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AIM: Paediatric patients with drug-resistant focal epilepsy (DRFE) who have no clear focal lesion identified on conventional structural magnetic resonance imaging (MRI) are a particularly challenging cohort to treat and form an increasing part of epilepsy surgery programs. A recently developed deep-learning-based MRI lesion detection algorithm, the Multicentre Lesion Detection (MELD) algorithm, has been shown to aid detection of focal cortical dysplasia (FCD). We applied this algorithm retrospectively to a cohort of MRI-negative children with refractory focal epilepsy who underwent stereoelectroencephalography (SEEG) to determine its accuracy in identifying unseen epileptic lesions, seizure onset zones and clinical outcomes. METHODS: We retrospectively applied the MELD algorithm to a consecutive series of MRI-negative patients who underwent SEEG at our tertiary Paediatric Epilepsy Surgery centre. We assessed the extent to which the identified MELD cluster or lesion area corresponded with the clinical seizure hypothesis, the epileptic network, and the positron emission tomography (PET) focal hypometabolic area. In those who underwent resective surgery, we analysed whether the region of MELD abnormality corresponded with the surgical target and to what extent this was associated with seizure freedom. RESULTS: We identified 37 SEEG studies in 28 MRI-negative children in whom we could run the MELD algorithm. Of these, 14 (50â¯%) children had clusters identified on MELD. Nine (32â¯%) children had clusters concordant with seizure hypothesis, 6 (21â¯%) had clusters concordant with PET imaging, and 5 (18â¯%) children had at least one cluster concordant with SEEG electrode placement. Overall, 4 MELD clusters in 4 separate children correctly predicted either seizure onset zone or irritative zone based on SEEG stimulation data. Sixteen children (57â¯%) went on to have resective or lesional surgery. Of these, only one patient (4â¯%) had a MELD cluster which co-localised with the resection cavity and this child had an Engel 1â¯A outcome. CONCLUSIONS: In our paediatric cohort of MRI-negative patients with drug-resistant focal epilepsy, the MELD algorithm identified abnormal clusters or lesions in half of cases, and identified one radiologically occult focal cortical dysplasia. Machine-learning-based lesion detection is a promising area of research with the potential to improve seizure outcomes in this challenging cohort of radiologically occult FCD cases. However, its application should be approached with caution, especially with regards to its specificity in detecting FCD lesions, and there is still work to be done before it adds to diagnostic utility.
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The adult mammalian heart harbors minute levels of cycling cardiomyocytes (CMs). Large numbers of images are needed to accurately quantify cycling events using microscopy-based methods. CardioCount is a new deep learning-based pipeline to rigorously score nuclei in microscopic images. When applied to a repository of 368,434 human microscopic images, we found evidence of coupled growth between CMs and cardiac endothelial cells in the adult human heart. Additionally, we found that vascular rarefaction and CM hypertrophy are interrelated in end-stage heart failure. CardioCount is available for use via GitHub and via Google Colab for users with minimal machine learning experience.
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Hypertension induces cardiac fibrotic remodelling characterised by the phenotypic switching of cardiac fibroblasts (CFs) and collagen deposition. We tested the hypothesis that Wnt1-inducible signalling pathway protein-1 (WISP-1) promotes CFs' phenotypic switch, type I collagen synthesis, and in vivo fibrotic remodelling. The treatment of human CFs (HCFs, n = 16) with WISP-1 (500 ng/mL) induced a phenotypic switch (α-smooth muscle actin-positive) and type I procollagen cleavage to an intermediate form of collagen (pC-collagen) in conditioned media after 24h, facilitating collagen maturation. WISP-1-induced collagen processing was mediated by Akt phosphorylation via integrin ß1, and disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAMTS-2). WISP-1 wild-type (WISP-1+/+) mice and WISP-1 knockout (WISP-1-/-) mice (n = 5-7) were subcutaneously infused with angiotensin II (AngII, 1000 ng/kg/min) for 28 days. Immunohistochemistry revealed the deletion of WISP-1 attenuated type I collagen deposition in the coronary artery perivascular area compared to WISP-1+/+ mice after a 28-day AngII infusion, and therefore, the deletion of WISP-1 attenuated AngII-induced cardiac fibrosis in vivo. Collectively, our findings demonstrated WISP-1 is a critical mediator in cardiac fibrotic remodelling, by promoting CFs' activation via the integrin ß1-Akt signalling pathway, and induced collagen processing and maturation via ADAMTS-2. Thereby, the modulation of WISP-1 levels could provide potential therapeutic targets in clinical treatment.
