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Axo-axonic cells (AACs), also called chandelier cells (ChCs) in the cerebral cortex, are the most distinctive type of GABAergic interneurons described in the neocortex, hippocampus, and basolateral amygdala (BLA). AACs selectively innervate glutamatergic projection neurons (PNs) at their axon initial segment (AIS), thus may exert decisive control over PN spiking and regulate PN functional ensembles. However, the brain-wide distribution, synaptic connectivity, and circuit function of AACs remain poorly understood, largely due to the lack of specific and reliable experimental tools. Here, we have established an intersectional genetic strategy that achieves specific and comprehensive targeting of AACs throughout the mouse brain based on their lineage (Nkx2.1) and molecular (Unc5b, Pthlh) markers. We discovered that AACs are deployed across essentially all the pallium-derived brain structures, including not only the dorsal pallium-derived neocortex and medial pallium-derived hippocampal formation, but also the lateral pallium-derived claustrum-insular complex, and the ventral pallium-derived extended amygdaloid complex and olfactory centers. AACs are also abundant in anterior olfactory nucleus, taenia tecta, and lateral septum. AACs show characteristic variations in density across neocortical areas and layers and across subregions of the hippocampal formation. Neocortical AACs comprise multiple laminar subtypes with distinct dendritic and axonal arborization patterns. Retrograde monosynaptic tracing from AACs across neocortical, hippocampal, and BLA regions reveal shared as well as distinct patterns of synaptic input. Specific and comprehensive targeting of AACs facilitates the study of their developmental genetic program and circuit function across brain structures, providing a ground truth platform for understanding the conservation and variation of a bona fide cell type across brain regions and species.
Whether we are memorising facts or reacting to a loud noise, nerve cells in different brain areas must be able to communicate with one another through precise, meaningful signals. Specialized nerve cells known as interneurons act as "traffic lights" to precisely regulate when and where this information flows in neural circuits. Axo-axonic cells are a rare type of inhibitory interneuron that are thought to be particularly important for controlling the passage of information between different groups of excitatory neurons. This is because they only connect to one key part of their target cell the axon-initial segment where the electrical signals needed for brain communication (known as action potentials) are initiated. Since axo-axonic cells are inhibitory interneurons, this connection effectively allows them to 'veto' the generation of these signals at their source. Although axo-axonic cells have been identified in three brain regions using traditional anatomical methods, there were no 'tags' readily available that can reliably identify them. Therefore, much about these cells remained unknown, including how widespread they are in the mammalian brain. To solve this problem, Raudales et al. investigated which genes are switched on in axo-axonic cells but not in other cells, identifying a unique molecular signature that could be used to mark, record, and manipulate these cells. Microscopy imaging of brain tissue from mice in which axo-axonic cells had been identified revealed that they are present in many more brain areas than previously thought, including nearly all regions of the broadly defined cerebral cortex and even the hypothalamus, which controls many innate behaviors. Axo-axonic cells were also 'wired up' differently, depending on where they were located; for example, those in brain areas associated with memory and emotions had wider-ranging input connections than other areas. The finding of Raudales et al. provide, for the first time, a method to directly track and manipulate axo-axonic cells in the brain. Since dysfunction in axo-axonic cells is also associated with neurological disorders like epilepsy and schizophrenia, gaining an insight into their distribution and connectivity could help to develop better treatments for these conditions.
