Norovirus is the leading cause of medically attended acute gastroenteritis in the United States. Efforts to reduce the disease burden are constrained by uncertainty around fundamental aspects of norovirus epidemiology. This study describes characteristics of norovirus infections and explores potential risk factors for symptomatic infections in early life. The Pediatric Respiratory and Enteric Virus Acquisition and Immunogenesis Longitudinal birth cohort study followed 245 children from birth to 2 years of age with weekly stool sample collection and symptom surveys. Stool samples were tested by reverse transcriptase-realtime polymerase chain reaction to detect norovirus genogroup (G)I and GII; positive samples were genotyped. Infections accompanied by diarrhea and/or vomiting were considered symptomatic. Children were categorized as adherent if they participated for ≥18 months and submitted ≥70% of samples. A total of 72 GI and 330 GII norovirus infections (among 156 children) were identified. One-fifth (20.8%) of adherent children experienced ≥1 norovirus infection by 6 months of age, increasing to 84.2% children by 2 years of age. About one-third of infections were symptomatic, including half of infections with cycle threshold values <25. Infection with norovirus genotype GII.4 Sydney was the strongest predictor of symptomatic infection in adjusted analyses, as was older age and higher viral load. Childcare attendance, breastfeeding, mother's secretor status, and prior infections were not predictive of symptom status. This study highlights fundamental characteristics of norovirus epidemiology in early life with implications for understanding the full natural history of the disease, disease transmission and prevention approaches.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory condition that may affect any organ. Prostatic involvement is uncommon and under-recognised. The presentation often mimics benign prostatic hyperplasia or prostate carcinoma, causing diagnostic uncertainty. This systematic review synthesises evidence on IgG4-related prostatitis, focusing on clinical manifestations, diagnostic approaches, treatment, and outcomes. Following PRISMA 2020 guidelines, PubMed, Scopus, Web of Science, and Ovid were searched from inception to 12 February 2025. Eligible studies included English-language case reports, case series, and observational studies describing prostatic involvement in IgG4-RD. Data on demographics, clinical and laboratory findings, management, and outcomes were extracted and analysed descriptively. Fifty studies reporting 66 cases were included. Median age was 64 years (range 20-82). Serum IgG4 concentrations were elevated in most (median 832 mg/dL, range 5-4,500), while prostate-specific antigen (PSA) levels varied widely (0.01-180 ng/mL). Multiorgan involvement occurred in 57.8%, isolated disease in 6.2%. Lower urinary tract symptoms were most frequent (39.6%). Glucocorticoids, mainly prednisone, were the main therapy (69.2%), followed by surgery, chiefly transurethral resection of the prostate. Complete and partial responses occurred in 50.9% and 43.4%. Treatment type correlated with outcome (χ²=49.70; p<0.001). Malignancy (18.5%) was associated with higher mortality (p=0.028). IgG4-related prostatitis is a rare and likely under-recognised manifestation of IgG4-RD. Its overlap with benign and malignant prostatic disorders delays diagnosis. Serum IgG4 and PSA are unreliable markers of disease and monitoring. Glucocorticoids remain first-line therapy, with surgery in obstructive cases. Multicentre studies are needed to define prevalence, natural history, and optimal management.

This essay aims to scientifically justify the incorporation of Michael Balint’s basic failure theory (BFT) into medical education. This theory postulates that human beings suffer a fault between their needs and what the environment provides during critical periods of development in childhood and possibly from intrauterine life. The fault can be biological, physical, psychological or social. The sooner the basic failure is compensated, the better the person’s subsequent health will be. Clinical illness, in this interpretation, is a symptom of an uncompensated basic failure. Balint proposed BFT in opposition to the theory of external agents penetrating the defenses of a basically healthy organism, which is usually taught in medical schools. BFT facilitates direct access to the person-centered clinical method, facilitates the approach through narrative-based medicine; and notably, admits compassion as a therapeutic element in the doctor-patient relationship. Conceptually, it clearly fits with salutogenic approaches such as “The natural history of health” that are emerging in medical education. The scientific foundations supporting TFB come from fields such as social genomics, sociology, and historical-cultural learning theory.