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Proteínas CCN de Señalización Intercelular , Fibroblastos , Fibrosis , Miocardio , Proteínas Proto-Oncogénicas , Animales , Proteínas CCN de Señalización Intercelular/metabolismo , Proteínas CCN de Señalización Intercelular/genética , Fibroblastos/metabolismo , Fibroblastos/patología , Fibroblastos/efectos de los fármacos , Humanos , Ratones , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Miocardio/patología , Miocardio/metabolismo , Colágeno/metabolismo , Angiotensina II/farmacología , Ratones Noqueados , Colágeno Tipo I/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Masculino , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
Human abdominal aortic aneurysms (AAAs) are characterized by increased activity of matrix metalloproteinases (MMP), including MMP-12, alongside macrophage accumulation and elastin degradation, in conjunction with superimposed atherosclerosis. Previous genetic ablation studies have proposed contradictory roles for MMP-12 in AAA development. In this study, we aimed to elucidate if pharmacological inhibition of MMP-12 activity with a phosphinic peptide inhibitor protects from AAA formation and progression in angiotensin (Ang) II-infused Apoe-/- mice. Complimentary studies were conducted in a human ex vivo model of early aneurysm development. Administration of an MMP-12 inhibitor (RXP470.1) protected hypercholesterolemia Apoe-/- mice from Ang II-induced AAA formation and rupture-related death, associated with diminished medial thinning and elastin fragmentation alongside increased collagen deposition. Proteomic analyses confirmed a beneficial effect of MMP-12 inhibition on extracellular matrix remodeling proteins combined with inflammatory pathways. Furthermore, RXP470.1 treatment of mice with pre-existing AAAs exerted beneficial effects as observed through suppressed aortic dilation and rupture, medial thinning, and elastin destruction. Our findings indicate that pharmacological inhibition of MMP-12 activity retards AAA progression and improves survival in mice providing proof-of-concept evidence to motivate translational work for MMP-12 inhibitor therapy in humans.
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Angiotensina II , Aneurisma de la Aorta Abdominal , Apolipoproteínas E , Metaloproteinasa 12 de la Matriz , Inhibidores de la Metaloproteinasa de la Matriz , Animales , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/prevención & control , Aneurisma de la Aorta Abdominal/etiología , Metaloproteinasa 12 de la Matriz/metabolismo , Ratones , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Humanos , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Inhibidores de la Metaloproteinasa de la Matriz/uso terapéutico , Masculino , Modelos Animales de Enfermedad , Ratones Noqueados , Ratones Endogámicos C57BL , Elastina/metabolismo , Proteómica/métodosRESUMEN
Over the last 40 years, object recognition studies have moved from using simple line drawings, to more detailed illustrations, to more ecologically valid photographic representations. Researchers now have access to various stimuli sets, however, existing sets lack the ability to independently manipulate item format, as the concepts depicted are unique to the set they derive from. To enable such comparisons, Rossion and Pourtois (2004) revisited Snodgrass and Vanderwart's (1980) line drawings and digitally re-drew the objects, adding texture and shading. In the current study, we took this further and created a set of stimuli that showcase the same objects in photographic form. We selected six photographs of each object (three color/three grayscale) and collected normative data and RTs. Naming accuracy and agreement was high for all photographs and appeared to steadily increase with format distinctiveness. In contrast to previous data patterns for drawings, naming agreement (H values) did not differ between grey and color photographs, nor did familiarity ratings. However, grey photographs received significantly lower mental imagery agreement and visual complexity scores than color photographs. This suggests that, in comparison to drawings, the ecological nature of photographs may facilitate deeper critical evaluation of whether they offer a good match to a mental representation. Color may therefore play a more vital role in photographs than in drawings, aiding participants in judging the match with their mental representation. This new photographic stimulus set and corresponding normative data provide valuable materials for a wide range of experimental studies of object recognition.
