y eficacia preliminar de una plataforma de TM de IC. Métodos: Se realizó un ensayo piloto apareado abierto, con un modelo de intervención de un solo grupo. Los pacientes con IC fueron incluidos en una consulta ambulatoria en enero de 2021. Se diseñó una pla taforma de TM las 24 h y 7 días de la semana. El punto final primario a 30 días fue la factibilidad, aceptabilidad y usabilidad. Resultados: Se incluyeron 20 pacientes, con una media de edad 62 ± 10 años. Se analizaron 542 cargas de parámetros. La autopercepción relacionada al estado de salud en comparación al inicio fue "levemente" o "marcadamente mejor" en el 60% de los pacientes, y en 75% "de acuerdo" o "totalmente de acuerdo" que el TM mejora el cuidado de la IC. En el 80% la carga diaria de parámetros no interfirió en su vida cotidiana. La media total de adherencia farmacológica previa a la intervención de TM fue de 6.8 ± 1.3 y posterior 7.7 ± 0,4 (p = 0.019), sin encontrar diferencias en las escalas de autocuidado. Conclusión: El TM de pacientes con IC parece ser factible, con un adecuado grado de aceptabilidad. Se observó un aumento significativo en la tasa de total adherencia, plantea una hipótesis de potencial beneficio a evaluar en una muestra mayor.

Abstract Introduction: There is growing evidence that telemonitoring (TM) in heart failure (HF) seems to improve their outcome. TM platforms have not been designed and evaluated in Argentina. The objective was to evaluate the feasibility, acceptability, usability and preliminary efficacy of a HF TM platform. Methods: An open-label, paired pilot trial was conducted with a single-group intervention model. HF patients were included in an outpatient clinic in January 2021. A 24-hour*7-day TM platform was designed. The primary endpoint at 30 days was feasibility, acceptability, and usability. Results: Twenty patients were included, mean age 62 ± 10 years; 542 parameter loads were analyzed. Self-perception related to health status compared to baseline was "slightly" or "markedly better" in 60% of patients, and in 75% "agree" or "totally agree" that TM improves patient care. In 80%, the load ing of parameters did not interfere with their daily activities. The total mean pharmacological adherence prior to the TM intervention was 6.8 ± 1.3 and 7.7 ± 0.4 afterward (p = 0.019), with no differences found in the self-care scales. Conclusion: The TM of patients with HF seems to be feasible, with an adequate degree of acceptability. A significant increase in the total adherence rate was reduced, raising a hypothesis of potential benefit to be evaluated in a larger sample.

Brodie abscess in the clavicle: an uncommon presentation. / Absceso de Brodie en la clavícula: una forma poco frecuente de presentación.

Osteomyelitis is defined as an inflammation of the bone caused by infection. Acute osteomyelitis is common in pediatrics. A Brodie abscess is a type of subacute osteomyelitis, with a historically low incidence; however, its incidence is currently increasing. Given its little clinical impact, with non-specific laboratory tests and radiological studies of difficult interpretation, diagnostic suspicion is crucial. It resembles neoplasms, either benign or malignant. An adequate diagnosis falls on the health care provider's experience. Treatment consists of antibiotics, both parenteral and oral, with potential surgical drainage. Here we describe the case of a healthy female patient with a tumor found in the topography of the left clavicle 3 months before. She was diagnosed with Brodie abscess; treatment was started with a good response. A high index of suspicion of Brodie abscess is critical to avoid invasive tests and studies or inadequate treatments, and to prevent future sequelae.

La osteomielitis (OM) se define como la inflamación ósea de origen infeccioso. La forma aguda es frecuente en la edad pediátrica. El absceso de Brodie es un tipo de osteomielitis subaguda, históricamente con baja incidencia, pero que actualmente se presenta un aumento de la misma. De poca repercusión clínica, con pruebas de laboratorio inespecíficas y estudios radiológicos de difícil interpretación, es crucial la sospecha diagnóstica. Se asemeja a procesos neoplásicos, benignos o malignos. Recae en la experiencia del profesional realizar el diagnóstico adecuado. El tratamiento consiste en antibioticoterapia, tanto parenteral como por vía oral, y eventualmente drenaje quirúrgico. Presentamos una paciente sana que consultó por una tumoración en topografía de clavícula izquierda de 3 meses de evolución. Se realizó diagnóstico de absceso de Brodie, inició tratamiento y se obtuvo una buena respuesta. Resulta imprescindible tener un alto índice de sospecha de esta entidad para no someter al paciente a estudios, pruebas invasivas o tratamientos erróneos, y evitar secuelas a futuro.

