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Combined or mixed hyperlipidaemia is characterised by hypercholesterolaemia together with high triglyceride concentrations. It is found in approximately 1 in 100 people in the United Kingdom. Most cases are secondary to an underlying condition such as the metabolic syndrome, diabetes mellitus (especially poorly controlled) or individuals with a high alcohol intake. Mixed hyperlipidaemia is also a feature of some primary hyperlipidaemia conditions such familial combined hyperlipidaemia (FCH) or type III hyperlipidaemia (dysbetalipoproteinaemia). One differential diagnosis for mixed hyperlipidaemia that can easily be overlooked is a patient with an underlying diagnosis of familial hypercholesterolaemia (FH) who also has a hypertriglyceridaemia due to any other cause. Those patients may have very high total and low-density lipoprotein cholesterol concentrations (LDL-C) with a moderately elevated triglyceride concentration. In this article, we report 4 cases of familial hypercholesterolaemia, confirmed by genetic testing, in patients initially presenting with hypertriglyceridaemia in addition to high total cholesterol and LDL-C. This article discusses the diagnostic challenges associated with this presentation and highlights the key role of directly measuring LDL-C to aid diagnosis in these specific situations.
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BACKGROUND: Prolonged changes to functional network connectivity as a result of a traumatic brain injury (TBI) may relate to long-term cognitive complaints reported by TBI survivors. No interventions have proven to be effective at treating long-term cognitive complaints after TBI but physical activity has been shown to promote cognitive function and modulate functional network connectivity in non-injured adults. Therefore, the objective of this study was to test if physical activity engagement was associated with functional connectivity of the cognitively relevant frontoparietal control network (FPCN) in adults with a TBI history. METHODS: In a case-control study design, resting state function magnetic resonance imaging and physical activity data from a subset of participants (18-81 years old) from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) study was analyzed. Fifty-seven participants reported a prior head injury with loss of consciousness and 57 age and sex matched controls were selected. Seed-based functional connectivity analyses were performed using seeds in the dorsolateral prefrontal cortex and the inferior parietal lobule, to test for differences in functional connectivity between groups, associations between physical activity and functional connectivity within TBI as well as differential associations between physical activity and functional connectivity between TBI and controls. RESULTS: Seed-based connectivity analyses from the dorsolateral prefrontal cortex showed that those with a history of TBI had decreased positive connectivity between dorsolateral prefrontal cortex and intracalcarine cortex, lingual gyrus, and cerebellum, and increased positive connectivity between dorsolateral prefrontal cortex and cingulate gyrus and frontal pole in the TBI group. Results showed that higher physical activity was positively associated with increased connectivity between the dorsolateral prefrontal cortex and inferior temporal gyrus. Differential associations were observed between groups whereby the strength of the physical activity-functional connectivity association was different between the inferior parietal lobule and inferior temporal gyrus in TBI compared to controls. DISCUSSION: Individuals with a history of TBI show functional connectivity alterations of the FPCN. Moreover, engagement in physical activity is associated with functional network connectivity of the FPCN in those with a TBI. These findings are consistent with the evidence that physical activity affects FPCN connectivity in non-injured adults; however, this effect presents differently in those with a history of TBI.