There is significant interest in research on the pathology, natural history and treatment of brachial plexus birth injury. This article comments on a few newly published papers in the Journal of Hand Surgery (European Volume) to highlight updates and new research. Classification of brachial plexus birth injury remains challenging. Intraoperative findings from a recent article allow the introduction of a new classification based on findings during surgical exploration, providing a more precise description of the extent and severity of injury. The classification correlates well with pre- and postoperative function and should allow more accurate comparisons of treatment outcomes. Knowledge of the natural history of brachial plexus birth injury can help guide management decisions, such as the proportion of patients who will spontaneously recover active shoulder abduction. In another recent article, almost all cases regained 90° or more abduction, indicating a good chance of a satisfactory function. However, in contrast to other studies, recovery of elbow flexion at age 4 months did not predict outcome. Shoulder external rotation is an important movement which often recovers poorly after brachial plexus birth injury. A third article reported no difference in long-term outcomes of nerve grafting or transfer for restoration of shoulder external rotation. Overall, about a third of children did not regain active external rotation, indicating the difficulties restoring this movement. These studies contribute to improving management of brachial plexus birth injury, but more investigation of both the natural history and treatment outcomes is needed.

Time to Revise Myeloma Diagnostic Criteria? A Decade of Accumulated Evidence on Serum Free Light Chain Ratio ≥100.

Obesity has been traditionally defined by BMI alone, but this metric has limitations in assessing body fat composition and adiposity complications. The Lancet Diabetes and Endocrinology Commission (LDEC) issuedanew obesity definition to address these challenges, stratified by preclinical and clinical groups. We evaluated the epidemiology of preclinical and clinical obesity in the UK Biobank and associations with incident cardiovascular disease (CVD). We performed retrospective cohort analyses of 502,233 adults enrolled in the UK Biobank. Obesity was categorized using the new definition from LDEC. Clinical obesity was defined as adiposity-related dysfunction assessed via ICD10 codes, physical immobility, and abnormal laboratory values. Preclinical obesity had no additional metabolic deficits. The prevalence of preclinical and clinical obesity was 31.2% and 36.6%, and most were in the WHO overweight category. Clinical obesity was more prevalent in men, elderly, South Asians, and lower education or income level groups. Individuals with clinical obesity without baseline CVD had an increased hazard of incident stroke, heart failure, and myocardial infarction. In a large UK cohort, preclinical and clinical obesity were common, but the risk for incident CVD was elevated for those with clinical obesity.

Video games have been used in education for several decades. However, their use in classrooms is still limited to the inclusion of online games created for educational purposes. The video game industry is one of the most powerful in the entertainment business, and much is invested in the search for increasingly accurate recreations, thanks to the work of documentary filmmakers. The aim of this work is to evaluate the potential of certain commercial video games of a historical nature for their possible application in the teaching of Social Sciences in Primary Education. In order to carry out this analysis, a report was drawn up on four sagas, according to their link with the educational curriculum, the conditions of playability and accessibility, and a discourse of advantages and disadvantages. These reports were then qualitatively analysed using ATLAS.ti software. Among the results, it is worth highlighting the potential of these video games for teaching concepts related to Geography and History, and their impact on the motivational level. However, some disadvantages are highlighted when integrating these games into the classroom. In the discussion, the results are contrasted with similar studies on other types of video games in terms of their didactic and motivational potential. In short, video games can be an attractive educational resource when used appropriately.

Natural history museums are invaluable resources for large-scale ecological and evolutionary studies, but certain ecological traits can be challenging to recover, particularly from fluid-preserved specimens. Stable isotope analysis is an elegant method for reconstructing the dietary niche over integrated timescales, and recovering this information from museum specimens can provide a critical axis of ecological information for studies of population dynamics through time and space. However, isotope ratios of tissues are known to be altered by extended contact with formalin and ethanol. Here, we assess whether intra- and interspecific variation in isotopic signature, which represent critical data used to assess metrics of niche diversity, can be reliably recovered following fluid preservation. We use a broad taxonomic distribution of squamates to compare niche metrics prior to and 8 weeks following a standard museum preservation process We could not recover intraindividual metrics of niche diversity but found that between-individual variation was not significantly altered, allowing for the reconstruction of community niche characteristics We present an example isotopic analysis from museum specimens representing generalist and specialist Thamnophis garter snake populations that aligns with empirical estimates of niche width We also present several additional analyses on tissue-specific effects, delipification and buffer storage, with useful insights for field collection and downstream analysis decisions.

