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A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1-4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5-8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6-12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.
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Encéfalo , Alucinógenos , Red Nerviosa , Psilocibina , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Encéfalo/citología , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Mapeo Encefálico , Red en Modo Predeterminado/citología , Red en Modo Predeterminado/diagnóstico por imagen , Red en Modo Predeterminado/efectos de los fármacos , Red en Modo Predeterminado/fisiología , Alucinógenos/farmacología , Alucinógenos/administración & dosificación , Voluntarios Sanos , Hipocampo/citología , Hipocampo/diagnóstico por imagen , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Imagen por Resonancia Magnética , Metilfenidato/farmacología , Metilfenidato/administración & dosificación , Red Nerviosa/citología , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiología , Psilocibina/farmacología , Psilocibina/administración & dosificación , Percepción Espacial/efectos de los fármacos , Percepción del Tiempo/efectos de los fármacos , EgoRESUMEN
Motor cortex (M1) has been thought to form a continuous somatotopic homunculus extending down the precentral gyrus from foot to face representations1,2, despite evidence for concentric functional zones3 and maps of complex actions4. Here, using precision functional magnetic resonance imaging (fMRI) methods, we find that the classic homunculus is interrupted by regions with distinct connectivity, structure and function, alternating with effector-specific (foot, hand and mouth) areas. These inter-effector regions exhibit decreased cortical thickness and strong functional connectivity to each other, as well as to the cingulo-opercular network (CON), critical for action5 and physiological control6, arousal7, errors8 and pain9. This interdigitation of action control-linked and motor effector regions was verified in the three largest fMRI datasets. Macaque and pediatric (newborn, infant and child) precision fMRI suggested cross-species homologues and developmental precursors of the inter-effector system. A battery of motor and action fMRI tasks documented concentric effector somatotopies, separated by the CON-linked inter-effector regions. The inter-effectors lacked movement specificity and co-activated during action planning (coordination of hands and feet) and axial body movement (such as of the abdomen or eyebrows). These results, together with previous studies demonstrating stimulation-evoked complex actions4 and connectivity to internal organs10 such as the adrenal medulla, suggest that M1 is punctuated by a system for whole-body action planning, the somato-cognitive action network (SCAN). In M1, two parallel systems intertwine, forming an integrate-isolate pattern: effector-specific regions (foot, hand and mouth) for isolating fine motor control and the SCAN for integrating goals, physiology and body movement.
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Mapeo Encefálico , Cognición , Corteza Motora , Mapeo Encefálico/métodos , Mano/fisiología , Imagen por Resonancia Magnética , Corteza Motora/anatomía & histología , Corteza Motora/fisiología , Humanos , Recién Nacido , Lactante , Niño , Animales , Macaca/anatomía & histología , Macaca/fisiología , Pie/fisiología , Boca/fisiología , Conjuntos de Datos como AsuntoRESUMEN
Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
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Diabetes Mellitus Tipo 2 , Proinsulina , Humanos , Proinsulina/genética , Proinsulina/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Estudio de Asociación del Genoma Completo/métodos , Insulina/genética , Insulina/metabolismo , Glucosa , Factores de Transcripción/genética , Proteínas de Homeodominio/genéticaRESUMEN
ABSTRACT: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.
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Moléculas de Adhesión Celular , Factor VIII , Quininógenos , Lectinas Tipo C , Receptores de Superficie Celular , Factor de von Willebrand , Humanos , Factor de von Willebrand/genética , Factor de von Willebrand/metabolismo , Factor VIII/genética , Factor VIII/metabolismo , Polimorfismo de Nucleótido Simple , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Análisis de la Aleatorización Mendeliana , Estudio de Asociación del Genoma Completo , Trombosis/genética , Trombosis/sangre , Estudios de Asociación Genética , Masculino , Células Endoteliales/metabolismo , FemeninoRESUMEN
Major depressive disorder (MDD) is widely hypothesized to result from disordered communication across brain-wide networks. Yet, prior resting-state-functional MRI (rs-fMRI) studies of MDD have studied zero-lag temporal synchrony (functional connectivity) in brain activity absent directional information. We utilize the recent discovery of stereotyped brain-wide directed signaling patterns in humans to investigate the relationship between directed rs-fMRI activity, MDD, and treatment response to FDA-approved neurostimulation paradigm termed Stanford neuromodulation therapy (SNT). We find that SNT over the left dorsolateral prefrontal cortex (DLPFC) induces directed signaling shifts in the left DLPFC and bilateral anterior cingulate cortex (ACC). Directional signaling shifts in the ACC, but not the DLPFC, predict improvement in depression symptoms, and moreover, pretreatment ACC signaling predicts both depression severity and the likelihood of SNT treatment response. Taken together, our findings suggest that ACC-based directed signaling patterns in rs-fMRI are a potential biomarker of MDD.
