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Pulmonary and systemic congestion as a consequence of heart failure are clinically recognized as alarm signals for clinical outcome and mortality. Although signs and symptoms of congestion are well detectable in patients, monitoring of congestion in small animals with heart failure lacks adequate noninvasive methodology yet. Here, we developed a novel ultrasonography-based scoring system to assess pulmonary and systemic congestion in experimental heart failure, by using lung ultrasound (LUS) and imaging of the inferior vena cava (Cava), termed CavaLUS. CavaLUS was established and tested in a rat model of supracoronary aortic banding and a mouse model of myocardial infarction, providing high sensitivity and specificity while correlating to numerous parameters of cardiac performance and disease severity. CavaLUS, therefore, provides a novel comprehensive tool for experimental heart failure in small animals to noninvasively assess congestion.NEW & NOTEWORTHY As thorough, noninvasive assessment of congestion is not available in small animals, we developed and validated an ultrasonography-based research tool to evaluate pulmonary and central venous congestion in experimental heart failure models.
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Insuficiência Cardíaca , Hiperemia , Humanos , Camundongos , Animais , Ratos , Hiperemia/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Ultrassonografia/métodos , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/etiologia , Veia Cava Inferior/diagnóstico por imagemRESUMO
IMPORTANCE: Human cytomegalovirus (HCMV) infection is the leading cause of non-heritable birth defects worldwide. HCMV readily infects the early progenitor cell population of the developing brain, and we have found that infection leads to significantly downregulated expression of key neurodevelopmental transcripts. Currently, there are no approved therapies to prevent or mitigate the effects of congenital HCMV infection. Therefore, we used human-induced pluripotent stem cell-derived organoids and neural progenitor cells to elucidate the glycoproteins and receptors used in the viral entry process and whether antibody neutralization was sufficient to block viral entry and prevent disruption of neurodevelopmental gene expression. We found that blocking viral entry alone was insufficient to maintain the expression of key neurodevelopmental genes, but neutralization combined with neurotrophic factor treatment provided robust protection. Together, these studies offer novel insight into mechanisms of HCMV infection in neural tissues, which may aid future therapeutic development.
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Anticorpos Neutralizantes , Infecções por Citomegalovirus , Citomegalovirus , Expressão Gênica , Fatores de Crescimento Neural , Humanos , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Anticorpos Neutralizantes/uso terapêutico , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/metabolismo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Células-Tronco Pluripotentes Induzidas/citologia , Fatores de Crescimento Neural/farmacologia , Fatores de Crescimento Neural/uso terapêutico , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/virologia , Organoides/citologia , Organoides/metabolismo , Organoides/virologia , Receptores Virais/antagonistas & inibidores , Receptores Virais/metabolismo , Proteínas do Envelope Viral/antagonistas & inibidores , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/metabolismo , Internalização do Vírus/efeitos dos fármacosRESUMO
OBJECTIVES: Postoperative atrial fibrillation (POAF) is the most common complication after cardiac surgery and affects around 30% of patients. Variable guidelines from multiple organizations exist for the prevention of POAF after cardiac surgery. A survey of UK practice was conducted to define "usual care" for a platform trial of interventions to prevent POAF after cardiac surgery. To provide context for the survey, all current guidelines for the prevention and management of atrial fibrillation (AF) after cardiac surgery were reviewed. DESIGN: Online survey and literature review. SETTING: All 35 UK National Health Service Cardiac Surgery Centres participated in the survey. Guidelines from specialist societies and other guideline-making organizations from the UK, Europe, and North America were reviewed. PARTICIPANTS: Established a link network of researchers. MEASUREMENTS AND MAIN RESULTS: Five relevant guidelines were identified from the literature review. All guidelines recommend ß-blockade for prevention of AF after cardiac surgery. Treatment of AF is recommended using either rate or rhythm control. Cardioversion is recommended only for the hemodynamically unstable patient. Patients who remain in AF for over 48 hours should be considered for anticoagulation. Patients should be followed up within 60 days to review the need for antiarrhythmic and anticoagulant therapy. Of 35 centers, 31 (89%) responded. A total of 11 of 31 (35.5%) centers followed local guidance for prevention of POAF, 4 (13%) centers followed Society of Cardiovascular Anesthesiologists/European Association of Cardiothoracic Anaesthesia guidelines, 4 (13%) followed UK National Institute of Health and Care Excellence guidance and 4 followed "other" guidance. Of 31 centers, 8 (26%) followed no guidelines to prevent POAF; 28 of 31 (90%) centers did not risk-stratify their patients for POAF. Most centers (23/31, 74%) did not have a care package in place to prevent POAF, but 14 of 31 (45%) try in some way to prevent AF in patients presenting with sinus rhythm. The most common interventions to prevent POAF are ß-blocker use postoperatively (23/31, 74%), magnesium (20/31, 64.5%), and maintaining a serum K+ ≥4.5 mmol/L (26/31, 84%). CONCLUSIONS: Guidance to prevent AF after cardiac surgery centers around the use of ß-blockade. Although patients in the UK do not appear to be risk-assessed for POAF, the main interventions used to prevent it are similar: ß-blockade and maintenance of serum K+ and Mg2+ levels.
