Hypoxia-Inducible Factor and Oxidative Stress in Tendon Degeneration: A Molecular Perspective.

Tendinopathy is a debilitating condition marked by degenerative changes in the tendons. Its complex pathophysiology involves intrinsic, extrinsic, and physiological factors. While its intrinsic and extrinsic factors have been extensively studied, the role of physiological factors, such as hypoxia and oxidative stress, remains largely unexplored. This review article delves into the contribution of hypoxia-associated genes and oxidative-stress-related factors to tendon degeneration, offering insights into potential therapeutic strategies. The unique aspect of this study lies in its pathway-based evidence, which sheds light on how these factors can be targeted to enhance overall tendon health.

Arthroscopic suprapectoral biceps tenodesis provided earlier shoulder function restoration compared with open subpectoral biceps tenodesis during the recovery phase.

BACKGROUND: This study compared the clinical outcomes of open subpectoral biceps tenodesis and arthroscopic suprapectoral biceps tenodesis for symptomatic biceps tenosynovitis. Although both techniques have pros and cons, no studies have compared clinical and functional outcomes during the recovery phase. Previous studies show that suprapectoral tenodesis has a higher probability of Popeye deformity and postoperative bicipital pain and stiffness, whereas subpectoral tenodesis has a higher risk of nerve complications and wound infections. This study aimed for clinical comparison between arthroscopic suprapectoral biceps tenodesis and open subpectoral biceps tenodesis. METHODS: This study is a retrospective review of institutional records of patients with biceps tendinitis who underwent open or arthroscopic biceps tenodesis. Surgical indications included biceps tenosynovitis, biceps partial tear, and biceps pulley lesion. Patients with prior shoulder surgery, preoperative shoulder stiffness, or full-thickness tear of rotator cuff were excluded. Tenodesis was considered when the pain recurs within 3 months despite conservative treatment including at least 2 triamcinolone injections on the biceps tendon sheath. Visual analog scale (VAS) score for pain, presence of the night pain, American Shoulder and Elbow Surgeons (ASES) score, Constant score, and range of motion were assessed preoperatively at 3, 6, 12, and 24 months postoperatively and the last follow-up. RESULTS: A total of 72 patients (33 with arthroscopic suprapectoral biceps tenodeses and 39 with open subpectoral biceps tenodeses) were included in analysis. At postoperative 6 months, lower VAS score (0.4 ± 0.8 vs. 1.7 ± 1.9, P < .001), and the presence of the night pain (2 [6%] vs. 14 [36%], P = .002), ASES score (89.6 ± 9.2 vs. 81.4 ± 14.6, P = .006), and Constant score (89.4 ± 5.6 vs. 82.0 ± 12.5, P = .003) compared with the subpectoral group. The mean number of postoperative steroid injections for pain control in the subpectoral group (0.51 ± 0.80) was significantly higher than that in the suprapectoral group (0.18 ± 0.40) (P = .031). However, postoperative clinical outcomes were restored similar between the 2 groups at 12 months and the last follow-up. DISCUSSION: Arthroscopic suprapectoral biceps tenodesis performed statistically better than the subpectoral biceps tenodesis for the VAS, ASES, night pain, and Constant score at postoperative 6 months. However, only night pain and the Constant score showed differences that exceeded minimum clinically important difference during the recovery phase. At postoperative 12 and 24 months, biceps tenodesis provided satisfactory clinical outcomes and pain relief regardless of the fixation technique and suture anchor location.

Occult, Incomplete, and Complete Posterior Labral Tears Without Glenohumeral Instability on Imaging Underestimate Labral Detachment.