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Trastorno Depresivo Mayor , Humanos , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/terapia , Depresión , Imagen por Resonancia Magnética , Encéfalo/diagnóstico por imagen , Giro del Cíngulo/diagnóstico por imagen , Corteza Prefrontal/diagnóstico por imagenRESUMEN
The distribution of brain aerobic glycolysis (AG) in normal young adults correlates spatially with amyloid-beta (Aß) deposition in individuals with symptomatic and preclinical Alzheimer disease (AD). Brain AG decreases with age, but the functional significance of this decrease with regard to the development of AD symptomatology is poorly understood. Using PET measurements of regional blood flow, oxygen consumption, and glucose utilization-from which we derive AG-we find that cognitive impairment is strongly associated with loss of the typical youthful pattern of AG. In contrast, amyloid positivity without cognitive impairment was associated with preservation of youthful brain AG, which was even higher than that seen in cognitively unimpaired, amyloid negative adults. Similar findings were not seen for blood flow nor oxygen consumption. Finally, in cognitively unimpaired adults, white matter hyperintensity burden was found to be specifically associated with decreased youthful brain AG. Our results suggest that AG may have a role in the resilience and/or response to early stages of amyloid pathology and that age-related white matter disease may impair this process.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Adulto Joven , Humanos , Enfermedad de Alzheimer/patología , Tomografía de Emisión de Positrones , Encéfalo/metabolismo , Péptidos beta-Amiloides/metabolismo , Disfunción Cognitiva/patología , Amiloide/metabolismo , Proteínas Amiloidogénicas , GlucólisisRESUMEN
The Utstein Out-of-Hospital Cardiac Arrest Resuscitation Registry Template, introduced in 1991 and updated in 2004 and 2015, standardizes data collection to enable research, evaluation, and comparisons of systems of care. The impetus for the current update stemmed from significant advances in the field and insights from registry development and regional comparisons. This 2024 update involved representatives of the International Liaison Committee on Resuscitation and used a modified Delphi process. Every 2015 Utstein data element was reviewed for relevance, priority (core or supplemental), and improvement. New variables were proposed and refined. All changes were voted on for inclusion. The 2015 domains-system, dispatch, patient, process, and outcomes-were retained. Further clarity is provided for the definitions of out-of-hospital cardiac arrest attended resuscitation and attempted resuscitation. Changes reflect advancements in dispatch, early response systems, and resuscitation care, as well as the importance of prehospital outcomes. Time intervals such as emergency medical service response time now emphasize precise reporting of the times used. New flowcharts aid the reporting of system effectiveness for patients with an attempted resuscitation and system efficacy for the Utstein comparator group. Recognizing the varying capacities of emergency systems globally, the writing group provided a minimal dataset for settings with developing emergency medical systems. Supplementary variables are considered useful for research purposes. These revisions aim to elevate data collection and reporting transparency by registries and researchers and to advance international comparisons and collaborations. The overarching objective remains the improvement of outcomes for patients with out-of-hospital cardiac arrest.
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BACKGROUND: Severe hypertriglyceridemia (HTG) has predominantly multifactorial causes (MCS). Yet a small subset of patients have the monogenetic form (FCS). It remains a challenge to distinguish patients clinically, since decompensated MCS might mimic FCS´s severity. Aim of the current study was to determine clinical criteria that could sufficiently distinguish both forms as well as to apply the FCS score proposed by Moulin and colleagues. METHODS: We retrospectively studied 72 patients who presented with severe HTG in our clinic during a time span of seven years and received genetic testing. We classified genetic variants (ACMG-criteria), followed by genetic categorization into MCS or FCS. Clinical data were gathered from the medical records and the FCS score was calculated for each patient. RESULTS: Molecular genetic screening revealed eight FCS patients and 64 MCS patients. Altogether, we found 13 pathogenic variants of which four have not been described before. The FCS patients showed a significantly higher median triglyceride level compared to the MCS. The FCS score yielded a sensitivity of 75% and a specificity of 93.7% in our cohort, and significantly differentiated between the FCS and MCS group (p<0.001). CONCLUSIONS: In our cohort we identified several variables that significantly differentiated FCS from MCS. The FCS score performed similar to the original study by Moulin, thereby further validating the discriminatory power of the FCS score in an independent cohort.
