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Heart structure and function change with age, and the notion that the heart may age faster for some individuals than for others has driven interest in estimating cardiac age acceleration. However, current approaches have limited feature richness (heart measurements; radiomics) or capture extraneous data and therefore lack cardiac specificity (deep learning [DL] on unmasked chest MRI). These technical limitations have been a barrier to efforts to understand genetic contributions to age acceleration. We hypothesized that a video-based DL model provided with heart-masked MRI data would capture a rich yet cardiac-specific representation of cardiac aging. In 61,691 UK Biobank participants, we excluded noncardiac pixels from cardiac MRI and trained a video-based DL model to predict age from one cardiac cycle in the 4-chamber view. We then computed cardiac age acceleration as the bias-corrected prediction of heart age minus the calendar age. Predicted heart age explained 71.1% of variance in calendar age, with a mean absolute error of 3.3 years. Cardiac age acceleration was linked to unfavorable cardiac geometry and systolic and diastolic dysfunction. We also observed links between cardiac age acceleration and diet, decreased physical activity, increased alcohol and tobacco use, and altered levels of 239 serum proteins, as well as adverse brain MRI characteristics. We found cardiac age acceleration to be heritable (h2g 26.6%); a genome-wide association study identified 8 loci related to linked to cardiomyopathy (near TTN, TNS1, LSM3, PALLD, DSP, PLEC, ANKRD1 and MYO18B) and an additional 16 loci (near MECOM, NPR3, KLHL3, HDGFL1, CDKN1A, ELN, SLC25A37, PI15, AP3M1, HMGA2, ADPRHL1, PGAP3, WNT9B, UHRF1 and DOK5). Of the discovered loci, 21 were not previously associated with cardiac age acceleration. Mendelian randomization revealed that lower genetically mediated levels of 6 circulating proteins (MSRA most strongly), as well as greater levels of 5 proteins (LXN most strongly) were associated with cardiac age acceleration, as were greater blood pressure and Lp(a). A polygenic score for cardiac age acceleration predicted earlier onset of arrhythmia, heart failure, myocardial infarction, and mortality. These findings provide a thematic understanding of cardiac age acceleration and suggest that heart- and vascular-specific factors are key to cardiac age acceleration, predominating over a more global aging program.
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The 2021 Arctic Monitoring Assessment Program (AMAP)'s Human Health Assessment report presents a summary of the presence of contaminants in human populations across the circumpolar Arctic and provides an update to the previous assessment released in 2015. The primary objective of this paper is to summarise some of these findings by describing the current levels of metals across the Arctic, including key regional and temporal trends based on available national data and literature, and highlight knowledge gaps. Many Arctic populations continue to have elevated levels of these contaminants, and the highest levels of mercury (Hg) were observed in populations from Greenland, Faroe Islands, and Nunavik (Canada). Still, concentrations of several metals are declining in Arctic populations in regions where time trends data exist, although the declines are not consistent across all regions. The 2021 AMAP human health assessment report and this paper provide an extensive summary of levels of metals and trace elements in adults, pregnant women, and children across the Arctic.
