Durability of Transcatheter Heart Valves: Standardized Definitions and Available Data

Transcatheter aortic valve replacement is a well-established alternative to surgical aortic valve replacement in high-risk patients with severe symptomatic aortic stenosis. Currently, this technique is shifting towards younger patient groups with intermediate- and low-risk profile, which raises the question about long-term durability. Despite acceptable results up to 5 years, little is currently known about valve performance beyond 5 years. Since valve deterioration, thrombosis and endocarditis seem to be the main factors affecting valve durability, precise and widely accepted definitions of these parameters were stated by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) in 2017, followed by the Valve in Valve International Data (VIVID) group definitions in 2018 and the Valve Academic Research Consortium 3 (VARC-3) definitions in 2021. Until the introduction of these definitions, interstudy comparisons were difficult due to missing uniformity. Since the release of these recommendations, an increasing number of studies have reported their data on long-term durability using these new criteria. The aim of the present article is to discuss the current definitions on bioprosthetic valve durability, and to summarize the available data on long-term durability of transcatheter aortic valves

In vivo load measurements with instrumented implants

Aquatic exercises are widely used for rehabilitation or preventive therapies in order to enable mobilization and muscle strengthening while minimizing joint loading of the lower limb. The load reducing effect of water due to buoyancy is a main advantage compared to exercises on land. However, also drag forces have to be considered that act opposite to the relative motion of the body segments and require higher muscle activity. Due to these opposing effects on joint loading, the load-reducing effect during aquatic exercises remains unknown. The aim of this study was to quantify the joint loads during various aquatic exercises and to determine the load reducing effect of water. Instrumented knee and hip implants with telemetric data transfer were used to measure the resultant joint contact forces in 12 elderly subjects (6x hip, 6x knee) in vivo. Different dynamic, weight-bearing and non-weight-bearing activities were performed by the subjects on land and in chest-high water. Non-weight-bearing hip and knee flexion/extension was performed at different velocities and with additional Aquafins. Joint forces during aquatic exercises ranged between 32 and 396% body weight (BW). Highest forces occurred during dynamic activities, followed by weight-bearing and slow non-weight-bearing activities. Compared to the same activities on land, joint forces were reduced by 36–55% in water with absolute reductions being greater than 100%BW during weight-bearing and dynamic activities. During non-weight-bearing activities, high movement velocities and additional Aquafins increased the joint forces by up to 59% and resulted in joint forces of up to 301%BW. This study confirms the load reducing effect of water during weight-bearing and dynamic exercises. Nevertheless, high drag forces result in increased joint contact forces and indicate greater muscle activity. By the choice of activity, movement velocity and additional resistive devices joint forces can be modulated individually in the course of rehabilitation or preventive therapies

Resting state networks of the canine brain under sevoflurane anaesthesia

Resting-state functional Magnetic Resonance Imaging (rs-fMRI) has become an established technique in humans and reliably determines several resting state networks (RSNs) simultaneously. Limited data exist about RSN in dogs. The aim of this study was to investigate the RSNs in 10 healthy beagle dogs using a 3 tesla MRI scanner and subsequently perform group-level independent component analysis (ICA) to identify functionally connected brain networks. Rs-fMRI sequences were performed under steady state sevoflurane inhalation anaesthesia. Anaesthetic depth was titrated to the minimum level needed for immobilisation and mechanical ventilation of the patient. This required a sevoflurane MAC between 0.8 to 1.2. Group-level ICA dimensionality of 20 components revealed distributed sensory, motor and higher-order networks in the dogs’ brain. We identified in total 7 RSNs (default mode, primary and higher order visual, auditory, two putative motor-somatosensory and one putative somatosensory), which are common to other mammals including humans. Identified RSN are remarkably similar to those identified in awake dogs. This study proves the feasibility of rs-fMRI in anesthetized dogs and describes several RSNs, which may set the basis for investigating pathophysiological characteristics of various canine brain diseases

Regulatory and coding sequences of TRNP1 co-evolve with brain size and cortical folding in mammals

