Short- and long-term morbidity after Taylor flap (oblique rectus abdominis flap) for perineal reconstruction after abdominoperineal resection: A single-center series of 140 patients.

BACKGROUND: Abdominoperineal resection (APR) leads to a substantial loss of tissue and a high rate of complications. The Taylor flap is a musculocutaneous flap used in reconstruction after APR. OBJECTIVES: We aimed to analyze the short and long-term morbidity of reconstruction with a Taylor flap (oblique rectus abdominis flap) after APR and to identify the risk factors for postoperative complications. METHODS: We retrospectively included all patients who had undergone APR with immediate reconstruction with a Taylor flap in our department between July 2000 and June 2018. Demographics, oncological data, treatment, and short- and long-term morbidity were reviewed. RESULTS: Among the 140 patients included, we identified early minor complications in 42 patients (30%) and 14 early major complications (10%). Total necrosis of the flap requiring its removal occurred in four patients (2.8%). Eleven patients (7.9%) presented with a midline incision hernia, and seven (5%) presented with a subcostal incision hernia. No perineal hernia was found. No risk factors for the complications were identified. CONCLUSION: The Taylor flap is a safe procedure with few complications and limited donor site morbidity. Moreover, it prevents perineal hernias. These results confirm that the Taylor flap is a well-suited procedure for reconstruction after APR.

A systematic qualitative study investigating why individuals attend, and what they like, dislike, and find most helpful about, smart recovery, alcoholics anonymous, both, or neither.

BACKGROUND: Some individuals seeking recovery from alcohol use disorder (AUD) attend Alcoholics Anonymous (AA) while others choose newer alternatives such as Self-Management and Recovery Training ("SMART" Recovery). Some even attend both, while some choose not to attend either. Little is known about why people choose which pathway(s), and what they like, dislike, and find helpful. Greater knowledge could provide insights into the phenomenology of recovery experiences and enhance the efficiency of clinical linkage to these resources. METHODS: Cross-sectional, qualitative, investigation (N = 80; n = 20 per condition; 50%female) of individuals attending either AA-only, SMART-only, both, or neither. Participants were asked why they initially chose that pathway, what they like and dislike, and what helps. Responses were coded using an inductive grounded theory approach with utterances recorded and categorized into superordinate domains and rank-ordered in terms of frequency across each question and recovery pathway. RESULTS: AA participants reported attending due to, as well as liking and finding most helpful, the common socio-community aspects, whereas SMART attendees went initially due to, as well as found most helpful, the different format as well as the CBT/science-based approach. Similar to AA, however, SMART participants liked the socio-community aspects most. "Both" participants reported liking and finding helpful these perceived relative strengths of each organization. "Neither" participants reported reasons for non-attendance related to lower problem severity - perceiving no need to attend, and anxiety about privacy, but reported using recovery-related change strategies similar to those prescribed by AA, SMART and treatment (e.g., stimulus control, competing behaviors). Common dislikes for AA and SMART centered around irritation due to other members behaviors, a need for more SMART meetings, and negative experiences with SMART facilitators. CONCLUSION: Common impressions exist among individuals selecting different recovery pathway choices, but also some differences in keeping with the group dynamics and distinct approaches inherent in AA and SMART. AA attendees appear to go initially for the recovery buoyancy derived from the social ethos and camaraderie of lived experience and may end up staying for the same reason; those choosing SMART, in contrast, appear to attend initially for the CBT/science-based content and different approach but, like AA participants, may end up staying due to the same camaraderie of lived experience. Those participating in both AA and SMART appear to capitalize on the strengths of each organization, suggesting that some can psychologically accommodate and make use of theoretically distinct, and sometimes opposing, philosophies and practices.

Clonal CD8 T Cells Accumulate in the Leptomeninges and Communicate with Microglia in Human Neurodegeneration.

