Complicaciones del cateterismo cardiaco en cardiopatías congénitas, 30 años de experiencia. Un nuevo score ajustado al riesgo / Complications of cardiac catheterisation in congenital heart disease, 30 years of experience. A new risk-adjusted score

Resumen Objetivo: Presentar un score ajustado al riesgo de complicaciones durante el cateterismo cardiaco en cardiopatías congénitas. Diseño: Observacional, analítico y ambispectivo de 3,504 casos. Se incluyeron edad, cardiopatía, procedimiento, complicaciones mayores y menores. Métodos: 3,504 procedimientos realizados entre octubre de 1987 y mayo de 2019. Variables independientes: edad, cardiopatía, procedimiento y estadio clínico. Se categorizó como bajo riesgo 5 a 7 puntos, moderado riesgo 8 a 11 puntos y alto riesgo 12 a 22 puntos. El score fue validado mediante la prueba de Hosmer-Lemeshow y la curva ROC (receiver operating characteristic). Resultados: Las complicaciones fueron 177 (5%), 66 mayores (1.9%) y 111 menores (3.1%). Mortalidad de 0.4% (15 pacientes). El grupo de bajo riesgo (n = 825) tuvo 1.5% de complicaciones, el de moderado riesgo (n = 2.221) 4.9% y el de alto riesgo (n = 458) 12% (p < 0.001). El análisis de los datos retrospectivos (n = 2,953) fue validado con los prospectivos (n = 551) mediante la prueba de Hosmer-Lemeshow; dejó en evidencia que los valores predichos son similares a los observados. Conclusiones: Las complicaciones siguen presentándose a pesar de la evolución de la técnica. El score resultó útil para estratificar a los pacientes y conocer la probabilidad de complicaciones antes del procedimiento.

Abstract Objetive: to present a risk-ajusted score of complications during cardias catheterization in congenital heart disease. Design: observational, analitic, ambispective of 3.504 cases. The data analyzed included age, heart disease, type of procedure, major and minor complications. Methods: 3.504 procedures performed between october 1987 and may 2019. The variables were age, heart disease, procedere and clinical stege. Each patients was categorized as low risk 5 to 7 points, moderate risk 8 to 11 points and higt risk 12 to 22 points. The score was validated using the Hosmer-Lemeshow test and the ROC curve (Receiver Operating Characteristic). Results: complications 177 (5%) 66 major (1.9%) and 111 minor (3.1%). Mortality was 0.4% (15 patients). The low-risk group (n = 825) had 1.5% complications; moderate risk (n = 2,221) 4.9%; high risk (n: 458) 12% (p < 0.001). The analysis of the retrospective data (n = 2953) was validated with prospective (n = 551) using the Hosmer-Lemeshow test, showed that the predicted values are similar to those observed. Conclusions: Complications continue to occur despite the evolution of the technique. The score was useful for stratifying patients and knowing the probability of complication before the procedere.

Effectiveness of a program for the reduction of central venous catheter-related bacteremias in a Pediatric Cardiovascular Unit / Efectividad de un programa de reducción de bacteriemias relacionadas con catéter venoso central en una unidad cardiovascular pediátrica

INTRODUCTION: Central venous catheter (CVC)- related bacteremias are common in pediatric patients following surgery for complex congenital heart disease admitted to a pediatric cardiac intensive care unit (PCICU) and have a high morbidity and mortality. OBJECTIVE: To analyze the effectiveness of an interdisciplinary program for the prevention of CVC-related bacteremias in the PCICU. MATERIAL AND METHODS: Quasi-experimental, before and after implementation study without a control group. Study period: 01-01-2008 to 12- 31-2018. Population: PCICU staff who care for patients following surgery for complex heart disease at a hospital. Pre-intervention period: 01- 01-2008 to 12-31-2008; intervention period: 01-01- 2009 to 01-01-2018. Intervention: implementation of an ongoing improvement program. The rate of CVC-related bacteremias/1000 days and CVC use/100 days, RACHS score, standardized infection ratio (SIR), relative risk (RR), and 95% confidence interval (CI) were analyzed and a p value < 0.05 was considered statistically significant. The reference rate was estimated as the average for the 2008-2009 period and the annual and reference rates were compared. RESULTS: The bacteremia reference rate for 2008- 2009 was 10.6/1000 days of CVC to analyze the SIR. A RACHS score over 3 was similar across all studied periods. The annual comparison showed a statistically significant reduction (p < 0.05) in the SIR. The comparison between the baseline bacteremia rate/1000 days of CVC (11.9) and the final rate (3.8) showed a significant reduction (RR: 0.16; 95 % CI: 0.07-0.35; p < 0.001). CONCLUSIONS: The program was effective; the rate of CVC-related bacteremias in the PCICU showed a progressive, significant reduction.