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Metales , Humanos , Regiones Árticas , Femenino , Niño , Metales/análisis , Adulto , Embarazo , Monitoreo del Ambiente , Contaminantes Ambientales/análisis , Exposición a Riesgos Ambientales/análisis , Exposición a Riesgos Ambientales/efectos adversos , Mercurio/análisis , MasculinoRESUMEN
BACKGROUND: Continuous monitoring for atrial fibrillation (AF) using photoplethysmography (PPG) from smartwatches or other wearables is challenging due to periods of poor signal quality during motion or suboptimal wearing. As a result, many consumer wearables sample infrequently and only analyze when the user is at rest, which limits the ability to perform continuous monitoring or to quantify AF. OBJECTIVES: This study aimed to compare 2 methods of continuous monitoring for AF in free-living patients: a well-validated signal processing (SP) heuristic and a convolutional deep neural network (DNN) trained on raw signal. METHODS: We collected 4 weeks of continuous PPG and electrocardiography signals in 204 free-living patients. Both SP and DNN models were developed and validated both on holdout patients and an external validation set. RESULTS: The results show that the SP model demonstrated receiver-operating characteristic area under the curve (AUC) of 0.972 (sensitivity 99.6%, specificity: 94.4%), which was similar to the DNN receiver-operating characteristic AUC of 0.973 (sensitivity 92.2, specificity: 95.5%); however, the DNN classified significantly more data (95% vs 62%), revealing its superior tolerance of tracings prone to motion artifact. Explainability analysis revealed that the DNN automatically suppresses motion artifacts, evaluates irregularity, and learns natural AF interbeat variability. The DNN performed better and analyzed more signal in the external validation cohort using a different population and PPG sensor (AUC, 0.994; 97% analyzed vs AUC, 0.989; 88% analyzed). CONCLUSIONS: DNNs perform at least as well as SP models, classify more data, and thus may be better for continuous PPG monitoring.
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Fibrilación Atrial , Aprendizaje Profundo , Humanos , Fibrilación Atrial/diagnóstico , Fotopletismografía/métodos , Heurística , Monitoreo FisiológicoRESUMEN
BACKGROUND: Artificial intelligence (AI) applied to 12-lead electrocardiographs (ECGs) can detect hypertrophic cardiomyopathy (HCM). OBJECTIVES: The purpose of this study was to determine if AI-enhanced ECG (AI-ECG) can track longitudinal therapeutic response and changes in cardiac structure, function, or hemodynamics in obstructive HCM during mavacamten treatment. METHODS: We applied 2 independently developed AI-ECG algorithms (University of California-San Francisco and Mayo Clinic) to serial ECGs (n = 216) from the phase 2 PIONEER-OLE trial of mavacamten for symptomatic obstructive HCM (n = 13 patients, mean age 57.8 years, 69.2% male). Control ECGs from 2,600 age- and sex-matched individuals without HCM were obtained. AI-ECG output was correlated longitudinally to echocardiographic and laboratory metrics of mavacamten treatment response. RESULTS: In the validation cohorts, both algorithms exhibited similar performance for HCM diagnosis, and exhibited mean HCM score decreases during mavacamten treatment: patient-level score reduction ranged from approximately 0.80 to 0.45 for Mayo and 0.70 to 0.35 for USCF algorithms; 11 of 13 patients demonstrated absolute score reduction from start to end of follow-up for both algorithms. HCM scores were significantly associated with other HCM-relevant parameters, including left ventricular outflow tract gradient at rest, postexercise, and with Valsalva, and NT-proBNP level, independent of age and sex (all P < 0.01). For both algorithms, the strongest longitudinal correlation was between AI-ECG HCM score and left ventricular outflow tract gradient postexercise (slope estimate: University of California-San Francisco 0.70 [95% CI: 0.45-0.96], P < 0.0001; Mayo 0.40 [95% CI: 0.11-0.68], P = 0.007). CONCLUSIONS: AI-ECG analysis longitudinally correlated with changes in echocardiographic and laboratory markers during mavacamten treatment in obstructive HCM. These results provide early evidence for a potential paradigm for monitoring HCM therapeutic response.