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Neuronas GABAérgicas , Interneuronas , Animales , Interneuronas/fisiología , Interneuronas/metabolismo , Neuronas GABAérgicas/fisiología , Neuronas GABAérgicas/metabolismo , Ratones , Encéfalo/fisiología , Encéfalo/citología , Sinapsis/fisiología , Sinapsis/metabolismo , Axones/fisiología , Axones/metabolismo , MasculinoAsunto(s)
Disnea , Humanos , Disnea/etiología , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos XRESUMEN
Background: Several studies have suggested a potential link between allergic rhinitis (AR) and gut microbiota. In response, we conducted a meta-analysis of Linkage Disequilibrium Score Regression (LDSC) and Mendelian randomization (MR) to detect their genetic associations. Methods: Summary statistics for 211 gut microbiota taxa were gathered from the MiBioGen study, while data for AR were sourced from the Pan-UKB, the FinnGen, and the Genetic Epidemiology Research on Aging (GERA). The genetic correlation between gut microbiota and AR was assessed using LDSC. The principal estimate of causality was determined using the Inverse-Variance Weighted (IVW) method. To assess the robustness of these findings, sensitivity analyses were conducted employing methods such as the weighted median, MR-Egger, and MR-PRESSO. The summary effect estimates of LDSC, forward MR and reverse MR were combined using meta-analysis for AR from different data resources. Results: Our study indicated a significant genetic correlation between genus Sellimonas (Rg = -0.64, p = 3.64 × 10-5, Adjust_P = 3.64 × 10-5) and AR, and a suggestive genetic correlation between seven bacterial taxa and AR. Moreover, the forward MR analysis identified genus Gordonibacter, genus Coprococcus2, genus LachnospiraceaeUCG010, genus Methanobrevibacter, and family Victivallaceae as being suggestively associated with an increased risk of AR. The reverse MR analysis indicated that AR was suggestively linked to an increased risk for genus Coprococcus2 and genus RuminococcaceaeUCG011. Conclusion: Our findings indicate a causal relationship between specific gut microbiomes and AR. This enhances our understanding of the gut microbiota's contribution to the pathophysiology of AR and lays the groundwork for innovative approaches and theoretical models for future prevention and treatment strategies in this patient population.
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Venas Braquiocefálicas , Diálisis Renal , Síndrome de la Vena Cava Superior , Humanos , Venas Braquiocefálicas/diagnóstico por imagen , Venas Braquiocefálicas/cirugía , Venas Braquiocefálicas/fisiopatología , Síndrome de la Vena Cava Superior/etiología , Síndrome de la Vena Cava Superior/diagnóstico por imagen , Síndrome de la Vena Cava Superior/cirugía , Síndrome de la Vena Cava Superior/fisiopatología , Síndrome de la Vena Cava Superior/terapia , Resultado del Tratamiento , Atrios Cardíacos/cirugía , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/fisiopatología , Masculino , Fallo Renal Crónico/terapia , Fallo Renal Crónico/cirugía , Persona de Mediana Edad , Femenino , Factores de TiempoRESUMEN
Valvular heart disease (VHD) has become a burden and a growing public health problem in humans, causing significant morbidity and mortality worldwide. An increasing number of patients with severe VHD need to undergo heart valve replacement surgery, and artificial heart valves are in high demand. However, allogeneic valves from donors are lacking and cannot meet clinical practice needs. A mechanical heart valve can activate the coagulation pathway after contact with blood after implantation in the cardiovascular system, leading to thrombosis. Therefore, bioprosthetic heart valves (BHVs) are still a promising way to solve this problem. However, there are still challenges in the use of BHVs. For example, their longevity is still unsatisfactory due to the defects, such as thrombosis, structural valve degeneration, calcification, insufficient re-endothelialization, and the inflammatory response. Therefore, strategies and methods are needed to effectively improve the biocompatibility and longevity of BHVs. This review describes the recent research advances in BHVs and strategies to improve their biocompatibility and longevity.
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Bioprótesis , Prótesis Valvulares Cardíacas , Humanos , Animales , Materiales Biocompatibles/química , Válvulas CardíacasRESUMEN
Axo-axonic cells (AACs), also called chandelier cells (ChCs) in the cerebral cortex, are the most distinctive type of GABAergic interneurons described in the neocortex, hippocampus, and basolateral amygdala (BLA). AACs selectively innervate glutamatergic projection neurons (PNs) at their axon initial segment (AIS), thus may exert decisive control over PN spiking and regulate PN functional ensembles. However, the brain-wide distribution, synaptic connectivity, and circuit function of AACs remains poorly understood, largely due to the lack of specific and reliable experimental tools. Here, we have established an intersectional genetic strategy that achieves specific and comprehensive targeting of AACs throughout the mouse brain based on their lineage (Nkx2.1) and molecular (Unc5b, Pthlh) markers. We discovered that AACs are deployed across essentially all the pallium-derived brain structures, including not only the dorsal pallium-derived neocortex and medial pallium-derived hippocampal formation, but also the lateral pallium-derived claustrum-insular complex, and the ventral pallium-derived extended amygdaloid complex and olfactory centers. AACs are also abundant in anterior olfactory nucleus, taenia tecta and lateral septum. AACs show characteristic variations in density across neocortical areas and layers and across subregions of the hippocampal formation. Neocortical AACs comprise multiple laminar subtypes with distinct dendritic and axonal arborization patterns. Retrograde monosynaptic tracing from AACs across neocortical, hippocampal and BLA regions reveal shared as well as distinct patterns of synaptic input. Specific and comprehensive targeting of AACs facilitates the study of their developmental genetic program and circuit function across brain structures, providing a ground truth platform for understanding the conservation and variation of a bona fide cell type across brain regions and species.