Introducción. Las bacteriemias relacionadas con catéteres venosos centrales (CVC) son frecuentes en pacientes pediátricos posquirúrgicos de cardiopatías congénitas complejas internados en la unidad de cuidados intensivos pediátricos cardiovascular (UCIP-CV) y tienen alta morbimortalidad. OBJETIVO: Analizar la efectividad de un programa interdisciplinario para prevención de bacteriemias relacionadas con CVC en la UCIP-CV. Material y métodos. Estudio de implementación, cuasiexperimental, antes-después, sin grupo control. Período de estudio del 1 de enero de 2008 al 31 de diciembre de 2018. Población: equipo de salud de la UCIP-CV que atiende pacientes posquirúrgicos de cardiopatías complejas de un hospital. Período preintervención del 1 de enero de 2008 al 31 de diciembre de 2008; período de intervención del 1 de enero de 2009 al 1 de enero de 2018. Intervención: implementación de un programa de mejora continua. Se analizaron tasas de bacteriemias CVC/1000 días y de uso de CVC/100 días, puntaje de RACHS, razón estandarizada de infecciones (REI), riesgo relativo (RR), intervalo de confianza del 95 % (IC95%), estimando una p < 0,05 como estadísticamente significativa. La tasa de referencia se estimó como el promedio del período 2008/2009 y se comparó la tasa anual con la tasa de referencia. RESULTADOS: La tasa de referencia de bacteriemia 2008/2009 fue 10,6/1000 días CVC para analizar la REI. El puntaje de RACHS mayor a 3 fue similar en todos los períodos analizados. Se observó una reducción de la REI estadísticamente significativa (p < 0,05) en la comparación anual. Al comparar la tasa de bacteriemia/1000 días de CVC inicial de 11,9 vs. final de 3,8, se observó una reducción significativa (RR: 0,16; IC95%: 0,07-0,35; p < 0,001). CONCLUSIONES: El programa fue efectivo; se observó reducción progresiva y significativa de la tasa de bacteriemias relacionadas con CVC en la UCIP-CV.

Efectividad de un programa de reducción de bacteriemias relacionadas con catéter venoso central en una unidad cardiovascular pediátrica / Effectiveness of a program for the reduction of central venous catheter-related bacteremias in a Pediatric Cardiovascular Unit