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BACKGROUND: Mitral valve prolapse (MVP) is a common valvulopathy, with a subset developing sudden cardiac death or cardiac arrest. Complex ventricular ectopy (ComVE) is a marker of arrhythmic risk associated with myocardial fibrosis and increased mortality in MVP. OBJECTIVES: The authors sought to evaluate whether electrocardiogram (ECG)-based machine learning can identify MVP at risk for ComVE, death and/or myocardial fibrosis on cardiac magnetic resonance (CMR) imaging. METHODS: A deep convolutional neural network (CNN) was trained to detect ComVE using 6,916 12-lead ECGs from 569 MVP patients from the University of California-San Francisco between 2012 and 2020. A separate CNN was trained to detect late gadolinium enhancement (LGE) using 1,369 ECGs from 87 MVP patients with contrast CMR. RESULTS: The prevalence of ComVE was 28% (160/569). The area under the receiver operating characteristic curve (AUC) of the CNN to detect ComVE was 0.80 (95% CI: 0.77-0.83) and remained high after excluding patients with moderate-severe mitral regurgitation [0.80 (95% CI: 0.77-0.83)] or bileaflet MVP [0.81 (95% CI: 0.76-0.85)]. AUC to detect all-cause mortality was 0.82 (95% CI: 0.77-0.87). ECG segments relevant to ComVE prediction were related to ventricular depolarization/repolarization (early-mid ST-segment and QRS from V1, V3, and III). LGE in the papillary muscles or basal inferolateral wall was present in 24% patients with available CMR; AUC for detection of LGE was 0.75 (95% CI: 0.68-0.82). CONCLUSIONS: CNN-analyzed 12-lead ECGs can detect MVP at risk for ventricular arrhythmias, death and/or fibrosis and can identify novel ECG correlates of arrhythmic risk. ECG-based CNNs may help select those MVP patients requiring closer follow-up and/or a CMR.
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Coronary angiography is the primary procedure for diagnosis and management decisions in coronary artery disease (CAD), but ad-hoc visual assessment of angiograms has high variability. Here we report a fully automated approach to interpret angiographic coronary artery stenosis from standard coronary angiograms. Using 13,843 angiographic studies from 11,972 adult patients at University of California, San Francisco (UCSF), between April 1, 2008 and December 31, 2019, we train neural networks to accomplish four sequential necessary tasks for automatic coronary artery stenosis localization and estimation. Algorithms are internally validated against criterion-standard labels for each task in hold-out test datasets. Algorithms are then externally validated in real-world angiograms from the University of Ottawa Heart Institute (UOHI) and also retrained using quantitative coronary angiography (QCA) data from the Montreal Heart Institute (MHI) core lab. The CathAI system achieves state-of-the-art performance across all tasks on unselected, real-world angiograms. Positive predictive value, sensitivity and F1 score are all ≥90% to identify projection angle and ≥93% for left/right coronary artery angiogram detection. To predict obstructive CAD stenosis (≥70%), CathAI exhibits an AUC of 0.862 (95% CI: 0.843-0.880). In UOHI external validation, CathAI achieves AUC 0.869 (95% CI: 0.830-0.907) to predict obstructive CAD. In the MHI QCA dataset, CathAI achieves an AUC of 0.775 (95%. CI: 0.594-0.955) after retraining. In conclusion, multiple purpose-built neural networks can function in sequence to accomplish automated analysis of real-world angiograms, which could increase standardization and reproducibility in angiographic coronary stenosis assessment.
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Background: It remains difficult to definitively distinguish supraventricular tachycardia (SVT) mechanisms using a 12-lead electrocardiogram (ECG) alone. Machine learning may identify visually imperceptible changes on 12-lead ECGs and may improve ability to determine SVT mechanisms. Objective: We sought to develop a convolutional neural network (CNN) that identifies the SVT mechanism according to the gold standard of SVT ablation and to compare CNN performance against experienced electrophysiologists among patients with atrioventricular nodal re-entrant tachycardia (AVNRT), atrioventricular reciprocating tachycardia (AVRT), and atrial tachycardia (AT). Methods: All patients with 12-lead surface ECG during sinus rhythm and SVT and had successful SVT ablation from 2013 to 2020 were included. A CNN was trained using data from 1505 surface ECGs that were split into 1287 training and 218 test ECG datasets. We compared the CNN performance against independent adjudication by 2 experienced cardiac electrophysiologists on the test dataset. Results: Our dataset comprised 1505 ECGs (368 AVNRT, 304 AVRT, 95 AT, and 738 sinus rhythm) from 725 patients. The CNN areas under the receiver-operating characteristic curve for AVNRT, AVRT, and AT were 0.909, 0.867, and 0.817, respectively. When fixing the specificity of the CNN to the electrophysiologist adjudicators' specificity, the CNN identified all SVT classes with higher sensitivity: (1) AVNRT (91.7% vs 65.9%), (2) AVRT (78.4% vs 63.6%), and (3) AT (61.5% vs 50.0%). Conclusion: A CNN can be trained to differentiate SVT mechanisms from surface 12-lead ECGs with high overall performance, achieving similar performance to experienced electrophysiologists at fixed specificities.