Brain size and cortical folding have increased and decreased recurrently during mammalian evolution. Identifying genetic elements whose sequence or functional properties co-evolve with these traits can provide unique information on evolutionary and developmental mechanisms. A good candidate for such a comparative approach is TRNP1, as it controls proliferation of neural progenitors in mice and ferrets. Here, we investigate the contribution of both regulatory and coding sequences of TRNP1 to brain size and cortical folding in over 30 mammals. We find that the rate of TRNP1 protein evolution (omega) significantly correlates with brain size, slightly less with cortical folding and much less with body size. This brain correlation is stronger than for >95% of random control proteins. This co-evolution is likely affecting TRNP1 activity, as we find that TRNP1 from species with larger brains and more cortical folding induce higher proliferation rates in neural stem cells. Furthermore, we compare the activity of putative cis-regulatory elements (CREs) of TRNP1 in a massively parallel reporter assay and identify one CRE that likely co-evolves with cortical folding in Old World monkeys and apes. Our analyses indicate that coding and regulatory changes that increased TRNP1 activity were positively selected either as a cause or a consequence of increases in brain size and cortical folding. They also provide an example how phylogenetic approaches can inform biological mechanisms, especially when combined with molecular phenotypes across several species

Políticas públicas para educação profissional: década de 1990 e a desvinculação do ensino médio e técnico

The aim of this article is to analyze the public policies for Professional Education, especially in the 1990s regarding the separation of Secondary and technical education. The research field was the Federal Institute of Santa Catarina - IFSC - Jaraguá do Sul Campus. From a qualitative perspective, the research included analysis of interviews and documentary analysis, which supported the interpretation of institutional documents, laws, decrees and ordinances related to Professional Education in the 1990s, in particular, Decree 2.208 / 1997. Content Analysis, endorsed by Bardin (2011), was used as a reference for data analysis. The results obtained through the interviews regarding the reform of Professional Education, the implementation of Decree 2.208 / 97 and the elimination of Technical Courses integrated to Secondary Education, indicated that this public policy significantly contributed to reducing the number of public and free of charge vacancies for Secondary Education at the institution. The specifications for the Professional Education Reform led to a reduction in the quality of education due to the elimination of integration between general education and professional education. Public policies should also respond to the challenges of meeting two demands: access to work and continuity of studies.El presente artículo objetiva analizar las políticas públicas para la Educación Profesional, en especial de la década de 90 con relación a la desvinculación de la Enseñanza Media y Técnica. El campo de investigación fue el Instituto Federal de Santa Catarina - IFSC - Campus Jaraguá do Sul. De abordaje cualitativo, la investigación contó con análisis de las entrevistas y el análisis documental, que dieron soporte a la interpretación de documentos institucionales, leyes, decretos y porterías, relacionados a la Educación Profesional en la década de 1990, principalmente el Decreto 2.208/1997.  Como referencial de análisis de los datos contamos con el Análisis de Contenido, refrendada por Bardin (2011). Los resultados obtenidos por medio de las entrevistas a respecto de la reforma de la Educación Profesional, de la implementación del Decreto 2.208/97 y la extinción de los Cursos Técnicos integrado a la Enseñanza Media, apuntaron que esta política pública contribuyó de manera significativa para la disminución de la oferta de vacantes públicas y gratuitas de la Enseñanza Media en la Institución. Las determinaciones de la Reforma de la Educación Profesional acarrearon la caída de la calidad de la enseñanza en virtud de la extinción de la integración entre educación general y educación profesional. Las políticas públicas deberían también responder a los desafíos de atender dos demandas: el acceso al trabajo y la continuidad de los estudios.O presente artigo objetiva analisar as políticas públicas para a educação profissional, em especial da década de 1990, com relação à desvinculação do ensino médio e técnico. O campo de pesquisa foi o Instituto Federal de Santa Catarina (IFSC) – Campus Jaraguá do Sul. De abordagem qualitativa, a pesquisa contou com análise de entrevistas e análise documental, que deram suporte à interpretação de documentos institucionais, leis, decretos e portarias relacionados à educação profissional na década de 1990, principalmente o Decreto n.º 2.208/1997. Como referencial de análise dos dados contamos com a Análise de Conteúdo, referendada por Bardin (2011). Os resultados obtidos por meio das entrevistas a respeito da reforma da educação profissional, da implementação do Decreto 2.208/97 e da extinção dos cursos técnicos integrados ao ensino médio apontaram que essa política pública contribuiu de maneira significativa para a diminuição da oferta de vagas públicas e gratuitas do ensino médio na instituição. As determinações da reforma da educação profissional acarretaram a queda da qualidade do ensino em virtude da extinção da integração entre educação geral e educação profissional. As políticas públicas deveriam também responder aos desafios de atender a duas demandas: o acesso ao trabalho e a continuidade dos estudos