Introducción. Las bacteriemias relacionadas con catéteres venosos centrales (CVC) son frecuentes en pacientes pediátricos posquirúrgicos de cardiopatías congénitas complejas internados en la unidad de cuidados intensivos pediátricos cardiovascular (UCIP-CV) y tienen alta morbimortalidad. Objetivo. Analizar la efectividad de un programa interdisciplinario para prevención de bacteriemias relacionadas con CVC en la UCIP-CV. Material y métodos. Estudio de implementación, cuasiexperimental, antes-después, sin grupo control. Período de estudio del 1 de enero de 2008 al 31 de diciembre de 2018. Población: equipo de salud de la UCIP-CV que atiende pacientes posquirúrgicos de cardiopatías complejas de un hospital. Período preintervención del 1 de enero de 2008 al 31 de diciembre de 2008; período de intervención del 1 de enero de 2009 al 1 de enero de 2018. Intervención: implementación de un programa de mejora continua. Se analizaron tasas de bacteriemias CVC/1000 días y de uso de CVC/100 días, puntaje de RACHS, razón estandarizada de infecciones (REI), riesgo relativo (RR), intervalo de confianza del 95 % (IC95%), estimando una p < 0,05 como estadísticamente significativa. La tasa de referencia se estimó como el promedio del período 2008/2009 y se comparó la tasa anual con la tasa de referencia. Resultados. La tasa de referencia de bacteriemia 2008/2009 fue 10,6/1000 días CVC para analizar la REI. El puntaje de RACHS mayor a 3 fue similar en todos los períodos analizados. Se observó una reducción de la REI estadísticamente significativa (p < 0,05) en la comparación anual. Al comparar la tasa de bacteriemia/1000 días de CVC inicial de 11,9 vs. final de 3,8, se observó una reducción significativa (RR: 0,16; IC95%: 0,07-0,35; p < 0,001). Conclusiones. El programa fue efectivo; se observó reducción progresiva y significativa de la tasa de bacteriemias relacionadas con CVC en la UCIP-CV.

Introduction. Central venous catheter (CVC)related bacteremias are common in pediatric patients following surgery for complex congenital heart disease admitted to a pediatric cardiac intensive care unit (PCICU) and have a high morbidity and mortality. Objective.To analyze the effectiveness of an interdisciplinary program for the prevention of CVC-related bacteremias in the PCICU. Material and methods. Quasi-experimental,before and after implementation study without a control group. Study period: 01-01-2008 to 1231-2018. Population: PCICU staff who care for patients following surgery for complex heart disease at a hospital. Pre-intervention period: 0101-2008 to 12-31-2008; intervention period: 01-012009 to 01-01-2018. Intervention: implementation of an ongoing improvement program. The rate of CVC-related bacteremias/1000 days and CVC use/100 days, RACHS score, standardized infection ratio (SIR), relative risk (RR), and 95% confidence interval (CI) were analyzed and a p value < 0.05 was considered statistically significant. The reference rate was estimated as the average for the 2008-2009 period and the annual and reference rates were compared. Results. The bacteremia reference rate for 20082009 was 10.6/1000 days of CVC to analyze the SIR. A RACHS score over 3 was similar across all studied periods. The annual comparison showed a statistically significant reduction (p < 0.05) in the SIR. The comparison between the baseline bacteremia rate/1000 days of CVC (11.9) and the final rate (3.8) showed a significant reduction (RR: 0.16; 95 % CI: 0.07­0.35; p < 0.001). Conclusions. The program was effective; the rate of CVC-related bacteremias in the PCICU showed a progressive, significant reduction.

Nonscanning large-area Raman imaging for ex vivo/in vivo skin cancer discrimination.

Imaging Raman spectroscopy can be used to identify cancerous tissue. Traditionally, a step-by-step scanning of the sample is applied to generate a Raman image, which, however, is too slow for routine examination of patients. By transferring the technique of integral field spectroscopy (IFS) from astronomy to Raman imaging, it becomes possible to record entire Raman images quickly within a single exposure, without the need for a tedious scanning procedure. An IFS-based Raman imaging setup is presented, which is capable of measuring skin ex vivo or in vivo. It is demonstrated how Raman images of healthy and cancerous skin biopsies were recorded and analyzed.

Management of hepatitis C in decentralised versus centralised drug substitution programmes and minimally invasive point-of-care tests to close gaps in the HCV cascade.