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Importance: Understanding left ventricular ejection fraction (LVEF) during coronary angiography can assist in disease management. Objective: To develop an automated approach to predict LVEF from left coronary angiograms. Design, Setting, and Participants: This was a cross-sectional study with external validation using patient data from December 12, 2012, to December 31, 2019, from the University of California, San Francisco (UCSF). Data were randomly split into training, development, and test data sets. External validation data were obtained from the University of Ottawa Heart Institute. Included in the analysis were all patients 18 years or older who received a coronary angiogram and transthoracic echocardiogram (TTE) within 3 months before or 1 month after the angiogram. Exposure: A video-based deep neural network (DNN) called CathEF was used to discriminate (binary) reduced LVEF (≤40%) and to predict (continuous) LVEF percentage from standard angiogram videos of the left coronary artery. Guided class-discriminative gradient class activation mapping (GradCAM) was applied to visualize pixels in angiograms that contributed most to DNN LVEF prediction. Results: A total of 4042 adult angiograms with corresponding TTE LVEF from 3679 UCSF patients were included in the analysis. Mean (SD) patient age was 64.3 (13.3) years, and 2212 patients were male (65%). In the UCSF test data set (n = 813), the video-based DNN discriminated (binary) reduced LVEF (≤40%) with an area under the receiver operating characteristic curve (AUROC) of 0.911 (95% CI, 0.887-0.934); diagnostic odds ratio for reduced LVEF was 22.7 (95% CI, 14.0-37.0). DNN-predicted continuous LVEF had a mean absolute error (MAE) of 8.5% (95% CI, 8.1%-9.0%) compared with TTE LVEF. Although DNN-predicted continuous LVEF differed 5% or less compared with TTE LVEF in 38.0% (309 of 813) of test data set studies, differences greater than 15% were observed in 15.2% (124 of 813). In external validation (n = 776), video-based DNN discriminated (binary) reduced LVEF (≤40%) with an AUROC of 0.906 (95% CI, 0.881-0.931), and DNN-predicted continuous LVEF had an MAE of 7.0% (95% CI, 6.6%-7.4%). Video-based DNN tended to overestimate low LVEFs and underestimate high LVEFs. Video-based DNN performance was consistent across sex, body mass index, low estimated glomerular filtration rate (≤45), presence of acute coronary syndromes, obstructive coronary artery disease, and left ventricular hypertrophy. Conclusion and relevance: This cross-sectional study represents an early demonstration of estimating LVEF from standard angiogram videos of the left coronary artery using video-based DNNs. Further research can improve accuracy and reduce the variability of DNNs to maximize their clinical utility.