[Telemonitoring and a real-time alert system in heart failure: a preliminary pilot study of feasibility, acceptability and efficacy]. / Telemonitoreo y sistema de alerta en tiempo real en insuficiencia cardiaca: estudio piloto de factibilidad, aceptabilidad y eficacia.

INTRODUCTION: There is growing evidence that telemonitoring (TM) in heart failure (HF) seems to improve their outcome. TM platforms have not been designed and evaluated in Argentina. The objective was to evaluate the feasibility, acceptability, usability and preliminary efficacy of a HF TM platform. METHODS: An open-label, paired pilot trial was conducted with a single-group intervention model. HF patients were included in an outpatient clinic in January 2021. A 24-hour 7-day TM platform was designed. The primary endpoint at 30 days was feasibility, acceptability, and usability. RESULTS: Twenty patients were included, mean age 62 ± 10 years; 542 parameter loads were analyzed. Self-perception related to health status compared to baseline was "slightly" or "markedly better" in 60% of patients, and in 75% "agree" or "totally agree" that TM improves patient care. In 80%, the loading of parameters did not interfere with their daily activities. The total mean pharmacological adherence prior to the TM intervention was 6.8 ± 1.3 and 7.7 ± 0.4 afterward (p = 0.019), with no differences found in the self-care scales. CONCLUSION: The TM of patients with HF seems to be feasible, with an adequate degree of acceptability. A significant increase in the total adherence rate was reduced, raising a hypothesis of potential benefit to be evaluated in a larger sample.

Introducción: Existe creciente evidencia que el telemonitoreo (TM) de pacientes con insuficiencia cardíaca (IC) parece mejorar su evolución. No se han diseñado y evaluado plataformas de TM en Argentina. El objetivo fue evaluar la factibilidad, aceptabilidad, usabilidad y eficacia preliminar de una plataforma de TM de IC. Métodos: Se realizó un ensayo piloto apareado abierto, con un modelo de intervención de un solo grupo. Los pacientes con IC fueron incluidos en una consulta ambulatoria en enero de 2021. Se diseñó una plataforma de TM las 24 h y 7 días de la semana. El punto final primario a 30 días fue la factibilidad, aceptabilidad y usabilidad. Resultados: Se incluyeron 20 pacientes, con una media de edad 62 ± 10 años. Se analizaron 542 cargas de parámetros. La autopercepción relacionada al estado de salud en comparación al inicio fue "levemente" o "marcadamente mejor" en el 60% de los pacientes, y en 75% "de acuerdo" o "totalmente de acuerdo" que el TM mejora el cuidado de la IC. En el 80% la carga diaria de parámetros no interfirió en su vida cotidiana. La media total de adherencia farmacológica previa a la intervención de TM fue de 6.8 ± 1.3 y posterior 7.7 ± 0,4 (p = 0.019), sin encontrar diferencias en las escalas de autocuidado. Conclusión: El TM de pacientes con IC parece ser factible, con un adecuado grado de aceptabilidad. Se observó un aumento significativo en la tasa de total adherencia, plantea una hipótesis de potencial beneficio a evaluar en una muestra mayor.

High-throughput screening of optimal process conditions using model predictive control.