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OBJECTIVES: To investigate the effect of an audiovisual distraction system on the dose of remifentanil for perioperative sedation during transcatheter aortic valve implantation under monitored anesthesia care. DESIGN: Single-center prospective randomized nonblinded study. SETTING: Tertiary referral academic hospital. PARTICIPANTS: Ninety patients who underwent transfemoral transcatheter aortic valve implantation between July 2019 and July 2021. INTERVENTIONS: Patients were randomized to use either a novel audiovisual distraction system during the intervention (n = 45) or standard care without an audiovisual distraction system (n = 45). MEASUREMENTS AND MAIN RESULTS: Standardized questionnaires were given to each patient at admission and before and after the intervention to assess their levels of anxiety. Primary endpoints were the average and peak infusion rates of remifentanil. All patients were considered for the final analysis according to an intention-to-treat design. No relevant differences in pre- and postinterventional anxiety status were observed between the groups. Similarly, there were no significant differences in reported pain scores (p = 0.364). The average infusion rate (p = 0.028) and peak infusion rate (p = 0.025) of remifentanil were lower in the group with an audiovisual distraction system. CONCLUSIONS: Audiovisual distraction is a useful adjunct to reduce the dose of remifentanil under monitored anesthesia care during transcatheter aortic valve implantation. Larger studies are needed to evaluate potential positive effects on patient satisfaction, incidence of delirium, and possible economic benefits.
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Substituição da Valva Aórtica Transcateter , Humanos , Feminino , Estudos Prospectivos , Masculino , Substituição da Valva Aórtica Transcateter/métodos , Idoso , Idoso de 80 Anos ou mais , Remifentanil/administração & dosagem , Manejo da Dor/métodos , Recursos Audiovisuais , Anestesia/métodosRESUMO
OBJECTIVE: Acute kidney injury (AKI) requiring renal-replacement therapy (RRT) after heart transplantation (OHT) is common and impairs outcomes. This study aimed to identify independent donor and recipient risk factors associated with RRT after OHT. DESIGN: A retrospective data analysis. SETTING: Data were collected from clinical routines in a maximum-care university hospital. PARTICIPANTS: Patients who underwent OHT. INTERVENTIONS: The authors retrospectively analyzed data from 264 patients who underwent OHT between 2012 and 2021; 189 patients were eligible and included in the final analysis. MEASUREMENTS AND MAIN RESULTS: The mean age was 48.0 ± 12.3 years, and 71.4% of patients were male. Ninety (47.6%) patients were on long-term mechanical circulatory support (lt-MCS). Posttransplant AKI with RRT occurred in 123 (65.1%) patients. In a multivariate analysis, preoperative body mass index >25 kg/m² (odds ratio [OR] 4.74, p < 0.001), elevated preoperative creatinine levels (OR for each mg/dL increase 3.44, p = 0.004), administration of red blood cell units during transplantation procedure (OR 2.31, p = 0.041) and ischemia time (OR for each hour increase 1.77, p = 0.004) were associated with a higher incidence of RRT. The use of renin-angiotensin-aldosterone system blockers before transplantation was associated with a reduced risk of RRT (OR 0.36, p = 0.013). The risk of mortality was 6.9-fold higher in patients who required RRT (hazard ratio 6.9, 95% CI: 2.1-22.6 p = 0.001). Previous lt-MCS, as well as donor parameters, were not associated with RRT after OHT. CONCLUSIONS: The implementation of guideline-directed medical therapy, weight reduction, minimizing ischemia time (ie, organ perfusion systems, workflow optimization), and comprehensive patient blood management potentially influences renal function and outcomes after OHT.