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BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player in lipid metabolism, as it degrades low-density lipoprotein (LDL) receptors from hepatic cell membranes. So far, only variants of the PCSK9 gene locus were found to be associated with PCSK9 levels. Here we aimed to identify novel genetic loci that regulate PCSK9 levels and how they relate to other lipid traits. Additionally, we investigated to what extend the causal effect of PCSK9 on coronary artery disease (CAD) is mediated by low-density lipoprotein-cholesterol (LDL-C). METHODS AND RESULTS: We performed a genome-wide association study meta-analysis of PCSK9 levels in up to 12 721 samples of European ancestry. The estimated heritability was 10.3%, which increased to 12.6% using only samples from patients without statin treatment. We successfully replicated the known PCSK9 hit consisting of three independent signals. Interestingly, in a study of 300 African Americans, we confirmed the locus with a different PCSK9 variant. Beyond PCSK9, our meta-analysis detected three novel loci with genome-wide significance. Co-localization analysis with cis-eQTLs and lipid traits revealed biologically plausible candidate genes at two of them: APOB and TM6SF2. In a bivariate Mendelian Randomization analysis, we detected a strong effect of PCSK9 on LDL-C, but not vice versa. LDL-C mediated 63% of the total causal effect of PCSK9 on CAD. CONCLUSION: Our study identified novel genetic loci with plausible candidate genes affecting PCSK9 levels. Ethnic heterogeneity was observed at the PCSK9 locus itself. Although the causal effect of PCSK9 on CAD is mainly mediated by LDL-C, an independent direct effect also occurs.
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Enfermedad de la Arteria Coronaria , Proproteína Convertasa 9 , Apolipoproteínas B/genética , LDL-Colesterol/genética , Enfermedad de la Arteria Coronaria/genética , Estudio de Asociación del Genoma Completo , Humanos , Proteínas de la Membrana/genética , Proproteína Convertasa 9/genética , Receptores de LDL/genéticaRESUMEN
Mitochondria have a complex communication network with the surrounding cell and can alter nuclear DNA methylation (DNAm). Variation in the mitochondrial DNA (mtDNA) has also been linked to differential DNAm. Genome-wide association studies have identified numerous DNAm quantitative trait loci, but these studies have not examined the mitochondrial genome. Herein, we quantified nuclear DNAm from blood and conducted a mitochondrial genome-wide association study of DNAm, with an additional emphasis on sex- and prediabetes-specific heterogeneity. We used the Young Finns Study (n = 926) with sequenced mtDNA genotypes as a discovery sample and sought replication in the Ludwigshafen Risk and Cardiovascular Health study (n = 2317). We identified numerous significant associations in the discovery phase (P < 10-9), but they were not replicated when accounting for multiple testing. In total, 27 associations were nominally replicated with a P < 0.05. The replication analysis presented no evidence of sex- or prediabetes-specific heterogeneity. The 27 associations were included in a joint meta-analysis of the two cohorts, and 19 DNAm sites associated with mtDNA variants, while four other sites showed haplogroup associations. An expression quantitative trait methylation analysis was performed for the identified DNAm sites, pinpointing two statistically significant associations. This study provides evidence of a mitochondrial genetic control of nuclear DNAm with little evidence found for sex- and prediabetes-specific effects. The lack of a comparable mtDNA data set for replication is a limitation in our study and further studies are needed to validate our results.
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Genoma Mitocondrial , Estado Prediabético , Metilación de ADN/genética , ADN Mitocondrial/genética , Epigénesis Genética , Genoma Mitocondrial/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Estado Prediabético/genética , Sitios de Carácter Cuantitativo/genéticaRESUMEN
Despite major advancements in cardiovascular medicine, sudden cardiac death (SCD) continues to be an enormous medical and societal challenge, claiming millions of lives every year. Efforts to prevent SCD are hampered by imperfect risk prediction and inadequate solutions to specifically address arrhythmogenesis. Although resuscitation strategies have witnessed substantial evolution, there is a need to strengthen the organisation of community interventions and emergency medical systems across varied locations and health-care structures. With all the technological and medical advances of the 21st century, the fact that survival from sudden cardiac arrest (SCA) remains lower than 10% in most parts of the world is unacceptable. Recognising this urgent need, the Lancet Commission on SCD was constituted, bringing together 30 international experts in varied disciplines. Consistent progress in tackling SCD will require a completely revamped approach to SCD prevention, with wide-sweeping policy changes that will empower the development of both governmental and community-based programmes to maximise survival from SCA, and to comprehensively attend to survivors and decedents' families after the event. International collaborative efforts that maximally leverage and connect the expertise of various research organisations will need to be prioritised to properly address identified gaps. The Commission places substantial emphasis on the need to develop a multidisciplinary strategy that encompasses all aspects of SCD prevention and treatment. The Commission provides a critical assessment of the current scientific efforts in the field, and puts forth key recommendations to challenge, activate, and intensify efforts by both the scientific and global community with new directions, research, and innovation to reduce the burden of SCD worldwide.