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Reconocimiento Visual de Modelos , Estimulación Luminosa , Fotograbar , Reconocimiento en Psicología , Humanos , Masculino , Femenino , Fotograbar/métodos , Reconocimiento en Psicología/fisiología , Reconocimiento Visual de Modelos/fisiología , Adulto , Tiempo de Reacción/fisiología , Adulto Joven , AdolescenteRESUMEN
INTRODUCTION: Standards to define and measure quality in healthcare for cardiovascular disease risk reduction and secondary prevention are available, but there is a paucity of indicators that could serve as facilitators of structural change at a system level. This research study aimed to develop a range of delivery indicators to help cardiac clinical networks assess delivery of and progress towards cardiovascular disease objectives. METHODS: This study used an adapted version of the European Society of Cardiology's four-step process for the development of quality indicators. The four steps in this study were as follows: identify critical factors of enablement, construct a list of candidate indicators, select a final set of indicators and assess availability of national data for each indicator. In this iterative process, a core project group of six members was supported by a wider review group of 21 people from the National Health Service (NHS) clinical and management personnel database. RESULTS: The core project group identified six relevant cardiovascular disease priorities in the NHS Long Term Plan and used an iterative process to identify 21 critical factors that impact on their implementation. A total of 57 potential indicators that could be measures of implementation were developed. The core project group agreed on a set of 38 candidate indicators that were circulated to the review group for rating. Based on these scores, the core project group excluded 5 indicators to arrive at a final set of 33 delivery indicators. National datasets were available for 22 of the final indicators, which were designated as delivery indicators. The remaining 11, for which national datasets were not available but locally available datasets could be used, were designated as delivery enablers. CONCLUSION: The suite of delivery indicators and delivery enablers for cardiovascular disease could allow a more focused evaluation of factors that impact on delivery of healthcare for cardiovascular disease.
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Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/prevención & control , Indicadores de Calidad de la Atención de Salud , Técnica Delphi , Medicina Estatal , Reino UnidoRESUMEN
BACKGROUND AND AIMS: Differences in the perceived prevalence of familial hypercholesterolemia (FH) by ethnicity are unclear. In this study, we aimed to assess the prevalence, determinants and management of diagnostically-coded FH in an ethnically diverse population in South London. METHODS: A cross-sectional analysis of 40 practices in 332,357 adult patients in Lambeth was undertaken. Factors affecting a (clinically coded) diagnosis of FH were investigated by multi-level logistic regression adjusted for socio-demographic and lifestyle factors, co-morbidities, and medications. RESULTS: The age-adjusted FH % prevalence rate (OR, 95%CI) ranged from 0.10 to 1.11, 0.00-1.31. Lower rates of FH coding were associated with age (0.96, 0.96-0.97) and male gender (0.75, 0.65-0.87), p < 0.001. Compared to a White British reference group, a higher likelihood of coded FH was noted in Other Asians (1.33, 1.01-1.76), p = 0.05, with lower rates in Black Africans (0.50, 0.37-0.68), p < 0.001, Indians (0.55, 0.34-0.89) p = 0.02, and in Black Caribbeans (0.60, 0.44-0.81), p = 0.001. The overall prevalence using Simon Broome criteria was 0.1%; we were unable to provide ethnic specific estimates due to low numbers. Lower likelihoods of FH coding (OR, 95%CI) were seen in non-native English speakers (0.66, 0.53-0.81), most deprived income quintile (0.68, 0.52-0.88), smokers (0.68,0.55-0.85), hypertension (0.62, 0.52-0.74), chronic kidney disease (0.64, 0.41-0.99), obesity (0.80, 0.67-0.95), diabetes (0.31, 0.25-0.39) and CVD (0.47, 0.36-0.63). 20% of FH coded patients were not prescribed lipid-lowering medications, p < 0.001. CONCLUSIONS: Inequalities in diagnostic coding of FH patients exist. Lower likelihoods of diagnosed FH were seen in Black African, Black Caribbean and Indian ethnic groups, in contrast to higher diagnoses in White and Other Asian ethnic groups. Hypercholesterolaemia requiring statin therapy was associated with FH diagnosis, however, the presence of cardiovascular disease (CVD) risk factors lowered the diagnosis rate for FH.