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Injúria Renal Aguda , Transplante de Coração , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Feminino , Estudos Retrospectivos , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Fatores de Risco , Terapia de Substituição Renal , Transplante de Coração/efeitos adversos , Isquemia/etiologiaRESUMO
IMPORTANCE: Supplementing potassium in an effort to maintain high-normal serum concentrations is a widespread strategy used to prevent atrial fibrillation after cardiac surgery (AFACS), but is not evidence-based, carries risks, and is costly. OBJECTIVE: To determine whether a lower serum potassium concentration trigger for supplementation is noninferior to a high-normal trigger. DESIGN, SETTING, AND PARTICIPANTS: This open-label, noninferiority, randomized clinical trial was conducted at 23 cardiac surgical centers in the United Kingdom and Germany. Between October 20, 2020, and November 16, 2023, patients with no history of atrial dysrhythmias scheduled for isolated coronary artery bypass grafting (CABG) surgery were enrolled. The last study patient was discharged from the hospital on December 11, 2023. INTERVENTIONS: Patients were randomly assigned to a strategy of tight or relaxed potassium control (only supplementing if serum potassium concentration fell below 4.5 mEq/L or 3.6 mEq/L, respectively). Patients wore an ambulatory heart rhythm monitor, which was analyzed by a core laboratory masked to treatment assignment. MAIN OUTCOMES AND MEASURES: The prespecified primary end point was clinically detected and electrocardiographically confirmed new-onset AFACS in the first 120 hours after CABG surgery or until hospital discharge, whichever occurred first. All primary outcome events were validated by an event validation committee, which was masked to treatment assignment. Noninferiority of relaxed potassium control was defined as a risk difference for new-onset AFACS with associated upper bound of a 1-sided 97.5% CI of less than 10%. Secondary outcomes included other heart rhythm-related events, clinical outcomes, and cost related to the intervention. RESULTS: A total of 1690 patients (mean age, 65 years; 256 [15%] females) were randomized. The primary end point occurred in 26.2% of patients (n = 219) in the tight group and 27.8% of patients (n = 231) in the relaxed group, which is a risk difference of 1.7% (95% CI, -2.6% to 5.9%). There was no difference between the groups in the incidence of at least 1 AFACS episode detected by any means or by ambulatory heart rhythm monitor alone, non-AFACS dysrhythmias, in-patient mortality, or length of stay. Per-patient cost for purchasing and administering potassium was significantly lower in the relaxed group (mean difference, $111.89 [95% CI, $103.60-$120.19]; P <.001). CONCLUSIONS AND RELEVANCE: For AFACS prophylaxis, supplementation only when serum potassium concentration fell below 3.6 mEq/L was noninferior to the current widespread practice of supplementing potassium to maintain a serum potassium concentration greater than or equal to 4.5 mEq/L. The lower threshold of supplementation was not associated with any increase in dysrhythmias or adverse clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04053816.