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Disfunción Ventricular Izquierda , Función Ventricular Izquierda , Adulto , Humanos , Masculino , Persona de Mediana Edad , Femenino , Función Ventricular Izquierda/fisiología , Angiografía Coronaria , Volumen Sistólico/fisiología , Inteligencia Artificial , Disfunción Ventricular Izquierda/diagnóstico por imagen , Estudios Transversales , AlgoritmosRESUMEN
Chest pain is a common clinical complaint for which myocardial injury is the primary concern and is associated with significant morbidity and mortality. To aid providers' decision-making, we aimed to analyze the electrocardiogram (ECG) using a deep convolutional neural network (CNN) to predict serum troponin I (TnI) from ECGs. We developed a CNN using 64,728 ECGs from 32,479 patients who underwent ECG within 2 h prior to a serum TnI laboratory result at the University of California, San Francisco (UCSF). In our primary analysis, we classified patients into groups of TnI < 0.02 or ≥ 0.02 µg/L using 12-lead ECGs. This was repeated with an alternative threshold of 1.0 µg/L and with single-lead ECG inputs. We also performed multiclass prediction for a set of serum troponin ranges. Finally, we tested the CNN in a cohort of patients selected for coronary angiography, including 3038 ECGs from 672 patients. Cohort patients were 49.0% female, 42.8% white, and 59.3% (19,283) never had a positive TnI value (≥ 0.02 µg/L). CNNs accurately predicted elevated TnI, both at a threshold of 0.02 µg/L (AUC = 0.783, 95% CI 0.780-0.786) and at a threshold of 1.0 µg/L (AUC = 0.802, 0.795-0.809). Models using single-lead ECG data achieved significantly lower accuracy, with AUCs ranging from 0.740 to 0.773 with variation by lead. Accuracy of the multi-class model was lower for intermediate TnI value-ranges. Our models performed similarly on the cohort of patients who underwent coronary angiography. Biomarker-defined myocardial injury can be predicted by CNNs from 12-lead and single-lead ECGs.
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Aprendizaje Profundo , Lesiones Cardíacas , Humanos , Femenino , Masculino , Troponina I , Área Bajo la Curva , Biomarcadores , Electrocardiografía , Lesiones Cardíacas/diagnósticoRESUMEN
BACKGROUND: Pulmonary hypertension (PH) is life-threatening, and often diagnosed late in its course. We aimed to evaluate if a deep learning approach using electrocardiogram (ECG) data alone can detect PH and clinically important subtypes. We asked: does an automated deep learning approach to ECG interpretation detect PH and its clinically important subtypes? METHODS AND RESULTS: Adults with right heart catheterization or an echocardiogram within 90 days of an ECG at the University of California, San Francisco (2012-2019) were retrospectively identified as PH or non-PH. A deep convolutional neural network was trained on patients' 12-lead ECG voltage data. Patients were divided into training, development, and test sets in a ratio of 7:1:2. Overall, 5016 PH and 19,454 patients without PH were used in the study. The mean age at the time of ECG was 62.29 ± 17.58 years and 49.88% were female. The mean interval between ECG and right heart catheterization or echocardiogram was 3.66 and 2.23 days for patients with PH and patients without PH, respectively. In the test dataset, the model achieved an area under the receiver operating characteristic curve, sensitivity, and specificity, respectively of 0.89, 0.79, and 0.84 to detect PH; 0.91, 0.83, and 0.84 to detect precapillary PH; 0.88, 0.81, and 0.81 to detect pulmonary arterial hypertension, and 0.80, 0.73, and 0.76 to detect group 3 PH. We additionally applied the trained model on ECGs from participants in the test dataset that were obtained from up to 2 years before diagnosis of PH; the area under the receiver operating characteristic curve was 0.79 or greater. CONCLUSIONS: A deep learning ECG algorithm can detect PH and PH subtypes around the time of diagnosis and can detect PH using ECGs that were done up to 2 years before right heart catheterization/echocardiogram diagnosis. This approach has the potential to decrease diagnostic delays in PH.
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Aprendizaje Profundo , Insuficiencia Cardíaca , Hipertensión Pulmonar , Adulto , Humanos , Femenino , Masculino , Hipertensión Pulmonar/diagnóstico , Estudios Retrospectivos , Electrocardiografía/métodosRESUMEN
Recent advances in machine learning (ML) have made it possible to analyze high-dimensional and complex data-such as free text, images, waveforms, videos, and sound-in an automated manner by successfully learning complex associations within these data. Cardiovascular medicine is particularly well poised to take advantage of these ML advances, due to the widespread digitization of medical data and the large number of diagnostic tests used to evaluate cardiovascular disease. Various ML approaches have successfully been applied to cardiovascular tests and diseases to automate interpretation, accurately perform measurements, and, in some cases, predict novel diagnoses from less invasive tests, effectively expanding the utility of more widely accessible diagnostic tests. Here, we present examples of some impactful advances in cardiovascular medicine using ML across a variety of modalities, with a focus on deep learning applications.