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Apéndice Atrial , Accidente Cerebrovascular , Femenino , Humanos , Masculino , Apéndice Atrial/cirugía , Apéndice Atrial/diagnóstico por imagen , Fibrilación Atrial/cirugía , Procedimientos Quirúrgicos Cardíacos/métodos , Ablación por Catéter/métodos , Ecocardiografía Transesofágica/métodos , Medición de Riesgo , Accidente Cerebrovascular/prevención & control , Accidente Cerebrovascular/etiología , Resultado del Tratamiento , AdultoRESUMEN
Skilled motor behaviors require orderly coordination of multiple constituent movements with sensory cues towards achieving a goal, but the underlying brain circuit mechanisms remain unclear. Here we show that target-guided reach-grasp-to-drink (RGD) in mice involves the ordering and coordination of a set of forelimb and oral actions. Cortex-wide activity imaging of multiple glutamatergic projection neuron (PN) types uncovered a network, involving the secondary motor cortex (MOs), forelimb primary motor and somatosensory cortex, that tracked RGD movements. Photo-inhibition highlighted MOs in coordinating RGD movements. Within the MOs, population neural trajectories tracked RGD progression and single neuron activities integrated across constituent movements. Notably, MOs intratelencephalic, pyramidal tract, and corticothalamic PN activities correlated with action coordination, showed distinct neural dynamics trajectories, and differentially contributed to movement coordination. Our results delineate a cortical network and key areas, PN types, and neural dynamics therein that articulate the serial order and coordination of a skilled behavior.
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BACKGROUND: Human hydatid disease occurs after infection with Echinococcus granulosus, mainly involves liver and lung, while hydatid involves heart is infrequent. A great majority of hydatid diseases could be asymptomatic, and incidentally found through examination. Here, we reported a woman who suffered an isolated cardiac hydatid cyst located at the interventricular septum. CASE PRESENTATION: A 48-year-old woman presented intermittent chest pain was admitted to the hospital. Imaging examination revealed a cyst located at the interventricular septum near the right ventricular apex. Considering medical history, radiological findings and serological results, cardiac hydatid disease was suspected. The cyst was successfully removed, while pathological biopsy confirmed the diagnosis of infection of Echinococcus granulosus. Postoperative course was uneventful, the patient was discharged from hospital without complications. CONCLUSION: For symptomatic cardiac hydatid cyst, surgical resection is necessary to avoid progression of disease. During surgical procedure, appropriate methods to reduce the potential risk of hydatid cyst metastasis are essential. Besides surgery, combined with regular drug therapy is an effective strategy to prevent reappearance.
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Quistes , Equinococosis , Echinococcus granulosus , Cardiopatías , Tabique Interventricular , Femenino , Animales , Humanos , Persona de Mediana Edad , Equinococosis/complicaciones , Equinococosis/diagnóstico , Equinococosis/cirugía , Tabique Interventricular/cirugía , Cardiopatías/cirugía , Dolor en el Pecho/etiología , Quistes/complicacionesAsunto(s)
Mareo , Vértigo , Masculino , Humanos , Mareo/etiología , Mareo/diagnóstico , Vértigo/diagnóstico , Diagnóstico DiferencialRESUMEN
BACKGROUND: Atrial fibrosis is one of the main causes of the onset and recurrence of atrial fibrillation (AF), for which there is no effective treatment. The aim of this study was to investigate the effect and mechanism of epigallocatechin-3-gallate (EGCG) on AF in rats. METHODS: The rat model of AF was established by rapid pacing induction after angiotensin-II (Ang-II) induced atrial fibrosis to verify the relationship between atrial fibrosis and the AF. The expression levels of TGF-ß/Smad3 pathway molecules and lysyl oxidase (LOX) in AF were detected. Subsequently, EGCG was used to intervene Ang-II-induced atrial fibrosis to explore the role of EGCG in the treatment of AF and its inhibitory mechanism on fibrosis. It was further verified that EGCG inhibited the production of collagen and the expression of LOX through the TGF-ß/Smad3 pathway at the cellular level. RESULTS: The results showed that the induction rate and maintenance time of AF in rats increased with the increase of the degree of atrial fibrosis. Meanwhile, the expressions of Col I, Col III, molecules related to TGF-ß/Smad3 pathway, and LOX increased significantly in the atrial tissues of rats in the Ang-II induced group. EGCG could reduce the occurrence and maintenance time of AF by inhibiting the degree of Ang-induced rat atrial fibrosis. Cell experiments confirmed that EGCG could reduce the synthesis of collagen and the expression of LOX in cardiac fibroblast induced by Ang-II. The possible mechanism is to down-regulate the expression of genes and proteins related to the TGF-ß/Smad3 pathway. CONCLUSION: EGCG could downregulate the expression levels of collagen and LOX by inhibiting the TGF-ß/Smad3 signaling pathway, alleviating Ang-II-induced atrial fibrosis, which in turn inhibited the occurrence and curtailed the duration of AF.