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Human cytomegalovirus (HCMV) is a prevalent betaherpesvirus that is asymptomatic in healthy individuals but can cause serious disease in immunocompromised patients. HCMV is also the leading cause of virus-mediated birth defects. Many of these defects manifest within the central nervous system and include microcephaly, sensorineural hearing loss, and cognitive developmental delays. Nitric oxide is a critical effector molecule produced as a component of the innate immune response during infection. Congenitally infected fetal brains show regions of brain damage, including necrotic foci with infiltrating macrophages and microglia, cell types that produce nitric oxide during infection. Using a 3-dimensional cortical organoid model, we demonstrate that nitric oxide inhibits HCMV spread and simultaneously disrupts neural rosette structures, resulting in tissue disorganization. Nitric oxide also attenuates HCMV replication in 2-dimensional cultures of neural progenitor cells (NPCs), a prominent cell type in cortical organoids that differentiate into neurons and glial cells. The multipotency factor SOX2 was decreased during nitric oxide exposure, suggesting that early neural differentiation is affected. Nitric oxide also reduced maximal mitochondrial respiration in both uninfected and infected NPCs. We determined that this reduction likely influences neural differentiation, as neurons (Tuj1+ GFAP- Nestin-) and glial populations (Tuj1- GFAP+ Nestin-) were reduced following differentiation. Our studies indicate a prominent, immunopathogenic role of nitric oxide in promoting developmental defects within the brain despite its antiviral activity during congenital HCMV infection. IMPORTANCE Human cytomegalovirus (HCMV) is the leading cause of virus-mediated congenital birth defects. Congenitally infected infants can have a variety of symptoms manifesting within the central nervous system. The use of 3-dimensional (3-D) cortical organoids to model infection of the fetal brain has advanced the current understanding of development and allowed broader investigation of the mechanisms behind disease. However, the impact of the innate immune molecule nitric oxide during HCMV infection has not been explored in neural cells or cortical 3-D models. Here, we investigated the effect of nitric oxide on cortical development during HCMV infection. We demonstrate that nitric oxide plays an antiviral role during infection yet results in disorganized cortical tissue. Nitric oxide contributes to differentiation defects of neuron and glial cells from neural progenitor cells despite inhibiting viral replication. Our results indicate that immunopathogenic consequences of nitric oxide during congenital infection promote developmental defects that undermine its antiviral activity.
Assuntos
Diferenciação Celular , Infecções por Citomegalovirus , Células-Tronco Neurais , Óxido Nítrico , Antivirais , Córtex Cerebral/virologia , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/patologia , Humanos , Nestina , Células-Tronco Neurais/virologia , Óxido Nítrico/farmacologia , Organoides/virologiaRESUMO
OBJECTIVES: The objectives of this study were to evaluate the incidence and to identify risk factors for acute kidney injury (AKI) in neonates undergoing cardiopulmonary bypass (CPB) with a miniaturized bloodless primed extracorporeal circuit. DESIGN: A retrospective cohort study. SETTING: A single-center, tertiary academic hospital. PARTICIPANTS: Data of 462 patients were analyzed. INTERVENTIONS: With a retrospective analysis of neonates undergoing CPB with bloodless priming between May 2007 and August 2019, the incidence of AKI was determined according to the neonatal Kidney Disease: Improving Global Outcomes classification. Multivariate logistic regression analyses were performed to determine risk factors for AKI. MEASUREMENTS AND MAIN RESULTS: The incidence of AKI was 41.1% (190 of 462); 30.3% (n = 140) had mild stage 1, 6.5% (n = 30) reached stage 2, and 4.3% (n = 20) reached stage 3. Multivariate logistic regression showed that degree of hypothermia (p = 0.05), duration of CPB (p = 0.03), and lower baseline serum creatinine (p < 0.001) were associated independently with AKI. In the authors' patient population, patients without transfusion of donor-derived erythrocytes had a lower incidence of AKI (p = 0.003). AKI stages 2 and 3 were associated with longer duration of mechanical ventilation (p = 0.008) and increased length of stay in the intensive care unit (p = 0.03). CONCLUSIONS: With a miniaturized CPB circuit and bloodless priming, the AKI incidence was well within the range consistent with previously reported studies from other institutions.