PURPOSE: To introduce a classification of posterior labral tear and describe clinical characteristics, magnetic resonance imaging (MRI)/magnetic resonance arthrography (MRA) findings, arthroscopic findings, and outcomes after arthroscopic repair for patients with posterior labral tears without glenohumeral instability. METHODS: Sixty patients with posterior labral tear who underwent arthroscopic repair were analyzed retrospectively. Patients with shoulder instability were excluded. Tear patterns were classified into 3 types; occult (type 1), incomplete (type 2), and complete (type 3) based on MRI/MRA studies. A visual analog scale score for pain, American Shoulder and Elbow Surgeons score, Single Assessment Numeric Evaluation score for satisfaction, and return to sports were evaluated at a minimum follow-up of 2 years. Computed tomography arthrography was performed at a year follow-up for assess labral healing. The diagnosis was confirmed in arthroscopy, and arthroscopic labral repair without capsular plication was performed. RESULTS: The mean patient age was 30.4 ± 6.9 years, and all patients were male. Forty-four patients (73.3%) were participating in sports. MRI/MRA studies identified 10 patients with type 1, 18 with type 2, and 32 with type 3 tears. Type 1 tear patients showed a significantly longer symptom duration than those with type 3 (32.5 ± 17.2 vs 18.2 ± 17.1 months; P = .015). In arthroscopic findings, 70% of type 1 tear was confirmed as incomplete or complete tears. The American Shoulder and Elbow Surgeons score improved from 79.6 ± 10.3 to 98.1 ± 3.7, and pain was relieved from 2.4 ± 0.7 to 0.2 ± 0.5 at the last follow-up visit with high labral healing rate (95%). Thirty-nine (88.6%) patients returned to sports at preinjury levels. CONCLUSIONS: In active young men with shoulder pain during daily activities or sports despite programmed conservative treatment, posterior labral tears should be considered even when MRI/MRA findings are ambiguous. Arthroscopic posterior labral repair without capsular plication provided satisfactory clinical outcomes and a high labral healing rate. LEVEL OF EVIDENCE: Level Ⅳ, case series.

Blanket antimicrobial resistance gene database with structural information, BOARDS, provides insights on historical landscape of resistance prevalence and effects of mutations in enzyme structure.

Antimicrobial resistance (AMR) in pathogenic bacteria poses a significant threat to public health, yet there is still a need for development in the tools to deeply understand AMR genes based on genetic or structural information. In this study, we present an interactive web database named Blanket Overarching Antimicrobial-Resistance gene Database with Structural information (BOARDS, sbml.unist.ac.kr), a database that comprehensively includes 3,943 reported AMR gene information for 1,997 extended spectrum beta-lactamase (ESBL) and 1,946 other genes as well as a total of 27,395 predicted protein structures. These structures, which include both wild-type AMR genes and their mutants, were derived from 80,094 publicly available whole-genome sequences. In addition, we developed the rapid analysis and detection tool of antimicrobial-resistance (RADAR), a one-stop analysis pipeline to detect AMR genes across whole-genome sequencing (WGSs). By integrating BOARDS and RADAR, the AMR prevalence landscape for eight multi-drug resistant pathogens was reconstructed, leading to unexpected findings such as the pre-existence of the MCR genes before their official reports. Enzymatic structure prediction-based analysis revealed that the occurrence of mutations found in some ESBL genes was found to be closely related to the binding affinities with their antibiotic substrates. Overall, BOARDS can play a significant role in performing in-depth analysis on AMR.IMPORTANCEWhile the increasing antibiotic resistance (AMR) in pathogen has been a burden on public health, effective tools for deep understanding of AMR based on genetic or structural information remain limited. In this study, a blanket overarching antimicrobial-resistance gene database with structure information (BOARDS)-a web-based database that comprehensively collected AMR gene data with predictive protein structural information was constructed. Additionally, we report the development of a RADAR pipeline that can analyze whole-genome sequences as well. BOARDS, which includes sequence and structural information, has shown the historical landscape and prevalence of the AMR genes and can provide insight into single-nucleotide polymorphism effects on antibiotic degrading enzymes within protein structures.