Modern biotechnological laboratories are equipped with advanced parallel mini-bioreactor facilities that can perform sophisticated cultivation strategies (e.g., fed-batch or continuous) and generate significant amounts of measurement data. These systems require not only optimal experimental designs that find the best conditions in very large design spaces, but also algorithms that manage to operate a large number of different cultivations in parallel within a well-defined and tightly constrained operating regime. Existing advanced process control algorithms have to be tailored to tackle the specific issues of such facilities such as: a very complex biological system, constant changes in the metabolic activity and phenotypes, shifts of pH and/or temperature, and metabolic switches, to name a few. In this study we implement a model predictive control (MPC) framework to demonstrate: (1) the challenges in terms of mathematical model structure, state, and parameter estimation, and optimization under highly nonlinear and stiff dynamics in biological systems, (2) the adaptations required to enable the application of MPC in high throughput bioprocess development, and (3) the added value of MPC implementations when operating parallel mini-bioreactors aiming to maximize the biomass concentration while coping with hard constrains on the dissolved oxygen tension profile.

In silico performance analysis of web tools for CRISPRa sgRNA design in human genes.

Angiogenic gene overexpression has been the main strategy in numerous vascular regenerative gene therapy projects. However, most have failed in clinical trials. CRISPRa technology enhances gene overexpression levels based on the identification of sgRNAs with maximum efficiency and safety. CRISPick and CHOP CHOP are the most widely used web tools for the prediction of sgRNAs. The objective of our study was to analyze the performance of both platforms for the sgRNA design to angiogenic genes (VEGFA, KDR, EPO, HIF-1A, HGF, FGF, PGF, FGF1) involving different human reference genomes (GRCH 37 and GRCH 38). The top 20 ranked sgRNAs proposed by the two tools were analyzed in different aspects. No significant differences were found on the DNA curvature associated with the sgRNA binding sites but the sgRNA predicted on-target efficiency was significantly greater when CRISPick was used. Moreover, the mean ranking variation was greater for the same platform in EPO, EGF, HIF-1A, PGF and HGF, whereas it did not reach statistical significance in KDR, FGF-1 and VEGFA. The rearrangement analysis of the ranking positions was also different between platforms. CRISPick proved to be more accurate in establishing the best sgRNAs in relation to a more complete genome, whereas CHOP CHOP showed a narrower classification reordering.

Multidimensional inhibitory signatures of sentential negation in behavioral variant frontotemporal dementia.

BACKGROUND: Processing of linguistic negation has been associated to inhibitory brain mechanisms. However, no study has tapped this link via multimodal measures in patients with core inhibitory alterations, a critical approach to reveal direct neural correlates and potential disease markers. METHODS: Here we examined oscillatory, neuroanatomical, and functional connectivity signatures of a recently reported Go/No-go negation task in healthy controls and behavioral variant frontotemporal dementia (bvFTD) patients, typified by primary and generalized inhibitory disruptions. To test for specificity, we also recruited persons with Alzheimer's disease (AD), a disease involving frequent but nonprimary inhibitory deficits. RESULTS: In controls, negative sentences in the No-go condition distinctly involved frontocentral delta (2-3 Hz) suppression, a canonical inhibitory marker. In bvFTD patients, this modulation was selectively abolished and significantly correlated with the volume and functional connectivity of regions supporting inhibition (e.g. precentral gyrus, caudate nucleus, and cerebellum). Such canonical delta suppression was preserved in the AD group and associated with widespread anatomo-functional patterns across non-inhibitory regions. DISCUSSION: These findings suggest that negation hinges on the integrity and interaction of spatiotemporal inhibitory mechanisms. Moreover, our results reveal potential neurocognitive markers of bvFTD, opening a new agenda at the crossing of cognitive neuroscience and behavioral neurology.

Multimodal Neurocognitive Markers of Naturalistic Discourse Typify Diverse Neurodegenerative Diseases.