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Lesões Encefálicas Traumáticas , Exercício Físico , Imageamento por Ressonância Magnética , Lobo Parietal , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Lesões Encefálicas Traumáticas/fisiopatologia , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lobo Parietal/fisiopatologia , Lobo Parietal/diagnóstico por imagem , Idoso , Estudos de Casos e Controles , Adulto Jovem , Exercício Físico/fisiologia , Idoso de 80 Anos ou mais , Adolescente , Rede Nervosa/fisiopatologia , Rede Nervosa/diagnóstico por imagem , Lobo Frontal/fisiopatologia , Lobo Frontal/diagnóstico por imagemRESUMO
BACKGROUND: Following acute and sub-acute rehabilitation from severe traumatic brain injury (TBI), minimal to no efficacious interventions to treat ongoing cognitive deficits are available. Aerobic exercise is a non-invasive behavioral intervention with promise to treat cognitive deficits in TBI populations. METHODS: Six individuals, aged 24-62 years, with chronic (> 8 months since injury) severe (Glasgow Coma Scale of 3-8) TBI were recruited from two outpatient rehabilitation centers. In an A-B-A study design, 20-weeks of supervised aerobic exercise interventions were delivered three times per week (phase B) in addition to participants typical rehabilitation schedules (phases A). The effect of phase B was tested on a trail making test part B (primary outcome measure of executive function) as well as objective daily physical activity (PA), using both group level (linear mixed effect models) and single subject statistics. RESULTS: Five of six participants increased trail-making test part B by more than 10% pre-to-post phase B, with three of six making a clinically meaningful improvement (+ 1SD in normative scores). A significant main effect of time was seen with significant improvement in trail-making test part B pre-to-post exercise (phase B). No significant effects in other planned comparisons were found. Statistically significant increases in daily moderate-to-vigorous PA were also seen during phase B compared to phase A with three of six individuals making a significant behaviour change. CONCLUSIONS: The addition of supervised aerobic exercise to typical rehabilitation strategies in chronic survivors of severe TBI can improve executive set shifting abilities and increase voluntary daily PA levels. TRIAL REGISTRATION: Retrospective trial registration on July 11 2024 with trial number: ISRCTN17487462.
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This is a case of a 61-year-old lady who presented to the lipid clinic with possible familial hypercholesterolaemia (Simon Broome Criteria). She was commenced on atorvastatin; however, 4 weeks later, she developed hepatitis, and therefore her atorvastatin was discontinued. Following that, her liver function tests normalized, and she was diagnosed with statin-induced hepatitis. Three years later, she was seen again in the lipid clinic with an uncontrolled lipid profile, and she was commenced on alirocumab, a Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitor. A few days later, she developed hepatitis, and subsequently, the alirocumab was discontinued. She underwent a liver biopsy, which confirmed that she had Autoimmune Hepatitis (AIH) with presumed superimposed drug injury. This is the first reported case of autoimmune hepatitis associated with alirocumab.
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Background: Postpartum haemorrhage is the leading cause of preventable maternal mortality worldwide. Early identification and prompt management of postpartum haemorrhage improve outcomes. Objective assessment of postpartum blood loss is an important step in identifying postpartum haemorrhage. The Brass-V drape and MaternaWell tray have been designed for routine measurement of postpartum blood loss. The perceived utility and acceptability of these devices to the parturients and birth attendants still begged exploring. Objective: To assess the perceived usefulness and ease of use of a Brass-V drape versus a MaternaWell tray for the collection of postpartum blood loss. Methods: We conducted a prospective parallel randomised trial, employing a questionnaire to assess the experiences of birth attendants and birthing women who used these devices. The study was conducted at site B midwife obstetric unit in Khayelitsha Cape Town. Pregnant women presenting in early labour were approached for voluntary participation. After informed consent was obtained, participants were randomly assigned to the Brass-V drape or the MaternaWell tray, which the birth attendant placed after the birth of the baby. Results: There were 63 participants, of which 33 were assigned to the MaternaWell tray and 30 to the Brass-V drape. Birth attendants indicated a desire to use the MaternaWell tray (30 (90%)) or Brass-V drape (26 (87%)) in future deliveries. The parturients were also in favour of the future use of MaternaWell tray (33 (100%)) and Brass-V drape (28 (93%)). Ease of measurement favoured the Brass V-drape, and ease of placement favoured the MaternaWell tray. Five (8%) participants experienced postpartum haemorrhage, two with the MaternaWell tray and three with the Brass-V drape. One parturient required hospital transfer. Conclusion: The responses of the birth attendants and parturients were positive. The MaternaWell tray has the benefit of reuse and lower cost and is an acceptable alternative to the Brass-V drape. Both devices aid in the early recognition of postpartum haemorrhage.