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Fármacos Cardiovasculares , Muerte Súbita Cardíaca , Humanos , Muerte Súbita Cardíaca/prevención & control , Gobierno , Instituciones de Salud , Estudios InterdisciplinariosRESUMEN
HIV-1 (HIV) infects CD4+ T cells, the gradual depletion of which can lead to AIDS in the absence of antiretroviral therapy (ART). Some cells, however, survive HIV infection and persist as part of the latently infected reservoir that causes recurrent viremia after ART cessation. Improved understanding of the mechanisms of HIV-mediated cell death could lead to a way to clear the latent reservoir. Death induced by survival gene elimination (DISE), an RNA interference (RNAi)-based mechanism, kills cells through short RNAs (sRNAs) with toxic 6-mer seeds (positions 2 to 7 of sRNA). These toxic seeds target the 3' untranslated region (UTR) of mRNAs, decreasing the expression of hundreds of genes critical for cell survival. In most cells under normal conditions, highly expressed cell-encoded nontoxic microRNAs (miRNAs) block access of toxic sRNAs to the RNA-induced silencing complex (RISC) that mediates RNAi, promoting cell survival. HIV has been shown to inhibit the biogenesis of host miRNAs in multiple ways. We now report that HIV infection of cells deficient in miRNA expression or function results in enhanced RISC loading of an HIV-encoded miRNA HIV-miR-TAR-3p, which can kill cells by DISE through a noncanonical (positions 3 to 8) 6-mer seed. In addition, cellular RISC-bound sRNAs shift to lower seed viability. This also occurs after latent HIV provirus reactivation in J-Lat cells, suggesting independence of permissiveness of cells to viral infection. More precise targeting of the balance between protective and cytotoxic sRNAs could provide new avenues to explore novel cell death mechanisms that could be used to kill latent HIV. IMPORTANCE Several mechanisms by which initial HIV infection is cytotoxic to infected cells have been reported and involve various forms of cell death. Characterizing the mechanisms underlying the long-term survival of certain T cells that become persistent provirus reservoirs is critical to developing a cure. We recently discovered death induced by survival gene elimination (DISE), an RNAi-based mechanism of cell death whereby toxic short RNAs (sRNAs) containing 6-mer seed sequences (exerting 6-mer seed toxicity) targeting essential survival genes are loaded into RNA-induced silencing complex (RISC) complexes, resulting in inescapable cell death. We now report that HIV infection in cells with low miRNA expression causes a shift of mostly cellular RISC-bound sRNAs to more toxic seeds. This could prime cells to DISE and is further enhanced by the viral microRNA (miRNA) HIV-miR-TAR-3p, which carries a toxic noncanonical 6-mer seed. Our data provide multiple new avenues to explore novel cell death mechanisms that could be used to kill latent HIV.