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Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Hipertensión , Adulto , Humanos , Masculino , Londres/epidemiología , Codificación Clínica , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/genética , Hipercolesterolemia/complicaciones , Hipertensión/complicaciones , Prevalencia , Factores de RiesgoRESUMEN
Objective: Direct oral anticoagulants (DOACs) are first-line therapy for stroke prevention for 1.4 million atrial fibrillation (AF) patients in the UK. However, the rates of DOAC dosing below evidence-based recommendations are estimated between 9% and 22%. This study explores specific patient and physician factors associated with prescribing inappropriate DOAC underdoses. Methods: DOAC-prescribing physicians within the UK completed both a clinical vignette survey, which contained 12 hypothetical patient profiles designed to replicate DOAC prescribing scenarios, and a physician survey to capture sociodemographic, clinical experience, and prescriber-related beliefs and motivations related to DOAC prescribing. Eight patient factors based on a literature search and an expert consultation process were varied within the vignettes. Associations between the prescribers' dosing choices and patient factors were explored via multilevel logistic regression. The analysis is focused on the most frequently selected DOACs, apixaban and rivaroxaban, both of which have different dosing guidelines. Results: In all, 336 prescribers (69% male; 233/336) completed the survey, mostly general physicians (GPs) (45%) or cardiology specialists (36%) with a mean of 17.9 years' experience. Most prescribers (73%; 244/336) inappropriately underdosed at least once; rates between GPs and specialists were nearly identical. Patient factors most strongly associated with apixaban inappropriate underdosing included a history of major bleeding and falls. For rivaroxaban, these were major bleeding and severe frailty. Only 32% (106/335) of prescribers reported DOAC dosing guidelines as the sole influence on their prescribing behaviour. Among prescribers who did not inappropriately underdose, greater prescribing confidence was aligned to increased perception of inappropriate underdose risk. Conclusions: Overall, patient factors such as major bleeding and severe frailty were found to be associated with inappropriate underdosing of apixaban and rivaroxaban. Furthermore, prescribers who were more confident in DOAC prescribing, and were more worried about the risk of stroke, were significantly less likely to inappropriately underdose. These findings suggest that all prescribers, regardless of speciality, may benefit from education and training to raise awareness of the risks associated with inappropriate DOAC underdosing.
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Rare earth elements (REEs) have been found to have numerous uses to trace geological and cosmochemical processes through analyses of elemental patterns, radioactive decay, nucleosynthetic anomalies, and cosmogenic effects. Stable isotopic fractionation is one aspect of REE geochemistry that has been seldom studied, with most publications focusing on the development of analytical methodologies for individual REEs, and most applications concerning terrestrial igneous rocks. In this study, we present a method to systematically analyze stable isotopic fractionations of 8 REEs, including Ce, Nd, Sm, Eu, Gd, Dy, Er, and Yb, using sample-standard bracketing (SSB) and double-spike (DS) approaches. All REEs are separated and purified using a fluoropolymer pneumatic liquid chromatography (FPLC) system. We introduce procedures for identifying and correcting some isobaric interferences in double-spike data reduction. Several geostandards, including igneous rocks and sediments, are analyzed using SSB and DS methods. The results indicate that REE isotopic fractionation in igneous processes is limited, except for Eu. Other REEs can still be isotopically fractionated by low-temperature processes and kinetic effects at a high temperature.
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BACKGROUND: We sought to understand the impact of the COVID-19 pandemic on lipid-lowering therapy prescribing as a potential cause of the excess cardiovascular mortality seen post-pandemic in England. We examined temporal changes over 3 years in the prescribing of high-intensity and non-high-intensity statin therapy and ezetimibe. SOURCES OF DATA: We utilized data available via the National Health Service (NHS) Business Services Authority (NHSBSA) Information Services Data Warehouse, extracting 3 monthly data from October 2018 to December 2021 on high- and low-intensity statin and ezetimibe prescribing, (commencement, cessation or continuation) through each time period of study and those before, and after, the period of interest. AREAS OF AGREEMENT: Optimizing lipid management is a key component of the NHS Long Term Plan ambition to reduce deaths from cardiovascular disease, stroke and dementia. AREAS OF CONTROVERSY: The COVID-19 pandemic and associated lockdown have seen a significant reduction in prescribing of lipid-lowering therapies. If cardiovascular risk is not to worsen in the forthcoming years, urgent action is needed to ensure that the impact of the pandemic upon optimization of cholesterol and the historical undertreatment of cholesterol is reversed and improved. AREAS TIMELY FOR DEVELOPING RESEARCH: Prescription data available via NHSBSA can support our understanding of the implications of policy and behaviour and highlight the impact of guidelines in practise. GROWING POINTS: Understanding the impact of the COVID-19 pandemic upon cholesterol management and the opportunities for newer lipid-lowering therapies delivered using a population health approach have the potential to enhance lipid-lowering and improve cardiovascular mortality and morbidity and reduce health inequalities.