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Injúria Renal Aguda , Ponte Cardiopulmonar , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Ponte Cardiopulmonar/efeitos adversos , Creatinina , Humanos , Recém-Nascido , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
OBJECTIVES: The aim was to evaluate changes in the coagulation profile of cyanotic neonates, to analyze the effects of cardiopulmonary bypass (CPB) with crystalloid priming on their coagulation status, and to determine factors predicting a requirement for hemostasis-derived transfusion. DESIGN: Retrospective cohort. SETTING: Single-center, tertiary academic hospital. PARTICIPANTS: In total, 100 consecutive neonates who underwent arterial switch surgery between December 2014 and June 2020. INTERVENTIONS: Rotational thromboelastometry (ROTEM) and coagulation parameters before surgery and before termination of CPB were evaluated. Transfusion of platelets, fresh frozen plasma, and fibrinogen, defined as hemostasis-derived transfusion (HD transfusion), were determined. Patients with and without HD transfusion were compared to identify predictors. MEASUREMENTS AND MAIN RESULTS: After CPB, fibrinogen was reduced by 24.5% (interquartile range [IQR] 8.9-32.1) to 201 mg/dL (IQR 172-249), resulting in a reduction of FIBTEM A10 by 20% (1.8-33.3) to 8 mm (6-11). The platelet count decreased by a median of 47.2% (25.6-61.3) to 162 × 103/µL (119-215). However, the median fibrinogen concentration and platelet count remained within normal range. Neonates with abnormal ROTEM results were more likely to receive HD transfusions. The HD transfusions were more likely with lower preoperative FIBTEM maximum clot firmness values (p = 0.031), lower hemoglobin concentrations at termination of CPB (p = 0.02), and longer CPB duration (p = 0.017). Perioperative hemostasis without any HD transfusion was achieved in 64 neonates. CONCLUSIONS: Guidance from ROTEM analyses facilitates hemostasis management after neonatal CPB. Circuit miniaturization with transfusion-free CPB is associated with acceptable changes in ROTEM in most patients, and allows sufficient hemostasis without any HD transfusions in most patients.
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Ponte Cardiopulmonar , Hemostáticos , Soluções Cristaloides , Fibrinogênio , Humanos , Recém-Nascido , Estudos Retrospectivos , Tromboelastografia/métodosRESUMO
Atrial fibrillation after cardiac surgery (AFACS) is a serious postoperative complication. There is significant research interest in this field but also relevant heterogeneity in reported AFACS definitions and approaches used for its identification. Few data exist on the extent of this variation in clinical studies. The authors reviewed the literature since 2001 and included manuscripts reporting outcomes of AFACS in adults. They excluded smaller studies and studies in which patients did not undergo a sternotomy. The documented protocol in each manuscript was analyzed according to six different categories to determine how AFACS was defined, which techniques were used to identify it, and the inclusion and/or exclusion criteria. They also noted when a category was not described in the documented protocol. The authors identified 302 studies, of which 92 were included. Sixty-two percent of studies were randomized controlled trials. There was significant heterogeneity in the manuscripts, including the exclusion of patients with preoperative AF, the definition and duration of AF needed to meet the primary endpoint, the type of screening approach (continuous, episodic, or opportunistic), the duration of monitoring during the study period in days, the diagnosis with predefined electrocardiogram criteria, and the requirement for independent confirmation by study investigators. Furthermore, the definitions of these criteria frequently were not described. Consistent reporting standards for AFACS research are needed to advance scientific progress in the field. The authors here propose pragmatic standards for trial design and reporting standards. These include adequate sample size estimation, a clear definition of the AFACS endpoints, and a protocol for AFACS detection.
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Fibrilação Atrial , Procedimentos Cirúrgicos Cardíacos , Adulto , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/etiologia , Fibrilação Atrial/prevenção & controle , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Eletrocardiografia , Humanos , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
This article reports on vowel clarity metrics based on spectrotemporal modulations of speech signals. Motivated by previous findings on the relevance of modulation-based metrics for speech intelligibility assessment and pathology classification, the current study used factor analysis to identify regions within a bi-dimensional modulation space, the magnitude power spectrum, as in Elliott and Theunissen [(2009). PLoS Comput. Biol. 5(3), e1000302] by relating them to a set of conventional acoustic metrics of vowel space area and vowel distinctiveness. Two indices based on the energy ratio between high and low modulation rates across temporal and spectral dimensions of the modulation space emerged from the analyses. These indices served as input for measurements of central tendency and classification analyses that aimed to identify vowel-related speech impairments in French native speakers with head and neck cancer (HNC) and Parkinson dysarthria (PD). Following the analysis, vowel-related speech impairment was identified in HNC speakers, but not in PD. These results were consistent with findings based on subjective evaluations of speech intelligibility. The findings reported are consistent with previous studies indicating that impaired speech is associated with attenuation in energy in higher spectrotemporal modulation bands.