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Enfermedades Cardiovasculares , Aprendizaje Automático , Humanos , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/terapiaRESUMEN
BACKGROUND: Valvular heart disease is an important contributor to cardiovascular morbidity and mortality and remains underdiagnosed. Deep learning analysis of electrocardiography (ECG) may be useful in detecting aortic stenosis (AS), aortic regurgitation (AR), and mitral regurgitation (MR). OBJECTIVES: This study aimed to develop ECG deep learning algorithms to identify moderate or severe AS, AR, and MR alone and in combination. METHODS: A total of 77,163 patients undergoing ECG within 1 year before echocardiography from 2005-2021 were identified and split into train (n = 43,165), validation (n = 12,950), and test sets (n = 21,048; 7.8% with any of AS, AR, or MR). Model performance was assessed using area under the receiver-operating characteristic (AU-ROC) and precision-recall curves. Outside validation was conducted on an independent data set. Test accuracy was modeled using different disease prevalence levels to simulate screening efficacy using the deep learning model. RESULTS: The deep learning algorithm model accuracy was as follows: AS (AU-ROC: 0.88), AR (AU-ROC: 0.77), MR (AU-ROC: 0.83), and any of AS, AR, or MR (AU-ROC: 0.84; sensitivity 78%, specificity 73%) with similar accuracy in external validation. In screening program modeling, test characteristics were dependent on underlying prevalence and selected sensitivity levels. At a prevalence of 7.8%, the positive and negative predictive values were 20% and 97.6%, respectively. CONCLUSIONS: Deep learning analysis of the ECG can accurately detect AS, AR, and MR in this multicenter cohort and may serve as the basis for the development of a valvular heart disease screening program.
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Insuficiencia de la Válvula Aórtica , Estenosis de la Válvula Aórtica , Aprendizaje Profundo , Enfermedades de las Válvulas Cardíacas , Insuficiencia de la Válvula Mitral , Insuficiencia de la Válvula Aórtica/diagnóstico , Estenosis de la Válvula Aórtica/diagnóstico , Electrocardiografía , Enfermedades de las Válvulas Cardíacas/diagnóstico , Enfermedades de las Válvulas Cardíacas/epidemiología , Humanos , Insuficiencia de la Válvula Mitral/diagnóstico , Insuficiencia de la Válvula Mitral/epidemiologíaRESUMEN
Polyfluoroalkyl substances and perfluoroalkyl substances (PFAS) are a family of anthropogenic chemicals that are used in food packaging, waterproof clothing, and firefighting foams for their water and oil resistant properties. Though levels of some PFAS appear to be decreasing in Canada's south, environmental levels have been increasing in the Arctic due to long-range transport. However, the implications of this on human exposures in sub-Arctic and Arctic populations in Canada have yet to be established. To address this data gap, human biomonitoring research was completed in Old Crow, Yukon, and the Dehcho region, Northwest Territories. Blood samples were collected from adults residing in seven northern First Nations and were analyzed by liquid chromatography mass spectrometry. A total of nine PFAS were quantified: perfluorooctanoic acid (PFOA), perfluorooctane sulphonic acid (PFOS), perfluorohexane sulphonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUdA), perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), and perfluorobutane sulphonic acid (PFBS). In the Dehcho (n = 124), five PFAS had a detection rate greater than 50% including PFOS, PFOA, PFHxS, PFNA, and PFDA. In addition to these PFAS, PFUdA was also detected in at least half of the samples collected in Old Crow (n = 54). Generally, male participants had higher concentrations of PFAS compared to female participants, and PFAS concentrations tended to increase with age. For most PFAS, Old Crow and Dehcho levels were similar or lower to those measured in the general Canadian population (as measured through the Canadian Health Measures Survey or CHMS) and other First Nations populations in Canada (as measured through the First Nations Biomonitoring Initiative or FNBI). The key exception to this was for PFNA which, relative to the CHMS (0.51 µg/L), was approximately 1.8 times higher in Old Crow (0.94 µg/L) and 2.8 times higher in Dehcho (1.42 µg/L) than observed in the general Canadian population. This project provides baseline PFAS levels for participating communities, improving understanding of human exposures to PFAS in Canada. Future research should investigate site-specific PFNA exposure sources and monitor temporal trends in these regions.