Article Ecto-Nucleotide Triphosphate Diphosphohydrolase-2 (NTPDase2) Deletion Increases Acetaminophen-Induced Hepatotoxicity

Ecto-nucleotidase triphosphate diphosphohydrolase-2 (NTPDase2) is an ecto-enzyme that is expressed on portal fibroblasts in the liver that modulates P2 receptor signaling by regulating local concentrations of extracellular ATP and ADP. NTPDase2 has protective properties in liver fibrosis and may impact bile duct epithelial turnover. Here, we study the role of NTPDase2 in acute liver injury using an experimental model of acetaminophen (APAP) intoxication in mice with global deletion of NTPDase2. Acute liver toxicity was caused by administration of acetaminophen in wild type (WT) and NTPDase2-deficient (Entpd2 null) mice. The extent of liver injury was compared by histology and serum alanine transaminase (ALT). Markers of inflammation, regeneration and fibrosis were determined by qPCR). We found that Entpd2 expression is significantly upregulated after acetaminophen-induced hepatotoxicity. Entpd2 null mice showed significantly more necrosis and higher serum ALT compared to WT. Hepatic expression of IL-6 and PDGF-B are higher in Entpd2 null mice. Our data suggest inducible and protective roles of portal fibroblast-expressed NTPDase2 in acute necrotizing liver injury. Further studies should investigate the relevance of these purinergic pathways in hepatic periportal and sinusoidal biology as such advances in understanding might provide possible therapeutic targets

Ecto-Nucleotide Triphosphate Diphosphohydrolase-2 (NTPDase2) Deletion Increases Acetaminophen-Induced Hepatotoxicity

Ecto-nucleotidase triphosphate diphosphohydrolase-2 (NTPDase2) is an ecto-enzyme that is expressed on portal fibroblasts in the liver that modulates P2 receptor signaling by regulating local concentrations of extracellular ATP and ADP. NTPDase2 has protective properties in liver fibrosis and may impact bile duct epithelial turnover. Here, we study the role of NTPDase2 in acute liver injury using an experimental model of acetaminophen (APAP) intoxication in mice with global deletion of NTPDase2. Acute liver toxicity was caused by administration of acetaminophen in wild type (WT) and NTPDase2-deficient (Entpd2 null) mice. The extent of liver injury was compared by histology and serum alanine transaminase (ALT). Markers of inflammation, regeneration and fibrosis were determined by qPCR). We found that Entpd2 expression is significantly upregulated after acetaminophen-induced hepatotoxicity. Entpd2 null mice showed significantly more necrosis and higher serum ALT compared to WT. Hepatic expression of IL-6 and PDGF-B are higher in Entpd2 null mice. Our data suggest inducible and protective roles of portal fibroblast-expressed NTPDase2 in acute necrotizing liver injury. Further studies should investigate the relevance of these purinergic pathways in hepatic periportal and sinusoidal biology as such advances in understanding might provide possible therapeutic targets

Adverse stem cell clones within a single patient’s tumor predict clinical outcome in AML patients

Acute myeloid leukemia (AML) patients suffer dismal prognosis upon treatment resistance. To study functional heterogeneity of resistance, we generated serially transplantable patient-derived xenograft (PDX) models from one patient with AML and twelve clones thereof, each derived from a single stem cell, as proven by genetic barcoding. Transcriptome and exome sequencing segregated clones according to their origin from relapse one or two. Undetectable for sequencing, multiplex fluorochrome-guided competitive in vivo treatment trials identified a subset of relapse two clones as uniquely resistant to cytarabine treatment. Transcriptional and proteomic profiles obtained from resistant PDX clones and refractory AML patients defined a 16-gene score that was predictive of clinical outcome in a large independent patient cohort. Thus, we identified novel genes related to cytarabine resistance and provide proof of concept that intra-tumor heterogeneity reflects inter-tumor heterogeneity in AML