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COVID-19 , Enfermedades Cardiovasculares , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Medicina Estatal , Pandemias , Factores de Riesgo , COVID-19/epidemiología , Control de Enfermedades Transmisibles , Ezetimiba , Colesterol , Factores de Riesgo de Enfermedad CardiacaRESUMEN
The release of phosphorus (P) from crustal rocks during weathering plays a key role in determining the size of Earth's biosphere, yet the concentration of P in crustal rocks over time remains controversial. Here, we combine spatial, temporal, and chemical measurements of preserved rocks to reconstruct the lithological and chemical evolution of Earth's continental crust. We identify a threefold increase in average crustal P concentrations across the Neoproterozoic-Phanerozoic boundary (600 to 400 million years), showing that preferential biomass burial on shelves acted to progressively concentrate P within continental crust. Rapid compositional change was made possible by massive removal of ancient P-poor rock and deposition of young P-rich sediment during an episode of enhanced global erosion. Subsequent weathering of newly P-rich crust led to increased riverine P fluxes to the ocean. Our results suggest that global erosion coupled to sedimentary P-enrichment forged a markedly nutrient-rich crust at the dawn of the Phanerozoic.
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The three subsets of human monocytes, classical, intermediate, and nonclassical, show phenotypic heterogeneity, particularly in their expression of CD14 and CD16. This has enabled researchers to delve into the functions of each subset in the steady state as well as in disease. Studies have revealed that monocyte heterogeneity is multi-dimensional. In addition, that their phenotype and function differ between subsets is well established. However, it is becoming evident that heterogeneity also exists within each subset, between health and disease (current or past) states, and even between individuals. This realisation casts long shadows, impacting how we identify and classify the subsets, the functions we assign to them, and how they are examined for alterations in disease. Perhaps the most fascinating is evidence that, even in relative health, interindividual differences in monocyte subsets exist. It is proposed that the individual's microenvironment could cause long-lasting or irreversible changes to monocyte precursors that echo to monocytes and through to their derived macrophages. Here, we will discuss the types of heterogeneity recognised in monocytes, the implications of these for monocyte research, and most importantly, the relevance of this heterogeneity for health and disease.
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Macrófagos , Monocitos , Humanos , Monocitos/metabolismo , Macrófagos/metabolismo , Fenotipo , Hematopoyesis , Receptores de IgG/metabolismo , Receptores de Lipopolisacáridos/metabolismoRESUMEN
ABSTRACTWe report three experiments designed to reveal the mechanisms that underlie subjective experiences of recognition by examining effects of how those experiences are measured. Prior research has explored the potential influences of collecting metacognitive measures on memory performance. Building on this work, here we systematically evaluated whether cross-measure contamination occurs when remember-know (RK) and/or confidence (C) judgments are made after old/new recognition decisions. In Experiment 1, making either RK or C judgments did not significantly influence recognition relative to a standard no-judgment condition. In Experiment 2, making RK judgments in addition to C judgments did not significantly affect recognition or confidence. In Experiment 3, making C judgments in addition to RK judgments did not significantly affect recognition or patterns of RK responses. Cross-contamination was not apparent regardless of whether items were studied using a shallow or deep levels-of-processing task - a manipulation that yielded robust effects on recognition, RK judgments, and C. Our results indicate that under some conditions, participants can independently evaluate their recognition, subjective recognition experience, and confidence. Though contamination across measures of metamemory and memory is always possible, it may not be inevitable. This has implications for the mechanisms that underlie subjective experiences that accompany recognition judgments.