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Myocardial infarction (MI) leads to massive cardiomyocyte death and deposition of collagen fibers. This fibrous tissue disrupts electrical signaling in the myocardium, leading to cardiac systolic and diastolic dysfunction, as well as arrhythmias. Conductive hydrogels are a promising therapeutic strategy for MI. Here, we prepared a highly water-soluble conductive material (GP) by grafting polypyrrole (PPy) onto non-conductive gelatin. This component was added to the gel system formed by the Schiff base reaction between oxidized xanthan gum (OXG) and gelatin to construct an injectable conductive hydrogel. The prepared self-healing OGGP3 (3 wt% GP) hydrogel had good biocompatibility, elastic modulus, and electrical conductivity that matched the natural heart. The prepared biomaterials were injected into the rat myocardial scar tissue 2 days after MI. We found that the cardiac function of the rats treated with OGGP3 was improved, making it more difficult to induce arrhythmias. The electrical resistivity of myocardial fibrous tissue was reduced, and the conduction velocity of myocardial tissue was increased. Histological analysis showed reduced infarct size, increased left ventricular wall thickness, increased vessel density, and decreased inflammatory response in the infarcted area. Our findings clearly demonstrate that the OGGP3 hydrogel attenuates ventricular remodeling and inhibits infarct dilation, thus showing its potential for the treatment of MI.
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BACKGROUND: Ventricular septal defect (VSD) is one of the most common congenital cardiac defects. However, in some cases, VSD sites are difficult to expose due to obstruction from chordal attachments and leaflets of the tricuspid valve (TV). To systematically review the efficacy and safety of tricuspid valve detachment, (TVD) versus conventional surgical repair (non-TVD) in the treatment of ventricular septal defect (VSD). This article is aimed to compare the many outcomes from existing studies and provide evidence regarding the necessity of performing TVD. METHODS: We searched the following databases: PubMed via NCBI, the Cochrane Central Register of Controlled Trials (no date restriction), Medline via Ovid (from 1966 to May 2020); Embase via Ovid (no date restriction), and China National Knowledge Infrastructure for studies comparing the efficacy of TVD and other surgical techniques in VSD repair. Cardiopulmonary bypass time, Cross-clamp time; postoperative complications including residual defect, postoperative atrioventricular block, implantation of pacemakers, tricuspid regurgitation; length of stay (LOS), length of intensive care unit (ICU) stay were analyzed. RESULTS: Only nine studies were included after selection, including seven retrospective cohort studies, one respective cohort study, and one prospective observational study, a patient pool of 1404 patients with 374 underwent TVD and 1030 underwent non-TVD procedures, met the inclusion criteria. Meta analysis has drawn to the following conclusions. First, TVD prolongs CPB time (MD = 7.75, 95% confidence interval [CI] = 2.60-12.89, p = .003) and cross-clamp time (MD = 7.77, 95% CI = 4.76-10.78, p < .001) compared with non-TVD techniques in VSD repair surgeries. Second, no significant difference exists in LOS, length of ICU stay, postoperative atrioventricular block, implantation of pacemakers, incidence of ≥mild tricuspid valve regurgitation (TR) postoperatively and at discharge, as well as the incidence of ≥small residual VSD after surgery and during follow-up (all p ï¼ .05). Third, application of TVD increases the risk of TR during follow-up (odds ratio [OR] = 2.42, 95% CI = 1.55-3.76, p < .001). CONCLUSION: VSD closure using TVD technique results in longer CPB and cross-clamp time, and increases risk of TR during follow-up. TVD provides equally viable and safe alternative in treating VSD.