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OBJECTIVES: Traumatic brain injury (TBI) is associated with sleep deficits, but it is not clear why some report sleep disturbances and others do not. The objective of this study was to assess the associations between axonal injury, sleep, and memory in chronic and acute TBI. METHODS: Data were acquired from two independent datasets which included 156 older adult veterans (69.8 years) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with prior moderate-to-severe TBIs and 90 (69.2 years) controls and 374 (39.6 years) from Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) with a recent mild TBI (mTBI) and 87 controls (39.6 years), all who completed an MRI, memory assessment, and sleep questionnaire. RESULTS: Older adults with a prior TBI had a significant association between axonal injury and sleep disturbances [ß = 9.52, 95% CI (4.1, 14.9), p = 0.01]. Axonal injury predicted changes in memory over 1-year in TBI [ß = -8.72, 95% CI (-18, -2.7), p = 0.03]. We externally validated those findings in TRACK-TBI where axonal injury within 2 weeks after mTBI was significantly associated with higher sleep disturbances in the TBI group at 2 weeks[ß = -7.2, 95% CI (-14, -0.50), p = 0.04], 6 months [ß = -16, 95% CI (-24, -7.6), p ≤ 0.01], and 12 months post-injury [ß = -11, 95% CI (-19, -0.85), p = 0.03]. These associations were not significant in controls. INTERPRETATIONS: Axonal injury, specifically to the left anterior internal capsule is robustly associated with sleep disturbances in multiple TBI populations. Early assessment of axonal injury following mTBI could identify those at risk for persistent sleep disturbances following injury.
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TOPIC IMPORTANCE: Acute pulmonary embolism (PE) is a common disease encountered by pulmonologists, cardiologists, and critical care physicians throughout the world. For patients with high-risk acute PE (defined by systemic hypotension) and intermediate high-risk acute PE (defined by the absence of systemic hypotension, but the presence of numerous other concerning clinical and imaging features), intensive care often is necessary. Initial management strategies should focus on optimization of right ventricle (RV) function while decisions about advanced interventions are being considered. REVIEW FINDINGS: We reviewed the existing literature of various vasoactive agents, IV fluids and diuretics, and pulmonary vasodilators in both animal models and human trials of acute PE. We also reviewed the potential complications of endotracheal intubation and positive pressure ventilation in acute PE. Finally, we reviewed the data of venoarterial extracorporeal membrane oxygenation use in acute PE. The above interventions are discussed in the context of the underlying pathophysiologic features of acute RV failure in acute PE with corresponding illustrations. SUMMARY: Norepinephrine is a reasonable first choice for hemodynamic support with vasopressin as an adjunct. IV loop diuretics may be useful if evidence of RV dysfunction or volume overload is present. Fluids should be given only if concern exists for hypovolemia and absence of RV dilatation. Supplemental oxygen administration should be considered even without hypoxemia. Positive pressure ventilation should be avoided if possible. Venoarterial extracorporeal membrane oxygenation cannulation should be implemented early if ongoing deterioration occurs despite these interventions.
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Emerald ash borer (EAB), Agrilus planipennis Fairmaire (Coleoptera: Buprestidae), has caused extensive mortality of ash across North America. Biological control offers a potential long-term management option, allowing for long-term survival of ash. Careful monitoring of populations of biocontrol agents is necessary to understand their relative impacts. Understanding the emergence and flight phenology of these species allows for the optimization of monitoring schemes and improves our understanding of host-parasitoid interactions. We used yellow pan trapping data to assess the adult phenology of both EAB and its associated native and introduced parasitoids in 3 New York counties. We monitored 2 introduced larval biocontrol agents, Tetrastichus planipennisi Yang (Hymenoptera: Eulophidae) and Spathius galinae Belokobylskij & Strazanac (Braconidae), for 3-4 years post-release, as well as the native parasitoid Phasgonophora sulcata Westword (Chalcididae). Results indicate a single discrete emergence event for both EAB and P. sulcata in all monitored counties, which is consistent with previously reported results. Our results also suggest there are 4 generations per year of T. planipennisi and 3 generations of S. galinae in the monitored counties. We recorded an additional generation of T. planipennisi that had not previously been reported in New York, and both T. planipennisi and S. galinae appeared to emerge earlier than previously documented.