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Recuerdo Mental , Metacognición , Humanos , Recuerdo Mental/fisiología , Reconocimiento en Psicología/fisiología , Juicio/fisiología , CogniciónRESUMEN
AIMS: To identify the needs, experiences and preferences of women with kidney disease in relation to their reproductive health to inform development of shared decision-making interventions. DESIGN: UK-wide mixed-methods convergent design (Sep 20-Aug 21). METHODS: Online questionnaire (n = 431) with validated components. Purposively sampled semi-structured interviews (n = 30). Patient and public input throughout. FINDINGS: Kidney disease was associated with defeminization, negatively affecting current (sexual) relationships and perceptions of future life goals. There was little evidence that shared decision making was taking place. Unplanned pregnancies were common, sometimes influenced by poor care and support and complicated systems. Reasons for (not) wanting children varied. Complicated pregnancies and miscarriages were common. Women often felt that it was more important to be a "good mother" than to address their health needs, which were often unmet and unrecognized. Impacts of pregnancy on disease and options for alternates to pregnancy were not well understood. CONCLUSION: The needs and reproductive priorities of women are frequently overshadowed by their kidney disease. High-quality shared decision-making interventions need to be embedded as routine in a feminized care pathway that includes reproductive health. Research is needed in parallel to examine the effectiveness of interventions and address inequalities. IMPACT: We do not fully understand the expectations, needs, experiences and preferences of women with kidney disease for planning and starting a family or deciding not to have children. Women lack the knowledge, resources and opportunities to have high-quality conversations with their healthcare professionals. Decisions are highly personal and related to a number of health, social and cultural factors; individualized approaches to care are essential. Healthcare services need to be redesigned to ensure that women are able to make informed choices about pregnancy and alternative routes to becoming a parent. PATIENT OR PUBLIC CONTRIBUTION: The original proposal for this research came from listening to the experiences of women in clinic who reported unmet needs and detailed experiences of their pregnancies (positive and negative). A patient group was involved in developing the funding application and helped to refine the objectives by sharing their experiences. Two women who are mothers living with kidney disease were co-opted as core members of the research team. We hosted an interim findings event and invited patients and wider support services (adoption, fertility, surrogacy, education and maternal chronic kidney disease clinics) from across the UK to attend. We followed the UK national standards for patient and public involvement throughout.
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Vías Clínicas , Toma de Decisiones , Enfermedades Renales , Responsabilidad Parental , Niño , Femenino , Humanos , Embarazo , ReproducciónRESUMEN
The lavas associated with mantle plumes may sample domains throughout Earth's mantle and probe its dynamics. However, plume studies are often only able to take snapshots in time, usually of the most recent plume activity, leaving the chemical and geodynamic evolution of major convective upwellings in Earth's mantle poorly constrained. Here, we report the geodynamically key information of how the lithology and density of a plume change from plume head phase to tail. We use iron stable isotopes and thermodynamic modeling to show that the Galápagos plume has contained small, nearly constant, amounts of dense recycled crust over its 90-million-year history. Despite a temporal evolution in the amount of recycled crust-derived melt in Galápagos-related lavas, we show that this can be explained by plume cooling alone, without associated changes in the plume's mantle source; results are also consistent with a plume rooted in a lower mantle low-velocity zone also sampling primordial components.
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BACKGROUND: There is a growing evidence base for the importance of spatial reasoning for the development of mathematics. However, the extent to which this translates into practice is unknown. AIMS: We aimed to understand practitioners' perspectives on their understanding of spatial reasoning, the extent to which they recognize and implement spatial activities in their practice, and the barriers and opportunities to support spatial reasoning in the practice setting. SAMPLE: Study 1 (questionnaire) included 94 participants and Study 2 (focus groups) consisted of nine participants. Participants were educational practitioners working with children from birth to 7 years. METHODS: The study was mixed methods and included a questionnaire (Study 1) and a series of focus groups (Study 2). RESULTS: We found that whilst practitioners engage in a variety of activities that support spatial reasoning, most practitioners reported little confidence in their understanding of what spatial reasoning is. CONCLUSION: Informative and accessible resources are needed to broaden understanding of the definition of spatial reasoning and to outline opportunities to support spatial reasoning.