Murine studies have highlighted a crucial role for immune cells in the meninges in surveilling the central nervous system (CNS) and influencing neuroinflammation. However, how meningeal immunity is altered in human neurodegeneration and its effects on CNS inflammation is understudied. We performed the first single-cell analysis of the transcriptomes and T cell receptor (TCR) repertoire of 104,635 immune cells from 55 postmortem human brain and leptomeningeal tissues from donors with neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. RNA and TCR sequencing from paired leptomeninges and brain allowed us to perform lineage tracing to identify the spatial trajectory of clonal T cells in the CNS and its borders. We propose that T cells activated in the brain emigrate to and establish residency in the leptomeninges where they likely contribute to impairments in lymphatic drainage and remotely to CNS inflammation by producing IFNγ and other cytokines. We identified regulatory networks local to the meninges including NK cell-mediated CD8 T cell killing which likely help to control meningeal inflammation. Collectively, these findings provide not only a foundation for future studies into brain border immune surveillance but also highlight important intercellular dynamics that could be leveraged to modulate neuroinflammation.

Plasma cell-free DNA hydroxymethylation profiling reveals anti-PD-1 treatment response and resistance biology in non-small cell lung cancer.

BACKGROUND: Treatment with immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1) can yield durable antitumor responses, yet not all patients respond to ICIs. Current approaches to select patients who may benefit from anti-PD-1 treatment are insufficient. 5-hydroxymethylation (5hmC) analysis of plasma-derived cell-free DNA (cfDNA) presents a novel non-invasive approach for identification of therapy response biomarkers which can tackle challenges associated with tumor biopsies such as tumor heterogeneity and serial sample collection. METHODS: 151 blood samples were collected from 31 patients with non-small cell lung cancer (NSCLC) before therapy started and at multiple time points while on therapy. Blood samples were processed to obtain plasma-derived cfDNA, followed by enrichment of 5hmC-containing cfDNA fragments through biotinylation via a two-step chemistry and binding to streptavidin coated beads. 5hmC-enriched cfDNA and whole genome libraries were prepared in parallel and sequenced to obtain whole hydroxymethylome and whole genome plasma profiles, respectively. RESULTS: Comparison of on-treatment time point to matched pretreatment samples from same patients revealed that anti-PD-1 treatment induced distinct changes in plasma cfDNA 5hmC profiles of responding patients, as judged by Response evaluation criteria in solid tumors, relative to non-responders. In responders, 5hmC accumulated over genes involved in immune activation such as inteferon (IFN)-γ and IFN-α response, inflammatory response and tumor necrosis factor (TNF)-α signaling, whereas in non-responders 5hmC increased over epithelial to mesenchymal transition genes. Molecular response to anti-PD-1 treatment, as measured by 5hmC changes in plasma cfDNA profiles were observed early on, starting with the first cycle of treatment. Comparison of pretreatment plasma samples revealed that anti-PD-1 treatment response and resistance associated genes can be captured by 5hmC profiling of plasma-derived cfDNA. Furthermore, 5hmC profiling of pretreatment plasma samples was able to distinguish responders from non-responders using T cell-inflamed gene expression profile, which was previously identified by tissue RNA analysis. CONCLUSIONS: These results demonstrate that 5hmC profiling can identify response and resistance associated biological pathways in plasma-derived cfDNA, offering a novel approach for non-invasive prediction and monitoring of immunotherapy response in NSCLC.

Who affiliates with SMART recovery? A comparison of individuals attending SMART recovery, alcoholics anonymous, both, or neither.