Barrett's esophagus is the known precursor to esophageal adenocarcinoma (EAC), a cancer with poor prognosis. While endoscopic surveillance detects early dysplasia and prevents progression, most Barrett's esophagus patients do not progress to EAC, leading to invasive and costly surveillance. This study aimed to identify cost-effective endoscopic surveillance strategies by risk stratifying patients based on Barrett's esophagus segment length and sex. A Markov cohort model was developed to simulate the natural history of Barrett's esophagus to EAC. The model assessed 85 surveillance strategies and varied endoscopy intervals from 2 to 10 years for nondysplastic Barrett's esophagus and 6-12 months for dysplasia. Risk stratification was based on segment length (≤ 2 and ≤ 3 cm) and sex. Costs, utilities and transition probabilities were derived from published literature and clinical databases. Deterministic and probabilistic sensitivity analyses were performed, and cost-effectiveness was evaluated from a third-party payer perspective using a threshold of AU$50 000/QALY (2023 US dollars 35 945/QALY). The most cost-effective strategy was biennial surveillance for long-segment BE (> 2 cm) and 12-month surveillance for LGD, excluding surveillance in low-risk patients (ICER US$23 737/QALY). Risk-based surveillance consistently outperformed nonstratified strategies. Sensitivity analyses confirmed the robustness of the model, with key drivers being transition rates and endoscopy costs. We identified cost-effective risk-stratified endoscopic surveillance strategies for Barrett's esophagus, particularly when excluding low-risk patients. Tailored risk-guided surveillance strategies could improve resource allocation and clinical outcomes in managing Barrett's esophagus. The conserved resources can then be utilized to identify high-risk individuals in the community.

Carotid atherosclerosis remains one of the primary etiological factors underlying ischemic stroke, contributing to adult neurological disability and mortality. In recent years, non-coding RNAs (ncRNAs) have emerged as key regulators of gene expression, actively modulating molecular pathways involved in atherogenesis. This systematic review, the first to be exclusively focused on carotid atherosclerosis, aimed at synthesizing current findings on the differential expression of ncRNAs throughout the natural history of the disease, thus providing the first comprehensive attempt to delineate a stage-specific ncRNA expression profile in carotid disease. A comprehensive literature search was conducted in PubMed and Scopus databases in January 2025, following PRISMA guidelines. Original studies involving human subjects with carotid atherosclerosis, evaluating the expression of intracellular or circulating ncRNAs, were included and then categorized according to their association with cardiovascular risk factors, carotid intima-media thickness (cIMT), presence of atherosclerotic plaques, plaque vulnerability, clinical symptoms, and ischemic stroke. Out of 148 articles initially identified, 49 met the inclusion criteria and were analyzed in depth. Among the different classes of ncRNAs, microRNAs (miRNAs) were the most frequently reported as dysregulated, followed by circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs). Notably, the majority of identified ncRNAs were implicated in key pathogenic mechanisms such as inflammatory signaling, vascular smooth muscle cell (VSMC) phenotypic modulation, and ABCA1-mediated cholesterol efflux. Collectively, the evidence underscores the association and possible involvement of ncRNAs in the initiation and progression of carotid atherosclerosis and its cerebrovascular complications. Their relative stability in biological fluids and cell-specific expression profiles highlight their strong potential as minimally invasive biomarkers and—possibly—novel therapeutic targets.

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality. It usually arises in cirrhotic liver, where chronic inflammation and fibrosis create a tumor-permissive microenvironment. Dysregulation of microRNAs (miRNAs), particularly upregulation of the oncomiR miR-221 and loss of the tumor suppressor miR-199a-3p represent key drivers of liver carcinogenesis. The TG221 transgenic mouse, designed to overexpress miR-221 in hepatocytes, provides a relevant in vivo platform for mechanistic studies and for testing preventive and therapeutic approaches. The TG221 model recapitulates miR-221-driven tumorigenesis, including suppression of p27, p57 and Bmf. It is characterized by steatohepatitic injury and accelerated tumor formation after genotoxic challenge. In the cirrhotic CCl4-induced background, TG221 mice develop fibrosis and cirrhosis followed by dysplastic and malignant lesions, mirroring the natural history of human HCC. Metformin administered during early fibrosis prevented macroscopic tumor formation and suppressed PI3K/AKT/mTOR signaling. Anti-miR-221 and miR-199a-3p mimics reduced tumor burden, restored tumor-suppressive pathways and improved liver integrity, thus indicating feasible chemopreventive strategies. From a therapeutic point of view, miR-199a-3p replacement synergized with palbociclib and overcame sorafenib resistance. A miR-199a-3p-responsive oncolytic adenovirus achieved tumor-selective replication with minimal toxicity. This review highlights the importance of the TG221 transgenic mouse as a powerful model for studying miRNA-driven hepatocarcinogenesis and enables preclinical evaluation of RNA-based chemopreventive and therapeutic approaches. Metformin, miRNA inhibition, miRNA replacement and miRNA-guided viral therapies emerge as promising approaches for advancing precision prevention and treatment strategies in HCC.