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Infecciones por VIH , VIH-1 , MicroARNs , Humanos , VIH-1/fisiología , Latencia del Virus/genética , MicroARNs/genética , MicroARNs/metabolismo , Complejo Silenciador Inducido por ARN/metabolismoRESUMEN
OBJECTIVES: The objective of this systematic review was to offer a comprehensive overview and explore the associated outcomes from imaging referral guidelines on various key stakeholders, such as patients and radiologists. MATERIALS AND METHODS: An electronic database search was conducted in Medline, Embase and Web of Science to retrieve citations published between 2013 and 2023. The search was constructed using medical subject headings and keywords. Only full-text articles and reviews written in English were included. The quality of the included papers was assessed using the mixed methods appraisal tool. A narrative synthesis was undertaken for the selected articles. RESULTS: The search yielded 4384 records. Following the abstract, full-text screening, and removal of duplication, 31 studies of varying levels of quality were included in the final analysis. Imaging referral guidelines from the American College of Radiology were most commonly used. Clinical decision support systems were the most evaluated mode of intervention, either integrated or standalone. Interventions showed reduced patient radiation doses and waiting times for imaging. There was a general reduction in radiology workload and utilisation of diagnostic imaging. Low-value imaging utilisation decreased with an increase in the appropriateness of imaging referrals and ratings and cost savings. Clinical effectiveness was maintained during the intervention period without notable adverse consequences. CONCLUSION: Using evidence-based imaging referral guidelines improves the quality of healthcare and outcomes while reducing healthcare costs. Imaging referral guidelines are one essential component of improving the value of radiology in the healthcare system. CLINICAL RELEVANCE STATEMENT: There is a need for broader dissemination of imaging referral guidelines to healthcare providers globally in tandem with the harmonisation of the application of these guidelines to improve the overall value of radiology within the healthcare system. KEY POINTS: The application of imaging referral guidelines has an impact and effect on patients, radiologists, and health policymakers. The adoption of imaging referral guidelines in clinical practice can impact healthcare costs and improve healthcare quality and outcomes. Implementing imaging referral guidelines contributes to the attainment of value-based radiology.
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BACKGROUND: Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total. METHODS: Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes. RESULTS: Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (GCKR, BAZ1B, and HP-TXNL4B) and 1 with PS levels (ORM1-ORM2). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (FCGRT), 1 with PC (GOLM2), and 1 with PS (MYL7). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of GCKR, SNX17, and HP genes in antithrombin regulation. CONCLUSIONS: The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.
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Proteína C , Proteína S , Proteína C/genética , Proteína S/genética , Estudio de Asociación del Genoma Completo , Antitrombinas , Transcriptoma , Anticoagulantes , Antitrombina III/genética , Polimorfismo de Nucleótido SimpleRESUMEN
INTRODUCTION: Restraint use in the emergency department (ED) can pose significant risks to patients and health care workers. We evaluate the effectiveness of Code De-escalation- a standardized, team-based approach for management and assessment of threatening behaviors- in reducing physical restraint use and workplace violence in a community ED. METHODS: A retrospective observational study of a pathway on physical restraint use among patients placed on an involuntary psychiatric hold in a community ED. This pathway includes a built-in step for the team members to systematically assess perceptions of threats from the patient behavior and threats perceived by the patient. Our primary outcome was the change in the rate of physical restraint use among patients on an involuntary psychiatric hold. Our secondary outcome was the change in the rate of workplace violence events involving all ED encounters. We evaluated our outcomes by comparing all encounters in a ten-month period before and after implementation, and compared our results to rates at neighboring community hospitals within the same hospital network. RESULTS: Pre intervention there were 434 ED encounters involving a psychiatric hold, post-intervention there were 535. We observed a significant decrease in physical restraint use, from 7.4% to 3.7% (ARR 0.028 [95% CI 0.002-0.055], p < 0.05). This was not seen at the control sites. CONCLUSIONS: A standardized de-escalation algorithm can be effective in helping ED's decrease their use of physical restraints in management of psychiatric patients experiencing agitation.
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Restricción Física , Violencia Laboral , Humanos , Restricción Física/métodos , Hospitales Comunitarios , Servicio de Urgencia en Hospital , AgresiónRESUMEN
Slow waves (SWs) are globally propagating, low-frequency (0.5- to 4-Hz) oscillations that are prominent during sleep and anesthesia. SWs are essential to neural plasticity and memory. However, much remains unknown about the mechanisms coordinating SW propagation at the macroscale. To assess SWs in the context of macroscale networks, we recorded cortical activity in awake and ketamine/xylazine-anesthetized mice using widefield optical imaging with fluorescent calcium indicator GCaMP6f. We demonstrate that unilateral somatosensory stimulation evokes bilateral waves that travel across the cortex with state-dependent trajectories. Under anesthesia, we observe that rhythmic stimuli elicit globally resonant, front-to-back propagating SWs. Finally, photothrombotic lesions of S1 show that somatosensory-evoked global SWs depend on bilateral recruitment of homotopic primary somatosensory cortices. Specifically, unilateral lesions of S1 disrupt somatosensory-evoked global SW initiation from either hemisphere, while spontaneous SWs are largely unchanged. These results show that evoked SWs may be triggered by bilateral activation of specific, homotopically connected cortical networks.