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Procesos Mentales , Niño , Humanos , Encuestas y CuestionariosRESUMEN
BACKGROUND: Late vein graft failure is caused by intimal thickening resulting from endothelial cell (EC) damage and inflammation which promotes vascular smooth muscle cell (VSMC) dedifferentiation, migration, and proliferation. Nonphosphorylatable PRH (proline-rich homeodomain) S163C:S177C offers enhanced stability and sustained antimitotic effect. Therefore, we investigated whether adenovirus-delivered PRH S163C:S177C protein attenuates intimal thickening via VSMC phenotype modification without detrimental effects on ECs. METHODS: PRH S163C:S177C was expressed in vitro (human saphenous vein-VSMCs and human saphenous vein-ECs) and in vivo (ligated mouse carotid arteries) by adenoviruses. Proliferation, migration, and apoptosis were quantified and phenotype was assessed using Western blotting for contractile filament proteins and collagen gel contraction. EC inflammation was quantified using VCAM (vascular cell adhesion protein)-1, ICAM (intercellular adhesion molecule)-1, interleukin-6, and monocyte chemotactic factor-1 measurement and monocyte adhesion. Next Generation Sequencing was utilized to identify novel downstream mediators of PRH action and these and intimal thickening were investigated in vivo. RESULTS: PRH S163C:S177C inhibited proliferation, migration, and apoptosis and promoted contractile phenotype (enhanced contractile filament proteins and collagen gel contraction) compared with virus control in human saphenous vein-VSMCs. PRH S163C:S177C expression in human saphenous vein-ECs significantly reduced apoptosis, without affecting cell proliferation and migration, while reducing TNF (tumor necrosis factor)-α-induced VCAM-1 and ICAM-1 and monocyte adhesion and suppressing interleukin-6 and monocyte chemotactic factor-1 protein levels. PRH S163C:S177C expression in ligated murine carotid arteries significantly impaired carotid artery ligation-induced neointimal proliferation and thickening without reducing endothelial coverage. Next Generation Sequencing revealed STAT-1 (signal transducer and activator of transcription 1) and HDAC-9 (histone deacetylase 9) as mediators of PRH action and was supported by in vitro and in vivo analyses. CONCLUSIONS: We observed PRH S163C:S177C attenuated VSMC proliferation, and migration and enhanced VSMC differentiation at least in part via STAT-1 and HDAC-9 signaling while promoting endothelial repair and anti-inflammatory properties. These findings highlight the potential for PRH S163C:S177C to preserve endothelial function whilst suppressing intimal thickening, and reducing late vein graft failure.
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Interleucina-6 , Túnica Íntima , Ratones , Animales , Humanos , Interleucina-6/metabolismo , Túnica Íntima/patología , Proliferación Celular , Neointima/patología , Factores Quimiotácticos/metabolismo , Factores Quimiotácticos/farmacología , Miocitos del Músculo Liso/metabolismo , Movimiento CelularRESUMEN
A potential record of Earth's magnetic field going back 4.2 billion years (Ga) ago is carried by magnetite inclusions in zircon grains from the Jack Hills. This magnetite may be secondary in nature, however, meaning that the magnetic record is much younger than the zircon crystallization age. Here, we use atom probe tomography to show that Pb-bearing nanoclusters in magnetite-bearing Jack Hills zircons formed during two discrete events at 3.4 and <2 Ga. The older population of clusters contains no detectable Fe, whereas roughly half of the younger population of clusters is Fe bearing. This result shows that the Fe required to form secondary magnetite entered the zircon sometime after 3.4 Ga and that remobilization of Pb and Fe during an annealing event occurred more than 1 Ga after deposition of the Jack Hills sediment at 3 Ga. The ability to date Fe mobility linked to secondary magnetite formation provides new possibilities to improve our knowledge of the Archean geodynamo.
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INTRODUCTION: The addition of cephalic drains (CDs) in extracorporeal membrane oxygenation (ECMO) to augment venous drainage may offer benefit, though their use is varied. Our objective was to describe our institution's experience with CDs including flow rates and patency. We also compared complication rates between patients with and without a CD. METHODS: This retrospective cohort study included infants <12 months of age cannulated for ECMO between January 1, 2010 and September 30, 2019 at a single institution. Flow data were obtained for those with a CD. Demographic and complication rates were obtained for all. RESULTS: Of 264 patients in the final cohort, 220 (83%) had a CD of which 93.2% remained patent to decannulation. CDs typically provided 30% or more of ECMO flow throughout the ECMO run. The median time to CD clot was 139 h (range 48-635 h). Patients with a clotted CD had longer ECMO runs than those whose CD remained patent (median 382 h [IQR 217-538] vs 139 h [IQR 91-246], p < 0.001). Survival to discharge was lower for those with clotted versus patent CD (14% vs 70%, p < 0.001). Mechanical complications were more common in patients with CD (p = 0.005). Seizures were more common in those without a CD (p = 0.021). CONCLUSIONS: In this cohort, the majority of CDs placed remained patent at decannulation and provided substantial additional venous drainage. Mechanical problems were common in patients with CDs, but without clinical sequelae. Further study is warranted to elucidate CD impact on short- and long-term outcomes.