BACKGROUND: In Switzerland, intravenous drug use accounts for the majority of hepatitis C virus (HCV) infections. Early HCV treatment prevents further transmissions and reduces morbidity and mortality due to decompensated liver cirrhosis and hepatocellular carcinoma. Nevertheless, patients in drug substitution programmes are often insufficiently screened and treated. AIM: The aim was to compare the current state of HCV management in centralised and decentralised drug substitution programmes of the canton Aargau. Objectives were human immunodeficiency virus (HIV) and HCV prevalence, compliance with guidelines and gaps in the HCV cascade, as well as feasibility/acceptance/validity of HIV/HCV rapid tests on finger-prick blood and noninvasive liver fibrosis assessment with Fibroscan®. METHODS: For the cross-sectional study, in June 2013, questionnaires and free rapid tests for HIV (Determine®) and HCV (OraQuick®) that used capillary blood (finger-stick) were sent to 161 physicians providing drug substitution treatment for 631 patients. Free liver fibrosis assessment with Fibroscan® by a member of the study team was offered to all patients. Additionally, patients were directly recruited by the study team in the heroin substitution programme and several addiction clinics visited every 4-6 months, as well as in the Infectious Diseases Outpatient Clinic (questionnaire, rapid tests and Fibroscan® in the same session). RESULTS: Between July 2013 and July 2015, 205 (32.5%) of the 631 patients receiving opioid substitution in the canton Aargau were enrolled, 192 (93.7%) with HIV/HCV rapid tests and 167 (81.5%) with Fibroscan®. Acceptance of Fibroscan® was higher when offered in the same session (94.1 vs 69.2%). Overall, 77.8% had ever used intravenous drugs. HCV seroprevalence was 53.7% (109/203), HCV RNA prevalence 27.8%. Overall, 7.4% (15/202) were HIV infected, all of whom were HCV co-infected and under antiretroviral treatment. Of the 205 patients included, 104 (50.7%) were recruited in a decentralised setting (family practice / pharmacy) and 101 (49.3%) in a centralised setting (heroin programme, addiction clinic, Infectious Diseases Outpatient Clinic). Compliance with guidelines (regular HIV/HCV screening, workup of HCV-positive patients, availability of HAV/HBV serology) was consistently lower in the decentralised setting, characterised by a higher proportion of females, longer median time in the programme, lower percentage of daily attendance, ever-use of intravenous drugs and HIV and HCV infections. We identified several gaps in the HCV cascade: 23.9% (49/205) had never been HCV screened; 18.9% (18/95) of the HCV positive patients had no HCV RNA test. Of the 61 patients developing chronic HCV infection, 19.7% (12) were not HCV genotyped, 52.5% (32) had no liver fibrosis assessment (liver biopsy) and 54.1% (33) never received treatment; 25.0% (7/28) did not achieve a sustained virological response with interferon-based treatment. The 192 HCV rapid tests showed a sensitivity of 90.4% (94/104; 95% confidence interval 84.7-96.1%) and a specificity of 100% (88/88), and provided 14 new HCV diagnoses. Eight of ten patients with a false-negative HCV rapid test were HCV RNA negative (2 unknown). Among the 88.6% (39/44) currently HCV RNA-positive individuals with valid Fibroscan® results, 24 (61.5%) had a liver stiffness <7.5 kPa. Both HIV co-infection and alcohol overconsumption doubled the risk of severe fibrosis/cirrhosis in HCV positive patients. CONCLUSION: In contrast to HIV, HCV transmission among intravenous drug users is still ongoing. The management of hepatitis C in drug substitution patients needs improvement, especially in family practices. Minimally invasive "point-of-care" diagnostics such as the HCV antibody rapid test using capillary blood and mobile Fibroscan® can close some of the gaps in the HCV cascade. HCV RNA determination in capillary blood is still an unmet need. A "one-stop strategy" might improve linkage to care. Restricting the new, highly efficient (90-100% sustained virological response for all genotypes) direct-acting antivirals to patients with at least stage F2 fibrosis withholds treatment from two thirds of the chronically infected and prevents us from reaching the WHO goal of 80% treatment uptake necessary to eliminate hepatitis C by 2030.

A novel locus for mycelial aggregation forms a gateway to improved Streptomyces cell factories.