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Ondas Encefálicas/fisiología , Estimulación Eléctrica , Potenciales Evocados Somatosensoriales , Sueño/fisiología , Corteza Somatosensorial/fisiología , Vigilia/fisiología , Animales , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
The hippocampus is critically important for a diverse range of cognitive processes, such as episodic memory, prospective memory, affective processing, and spatial navigation. Using individual-specific precision functional mapping of resting-state functional MRI data, we found the anterior hippocampus (head and body) to be preferentially functionally connected to the default mode network (DMN), as expected. The hippocampal tail, however, was strongly preferentially functionally connected to the parietal memory network (PMN), which supports goal-oriented cognition and stimulus recognition. This anterior-posterior dichotomy of resting-state functional connectivity was well-matched by differences in task deactivations and anatomical segmentations of the hippocampus. Task deactivations were localized to the hippocampal head and body (DMN), relatively sparing the tail (PMN). The functional dichotomization of the hippocampus into anterior DMN-connected and posterior PMN-connected parcels suggests parallel but distinct circuits between the hippocampus and medial parietal cortex for self- versus goal-oriented processing.
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Mapeo Encefálico , Hipocampo/fisiología , Red Nerviosa/fisiología , Lóbulo Parietal/fisiología , Adulto , Bases de Datos Factuales , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Memoria Episódica , Vías Nerviosas , Análisis y Desempeño de Tareas , Adulto JovenRESUMEN
Whole-brain resting-state functional MRI (rs-fMRI) during 2 wk of upper-limb casting revealed that disused motor regions became more strongly connected to the cingulo-opercular network (CON), an executive control network that includes regions of the dorsal anterior cingulate cortex (dACC) and insula. Disuse-driven increases in functional connectivity (FC) were specific to the CON and somatomotor networks and did not involve any other networks, such as the salience, frontoparietal, or default mode networks. Censoring and modeling analyses showed that FC increases during casting were mediated by large, spontaneous activity pulses that appeared in the disused motor regions and CON control regions. During limb constraint, disused motor circuits appear to enter a standby mode characterized by spontaneous activity pulses and strengthened connectivity to CON executive control regions.
Asunto(s)
Giro del Cíngulo/fisiología , Plasticidad Neuronal/fisiología , Descanso/fisiología , Adulto , Mapeo Encefálico , Función Ejecutiva/fisiología , Femenino , Giro del Cíngulo/citología , Giro del Cíngulo/diagnóstico por imagen , Voluntarios Sanos , Humanos , Imagen por Resonancia Magnética , Masculino , Red Nerviosa/fisiologíaRESUMEN
AIMS: Apolipoprotein C-II (ApoC-II) is thought to activate lipoprotein lipase (LPL) and is therefore a possible target for treating hypertriglyceridemia. Its relationship with cardiovascular risk has not been investigated in large-scale epidemiologic studies, particularly allowing for apolipoprotein C-III (ApoC-III), an LPL antagonist. Furthermore, the exact mechanism of ApoC-II-mediated LPL activation is unclear. METHODS AND RESULTS: ApoC-II was measured in 3141 LURIC participants of which 590 died from cardiovascular diseases during a median (inter-quartile range) follow-up of 9.9 (8.7-10.7) years. Apolipoprotein C-II-mediated activation of the glycosylphosphatidylinositol high-density lipoprotein binding protein 1 (GPIHBP1)-LPL complex was studied using enzymatic activity assays with fluorometric lipase and very low-density lipoprotein (VLDL) substrates. The mean ApoC-II concentration was 4.5 (2.4) mg/dL. The relationship of ApoC-II quintiles with cardiovascular mortality exhibited a trend toward an inverse J-shape, with the highest risk in the first (lowest) quintile and lowest risk in the middle quintile. Compared with the first quintile, all other quintiles were associated with decreased cardiovascular mortality after multivariate adjustments including ApoC-III as a covariate (all P < 0.05). In experiments using fluorometric substrate-based lipase assays, there was a bell-shaped relationship for the effect of ApoC-II on GPIHBP1-LPL activity when exogenous ApoC-II was added. In ApoC-II-containing VLDL substrate-based lipase assays, GPIHBP1-LPL enzymatic activity was almost completely blocked by a neutralizing anti-ApoC-II antibody. CONCLUSION: The present epidemiologic data suggest that increasing low circulating ApoC-II levels may reduce cardiovascular risk. This conclusion is supported by the observation that optimal ApoC-II concentrations are required for maximal GPIHBP1-LPL enzymatic activity.