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Ácidos Alcanesulfónicos , Contaminantes Ambientales , Fluorocarburos , Monitoreo Biológico , Biomarcadores , Canadá , Femenino , Fluorocarburos/análisis , Humanos , MasculinoRESUMEN
Whereas humans and other adult mammals lack the ability to regain locomotor function after spinal cord injury, zebrafish are able to recover swimming behavior even after complete spinal cord transection. We have previously shown that zebrafish larvae regenerate lost spinal cord neurons within 9 days post-injury (dpi), but it is unknown whether these neurons are physiologically active or integrate into functional circuitry. Here we show that genetically defined premotor interneurons are regenerated in injured spinal cord segments as functional recovery begins. Further, we show that these newly-generated interneurons receive excitatory input and fire synchronously with motor output by 9 dpi. Taken together, our data indicate that regenerative neurogenesis in the zebrafish spinal cord produces interneurons with the ability to integrate into existing locomotor circuitry.
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Interneuronas/fisiología , Locomoción/fisiología , Red Nerviosa/fisiología , Regeneración Nerviosa/fisiología , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Animales , Animales Modificados Genéticamente , Plasticidad Neuronal/fisiología , Traumatismos de la Médula Espinal/genética , Pez CebraRESUMEN
Several large-scale human biomonitoring projects have been conducted in Canada, including the Canadian Health Measures Survey (CHMS) and the First Nations Biomonitoring Initiative (FNBI). However, neither of these studies included participants living in the Yukon. To address this data gap, a human biomonitoring project was implemented in Old Crow, a fly-in Gwich'in community in the northern Yukon. The results of this project provide baseline levels of contaminant and nutrient biomarkers from Old Crow in 2019. Samples of hair, blood, and/or urine were collected from approximately 44% of community residents (77 of 175 adults). These samples were analyzed for contaminants (including heavy metals and persistent organic pollutants (POPs)), and nutrients (including trace elements and omega-3 fatty acids). Levels of these analytes were compared to health-based guidance values, when available, and results from other human biomonitoring projects in Canada. Levels of lead (GM 0.64 µg/g creatinine in urine/24 µg/L blood), cadmium (GM 0.32 µg/g creatinine in urine/0.85 µg/L blood), and mercury (GM < LOD in urine/0.76 µg/L blood/0.31 µg/g hair) were below select health-based guidance values for more than 95% of participants. However, compared to the general Canadian population, elevated levels of some contaminants, including lead (approximately 2× higher), cobalt (approximately 1.5× higher), manganese (approximately 1.3× higher), and hexachlorobenzene (approximately 1.5× higher) were observed. In contrast, levels of other POPs, including insecticides such as dichlorodiphenyltrichloroethane (DDT), its metabolite, dichlorodiphenyldichloroethylene (DDE), and polychlorinated biphenyls (PCBs) were similar to, or lower than, those reported in the general Canadian population. This study can be used along with future biomonitoring programs to evaluate the effectiveness of international initiatives designed to reduce the contaminant burden in the Arctic, including the Stockholm Convention and the Minamata Convention. Regionally, this project complements environmental monitoring being conducted in the region, informing local and regional traditional food consumption advisories.