BACKGROUND: Streptomycetes produce a plethora of natural products including antibiotics and anticancer drugs, as well as many industrial enzymes. Their mycelial life style is a major bottleneck for industrial exploitation and over decades strain improvement programs have selected production strains with better growth properties. Uncovering the nature of the underlying mutations should allow the ready transfer of desirable traits to other production hosts. RESULTS: Here we report that the mat gene cluster, which was identified through reverse engineering of a non-pelleting mutant selected in a chemostat, is key to pellet formation of Streptomyces lividans. Deletion of matA or matB, which encode putative polysaccharide synthases, effects mycelial metamorphosis, with very small and open mycelia. Growth rate and productivity of the matAB null mutant were increased by over 60% as compared to the wild-type strain. CONCLUSION: Here, we present a way to counteract pellet formation by streptomycetes, which is one of the major bottlenecks in their industrial application. The mat locus is an ideal target for rational strain design approaches aimed at improving streptomycetes as industrial production hosts.

Exploiting enzymatic promiscuity to engineer a focused library of highly selective antifungal and antiproliferative aureothin analogues.

Aureothin is a shikimate-polyketide hybrid metabolite from Streptomyces thioluteus with a rare nitroaryl moiety, a chiral tetrahydrofuran ring, and an O-methylated pyrone ring. The antimicrobial and antitumor activities of aureothin have caught our interest in modulating its structure as well as its bioactivity profile. In an integrated approach using mutasynthesis, biotransformation, and combinatorial biosynthesis, a defined library of aureothin analogues was generated. The promiscuity of the polyketide synthase assembly line toward different starter units and the plasticity of the pyrone and tetrahydrofuran ring formation were exploited. A selection of 15 new aureothin analogues with modifications at the aryl residue, the pyrone ring, and the oxygenated backbone was produced on a preparative scale and fully characterized. Remarkably, various new aureothin derivatives are less cytotoxic than aureothin but have improved antiproliferative activities. Furthermore, we found that the THF ring is crucial for the remarkably selective activity of aureothin analogues against certain pathogenic fungi.

C/EBPalpha initiates primitive myelopoiesis in pluripotent embryonic cells.

The molecular mechanisms that underlie the development of primitive myeloid cells in vertebrate embryos are not well understood. Here we characterize the role of cebpa during primitive myeloid cell development in Xenopus. We show that cebpa is one of the first known hematopoietic genes expressed in the embryo. Loss- and gain-of-function studies show that it is both necessary and sufficient for the development of functional myeloid cells. In addition, we show that cebpa misexpression leads to the precocious induction of myeloid cell markers in pluripotent prospective ectodermal cells, without the cells transitioning through a general mesodermal state. Finally, we use live imaging to show that cebpa-expressing cells exhibit many attributes of terminally differentiated myeloid cells, such as highly active migratory behavior, the ability to quickly and efficiently migrate toward wounds and phagocytose bacteria, and the ability to enter the circulation. Thus, C/EPBalpha is the first known single factor capable of initiating an entire myelopoiesis pathway in pluripotent cells in the embryo.

Polyketide-chain branching by an enzymatic Michael addition.

A new "branch" for polyketide synthases was discovered in the biosynthesis of the antimitotic rhizoxin complex in the endofungal bacterium Burkholderia rhizoxinica. Genetic engineering and the structural elucidation of pathway intermediates revealed that a complex polyketide chain is branched at the beta position by an unprecedented conjugate addition of an acetyl building block to an acryloyl precursor (see scheme).

The neural progenitor-specifying activity of FoxG1 is antagonistically regulated by CKI and FGF.

FoxG1 is an evolutionarily conserved, winged-helix transcriptional repressor that maintains progenitor cells in the vertebrate forebrain. How the activity of FoxG1 is regulated is not known. Here, we report that in the developing Xenopus and mouse forebrain, FoxG1 is nuclear in progenitor cells but cytoplasmic in differentiating cells. The subcellular localisation of FoxG1 is regulated at the post-translational level by casein kinase I (CKI) and fibroblast growth factor (FGF) signalling. CKI phosphorylation of Ser 19 of FoxG1 promotes nuclear import, whereas FGF-induced phosphorylation of Thr 226 promotes nuclear export. Interestingly, FGF-induced phosphorylation of FoxG1 is mediated Akt kinase (also known as protein B kinase, PKB) kinase, rather than the MAPK pathway. Phosphorylation of endogenous FoxG1 is blocked by CKI and Akt inhibitors. In the mouse olfactory placode cell line OP27, and in cortical progenitors, increased FGF signalling causes FoxG1 to exit the nucleus and promotes neuronal differentiation, whereas FGF and Akt inhibitors block this effect. Thus, CKI and FGF signalling converge on an antagonistic regulation of FoxG1, which in turn controls neurogenesis in the forebrain.