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Bloqueo Atrioventricular , Defectos del Tabique Interventricular , Insuficiencia de la Válvula Tricúspide , Humanos , Estudios de Cohortes , Estudios de Seguimiento , Defectos del Tabique Interventricular/cirugía , Defectos del Tabique Interventricular/complicaciones , Estudios Observacionales como Asunto , Complicaciones Posoperatorias , Estudios Retrospectivos , Resultado del Tratamiento , Válvula Tricúspide/cirugía , Insuficiencia de la Válvula Tricúspide/complicacionesRESUMEN
We reported a case of a 53-year-old patient with coarctation of the aorta and multiple aneurysmatic changes on the aortic arch. Enhanced computed tomography and reconstruction revealed significant coarctation and multiple aneurysmatic dilatations. The patient underwent stent implantation and was discharged with symptoms relieved. Follow-up examination progression of aneurysms, however, without symptoms.
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Aneurisma , Coartación Aórtica , Humanos , Persona de Mediana Edad , Coartación Aórtica/complicaciones , Coartación Aórtica/diagnóstico por imagen , Coartación Aórtica/cirugía , Aorta/cirugía , Aorta Torácica/cirugía , Tomografía Computarizada por Rayos XRESUMEN
Objective.The oscillometric blood pressure (BP) measurement technique estimates BPs from analyzing the oscillometric cuff pressure waveform (oscillogram) envelope. The oscillogram envelope maximum is associated with physiological changes and influences BP measurement accuracy. We aim to quantitatively investigate the effect of BP and aging on the changes of oscillogram envelope maximum.Approach.Four hundred and sixty-two subjects (214 female, 248 male) were recruited. The cuff pressure was digitally recorded during linear cuff deflation to derive oscillogram envelopes and their maximums. Moderation analysis was performed to investigate whether the relationship between BP and envelope maximum was moderated by age. Subjects were divided into five age categories and three BP groups. The envelope maximums were compared between different BP and age categories to qualify their changes with increased BP and aging.Main results.Age has a significant moderating effect on the relationship between BP and envelope maximum (P < 0.05). The oscillogram envelope maximums increased significantly with increased BPs (P < 0.05 between each BP groups) and aging (P < 0.05 for > 60 years old groups in comparison with younger groups).Significance.This study experientially and theoretically concluded the BPs and aging are two important factors that influence the maximum value of the oscillogram envelope.
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Envejecimiento , Determinación de la Presión Sanguínea , Masculino , Femenino , Humanos , Persona de Mediana Edad , Presión Sanguínea/fisiología , Determinación de la Presión Sanguínea/métodos , Oscilometría/métodos , Recolección de DatosRESUMEN
Atrial fibrillation (AF) is one of the most common sustained tachyarrhythmias worldwide, and its prevalence is positively correlated with aging. AF not only significantly reduces the quality of life of patients but also causes a series of complications, such as thromboembolism, stroke, and heart failure, increases the average number of hospitalizations of patients, and places a huge economic burden on patients and society. Traditional drug therapy and ablation have unsatisfactory success rates, high recurrence rates, and the risk of serious complications. Surgical treatment is highly traumatic. The nano drug delivery system has unique physical and chemical properties, and in the application of AF treatment, whether it is used to assist in enhancing the ablation effect or for targeted therapy, it provides a safer, more effective and more economical treatment strategy.