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Disartria , Distúrbios da Fala , Humanos , Disartria/diagnóstico , Inteligibilidade da Fala , Acústica , IdiomaRESUMO
Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletions or mutations in survival motor neuron 1 (SMN1). The molecular mechanisms underlying motor neuron degeneration in SMA remain elusive, as global cellular dysfunction obscures the identification and characterization of disease-relevant pathways and potential therapeutic targets. Recent reports have implicated microRNA (miRNA) dysregulation as a potential contributor to the pathological mechanism in SMA. To characterize miRNAs that are differentially regulated in SMA, we profiled miRNA levels in SMA induced pluripotent stem cell (iPSC)-derived motor neurons. From this array, miR-23a downregulation was identified selectively in SMA motor neurons, consistent with previous reports where miR-23a functioned in neuroprotective and muscle atrophy-antagonizing roles. Reintroduction of miR-23a expression in SMA patient iPSC-derived motor neurons protected against degeneration, suggesting a potential miR-23a-specific disease-modifying effect. To assess this activity in vivo, miR-23a was expressed using a self-complementary adeno-associated virus serotype 9 (scAAV9) viral vector in the Smn2B/- SMA mouse model. scAAV9-miR-23a significantly reduced the pathology in SMA mice, including increased motor neuron size, reduced neuromuscular junction pathology, increased muscle fiber area, and extended survival. These experiments demonstrate that miR-23a is a novel protective modifier of SMA, warranting further characterization of miRNA dysfunction in SMA.
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Vetores Genéticos/administração & dosagem , MicroRNAs/genética , Atrofia Muscular Espinal/terapia , Animais , Dependovirus/genética , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , MicroRNAs/metabolismo , Neurônios Motores/metabolismo , Atrofia Muscular Espinal/genética , Índice de Gravidade de Doença , Proteína 2 de Sobrevivência do Neurônio Motor/genéticaRESUMO
BACKGROUND: PAD increases the risk of cardiovascular mortality and limb loss, and disparities in treatment and outcomes have been described. However, the association of patient-specific characteristics with variation in outcomes is less well known. METHODS: Patients with PAD from Duke University Health System (DUHS) between January 1, 2015 and March 31, 2016 were identified. PAD status was confirmed through ground truth adjudication and predictive modeling using diagnosis codes, procedure codes, and other administrative data. Symptom severity, lower extremity imaging, and ankle-brachial index (ABI) were manually abstracted from the electronic health record (EHR). Data was linked to Centers for Medicare and Medicaid Services data to provide longitudinal follow up. Primary outcome was major adverse vascular events (MAVE), a composite of all-cause mortality, myocardial infarction (MI), stroke, lower extremity revascularization and amputation. RESULTS: Of 1,768 patients with PAD, 31.6% were asymptomatic, 41.2% had intermittent claudication (IC), and 27.3% had chronic limb-threatening ischemia (CLTI). At 1 year, patients with CLTI had higher rates of MAVE compared with asymptomatic or IC patients. CLTI and Medicaid dual eligibility were independent predictors of mortality. CLTI and Black race were associated with amputation. CONCLUSIONS: Rates of MAVE were highest in patients with CLTI, but patients with IC or asymptomatic disease also had high rates of adverse events. Black and Medicaid dual-eligible patients were disproportionately present in the CLTI subgroup and were at higher risk of amputation and mortality, respectively. Future studies must focus on early identification of high-risk patient groups to improve outcomes in patients with PAD.