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Besouros , Fraxinus , Controle Biológico de Vetores , Vespas , Animais , Feminino , Masculino , Besouros/parasitologia , Besouros/crescimento & desenvolvimento , Fraxinus/parasitologia , Interações Hospedeiro-Parasita , Espécies Introduzidas , Larva/crescimento & desenvolvimento , Larva/parasitologia , New York , Estações do Ano , Vespas/fisiologia , Vespas/crescimento & desenvolvimentoRESUMO
Reported changes in electroencephalography (EEG)-derived spectral power after mild traumatic brain injury (mTBI) remains inconsistent across existing literature. However, this may be a result of previous analyses depending solely on observing spectral power within traditional canonical frequency bands rather than accounting for the aperiodic activity within the collected neural signal. Therefore, the aim of this study was to test for differences in rhythmic and arrhythmic time series across the brain, and in the cognitively relevant frontoparietal (FP) network, and observe whether those differences were associated with cognitive recovery post-mTBI. Resting-state electroencephalography (rs-EEG) was collected from 88 participants (56 mTBI and 32 age- and sex-matched healthy controls) within 14 days of injury for the mTBI participants. A battery of executive function (EF) tests was collected at the first session with follow-up metrics collected approximately 2 and 4 months after the initial visit. After spectral parameterization, a significant between-group difference in aperiodic-adjusted alpha center peak frequency within the FP network was observed, where a slowing of alpha peak frequency was found in the mTBI group in comparison to the healthy controls. This slowing of week 2 (collected within 2 weeks of injury) aperiodic-adjusted alpha center peak frequency within the FP network was associated with increased EF over time (evaluated using executive composite scores) post-mTBI. These findings suggest alpha center peak frequency within the FP network as a candidate prognostic marker of EF recovery and may inform clinical rehabilitative methods post-mTBI.
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BACKGROUND: Cardiac dysfunction from pulmonary vascular disease causes characteristic findings on cardiopulmonary exercise testing (CPET). We tested the accuracy of CPET for detecting inadequate stroke volume (SV) augmentation during exercise, a pivotal manifestation of cardiac limitation in patients with pulmonary vascular disease. METHODS: We reviewed patients with suspected pulmonary vascular disease in whom CPET and right heart catheterization (RHC) measurements were taken at rest and at anaerobic threshold (AT). We correlated CPET-determined O2·pulseAT/O2·pulserest with RHC-determined SVAT/SVrest. We evaluated the sensitivity and specificity of O2·pulseAT/O2·pulserest to detect SVAT/SVrest below the lower limit of normal (LLN). For comparison, we performed similar analyses comparing echocardiographically-measured peak tricuspid regurgitant velocity (TRVpeak) with SVAT/SVrest. RESULTS: From July 2018 through February 2023, 83 simultaneous RHC and CPET were performed. Thirty-six studies measured O2·pulse and SV at rest and at AT. O2·pulseAT/O2·pulserest correlated highly with SVAT/SVrest (r = 0.72, 95% CI 0.52, 0.85; p < 0.0001), whereas TRVpeak did not (r = -0.09, 95% CI -0.47, 0.33; p = 0.69). The AUROC to detect SVAT/SVrest below the LLN was significantly higher for O2·pulseAT/O2·pulserest (0.92, SE 0.04; p = 0.0002) than for TRVpeak (0.69, SE 0.10; p = 0.12). O2·pulseAT/O2·pulserest of less than 2.6 was 92.6% sensitive (95% CI 76.6%, 98.7%) and 66.7% specific (95% CI 35.2%, 87.9%) for deficient SVAT/SVrest. CONCLUSIONS: CPET detected deficient SV augmentation more accurately than echocardiography. CPET-determined O2·pulseAT/O2·pulserest may have a prominent role for noninvasive screening of patients at risk for pulmonary vascular disease, such as patients with persistent dyspnea after pulmonary embolism.
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Cardiopatias , Hipertensão Pulmonar , Humanos , Teste de Esforço , Pulmão , Circulação Pulmonar , Tolerância ao Exercício , Consumo de OxigênioRESUMO
PURPOSE: Peer-assisted learning (PAL) can occur informally as part of a medical programme and complements the formal curriculum. However, little is known about the mechanisms and processes of how informal peer-assisted learning (IPAL) is enacted. MATERIALS AND METHODS: This paper presents data from an ethnographic and semi-structured interview study with Year 1 and 2 undergraduate medical students at a UK university. RESULTS: Peers were observed assisting each other informally: a process that developed as part of the integrated, group-based approach to undergraduate medical education at a UK university. IPAL took place both within and outside of formal teaching sessions and included explanation/clarification of particular points, sharing resources, guiding pronunciation and demonstrating skills. Students placed a high value on IPAL and believed that it was beneficial. When IPAL broke down, this led to negative emotions that presented obstacles to learning, such as resentment. CONCLUSIONS: IPAL is an important part of academic support for medical students, and this work shows both its scope, extending from formal to informal teaching, and how it is enacted. This understanding can help educators situate IPAL within student education.