Detection of Abnormal Changes on the Dorsal Tongue Surface Using Deep Learning.

Background and Objective: The tongue mucosa often changes due to various local and systemic diseases or conditions. This study aimed to investigate whether deep learning can help detect abnormal regions on the dorsal tongue surface in patients and healthy adults. Materials and Methods: The study collected 175 clinical photographic images of the dorsal tongue surface, which were divided into 7782 cropped images classified into normal, abnormal, and non-tongue regions and trained using the VGG16 deep learning model. The 80 photographic images of the entire dorsal tongue surface were used for the segmentation of abnormal regions using point mapping segmentation. Results: The F1-scores of the abnormal and normal classes were 0.960 (precision: 0.935, recall: 0.986) and 0.968 (precision: 0.987, recall: 0.950), respectively, in the prediction of the VGG16 model. As a result of evaluation using point mapping segmentation, the average F1-scores were 0.727 (precision: 0.717, recall: 0.737) and 0.645 (precision: 0.650, recall: 0.641), the average intersection of union was 0.695 and 0.590, and the average precision was 0.940 and 0.890, respectively, for abnormal and normal classes. Conclusions: The deep learning algorithm used in this study can accurately determine abnormal areas on the dorsal tongue surface, which can assist in diagnosing specific diseases or conditions of the tongue mucosa.

Model-driven experimental design workflow expands understanding of regulatory role of Nac in Escherichia coli.

The establishment of experimental conditions for transcriptional regulator network (TRN) reconstruction in bacteria continues to be impeded by the limited knowledge of activating conditions for transcription factors (TFs). Here, we present a novel genome-scale model-driven workflow for designing experimental conditions, which optimally activate specific TFs. Our model-driven workflow was applied to elucidate transcriptional regulation under nitrogen limitation by Nac and NtrC, in Escherichia coli. We comprehensively predict alternative nitrogen sources, including cytosine and cytidine, which trigger differential activation of Nac using a model-driven workflow. In accordance with the prediction, genome-wide measurements with ChIP-exo and RNA-seq were performed. Integrative data analysis reveals that the Nac and NtrC regulons consist of 97 and 43 genes under alternative nitrogen conditions, respectively. Functional analysis of Nac at the transcriptional level showed that Nac directly down-regulates amino acid biosynthesis and restores expression of tricarboxylic acid (TCA) cycle genes to alleviate nitrogen-limiting stress. We also demonstrate that both TFs coherently modulate α-ketoglutarate accumulation stress due to nitrogen limitation by co-activating amino acid and diamine degradation pathways. A systems-biology approach provided a detailed and quantitative understanding of both TF's roles and how nitrogen and carbon metabolic networks respond complementarily to nitrogen-limiting stress.

Simple method of measuring ocular rotation in supine position during small incision lenticule extraction.

AIM: To introduce a novel measurement method of static cyclotorsion in small incision lenticule extraction (SMILE) and to investigate the effect of preoperative parameters on cyclotorsion and the effect of cyclotorsion on postoperative outcomes. METHODS: The medical records of 242 patients and 484 eyes who underwent SMILE surgery were retrospectively reviewed. Preoperative intraocular pressure, refractive error, and corneal thickness were investigated. Refractive values and visual acuity were measured at 1d, 1, 3, and 6mo. Ocular cyclotorsion in the supine position was measured by calculating the location and angle of the incision site of the cornea in the anterior slit photograph taken after surgery. RESULTS: Of the total 484 eyes in 242 patients, preoperative mean spherical equivalent (SE) was -4.10±1.64 D, and the mean astigmatism was -0.82±0.74 D. Uncorrected distance visual acuity (UCVA) and SE improved significantly after the surgery. Moreover, 219 (45.2%) eyes had excyclotorsion, 235 (48.6%) eyes had incyclotorsion, and 30 (6.2%) eyes had no torsion. The right eyes tended to be excyclotorted, and the left eyes tended to be incyclotorted (P<0.01). The mean cyclotorsion was 1.18°±3.69°, and the mean absolute value of cyclotorsion was 3.14°±2.26°. The range of cyclotorsion was 0.5°-11.4°. It was found that the smaller the preoperative sphere, the higher the amount of cyclotorsion (r=0.11, P=0.016). There was no significant association between the amount of cyclotorsion and preoperative astigmatism. There was no correlation between sex, preoperative corneal thickness, preoperative intraocular pressure, amount of cyclotorsion, and direction of cyclotorsion. The ratio of right eye excyclotorsion and left eye incyclotorsion on 1d was higher than that at 1, 3, and 6mo (all P<0.01). There was no difference between the 1, 3, and 6mo results in the right and left eyes (P=0.15, P=0.16, respectively). CONCLUSION: The newly devised ocular cyclotorsion measurement method can be used to evaluate ocular cyclotorsion after SMILE. Preoperative SE is associated with the amount of cyclotorsion, however, cyclotorsion doesn't have a significant effect on the results of SMILE surgery.