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Amputação Cirúrgica/estatística & dados numéricos , Disparidades em Assistência à Saúde/organização & administração , Extremidade Inferior , Infarto do Miocárdio/epidemiologia , Doença Arterial Periférica , Acidente Vascular Cerebral/epidemiologia , Procedimentos Cirúrgicos Vasculares , Doenças Assintomáticas/epidemiologia , População Negra/estatística & dados numéricos , Feminino , Necessidades e Demandas de Serviços de Saúde , Humanos , Extremidade Inferior/irrigação sanguínea , Extremidade Inferior/cirurgia , Masculino , Medicaid/estatística & dados numéricos , Pessoa de Meia-Idade , Mortalidade , Doença Arterial Periférica/complicações , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/epidemiologia , Doença Arterial Periférica/fisiopatologia , Fatores de Risco , Estados Unidos/epidemiologia , Procedimentos Cirúrgicos Vasculares/métodos , Procedimentos Cirúrgicos Vasculares/estatística & dados numéricosRESUMO
The herpesvirus human cytomegalovirus (HCMV) is a leading cause of congenital birth defects. Infection can result in infants born with a variety of symptoms, including hepatosplenomegaly, microcephaly, and developmental disabilities. Microcephaly is associated with disruptions in the neural progenitor cell (NPC) population. Here, we defined the impact of HCMV infection on neural tissue development and calcium regulation, a critical activity in neural development. Regulation of intracellular calcium involves purinergic receptors and voltage-gated calcium channels (VGCC). HCMV infection compromised the ability of both pathways in NPCs as well as fibroblasts to respond to stimulation. We observed significant drops in basal calcium levels in infected NPCs which were accompanied by loss in VGCC activity and purinergic receptor responses. However, uninfected cells in the population retained responsiveness. Addition of the HCMV inhibitor maribavir reduced viral spread but failed to restore activity in infected cells. To study neural development, we infected three-dimensional cortical organoids with HCMV. Infection spread to a subset of cells over time and disrupted organoid structure, with alterations in developmental and neural layering markers. Organoid-derived infected neurons and astrocytes were unable to respond to stimulation whereas uninfected cells retained nearly normal responses. Maribavir partially restored structural features, including neural rosette formation, and dampened the impact of infection on neural cellular function. Using a tissue model system, we have demonstrated that HCMV alters cortical neural layering and disrupts calcium regulation in infected cells.IMPORTANCE Human cytomegalovirus (HCMV) replicates in several cell types throughout the body, causing disease in the absence of an effective immune response. Studies on HCMV require cultured human cells and tissues due to species specificity. In these studies, we investigated the impact of infection on developing three-dimensional cortical organoid tissues, with specific emphasis on cell-type-dependent calcium signaling. Calcium signaling is an essential function during neural differentiation and cortical development. We observed that HCMV infects and spreads within these tissues, ultimately disrupting cortical structure. Infected cells exhibited depleted calcium stores and loss of ATP- and KCl-stimulated calcium signaling while uninfected cells in the population maintained nearly normal responses. Some protection was provided by the viral inhibitor maribavir. Overall, our studies provide new insights into the impact of HCMV on cortical tissue development and function.
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Sinalização do Cálcio , Infecções por Citomegalovirus/metabolismo , Citomegalovirus/patogenicidade , Células-Tronco Neurais/virologia , Organoides/virologia , Benzimidazóis/farmacologia , Diferenciação Celular , Linhagem Celular , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Técnicas de Cultura de Órgãos , Organoides/citologia , Organoides/metabolismo , Receptores Purinérgicos/metabolismo , Ribonucleosídeos/farmacologia , Replicação Viral/efeitos dos fármacos , Canais de Sódio Disparados por Voltagem/metabolismoRESUMO
This study investigates whether real-time auditory feedback has a direct behavioural or perceptual effect on novices performing a golf putting task with limited visual feedback. Due to its significant role in the success of a putt, club head speed was selected as the parameter for sonification. Different combinations of synthesisers, timbral modulations, scales, and mappings were developed to examine whether particular sound classes influenced performance. When compared to trials with static pink noise, we found that, despite their vision being limited at impact, participants were able to use different types of sonification to significantly reduce variability in their distance from the target and ball location estimation. These results suggest that concurrent sound can play an important role in reducing variability in behavioural performance and related perceptual estimations. In addition, we found that, when compared to trials with static pink noise, participants were able to use sonification to significantly lower their average impact velocity. In the discussion, we offer some trends and observations relative to the different sound synthesis parameters and their effects on behavioural and perceptual performance.