BACKGROUND: Mutual-help organizations (MHOs) play a crucial role for many individuals with alcohol use disorder (AUD) or other substance use disorders in achieving stable remission. While there is now substantial research characterizing who uses 12-step MHOs, very little is known about who becomes affiliated with newer and rapidly growing MHOs, such as Self-Management and Recovery Training ("SMART" Recovery). More research could inform knowledge regarding who may be best engaged by these differing pathways. METHODS: We conducted a cross-sectional analysis of participants (N = 361) with AUD recruited mostly from the community who were starting a new recovery attempt and self-selected into one of four different recovery paths: (1) SMART Recovery ("SMART-only"; n = 75); (2) Alcoholics Anonymous ("AA-only"; n = 73); (3) Both SMART and AA ("Both"; n = 53); and (4) Neither SMART nor AA ("Neither"; n = 160). We compared the groups on demographics, clinical history, treatment and recovery support service use, and indices of functioning and well-being. We computed descriptives and conducted inferential analyses according to the data structure. RESULTS: Compared to study participants choosing AA-only or Both, SMART-only participants were more likely to be White, married, have higher income and more education, be full-time employed, and evince a pattern of lower clinical severity characterized by less lifetime and recent treatment and recovery support services usage, lower alcohol use intensity and fewer consequences, and less legal involvement. AUD symptom levels, lifetime psychiatric diagnoses, psychiatric distress, and functioning were similar across MHO-engaged groups. CONCLUSION: SMART Recovery appears to attract individuals with greater psychosocial stability and economic advantage and less severe histories of alcohol-related impairment and legal involvement. Findings suggest that certain aspects specific to the SMART Recovery group approach, format, and/or contents may appeal to individuals exhibiting this type of profile. As such, SMART appears to provide an additional resource that expands the repertoire of options for individuals with AUD who seek recovery.

Clonal CD8 T cells in the leptomeninges are locally controlled and influence microglia in human neurodegeneration.

Recent murine studies have highlighted a crucial role for the meninges in surveilling the central nervous system (CNS) and influencing CNS inflammation. However, how meningeal immunity is altered in human neurodegeneration and its potential effects on neuroinflammation is understudied. In the present study, we performed single-cell analysis of the transcriptomes and T cell receptor repertoire of 72,576 immune cells from 36 postmortem human brain and leptomeninges tissues from donors with neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. We identified the meninges as an important site of antigen presentation and CD8 T cell activation and clonal expansion and found that T cell activation in the meninges is a requirement for infiltration into the CNS. We further found that natural killer cells have the potential to negatively regulate T cell activation locally in the meninges through direct killing and are one of many regulatory mechanisms that work to control excessive neuroinflammation.

Education and electronic medical records and genomics network, challenges, and lessons learned from a large-scale clinical trial using polygenic risk scores.

Polygenic risk scores (PRS) have potential to improve health care by identifying individuals that have elevated risk for common complex conditions. Use of PRS in clinical practice, however, requires careful assessment of the needs and capabilities of patients, providers, and health care systems. The electronic Medical Records and Genomics (eMERGE) network is conducting a collaborative study which will return PRS to 25,000 pediatric and adult participants. All participants will receive a risk report, potentially classifying them as high risk (∼2-10% per condition) for 1 or more of 10 conditions based on PRS. The study population is enriched by participants from racial and ethnic minority populations, underserved populations, and populations who experience poorer medical outcomes. All 10 eMERGE clinical sites conducted focus groups, interviews, and/or surveys to understand educational needs among key stakeholders-participants, providers, and/or study staff. Together, these studies highlighted the need for tools that address the perceived benefit/value of PRS, types of education/support needed, accessibility, and PRS-related knowledge and understanding. Based on findings from these preliminary studies, the network harmonized training initiatives and formal/informal educational resources. This paper summarizes eMERGE's collective approach to assessing educational needs and developing educational approaches for primary stakeholders. It discusses challenges encountered and solutions provided.

Epigenomic Blood-Based Early Detection of Pancreatic Cancer Employing Cell-Free DNA.

BACKGROUND & AIMS: Early detection of pancreatic cancer (PaC) can drastically improve survival rates. Approximately 25% of subjects with PaC have type 2 diabetes diagnosed within 3 years prior to the PaC diagnosis, suggesting that subjects with type 2 diabetes are at high risk of occult PaC. We have developed an early-detection PaC test, based on changes in 5-hydroxymethylcytosine (5hmC) signals in cell-free DNA from plasma. METHODS: Blood was collected from 132 subjects with PaC and 528 noncancer subjects to generate epigenomic and genomic feature sets yielding a predictive PaC signal algorithm. The algorithm was validated in a blinded cohort composed of 102 subjects with PaC, 2048 noncancer subjects, and 1524 subjects with non-PaCs. RESULTS: 5hmC differential profiling and additional genomic features enabled the development of a machine learning algorithm capable of distinguishing subjects with PaC from noncancer subjects with high specificity and sensitivity. The algorithm was validated with a sensitivity for early-stage (stage I/II) PaC of 68.3% (95% confidence interval [CI], 51.9%-81.9%) and an overall specificity of 96.9% (95% CI, 96.1%-97.7%). CONCLUSIONS: The PaC detection test showed robust early-stage detection of PaC signal in the studied cohorts with varying type 2 diabetes status. This assay merits further clinical validation for the early detection of PaC in high-risk individuals.