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With the aging of the population in worldwide, valvular heart disease has become one of the most prominent life-threatening diseases in human health, and heart valve replacement surgery is one of the therapeutic methods for valvular heart disease. Currently, commercial bioprosthetic heart valves (BHVs) for clinical application are prepared with xenograft heart valves or pericardium crosslinked by glutaraldehyde. Due to the residual cell toxicity from glutaraldehyde, heterologous antigens, and immune response, there are still some drawbacks related to the limited lifespan of bioprosthetic heart valves, such as thrombosis, calcification, degeneration, and defectiveness of re-endothelialization. Therefore, the problems of calcification, defectiveness of re-endothelialization, and poor biocompatibility from the use of bioprosthetic heart valve need to be solved. In this study, hydrogel hybrid heart valves with improved anti-calcification and re-endothelialization were prepared by taking decellularized porcine heart valves as scaffolds following grafting with double bonds. Then, the anti-biofouling zwitterionic monomers 2-methacryloyloxyethyl phosphorylcholine (MPC) and vascular endothelial growth factor (VEGF) were utilized to obtain a hydrogel-coated hybrid heart valve (PEGDA-MPC-DHVs@VEGF). The results showed that fewer platelets and thrombi were observed on the surface of the PEGDA-MPC-DHVs@VEGF. Additionally, the PEGDA-MPC-DHVs@VEGF exhibited excellent collagen stability, biocompatibility and re-endothelialization potential. Moreover, less calcification deposition and a lower immune response were observed in the PEGDA-MPC-DHVs@VEGF compared to the glutaraldehyde-crosslinked DHVs (Glu-DHVs) after subcutaneous implantation in rats for 30 days. These studies demonstrated that the strategy of zwitterionic hydrogels loaded with VEGF may be an effective approach to improving the biocompatibility, anti-calcification and re-endothelialization of bioprosthetic heart valves.
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RNA is a central and universal mediator of genetic information underlying the diversity of cell types and cell states, which together shape tissue organization and organismal function across species and lifespans. Despite numerous advances in RNA sequencing technologies and the massive accumulation of transcriptome datasets across the life sciences1,2, the dearth of technologies that use RNAs to observe and manipulate cell types remains a bottleneck in biology and medicine. Here we describe CellREADR (Cell access through RNA sensing by Endogenous ADAR), a programmable RNA-sensing technology that leverages RNA editing mediated by ADAR to couple the detection of cell-defining RNAs with the translation of effector proteins. Viral delivery of CellREADR conferred specific cell-type access in mouse and rat brains and in ex vivo human brain tissues. Furthermore, CellREADR enabled the recording and control of specific types of neurons in behaving mice. CellREADR thus highlights the potential for RNA-based monitoring and editing of animal cells in ways that are specific, versatile, simple and generalizable across organ systems and species, with wide applications in biology, biotechnology and programmable RNA medicine.
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Edición de ARN , ARN , Animales , Humanos , Ratones , Ratas , ARN/análisis , ARN/genética , ARN/metabolismo , Análisis de Secuencia de ARN , Transcriptoma/genética , Conducta Animal , Encéfalo/citología , Encéfalo/metabolismo , Neuronas , Biosíntesis de ProteínasRESUMEN
Objective: We aimed to compare non-vitamin K oral anticoagulants (NOACs) with a traditional antithrombotic such as vitamin K antagonist (VKA) and antiplatelet agents in patients after transcatheter aortic valve replacement (TAVR). Methods: We conducted a search in PubMed, EMBASE, and the Cochrane Library until November 2021 for studies involving comparisons of any type of NOACs, including dabigatran, apixaban, rivaroxaban, and edoxaban, with VKA or antiplatelet agents after TAVR. A comparison of NOACs versus VKA was performed in patients with an indication for oral anticoagulation. In addition, we compared NOACs versus antiplatelet in patients without such indication. We calculated the hazard ratios with 95% confidence intervals (CIs) to determine long-term outcomes. The primary outcome was a combined endpoint consisting of all-cause mortality, stroke, major bleeding, or any related clinical adverse events. Secondary outcomes were all-cause mortality, major bleeding, and stroke, respectively. Results: A total of 10 studies including 10,563 patients after TAVR were included in this meta-analysis. There were no significant differences in any of the long-term outcomes between the NOAC and VKA groups. Although there were no significant differences in the combined endpoint, major bleeding, or stroke, a significant difference was observed in the all-cause mortality (HR 1.74, 95% CI 1.25-2.43, p = 0.001) between the NOAC and antiplatelet groups. Conclusion: For patients with an indication for oral anticoagulation after TAVR, NOACs seem to be associated with noninferior outcomes compared with VKA therapy. However, for patients without an indication for oral anticoagulation, NOACs appear to be associated with a higher risk of all-cause death as compared with antiplatelet treatment. Systematic Review Registration: https://clinicaltrials.gov/, identifier CRD42020155122.