Comparación de tres técnicas de inducción anestésica para la inserción segura de máscara laríngea en adultos. Estudio prospectivo, controlado, randomizado y doble ciego / Comparison of three anesthetic induction techniques for safe insertion of laryngeal mask in adults. Prospective, controlled, randomized and double blind study

Introducción: En cirugía ambulatoria, la máscara laríngea (ML) es el dispositivo de elección para el manejo de la vía aérea. La ML provoca pocos reflejos faríngeos, pero su colocación requiere de una adecuada profundidad anestésica. El sevofluorano es un agente volátil que causa una rápida y suave inducción con una pronta recuperación. El propofol es el agente endovenoso más utilizado en estos casos y la literatura médica lo menciona como el agente de elección. Objetivo: Comparar las condiciones de inserción de la ML durante la inducción inhalatoria por el método de la capacidad vital con sevofluorano, versus la dosis única de propofol endovenoso y la técnica que combina bajas dosis de propofol y sevofluorano inhalatorio completando la inducción. Material y métodos: Se estudiaron 91 pacientes ASA I, II, randomizados que recibieron: inducción con (GS) sevofluorano como único agente, (GP) propofol como único agente o inducción con bajas dosis de propofol y ventilación manual con sevofluorano (GPS). Ningún paciente recibió relajantes musculares. Resultados: El propofol alcanzó mejores tiempos de desaparición del reflejo ciliar, tiempo de relajación mandibular y de inserción de la máscara laríngea (p = 0,0001). Sin embargo, fue el único agente que no impidió la aparición de tos durante la colocación de la ML (Chi2: p = 0,03) y movimientos luego de su inserción. (Chi2: p = 0,047). Discusión: Verificamos en nuestro estudio que la inducción con sevofluorano inhalatorio, o la que combina bajas dosis de propofol con sevofluorano, presenta mejores condiciones que el propofol como único agente para la colocación de la ML.

Initiation of Smad-dependent and Smad-independent signaling via distinct BMP-receptor complexes.

BACKGROUND: BMP-2 (bone morphogenetic protein-2) signals via two types of transmembrane serine/threonine kinase receptors (BRI and BRII), which form heteromeric complexes prior to and after ligand binding. Within a BMP-bound receptor complex, BRII transphosphorylates and activates BRI-a for further signaling. We investigated which signaling pathway is initiated by BMP-2 via preformed receptor complexes versus BMP-2-induced signaling receptor complexes. METHODS: Immunofluorescence co-patching was used to study the oligomerization of receptors at the surface of live cells. Binding and chemical cross-linking of iodinated BMP-2 followed by immunoprecipitation was used to show association of receptors in the presence of ligand. Western blots with use of anti-phospho-Smad1 antibodies and reporter gene assays with use of SBE-lux were employed to show activation of the Smad pathway. Phosphorylation of p38-MAPK was shown by Western blots. Induction of alkaline phosphatase was determined by staining the cells. The cluster density of receptors was determined with use of image correlation spectroscopy. RESULTS AND CONCLUSION: We showed that the Smad pathway is induced by preformed receptor complexes, whereas BMP-2-induced signaling complexes result in the activation of p38-MAPK. We also found evidence that the clustering of BRI-a at the membrane is altered in the presence of BRII, suggesting that it associates with existing clusters of BRII to initiate efficient Smad signaling. These data clearly demonstrate that it is critical to fully understand receptor oligomerization in order to estimate signaling outcome for distinct receptor and ligand mutants.