An investigation of SMART Recovery: protocol for a longitudinal cohort study of individuals making a new recovery attempt from alcohol use disorder.

INTRODUCTION: Alcohol use disorder (AUD) remains one of the most pervasive of all psychiatric illnesses conferring a massive health and economic burden. In addition to professional treatments to address AUD, mutual-help organisations such as Alcoholics Anonymous (AA) and newer entities like Self-Management and Recovery Training (SMART Recovery) play increasingly important roles in many societies. While much is known about the positive effects of AA, very little is known about SMART. Hence, this study seeks to estimate real-world patterns of utilisation and benefit from SMART Recovery as well as explore for whom (moderators) and how (mechanisms) SMART confers recovery benefits. METHODS AND ANALYSIS: Naturalistic, longitudinal, cohort study (n=368) of individuals with AUD recruited between February 2019 and February 2022, initiating a new recovery attempt who self-select into one of four groups at study entry: (1) SMART Recovery; (2) AA; (3) SMART+AA; (4) Neither SMART nor AA; (stratified by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM 5) severity markers), with assessments conducted at intake, and 3 months, 6 months, 9 months, 12 months, 18 months and 24 months. Primary outcomes are: frequency of SMART and AA meetings attendance; per cent days abstinent and per cent days heavy drinking. Secondary outcomes include psychiatric distress; quality of life and functioning. Moderator variables include sex/gender; race/ethnicity; spirituality. Mediational variables include social networks; coping skills; self-efficacy; impulsivity. Multivariable regression with propensity score matching will test for patterns of attendance and effects of participation over time on outcomes and test for mechanisms and moderators. ETHICS AND DISSEMINATION: This study involves human participants and was approved by the Massachusetts General Hospital Institutional Review Board (Protocol #: 2017P002029/PHS). Results will be published in peer-reviewed journals and presented at conferences. REGISTRATION: This is a non-randomised, naturalistic, longitudinal, cohort study, and thus was not registered in advance. Results, therefore, should be considered exploratory.

Machine Learning Analysis of the Cerebrovascular Thrombi Lipidome in Acute Ischemic Stroke.

ABSTRACT: OBJECTIVE: The aim of this study was to identify a signature lipid profile from cerebral thrombi in acute ischemic stroke (AIS) patients at the time of ictus. METHODS: We performed untargeted lipidomics analysis using liquid chromatography-mass spectrometry on cerebral thrombi taken from a nonprobability, convenience sampling of adult subjects (≥18 years old, n = 5) who underwent thrombectomy for acute cerebrovascular occlusion. The data were classified using random forest, a machine learning algorithm. RESULTS: The top 10 metabolites identified from the random forest analysis were of the glycerophospholipid species and fatty acids. CONCLUSION: Preliminary analysis demonstrates feasibility of identification of lipid metabolomic profiling in cerebral thrombi retrieved from AIS patients. Recent advances in omic methodologies enable lipidomic profiling, which may provide insight into the cellular metabolic pathophysiology caused by AIS. Understanding of lipidomic changes in AIS may illuminate specific metabolite and lipid pathways involved and further the potential to develop personalized preventive strategies.

Endothelial Responses to Curvature-Induced Flow Patterns in Engineered Cerebral Aneurysms.