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Educação de Graduação em Medicina , Grupo Associado , Pesquisa Qualitativa , Estudantes de Medicina , Humanos , Estudantes de Medicina/psicologia , Educação de Graduação em Medicina/métodos , Reino Unido , Aprendizagem , Masculino , Feminino , Entrevistas como AssuntoRESUMO
Children with salt-wasting adrenal insufficiency are managed with glucocorticoid and mineralocorticoid replacement. Measurement of renin activity or concentration alongside blood electrolyte levels is used to monitor the adequacy of mineralocorticoid replacement. Our unit changed from using renin activity to renin concentration and carried out a service review to assess whether this influenced decision-making for fludrocortisone dosing. In total, 50 measurements of plasma renin activity and 50 of renin concentration were analysed on separate cohorts before and after the assay change, with values standardised to multiples of the upper limit of normal (MoU) to allow comparison between assays. We were more likely to increase the fludrocortisone dose for a raised renin concentration than a raised renin activity. The renin concentration MoU was more strongly related to plasma sodium (negatively) and 17α-hydroxyprogesterone (17α-OHP) (positively) than the renin activity MoU. Using a MoU cut-off of 1.5, a decision to increase the dose of fludrocortisone was more likely to be made when using the renin concentration assay compared with the activity assay. Using a cut-off of 40 nmol/L for 17α-OHP, a decision not to change the fludrocortisone dose when 17α-OHP was <40 was more likely when using the renin concentration assay. For both assays, a plasma sodium <140 mmol/L was more likely to lead to a fludrocortisone dose increase, and most likely for the renin concentration assay. Overall, the decision to adjust fludrocortisone dose in this cohort of children with adrenal insufficiency was better supported by the biochemical parameters when based on renin concentration results and clinical status.
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Previous research has indicated that cardiorespiratory fitness (CRF) is structurally and functionally neuroprotective in older adults. However, questions remain regarding the mechanistic role of CRF on cognitive and brain health. The purposes of this study were to investigate if higher pre-intervention CRF was associated with greater change in functional brain connectivity during an exercise intervention and to determine if the magnitude of change in connectivity was related to better post-intervention cognitive performance. The sample included low-active older adults (n = 139) who completed a 6-month exercise intervention and underwent neuropsychological testing, functional neuroimaging, and CRF testing before and after the intervention. A data-driven multi-voxel pattern analysis was performed on resting-state MRI scans to determine changes in whole-brain patterns of connectivity from pre- to post-intervention as a function of pre-intervention CRF. Results revealed a positive correlation between pre-intervention CRF and changes in functional connectivity in the precentral gyrus. Using the precentral gyrus as a seed, analyses indicated that CRF-related connectivity changes within the precentral gyrus were derived from increased correlation strength within clusters located in the Dorsal Attention Network (DAN) and increased anti-correlation strength within clusters located in the Default Mode Network (DMN). Exploratory analysis demonstrated that connectivity change between the precentral gyrus seed and DMN clusters were associated with improved post-intervention performance on perceptual speed tasks. These findings suggest that in a sample of low-active and mostly lower-fit older adults, even subtle individual differences in CRF may influence the relationship between functional connectivity and aspects of cognition following a 6-month exercise intervention.
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Cognição , Rede de Modo Padrão , Humanos , Idoso , Encéfalo , Imageamento por Ressonância Magnética , Terapia por Exercício , Mapeamento EncefálicoRESUMO
The relationship between midlife physical activity (PA), and cognition and brain health in later life is poorly understood with conflicting results from previous research. Investigating the contribution of midlife PA to later-life cognition and brain health in high-risk populations will propel the development of health guidance for those most in need. The current study examined the association between midlife PA engagement and later-life cognition, grey matter characteristics and resting-state functional connectivity in older individuals at high-risk for Alzheimer's disease. The association between midlife PA and later-life cognitive function was not significant but was moderated by later-life PA. Meanwhile, greater midlife moderate-to-vigorous PA was associated with greater grey matter surface area in the left middle frontal gyrus. Moreover, greater midlife total PA was associated with diminished functional connectivity between bilateral middle frontal gyri and middle cingulum, supplementary motor areas, and greater functional connectivity between bilateral hippocampi and right cerebellum, Crus II. These results indicate the potentially independent contribution of midlife PA to later-life brain health.