Transcriptional Heterogeneity of Cellular Senescence in Cancer.

Cellular senescence plays a paradoxical role in tumorigenesis through the expression of diverse senescence-associated (SA) secretory phenotypes (SASPs). The heterogeneity of SA gene expression in cancer cells not only promotes cancer stemness but also protects these cells from chemotherapy. Despite the potential correlation between cancer and SA biomarkers, many transcriptional changes across distinct cell populations remain largely unknown. During the past decade, single-cell RNA sequencing (scRNA-seq) technologies have emerged as powerful experimental and analytical tools to dissect such diverse senescence-derived transcriptional changes. Here, we review the recent sequencing efforts that successfully characterized scRNA-seq data obtained from diverse cancer cells and elucidated the role of senescent cells in tumor malignancy. We further highlight the functional implications of SA genes expressed specifically in cancer and stromal cell populations in the tumor microenvironment. Translational research leveraging scRNA-seq profiling of SA genes will facilitate the identification of novel expression patterns underlying cancer susceptibility, providing new therapeutic opportunities in the era of precision medicine.

Long-Term Treatment with the Combination of Rivaroxaban and Aspirin in Patients with Chronic Coronary or Peripheral Artery Disease: Outcomes During the Open Label Extension of the COMPASS trial.

AIMS: To describe outcomes of patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD) enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) randomized trial who were treated with the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily during long-term open-label extension (LTOLE). METHODS AND RESULTS: Of the 27 395 patients enrolled in COMPASS, 12 964 (mean age at baseline 67.2 years) from 455 sites in 32 countries were enrolled in LTOLE and treated with the combination of rivaroxaban and aspirin for a median of 374 additional days (range 1-1191 days). During LTOLE, the incident events per 100 patient years were as follows: for the primary outcome [cardiovascular death, stroke, or myocardial infarction (MI)] 2.35 [95% confidence interval (CI) 2.11-2.61], mortality 1.87 (1.65-2.10), stroke 0.62 (0.50-0.76), and MI 1.02 (0.86-1.19), with CIs that overlapped those seen during the randomized treatment phase with the combination of rivaroxaban and aspirin. The incidence rates for major and minor bleeding were 1.01 (0.86-1.19) and 2.49 (2.24-2.75), compared with 1.67 (1.48-1.87) and 5.11 (95% CI 4.77-5.47), respectively, during the randomized treatment phase with the combination. CONCLUSION: In patients with chronic CAD and/or PAD, extended combination treatment for a median of 1 year and a maximum of 3 years was associated with incidence rates for efficacy and bleeding that were similar to or lower than those seen during the randomized treatment phase, without any new safety signals.

Predictive value of the videofluoroscopic swallowing study for long-term mortality in patients with subacute stroke.