Hemodynamic factors have long been associated with clinical outcomes in the treatment of cerebral aneurysms. Computational studies of cerebral aneurysm hemodynamics have provided valuable estimates of the mechanical environment experienced by the endothelium in both the parent vessel and aneurysmal dome walls and have correlated them with disease state. These computational-clinical studies have recently been correlated with the response of endothelial cells (EC) using either idealized or patient-specific models. Here, we present a robust workflow for generating anatomic-scale aneurysm models, establishing luminal cultures of ECs at physiological relevant flow profiles, and comparing EC responses to curvature mediated flow. We show that flow patterns induced by parent vessel curvature produce changes in wall shear stress (WSS) and wall shear stress gradients (WSSG) that are correlated with differences in cell morphology and cellular protein localization. Cells in higher WSS regions align better with the flow and display strong Notch1-extracellular domain (ECD) polarization, while, under low WSS, differences in WSSG due to curvature change were associated with less alignment and attenuation of Notch1-ECD polarization in ECs of the corresponding regions. These proof-of-concept results highlight the use of engineered cellularized aneurysm models for connecting computational fluid dynamics to the underlying endothelial biology that mediates disease.

The 5-Hydroxymethylcytosine Landscape of Prostate Cancer.

Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease. SIGNIFICANCE: In prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880.

Clopidogrel hyper-response increases peripheral hemorrhagic complications without increasing intracranial complications in endovascular aneurysm treatments requiring dual antiplatelet therapy.

Clinical significance of increased clopidogrel response measured by VerifyNow P2Y12 assay is unclear; management guidelines are lacking in the context of neuroendovascular intervention. Our objective was to assess whether increased clopidogrel response predicts complications from endovascular aneurysm treatment requiring dual antiplatelet therapy. A single-institution, 9-year retrospective study of patients undergoing endovascular treatments for ruptured and unruptured aneurysms requiring aspirin and clopidogrel was conducted. Patients were grouped according to preoperative platelet inhibition in response to clopidogrel measured by the VerifyNow P2Y12 assay (VNP; P2Y12 reactivity units, PRU). Demographic and clinical features were compared across groups. Hemorrhagic complication rates (intracranial, major extracranial, minor extracranial) and thromboembolic complications (in-stent stenosis, stroke/transient ischemic attack) were compared, controlling for potential confounders and multiple comparisons. Data were collected from 284 patients across 317 procedures. Pre-operative VNP assays identified 9 % Extreme Responders (PRU ≤ 15), 13 % Hyper-Responders (PRU 16-60), 62 % Therapeutic Responders (PRU 61-214), 16 % Hypo-Responders (PRU ≥ 215). Increased response to clopidogrel was associated with increased risk of any hemorrhagic complication (≤60 PRU vs > 60 PRU; 39 % vs 24 %, P = 0.050); all intracranial hemorrhages occurred in patients with PRU > 60. Thromboembolic complications were similar between therapeutic and subtherapeutic patients (<215 PRU vs ≥ 215 PRU; 15 % vs 16 %, P = 0.835). Increased preoperative clopidogrel response is associated with increased rate of extracranial hemorrhagic complications in endovascular aneurysm treatments. Hyper-responders (16-60 PRU) and Extreme Responders (≤15 PRU) were not associated with intracranial hemorrhagic or thrombotic complications. Hypo-responders who underwent adjustment of antiplatelet therapy and neurointerventions did not experience higher rates of complications.

Thrombus-associated microbiota in acute ischemic stroke patients.

Background: Despite a reduction in stroke incidence and age-standardized death rates, stroke remains a leading cause of death and disability worldwide. Significant interest in recent years has focused on the microbiota-host interaction because accumulating evidence has revealed myriad ways in which bacteria may contribute to risk of stroke and adverse outcomes after stroke. The emergence of endovascular thrombectomy as a treatment provides a unique opportunity to utilize thrombus retrieved from cerebral arteries to fill knowledge gaps about the influence of bacteria on stroke pathophysiology. While bacterial signatures have been confirmed in cerebral thrombi, the exact nature of the pathogenesis has not been established. Methods: Thrombi were obtained from a cohort of adult ischemic stroke patients during standard of care thrombectomy. After DNA extraction and quantification, thrombi underwent 16S rRNA amplicon-based metagenomic sequencing, followed by bioinformatics processing. Taxonomic identification of bacterial colonies isolated on Agar plates from plated suspension was performed using DNA extraction and full length 16S Sanger sequencing. Results: A broad diversity of bacterial signatures was identified in specimens, primarily of cariogenic origin. Conclusion: In this small study, we demonstrate proof of concept and technical feasibility for amplicon-based metagenomic sequencing of arterial thrombi and briefly discuss preliminary findings, challenges, and near-term translational opportunities for thrombus genomics.