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Cuervos , Contaminantes Ambientales , Adulto , Animales , Regiones Árticas , Monitoreo Biológico , Biomarcadores , Canadá , Monitoreo del Ambiente , Contaminantes Ambientales/análisis , Humanos , El YukónRESUMEN
Dopamine (DA)-producing neurons are critically involved in the production of motor behaviors in multiple circuits that are conserved from basal vertebrates to mammals. Although there is increasing evidence that DA neurons in the hypothalamus play a locomotor role, their precise contributions to behavior and the circuit mechanisms by which they are achieved remain unclear. Here, we demonstrate that tyrosine-hydroxylase-2-expressing (th2+) DA neurons in the zebrafish hypothalamus fire phasic bursts of activity to acutely promote swimming and modulate audiomotor behaviors on fast timescales. Their anatomy and physiology reveal two distinct functional DA modules within the hypothalamus. The first comprises an interconnected set of cerebrospinal-fluid-contacting DA nuclei surrounding the 3rd ventricle, which lack distal projections outside of the hypothalamus and influence locomotion through unknown means. The second includes neurons in the preoptic nucleus, which send long-range projections to targets throughout the brain, including the mid- and hindbrain, where they activate premotor circuits involved in swimming and sensorimotor integration. These data suggest a broad regulation of motor behavior by DA neurons within multiple hypothalamic nuclei and elucidate a novel functional mechanism for the preoptic DA neurons in the initiation of movement.
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Tronco Encefálico/fisiología , Neuronas Dopaminérgicas/metabolismo , Área Preóptica/fisiología , Natación/fisiología , Animales , Tronco Encefálico/citología , Potenciales Evocados Motores/fisiología , Genes Reporteros/genética , Proteínas Fluorescentes Verdes/genética , Microscopía Intravital/métodos , Masculino , Microscopía de Fluorescencia por Excitación Multifotónica , Modelos Animales , Red Nerviosa/fisiología , Optogenética , Área Preóptica/citología , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/metabolismo , Grabación en Video , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Animals have evolved specialized neural circuits to defend themselves from pain- and injury-causing stimuli. Using a combination of optical, behavioral and genetic approaches in the larval zebrafish, we describe a novel role for hypothalamic oxytocin (OXT) neurons in the processing of noxious stimuli. In vivo imaging revealed that a large and distributed fraction of zebrafish OXT neurons respond strongly to noxious inputs, including the activation of damage-sensing TRPA1 receptors. OXT population activity reflects the sensorimotor transformation of the noxious stimulus, with some neurons encoding sensory information and others correlating more strongly with large-angle swims. Notably, OXT neuron activation is sufficient to generate this defensive behavior via the recruitment of brainstem premotor targets, whereas ablation of OXT neurons or loss of the peptide attenuates behavioral responses to TRPA1 activation. These data highlight a crucial role for OXT neurons in the generation of appropriate defensive responses to noxious input.
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Tronco Encefálico/fisiología , Vías Nerviosas/fisiología , Nocicepción/fisiología , Nociceptores/fisiología , Animales , Tronco Encefálico/citología , Hipotálamo/citología , Hipotálamo/fisiología , Vías Nerviosas/citología , Nociceptores/citología , Oxitocina , Pez CebraRESUMEN
Down syndrome cell adhesion molecules (DSCAMs) are broadly expressed in nervous systems and play conserved roles in programmed cell death, neuronal migration, axon guidance, neurite branching and spacing, and synaptic targeting. However, DSCAMs appear to have distinct functions in different vertebrate animals, and little is known about their functions outside the retina. We leveraged the genetic tractability and optical accessibility of larval zebrafish to investigate the expression and function of a DSCAM family member, dscamb. Using targeted genome editing to create transgenic reporters and loss-of-function mutant alleles, we discovered that dscamb is expressed broadly throughout the brain, spinal cord, and peripheral nervous system, but is not required for overall structural organization of the brain. Despite the absence of obvious anatomical defects, homozygous dscamb mutants were deficient in their ability to ingest food and rarely survived to adulthood. Thus, we have discovered a novel function for dscamb in feeding behavior. The mutant and transgenic lines generated in these studies will provide valuable tools for identifying the molecular and cellular bases of these behaviors.