Neurodegeneration has multiscalar impacts, including behavioral, neuroanatomical, and neurofunctional disruptions. Can disease-differential alterations be captured across such dimensions using naturalistic stimuli? To address this question, we assessed comprehension of four naturalistic stories, highlighting action, nonaction, social, and nonsocial events, in Parkinson's disease (PD) and behavioral variant frontotemporal dementia (bvFTD) relative to Alzheimer's disease patients and healthy controls. Text-specific correlates were evaluated via voxel-based morphometry, spatial (fMRI), and temporal (hd-EEG) functional connectivity. PD patients presented action-text deficits related to the volume of action-observation regions, connectivity across motor-related and multimodal-semantic hubs, and frontal hd-EEG hypoconnectivity. BvFTD patients exhibited social-text deficits, associated with atrophy and spatial connectivity patterns along social-network hubs, alongside right frontotemporal hd-EEG hypoconnectivity. Alzheimer's disease patients showed impairments in all stories, widespread atrophy and spatial connectivity patterns, and heightened occipitotemporal hd-EEG connectivity. Our framework revealed disease-specific signatures across behavioral, neuroanatomical, and neurofunctional dimensions, highlighting the sensitivity and specificity of a single naturalistic task. This investigation opens a translational agenda combining ecological approaches and multimodal cognitive neuroscience for the study of neurodegeneration.

Volume electron microscopy reveals age-related circuit remodeling in the auditory brainstem.

The medial nucleus of the trapezoid body (MNTB) is an integral component of the auditory brainstem circuitry involved in sound localization. The giant presynaptic nerve terminal with multiple active zones, the calyx of Held (CH), is a hallmark of this nucleus, which mediates fast and synchronized glutamatergic synaptic transmission. To delineate how these synaptic structures adapt to reduced auditory afferents due to aging, we acquired and reconstructed circuitry-level volumes of mouse MNTB at different ages (3 weeks, 6, 18, and 24 months) using serial block-face electron microscopy. We used C57BL/6J, the most widely inbred mouse strain used for transgenic lines, which displays a type of age-related hearing loss. We found that MNTB neurons reduce in density with age. Surprisingly we observed an average of approximately 10% of poly-innervated MNTB neurons along the mouse lifespan, with prevalence in the low frequency region. Moreover, a tonotopy-dependent heterogeneity in CH morphology was observed in young but not in older mice. In conclusion, our data support the notion that age-related hearing impairments can be in part a direct consequence of several structural alterations and circuit remodeling in the brainstem.

Utilización de oxigenación por membrana extracorpórea venoarterial en el shock cardiogénico y paro cardiorrespiratorio refractarios: experiencia inicial de 7 años en un centro de cardiología de adultos / Venoarterial Extracorporeal Membrane Oxygenation for Refractory Cardiogenic Shock and Cardiac Arrest: An Initial 7-Year Experience in an Adult Cardiology Center

RESUMEN Introducción: La oxigenación por membrana extracorpórea venoarterial (ECMO VA) es una intervención de rescate en pacientes con shock cardiogénico (SC), y paro cardiorrespiratorio (PCR) refractarios a las terapias convencionales. Objetivo: Describir las características, y resumir nuestra experiencia inicial de 7 años de pacientes que requirieron ECMO VA por SC o PCR. Material y métodos: Se realizó un estudio de cohorte unicéntrico. Se analizaron retrospectivamente los pacientes adultos consecutivos que fueron asistidos con ECMO VA por SC o PCR refractarios entre 2014 y 2020 en el ICBA Instituto Cardiovascular. Resultados: Se incluyeron 54 pacientes, (54 ± 12 años). El 36,5% presentó miocardiopatía isquémica, y el 23,1% enfermedad valvular significativa. Las indicaciones para ECMO VA fueron: poscardiotomía (43,4%), SC refractario (28,3%), y falla primaria del injerto (20,8%). La reanimación cardiopulmonar previa a la ECMO VA se realizó en el 18,5%. La canulación fue periférica en el 81,5%, el 83,3% se asistió en INTERMACS 1, y el 87% presentaba balón de contrapulsación intraaórtico. La duración de asistencia en ECMO VA fue de 5,5 días (RIC 2,8-10). La tasa de supervivencia en ECMO VA fue del 63% (37% puente a trasplante cardíaco, y 26% recuperación), y al alta del 42,6%. Las complicaciones más frecuentes fueron: sangrado (61,1%), infección (51,9%), y complicaciones tromboembólicas (46,3%). Conclusión: La ECMO VA como tratamiento del SC o PCR refractarios en nuestro centro presentó una sobrevida aceptable al alta hospitalaria. La ECMO VA es un tratamiento efectivo cuando las terapias convencionales fallan, siendo aparentemente útil y aplicable en un país donde existe acceso limitado a los dispositivos de asistencia ventricular compleja.