ABSTRACT: To investigate the usefulness of the videofluoroscopic swallowing study (VFSS) for subacute stroke in predicting long-term all-cause mortality, including not only simple parameters obtained from VFSS results, but also recommended dietary type as an integrated parameter.This was a retrospective study of patients with subacute (<1 month) stroke at a university hospital between February 2014 and September 2019. The independent risk factors were investigated using stepwise Cox regression analysis, which increased the all-cause mortality of patients with stroke among VFSS parameters.A total of 242 patients with subacute stroke were enrolled. The significant mortality-associated factors were age, history of cancer, recommended dietary type (modified dysphagia diet; adjusted hazard ratio [HR], 6.971; P = .014; tube diet, adjusted HR: 10.169; P = .019), and Modified Barthel Index. In the subgroup survival analysis of the modified dysphagia diet group (n = 173), the parameters for fluid penetration (adjusted HR: 1.911; 95% confidence interval, 1.086-3.363; P = .025) and fluid aspiration (adjusted HR: 2.236; 95% confidence interval, 1.274-3.927; P = .005) were significantly associated with mortality.The recommended dietary type determined after VFSS in subacute stroke was a significant risk factor for all-cause mortality as an integrated parameter for dysphagia. Among the VFSS parameters, fluid penetration and aspiration were important risk factors for all-cause mortality in patients with moderate dysphagia after stroke. Therefore, it is important to classify the degree of dysphagia by performing the VFSS test in the subacute period of stroke and to determine the appropriate diet and rehabilitation intervention for mortality-related prognosis.

Characterization of Klebsiella pneumoniae bacteriophages, KP1 and KP12, with deep learning-based structure prediction.

Concerns over Klebsiella pneumoniae resistance to the last-line antibiotic treatment have prompted a reconsideration of bacteriophage therapy in public health. Biotechnological application of phages and their gene products as an alternative to antibiotics necessitates the understanding of their genomic context. This study sequenced, annotated, characterized, and compared two Klebsiella phages, KP1 and KP12. Physiological validations identified KP1 and KP12 as members of Myoviridae family. Both phages showed that their activities were stable in a wide range of pH and temperature. They exhibit a host specificity toward K. pneumoniae with a broad intraspecies host range. General features of genome size, coding density, percentage GC content, and phylogenetic analyses revealed that these bacteriophages are distantly related. Phage lytic proteins (endolysin, anti-/holin, spanin) identified by the local alignment against different databases, were subjected to further bioinformatic analyses including three-dimensional (3D) structure prediction by AlphaFold. AlphaFold models of phage lysis proteins were consistent with the published X-ray crystal structures, suggesting the presence of T4-like and P1/P2-like bacteriophage lysis proteins in KP1 and KP12, respectively. By providing the primary sequence information, this study contributes novel bacteriophages for research and development pipelines of phage therapy that ultimately, cater to the unmet clinical and industrial needs against K. pneumoniae pathogens.

STAT3 maintains skin barrier integrity by modulating SPINK5 and KLK5 expression in keratinocytes.

Skin barrier dysfunction induces skin inflammation. Signal transducer and activator of transcription 3 (STAT3) is known to be involved in Th17-mediated immune responses and barrier integrity in the cornea and intestine; however, its role in the skin barrier remains largely unknown. In this study, we elucidated the potential role of STAT3 in the skin barrier and its effect on kallikrein-related peptidase 5 (KLK5) and serine protease inhibitor Kazal-type 5 (SPINK5) expression using a mouse model with keratinocyte-specific ablation of STAT3. Keratinocyte-specific loss of STAT3 induced a cutaneous inflammatory phenotype with pruritus and intense scratching behaviour in mice. Transcriptomic analysis revealed that the genes associated with impaired skin barrier function, including KLK5, were upregulated. The effect of STAT3 on KLK5 expression in keratinocytes was not only substantiated by the increase in KLK5 expression following treatment with STAT3 siRNA but also by its decreased expression following STAT3 overexpression. Overexpression and IL-17A-mediated stimulation of STAT3 increased the expression of SPINK5, which was blocked by STAT3 siRNA. These results suggest that the expression of SPINK5 and KLK5 in keratinocytes could be dependent on STAT3 and that STAT3 might play an essential role in the maintenance of skin barrier homeostasis.