ABSTRACTBiodiversity is facing global change at an unprecedented rate. Understanding how populations have responded to accelerated change over the last century is key to informing effective conservation policies. Serially collected specimens from natural history repositories can provide a window into how populations change over time and highlight further vulnerabilities in remaining populations. Changes in observed population abundance during field surveys suggest that some Plethodon salamander populations experienced declines since the 1960s, but the potential population genetic consequences of these declines remain unstudied. Thanks to decades of sustained collection‐based efforts, Plethodon salamanders serve as a model to test the utility of historical DNA to identify shifts in genetic diversity at recent time scales. Here, we investigate demographic change in six Plethodon species through time using DNA from formalin‐fixed museum specimens (1960s–1970s), historic frozen blood (1980s–1990s), and contemporary sampling. We generated several reduced representation SNP datasets using a target‐capture approach to investigate two sites in the Appalachian Range: one with documented declines (Indian Grave Gap) and one without (Skull's Gap). We quantify the impact of bioinformatic choices on estimates of genetic diversity, quantify demographic shifts, and trace changes in allele frequencies in immune‐related loci to explore the potential impact of pathogens on putative declines. We found consistent patterns of genetic diversity change across datasets and filtering regimes. At Skull's Gap, our results suggest that populations were stable or expanding, while at Indian Grave Gap, our results suggest contraction in one species and mixed signals of contraction and expansion in the others. Analyses of immune loci suggest that balancing selection is maintaining shared polymorphism through time in all but one species. Our study outlines important considerations for leveraging historical DNA in time series collections to quantify the genomic effects of localized population declines.

Rangitāhua is a tupuna to Ngāti Kuri and represents the iwi's geographic and ancestral connection to the Pacific. Despite this millennium‐long ancestral tie, Ngāti Kuri's access to Rangitāhua has been severed for two centuries. Meanwhile, many European expeditions visited the islands, extracting and distributing natural history taonga across institutions, mostly in the Northern Hemisphere. In this context of disconnection, Ngāti Kuri engaged partners to reclaim research leadership over Rangitāhua, leading to the Indigenous‐led Te Mana o Rangitāhua program, embedding Māori values and tikanga within the environmental wellbeing research project. This study is part of the program and documents our collaborative approach to identifying expeditions to Rangitāhua, mapping where their taonga and data are held worldwide, and examining institutional responses to our data requests. We identified 127 expeditions that distributed 1.73 million objects across 88 institutions. Our provenance mapping successfully cross‐linked specimens to the expeditions that collected them and the institutions that house them today. However, our research also revealed ongoing institutional barriers to data access, emphasizing colonial gatekeeping practices embedded in contemporary museology systems. We stress the urgent need for accessible and reciprocal data request systems if museum practitioners hope to advance the ultimate goal of Indigenous data sovereignty.