ABSTRACT Background: Venoarterial extra corporeal membrane oxygenation (VA-ECMO) is a rescue intervention used in patients with cardiogenic shock (CS) or cardiac arrest (CA) refractory to conventional medical therapies. Objective: The aim of the present study is to describe the characteristics and summarize our 7-year experience in patients with CS or CA supported with VA-ECMO. Methods: We conducted a single-center retrospective study analyzing consecutive adult patients requiring VA-ECMO due to refractory CS or CA at ICBA, Instituto Cardiovascular between January 2014 and December 2020. Results: A total age 54 patients were included (54 ± 12 years), 36.5% presented ischemic cardiomyopathy and 23.1% significant valvular heart disease. The indications for VA-ECMO implantation were post-cardiotomy (43.4%), refractory CS (28.3%) and primary graft dysfunction (20.8%). Cardiopulmonary resuscitation before VA-ECMO occurred in 18.5% of the cases. Peripheral cannulation was performed in 81.5% of the cases, 83.3% had INTERMACS profile 1 and 87% were on intraaortic balloon pump. Duration of ventricular assistance on VA- ECMO was 5.5 days (IQR 2.8-10). Survival rate on ECMO VA was 63% (37% as a bridge to cardiac transplantation and 26% as a bridge to recovery) and survival to discharge was 42.6%. The most common complications were hemorrhage (61.1%), infections (51.9%), and thromboembolic complications (46.3%). Conclusion: In our center, VA-ECMO as a treatment for refractory CS or CA showed acceptable survival during ventricular support and on hospital discharge. It is an effective life support treatment to rescue critically ill patients when conventional therapies fail, is apparently useful and can be implemented in a country with limited resources and access to complex ventricular assist devices.

Knowledge transfer across cell lines using hybrid Gaussian process models with entity embedding vectors.

To date, a large number of experiments are performed to develop a biochemical process. The generated data is used only once, to take decisions for development. Could we exploit data of already developed processes to make predictions for a novel process, we could significantly reduce the number of experiments needed. Processes for different products exhibit differences in behaviour, typically only a subset behave similar. Therefore, effective learning on multiple product spanning process data requires a sensible representation of the product identity. We propose to represent the product identity (a categorical feature) by embedding vectors that serve as input to a Gaussian process regression model. We demonstrate how the embedding vectors can be learned from process data and show that they capture an interpretable notion of product similarity. The improvement in performance is compared to traditional one-hot encoding on a simulated cross product learning task. All in all, the proposed method could render possible significant reductions in wet-lab experiments.

Effect of intramuscular baculovirus encoding mutant hypoxia-inducible factor 1-alpha on neovasculogenesis and ischemic muscle protection in rabbits with peripheral arterial disease.

BACKGROUND AIMS: Peripheral arterial disease (PAD) is a progressive, disabling ailment for which no effective treatment exists. Gene therapy-mediated neovascularization has emerged as a potentially useful strategy. We tested the angiogenic and arteriogenic efficacy and safety of a baculovirus (BV) encoding mutant, oxygen-resistant hypoxia-inducible factor 1-alpha (mHIF-1α), in rabbits with PAD. METHODS: After assessing the transfection efficiency of the BV.mHIF-1α vector and its tubulogenesis potential in vitro, we randomized rabbits with experimental PAD to receive 1 × 109 copies of BV.mHIF-1α or BV.null (n = 6 per group) 7 days after surgery. Two weeks post-treatment, collateralization (digital angiography) and capillary and arteriolar densities (immunohistochemistry) were measured in the posterior limbs. Ischemic damage was evaluated in adductor and gastrocnemius muscle samples. Tracking of viral DNA in injected zones and remote tissues at different time points was performed in additional rabbits using a BV encoding GFP. RESULTS: Angiographically visible collaterals were more numerous in BV.mHIF-1α-treated rabbits (8.12 ± 0.42 vs 6.13 ± 1.15 collaterals/cm2, P < 0.05). The same occurred with arteriolar (27.9 ± 7.0 vs 15.3 ± 4.0 arterioles/mm2) and capillary (341.8 ± 109.9 vs 208.8 ± 87.7 capillaries/mm2, P < 0.05) densities. BV.mHIF-1α-treated rabbits displayed less ischemic muscle damage than BV.null-treated animals. Viral DNA and GFP mRNA were detectable only at 3 and 7 days after injection in hind limbs. Neither the virus nor GFP mRNA was detected in remote tissues. CONCLUSIONS: In rabbits with PAD, BV.mHIF-1α induced neovascularization and reduced ischemic damage, exhibiting a good safety profile at 14 days post-treatment. Complementary studies to evaluate its potential usefulness in the clinic are needed.