Post-pregnancy osteoporosis-related multiple vertebral fractures associated with post-partum thyroiditis: A CARE-compliant case report.

INTRODUCTION: Osteoporosis is a condition commonly observed in elderly and postmenopausal women. Pregnancy and lactation-induced osteoporosis are rare, and the development of severe vertebral fractures is uncommon. Postpartum thyroiditis (PPT) is a minor cause of osteoporosis. To the best of our knowledge, the development of osteoporosis associated with pregnancy has not yet been reported. PATIENT CONCERNS: Here, we report a rare case of post-pregnancy osteoporosis-related multiple vertebral fractures associated with PPT. A 25-year-old woman developed lower back pain after her first delivery. She was then admitted to our medical center because of aggravated back pain. DIAGNOSIS: On radiographic examination, she had multiple compressions of the lumbar spine. Bone mineral density was associated with osteoporosis. Laboratory tests, thyroid scans, and thyroid ultrasonography were performed. The patient was diagnosed with PPT. INTERVENTIONS: The patient stopped lactating immediately. She was administered bisphosphate at 3 mg/3 months intravenously, elementary calcium at 1000 mg/day, and calcitriol 0.5 µg/day. OUTCOMES: A month later, her pain was relieved by proper management and she could independently walk indoors. CONCLUSION: PPT might play a role in aggravating post-pregnancy osteoporosis. It should be considered as a differential diagnosis in patients presenting with postpartum osteoporosis-related multiple spine fractures.

PPARγ Targets-Derived Diagnostic and Prognostic Index for Papillary Thyroid Cancer.

In most cases, papillary thyroid cancer (PTC) is highly curable and associated with an excellent prognosis. Yet, there are several clinicopathological features that lead to a poor prognosis, underscoring the need for a better genomic strategy to refine prognostication and patient management. We hypothesized that PPARγ targets could be potential markers for better diagnosis and prognosis due to the variants found in PPARG in three pairs of monozygotic twins with PTC. Here, we developed a 10-gene personalized prognostic index, designated PPARGi, based on gene expression of 10 PPARγ targets. Through scRNA-seq data analysis of PTC tissues derived from patients, we found that PPARGi genes were predominantly expressed in macrophages and epithelial cells. Machine learning algorithms showed a near-perfect performance of PPARGi in deciding the presence of the disease and in selecting a small subset of patients with poor disease-specific survival in TCGA-THCA and newly developed merged microarray data (MMD) consisting exclusively of thyroid cancers and normal tissues.

Surface electromyography for evaluating patients with oromandibular dystonia.

OBJECTIVE: To investigate myoelectric signals of dystonic activities in oromandibular dystonia (OMD) subjects using surface electromyography (EMG). METHODS: Twelve OMD subjects were included in this study. Resting myoelectric activities of the superficial masseter, anterior temporalis, and anterior belly of the digastric muscle on both sides were monitored, and dystonic muscle contractions were recorded using surface EMG. Myoelectric signal amplitude, the type of muscle contraction, and contraction rate for phasic activities were evaluated. RESULTS: Surface EMG revealed that eight subjects had dystonic muscle activities in the phasic contraction pattern, three subjects had a tonic contraction pattern, and one subject had a mixed pattern. Synchronous contraction of dystonic muscles was frequently observed. Many of the monitored muscles showed high resting amplitudes. CONCLUSION: Surface EMG detects abnormal muscle activities related to oromandibular dystonia. Surface EMG can serve as an objective method for diagnosing oromandibular dystonia.

A technique for repairing rotator cuff transtendinous tears with a remnant attached to the footprint.