Background: The vestibular schwannoma (VS) is the most common cerebellopontine angle tumor in adults, exhibiting a highly variable natural history, from stability to rapid growth. Accurate, the non-invasive prediction of tumor behavior is essential to guide personalized management and avoid overtreatment or delayed intervention. Objective: To systematically review and synthesize the evidence on MRI-based biomarkers for predicting VS growth and treatment responses. Methods: We conducted a PRISMA-compliant search of PubMed, EMBASE, and Cochrane databases for studies published between 1 January 2000 and 1 January 2025, addressing MRI predictors of VS growth. Cohort studies evaluating texture features, signal intensity ratios, perfusion parameters, and apparent diffusion coefficient (ADC) metrics were included. Study quality was assessed using the NOS (Newcastle–Ottawa Scale) score, GRADE (Grading of Recommendations, Assessment, Development and Evaluation), and ROBIS (Risk of Bias in Systematic reviews) tool. Data on diagnostic performance, including the area under the receiver operating characteristic (ROC) curve (AUC), sensitivity, specificity, and p value, were extracted and descriptively analyzed. Results: Ten cohort studies (five retrospective, five prospective, total n = 525 patients) met the inclusion criteria. Texture analysis metrics, such as kurtosis and gray-level co-occurrence matrix (GLCM) features, yielded AUCs of 0.65–0.99 for predicting volumetric or linear growth thresholds. Signal intensity ratios on gadolinium-enhanced T1-weighted images for tumor/temporalis muscle achieved a 100% sensitivity and 93.75% specificity. Perfusion MRI parameters (Ktrans, ve, ASL, and DSC derived blood-flow metrics) differentiated growing from stable tumors with AUCs up to 0.85. ADC changes post-gamma knife surgery predicted a favorable response, though the baseline ADC had limited value for natural growth prediction. The heterogeneity in growth definitions, MRI protocols, and retrospective designs remains a key limitation. Conclusions: MRI-based biomarkers may provide exploratory signals associated with VS growth and treatment responses. However, substantial heterogeneity in growth definitions and MRI protocols, small single-center cohorts, and the absence of external validation currently limit clinical implementation.

Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of pancreatic neoplasms that originate from the endocrine cells of the pancreas, whose prevalence and incidence are constantly increasing worldwide. Based on current knowledge of their natural history, pNETs can be divided into functioning pNET and nonfunctioning pNET tumors, characterized by hormone hypersecretion, which results distinct clinical presentations. Treatment options include observation, medical or surgical therapy, and the choice depends on various factors such as staging and grading of the pancreatic lesion and the presence of a specific hormonal syndrome. Surgical resection has long been considered the gold standard for treatment, with related risks of morbidity and mortality. Endoscopic ultrasound (EUS)-guided radiofrequency ablation (RFA) plays a crucial role as minimally invasive procedure for loco-regional treatment of pNETs in selected patients, showing promising results in terms of clinical outcome. EUS-RFA causes a coagulative necrosis with minimal damage to surrounding tissue, allowing for local ablation. This review summarizes the most recent evidences on the use of EUS-RFA as local ablation therapy describing the main endoscopic steps and providing a critical overview of patient selection criteria, side effects, and long-term outcomes.

Early Onset Scoliosis (EOS), defined as presenting before 10 years of age, often has a significant adverse impact on pulmonary function, due to a complex interrelationship between the spine, chest, pulmonary structures and their development. Left untreated, EOS leads to premature death, with early fusion surgery to arrest curve progression making little impact on this. To date, the natural history has not been clearly established as compounded by the heterogeneity of pathologies, causing EOS and challenges in objective measurements of pulmonary function in this young age group. A desire to address this poor natural history has motivated interest in pursuing ‘growth friendly’ surgical strategies. The implants used have evolved with time, often to address compromises and poor results, with multiple options now available based on treatment principles (distraction, compression, or guided growth systems). The aims of such strategies are to control the structural spinal deformity, whilst allowing spinal and thoracic growth, with the seemingly reasonable expectation that this will result in improved pulmonary function and avoidance of premature death. Most studies have focused on radiological outcome measures such as Cobb angle and thoracic height to gauge the success of surgery, with these measures acting as surrogate markers of improved pulmonary outcome. This assumption, however, is not supported by more recent clinical data which has attempted to assess directly the pulmonary outcomes associated with growth-friendly surgical strategies. This literature review therefore sets out to characterise the effect of EOS on pulmonary function and to critically analyse the impact surgical treatment options will have while addressing this.