Novel insights into cardiac regeneration based on differential fetal and adult ovine heart transcriptomic analysis.

The adult mammalian cardiomyocyte has a very limited capacity to reenter the cell cycle and advance into mitosis. Therefore, diseases characterized by lost contractile tissue usually evolve into myocardial remodeling and heart failure. Analyzing the cardiac transcriptome at different developmental stages in a large mammal closer to the human than laboratory rodents may serve to disclose positive and negative cardiomyocyte cell cycle regulators potentially targetable to induce cardiac regeneration in the clinical setting. Thus we aimed at characterizing the transcriptomic profiles of the early fetal, late fetal, and adult sheep heart by employing RNA-seq technique and bioinformatic analysis to detect protein-encoding genes that in some of the stages were turned off, turned on, or differentially expressed. Genes earlier proposed as positive cell cycle regulators such as cyclin A, cdk2, meis2, meis3, and PCNA showed higher expression in fetal hearts and lower in AH, as expected. In contrast, genes previously proposed as cell cycle inhibitors, such as meis1, p16, and sav1, tended to be higher in fetal than in adult hearts, suggesting that these genes are involved in cell processes other than cell cycle regulation. Additionally, we described Gene Ontology (GO) enrichment of different sets of genes. GO analysis revealed that differentially expressed gene sets were mainly associated with metabolic and cellular processes. The cell cycle-related genes fam64a, cdc20, and cdk1, and the metabolism-related genes pitx and adipoq showed strong differential expression between fetal and adult hearts, thus being potent candidates to be targeted in human cardiac regeneration strategies.NEW & NOTEWORTHY We characterized the transcriptomic profiles of the fetal and adult sheep hearts employing RNAseq technique and bioinformatic analyses to provide sets of transcripts whose variation in expression level may link them to a specific role in cell cycle regulation. It is important to remark that this study was performed in a large mammal closer to humans than laboratory rodents. In consequence, the results can be used for further translational studies in cardiac regeneration.

Identification of Multiple Replication Stages and Origins in the Nucleopolyhedrovirus of Anticarsia gemmatalis.

To understand the mechanism of replication used by baculoviruses, it is essential to describe all the factors involved, including virus and host proteins and the sequences where DNA synthesis starts. A lot of work on this topic has been done, but there is still confusion in defining what sequence/s act in such functions, and the mechanism of replication is not very well understood. In this work, we performed an AgMNPV replication kinetics into the susceptible UFL-Ag-286 cells to estimate viral genome synthesis rates. We found that the viral DNA exponentially increases in two different phases that are temporally separated by an interval of 5 h, probably suggesting the occurrence of two different mechanisms of replication. Then, we prepared a plasmid library containing virus fragments (0.5-2 kbp), which were transfected and infected with AgMNPV in UFL-Ag-286 cells. We identified 12 virus fragments which acted as origins of replication (ORI). Those fragments are in close proximity to core genes. This association to the core genome would ensure vertical transmission of ORIs. We also predict the presence of common structures on those fragments that probably recruit the replication machinery, a structure also present in previously reported ORIs in baculoviruses.