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Doença de Alzheimer , Encéfalo , Humanos , Idoso , Encéfalo/diagnóstico por imagem , Exercício Físico , Cognição , Doença de Alzheimer/etiologia , Doença de Alzheimer/prevenção & controle , Substância Cinzenta , Imageamento por Ressonância MagnéticaRESUMO
Objective: To determine the prevalence of secondary hyperparathyroidism in a cohort of pediatric patients receiving home parenteral nutrition. Methods: For a service review, a population-based cohort of 37 pediatric intestinal failure patients receiving long-term parenteral nutrition that underwent serial biochemical monitoring during a study period of approximately 4 years were examined. Following the production of an algorithm, a follow-up audit was carried out (n = 33) after approximately 6 months. Results: Of the 37 patients examined in the initial service review, 22 (59%) were found to have an elevated parathyroid hormone (PTH) during the period of monitoring and 5 (14%) had a persistently elevated PTH. In the follow-up audit following the implementation of an algorithm, the number with elevated PTH reduced to 6 (18%) and no patients had persistently high levels. Conclusion: Elevated PTH is a common biochemical finding in pediatric intestinal failure patients receiving home parenteral nutrition and its presence should alert clinicians to the need to optimize nutritional parameters such as calcium to phosphate molar ratio and vitamin D status; failure to do so may increase the future burden of metabolic bone disease in such patients. We propose that an algorithm may help in this endeavor.
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BACKGROUND: Chronic dyspnoea and exercise impairment are common after acute pulmonary embolism (PE) but are not defined and quantified sufficiently to serve as outcomes in clinical trials. The planned project will clinically validate a novel method to determine discrete, clinically meaningful diagnoses after acute PE. The method uses an algorithm entitled SEARCH, for symptom screen, exercise testing, arterial perfusion, resting echocardiography, confirmatory imaging and haemodynamic measurements. SEARCH is a stepwise algorithm that sorts patients by a hierarchical series of dichotomous tests into discreet categories of long-term outcomes after PE: asymptomatic, post-PE deconditioning, symptoms from other causes, chronic thromboembolism with ventilatory inefficiency, chronic thromboembolism with small stroke volume augmentation, chronic thromboembolic disease and chronic thromboembolic pulmonary hypertension. METHODS: The project will test the inter-rater reliability of the SEARCH algorithm by determining whether it will yield concordant post-PE diagnoses when six independent reviewers review the same diagnostic data on 150 patients evaluated at two time points after PE. The project will also determine whether the post-PE diagnoses are stable, according to the SEARCH algorithm, between the first evaluation and the subsequent one 6 months later. IMPLICATIONS: Validation of the SEARCH algorithm would offer clinicians a straightforward method to diagnose post-PE conditions that are rarely distinguished clinically. Their categorisation and definition will allow post-PE conditions to be used as endpoints in clinical trials of acute PE treatment. TRIAL REGISTRATION NUMBER: NCT05568927.
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Embolia Pulmonar , Tromboembolia , Humanos , Reprodutibilidade dos Testes , Fatores de Risco , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/diagnóstico por imagem , Estudos de Coortes , Doença Crônica , Doença Aguda , AlgoritmosRESUMO
Transient delivery of CRISPR-Cas9 ribonucleoproteins (RNPs) into the central nervous system (CNS) for therapeutic genome editing could avoid limitations of viral vector-based delivery including cargo capacity, immunogenicity, and cost. Here, we tested the ability of cell-penetrant Cas9 RNPs to edit the mouse striatum when introduced using a convection-enhanced delivery system. These transient Cas9 RNPs showed comparable editing of neurons and reduced adaptive immune responses relative to one formulation of Cas9 delivered using AAV serotype 9. The production of ultra-low endotoxin Cas9 protein manufactured at scale further improved innate immunity. We conclude that injection-based delivery of minimally immunogenic CRISPR genome editing RNPs into the CNS provides a valuable alternative to virus-mediated genome editing.