BACKGROUND: Some unusual rotator cuff (RC) tears are located in more proximal tendinous portions, with substantial remnant tissue attached to the footprint. The two options for surgical repair are sacrificing or preserving the remnant tissue. We introduce a surgical repair technique that preserves as much of the remnant footprint as possible. SURGICAL TECHNIQUE: A double-loaded suture anchor is inserted into the subchondral bone at the medial portion of the RC footprint; the lateral remnant tissue is preserved. Each strand is shuttled and repassed through the medial portion of the tendon in a mattress fashion using a suture hook device. Then, multiple no. 1 PDS sutures are passed through the medial and lateral stumps and left untied. Strands from the suture anchor are first tied in a double mattress fashion. Then, the repair is completed by tying the remaining no. 1 PDS sutures. CONCLUSIONS: We propose a remnant-preserving RC repair technique for transtendinous RC tears with sufficient tissue remaining within the RC footprint. This technique appears advantageous in terms of re-establishing an environment that promotes tendon healing after repair.

Inferior vena cava filter fracture and migration to the pulmonary artery.

Inferior vena cava (IVC) filters provide a safe and effective method for protecting against pulmonary embolisms in patients for whom standard anticoagulation therapy for acute deep vein thrombosis is contraindicated. Common complications of IVC filter placement include erosion through the wall of the vena cava, visceral perforation, and filter thrombosis, obstruction, and migration. In this report, we describe the case of a 60-year-old woman who presented with an IVC filter fracture and subsequent migration of the filter to the lung detected via chest radiography.

Rivaroxaban for Prevention of Covert Brain Infarcts and Cognitive Decline: The COMPASS MRI Substudy.

BACKGROUND AND PURPOSE: Covert brain infarcts are associated with cognitive decline. It is not known whether therapies that prevent symptomatic stroke prevent covert infarcts. COMPASS compared rivaroxaban with and without aspirin with aspirin for the prevention of stroke, myocardial infarction, and vascular death in participants with stable vascular disease and was terminated early because of benefits of rivaroxaban 2.5 mg twice daily plus aspirin over aspirin. We obtained serial magnetic resonance imagings and cognitive tests in a consenting subgroup of COMPASS patients to examine treatment effects on infarcts, cerebral microbleeds, and white matter hyperintensities. METHODS: Baseline and follow-up magnetic resonance imagings were completed in 1445 participants with a mean (SD) interval of 2.0 (0.7) years. Whole-brain T1, T2 fluid-attenuated inversion recovery, T2* sequences were centrally interpreted by blinded, trained readers. Participants had serial measurements of cognition and function. The primary end point was the proportion of participants with incident covert infarcts. Secondary end points were the composite of clinical stroke and covert brain infarcts, cerebral microbleeds, and white matter hyperintensities. RESULTS: At baseline, 493 (34.1%) participants had infarcts. Incident covert infarcts occurred in 55 (3.8%) participants. In the overall trial rivaroxaban plus aspirin reduced ischemic stroke by 49% (0.7% versus 1.4%; hazard ratio [95% CI], 0.51 [0.38-0.68]). In the magnetic resonance imaging substudy the effects of rivaroxaban+aspirin versus aspirin were: covert infarcts: 2.7% versus 3.5% (odds ratio [95% CI], 0.77 [0.37-1.60]); Covert infarcts or ischemic stroke: 2.9% versus 5.3% (odds ratio [95% CI], 0.53 [0.27-1.03]). Incident microbleeds occurred in 6.6% of participants and 65.7% of participants had an increase in white matter hyperintensities volume with no effect of treatment for either end point. There was no effect on cognitive tests. CONCLUSIONS: Covert infarcts were not significantly reduced by treatment with rivaroxaban and aspirin but estimates for the combination of ischemic stroke and covert infarcts were consistent with the effect on ischemic stroke in the overall trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.