The Cell Type-Specific 5hmC Landscape and Dynamics of Healthy Human Hematopoiesis and TET2-Mutant Preleukemia.

The conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) is a key step in DNA demethylation that is mediated by ten-eleven translocation (TET) enzymes, which require ascorbate/vitamin C. Here, we report the 5hmC landscape of normal hematopoiesis and identify cell type-specific 5hmC profiles associated with active transcription and chromatin accessibility of key hematopoietic regulators. We utilized CRISPR/Cas9 to model TET2 loss-of-function mutations in primary human hematopoietic stem and progenitor cells (HSPC). Disrupted cells exhibited increased colonies in serial replating, defective erythroid/megakaryocytic differentiation, and in vivo competitive advantage and myeloid skewing coupled with reduction of 5hmC at erythroid-associated gene loci. Azacitidine and ascorbate restored 5hmC abundance and slowed or reverted the expansion of TET2-mutant clones in vivo. These results demonstrate the key role of 5hmC in normal hematopoiesis and TET2-mutant phenotypes and raise the possibility of utilizing these agents to further our understanding of preleukemia and clonal hematopoiesis. SIGNIFICANCE: We show that 5-hydroxymethylation profiles are cell type-specific and associated with transcriptional abundance and chromatin accessibility across human hematopoiesis. TET2 loss caused aberrant growth and differentiation phenotypes and disrupted 5hmC and transcriptional landscapes. Treatment of TET2 KO HSPCs with ascorbate or azacitidine reverted 5hmC profiles and restored aberrant phenotypes. This article is highlighted in the In This Issue feature, p. 265.

Management of atrial fibrillation: two decades of progress - a scientific statement from the European Cardiac Arrhythmia Society.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. The aim of this review was to evaluate the progress made in the management of AF over the two last decades. RESULTS: Clinical classification of AF is usually based on the presence of symptoms, the duration of AF episodes and their possible recurrence over time, although incidental diagnosis is not uncommon. The majority of patients with AF have associated cardiovascular diseases and more recently the recognition of modifiable risk factors both cardiovascular and non-cardiovascular which should be considered in its management. Among AF-related complications, stroke and transient ischaemic accidents (TIAs) carry considerable morbidity and mortality risk. The use of implantable devices such as pacemakers and defibrillators, wearable garments and subcutaneous cardiac monitors with recording capabilities has enabled to access the burden of "subclinical AF". The recent introduction of non-vitamin K antagonists has led to improve the prevention of stroke and peripheral embolism. Agents capable of reversing non-vitamin K antagonists have also become available in case of clinically relevant major bleeding. Transcatheter closure of left atrial appendage represents an option for patients unable to take oral anticoagulation. When treating patients with AF, clinicians need to select the most suitable strategy, i.e. control of heart rate and/or restoration and maintenance of sinus rhythm. The studies comparing these two strategies have not shown differences in terms of mortality. If an AF episode is poorly tolerated from a haemodynamic standpoint, electrical cardioversion is indicated. Otherwise, restoration of sinus rhythm can be obtained using intravenous pharmacological cardioversion and oral class I or class III antiarrhythmic is used to prevent recurrences. During the last two decades after its introduction in daily practice, catheter ablation has gained considerable escalation in popularity. Progress has also been made in AF associated with heart failure with reduced or preserved ejection fraction. CONCLUSIONS: Significant progress has been made within the past 2 decades both in the pharmacological and non-pharmacological managements of this cardiac arrhythmia.