Fetal/neonatal alloimmune thrombocytopenia (FNAIT) caused by antibodies to human platelet antigen (HPA)-1a in white HPA-1a-negative mothers is the most frequent cause of intracranial hemorrhage (ICH) in otherwise healthy newborns. To investigate the natural history of FNAIT and establish a biobank from HPA-1a-negative alloimmunized and nonimmunized pregnancies. A total of 24,259 pregnant women were recruited to the study during 2013-2017 and 24,236 were screened for HPA-1a. Anti-HPA-1a antibodies were tested by Monoclonal Antibody Immobilization of Platelet Antigens (MAIPA) and some samples (MAIPA-negative), with Luminex bead-based immunoassay (PAKLx) if the neonate had thrombocytopenia and/or ICH. HPA-1 genotyping of fathers, fetuses (from maternal plasma), and newborns was performed. Biological material was stored in biobanks in Norway and Poland. Among 583/24,236 (2.4%) HPA-1a-negative women, samples were obtained from 529, of which 513 were examined during pregnancy. Anti-HPA-1a antibodies were detected in 48/529 (9.1%) women; whereof 34/513 (6.6%) during pregnancy, either by prospective MAIPA (n = 27) or in retrospect by PAKLx in MAIPA-negatives (n = 7). FNAIT was diagnosed in 11/34 (32%) neonates from alloimmunized pregnancies: in 6/11 cases by prospective MAIPA and in 5/11 by retrospective PAKLx. There were no neonates with FNAIT-associated ICH delivered by MAIPA-positive women, but 3 ICH/severe thrombocytopenia cases were diagnosed by PAKLx. Among nonimmunized HPA-1a-negative women, 28 newborns had thrombocytopenia and 2 others had ICH. Feasibility of HPA-1 antenatal screening was demonstrated, and a comprehensive biobank was established. The FNAIT detection rate was improved by retrospective diagnostics by PAKLx, including 3 newborns with ICH not identified by prospective MAIPA.

The natural history of a species reflects its present and past adaptations, providing crucial evidence about the evolution and ecology of the group. Understanding these aspects allows for identifying the complex intra- and interspecific interactions that influence population dynamics. In this study, we investigated Coleodactylus meridionalis, a small terrestrial lizard with a broad distribution, in an Atlantic Forest fragment. Specifically, we analyzed the usage of microhabitats, morphological characteristics, reproductive aspects, diet, and associated endoparasites. We conducted monthly seven-day expeditions from August 2014 to July 2015 in the Campo de Instrução Marechal Newton Cavalcante, Pernambuco, Brazil. We recorded spatial use by 285 individuals, 271 (95%) of which were found in the forest interior, predominantly in leaf litter microhabitats (90.5%; N = 258). Females were significantly larger than males and had proportionally higher head heights. The diet included 22 prey categories, with Isopoda being the most frequent and voluminous and Psocoptera the most numerous prey categories found in the stomachs. The population reproduces continuously throughout the year, with fixed clutches of a single egg. The macro endoparasites found was an acanthocephalan cystacanth, with a prevalence of 13% and a mean infection intensity of 1.5 ± 0.74, and a Brachycoeliidae trematode, with a prevalence of 1.9% and a mean intensity of 3 ± 1.9. This is the first record of parasites for C. meridionalis, both as a paratenic host for cystacanth and as a definitive host for Brachycoeliidae.

Atrial fibrillation (AF) is a major public health problem, associated with increased risks of heart failure, stroke, dementia, and mortality. The treatment of AF involves multiple potential approaches, all of which presently have significant limitations. Over the past 20 years, tremendous advances have been made in understanding the pathophysiological determinants of AF. The present narrative review article aims to address selected issues that are highly relevant to clinically important questions in AF pathophysiology, by reviewing insights from both experimental observations and complementary clinical investigations. Issues that we address include: 1) Introduction and mechanistic concepts; 2) The mechanistic basis for the crucial role of the pulmonary veins in AF; 3) The progressive natural history of AF; 4) The nature and mechanisms of secondary AF; 5) AF and heart failure with reduced ejection fraction; 6) AF and heart failure with preserved ejection fraction; 7) AF burden- importance and mechanistic determinants; and 8) The clinical importance of better understanding AF pathophysiology, leveraging new physiological knowledge and technologies to improve AF prevention. We consider in detail changes in ion channel and transporter function, the importance of inflammatory signaling, and the contribution of changes in tissue structure and composition in the development of AF-promoting atrial cardiomyopathy. The developments in our understanding of AF pathophysiology have been enormous and have produced many new conceptual and therapeutic opportunities, along with a wide range of important new questions. To capitalize on these opportunities and address the new questions that have emerged will require substantial additional investigation.

Editorial: Risk and protective factors in the natural history of autoimmunity