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ImportanceThyroid cancer incidence has tripled in the past 3 decades, largely driven by increased detection of small, indolent papillary thyroid cancers. Overuse of thyroid ultrasonography (TUS) contributes to overdiagnosis, leading to unnecessary biopsies, procedures, and potential patient harm.ObjectiveTo evaluate the frequency of and factors associated with inappropriate TUS (iTUS) orders and assess related clinical outcomes.Design, Setting, and ParticipantsThis retrospective cohort study analyzed adult patients 18 years and older who underwent their first TUS from January 1, 2017, to December 30, 2021, at 4 Mayo Clinic sites. Patients with previous thyroid nodule, thyroid cancer, thyroid surgery, or TUS were excluded. Based on documented clinical indications, a validated natural language processing model classified TUS orders as appropriate or inappropriate. Data were analyzed from April 2024 to May 2025.ExposuresBaseline characteristics of patients, clinicians, and clinical encounters investigated for their association with an iTUS order.Main Outcomes and MeasuresThe primary outcome was the proportion of iTUS orders. Secondary outcomes included factors associated with iTUS (sociodemographic, clinical, order-specific, and clinician-related factors) and clinical outcomes following iTUS, including the detection of thyroid nodules, thyroid procedures, and thyroid cancer diagnoses.ResultsOf 11 442 included patients, 8422 (73.6%) were female, and the mean (SD) age was 57.3 (15.8) years with a mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 29.7 (7.0). Among 11 442 TUS orders, 866 (7.6%) were classified as inappropriate. In multivariable analysis, younger age (age of 18 to 54 years vs older than 65 years; odds ratio [OR], 1.86; 95% CI, 1.56-2.22), hyperthyroidism (OR, 9.04; 95% CI, 6.75-12.11), ordering by nonendocrinology specialties (eg, oncology/hematology; OR, 3.43; 95% CI, 2.47-4.76), and orders not linked to an in-person appointment (eg, portal messages; OR, 2.42; 95% CI, 2.08-2.82) were strongly associated with increased odds of iTUS. Compared with appropriate TUS, iTUS led to lower rates of thyroid nodule detection (202 of 866 [23.3%] vs 6885 of 10 576 [65.1%]; OR, 0.16; 95% CI, 0.14-0.19), biopsies (89 [10.3%] vs 2647 [25.0%]; OR, 0.34; 95% CI, 0.27-0.43), partial thyroidectomies (14 [1.6%] vs 424 [4.0%]; OR, 0.39; 95% CI, 0.23-0.67), and confirmed thyroid cancer cases (16 [1.8%] vs 425 [4.0%]; OR, 0.45; 95% CI, 0.27-0.74).Conclusions and RelevanceIn this cohort study, approximately 1 in 13 TUS orders were inappropriate. iTUS was more common in younger patients, those with thyroid dysfunction, those not seen in person, and in those referred by nonendocrinology specialties. These findings highlight the need for targeted strategies to optimize TUS use and mitigate overdiagnosis and overtreatment.

Background Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and multiple sclerosis (MS) have both overlapping and distinct MRI lesion features, which vary with imaging timing. This study identified distinguishing MRI characteristics using paired MRIs at clinical attack and remission. Methods We retrospectively identified Mayo Clinic patients with MOGAD and MS that: (1) fulfilled respective diagnostic criteria; (2) had paired attack (≤30 days) and remission MRI scans (≥12 months) without interval attacks. MRIs were compared between groups for key features. Results We included 43 patients with MOGAD (median age 31 years (range, 3–67); 63% female) and 49 patients with MS (median age 39 years (range, 17–65); 65% female). Resolution of at least one T2-lesion differentiated MOGAD from MS (sensitivity, (95% CI 77% to 100%), specificity, (95% CI 86% to 99%); Youden’s index (YI)=0.90). Resolution of at least two T2-lesions indicated MOGAD (sensitivity 62% (95% CI 41% to 79%); specificity, 100% (95% CI 94% to 100%); YI=0.62). MOGAD patients were more likely to have normal MRI scans at follow-up compared with MS (brain 14/44 (32%) vs 0/60 (0%), p<0.001; spine 21/27 (78%) vs 7/36 (19%), p<0.001). In addition, the presence of T1-hypointense, ovoid periventricular T2, and enhancing lesions were more common in MS versus MOGAD at attack and remission and in the spine, longitudinally extensive T2 lesions were more common in MOGAD attacks (8/27 (30%)). Conclusion Paired MRI at attack and remission revealed distinctive characteristics of MOGAD and MS, with greater diagnostic value at remission driven by the discriminating power of T2-lesion resolution. In MOGAD patients with initial parenchymal involvement, a 1-year follow-up MRI may aid diagnosis and serve as a new baseline.

Abstract Background and Aims Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (&lt;30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

ABSTRACT Despite remarkable interest in the biomarker potential of urinary extracellular vesicles (uEVs) and the identification of numerous promising candidates, their clinical translation still presents multiple challenges. The opportunities for successful translation are obvious, yet the main roadblocks on the way have hardly been systematically considered and more coordinated approaches are needed to overcome them. In the present review article, we have identified the most relevant roadblocks of clinical translation of urinary EV‐based biomarkers and discuss possible solutions to overcome them. These roadblocks are categorized as fundamental and technical but also related to development of novel biomarker assays and clinical acceptance. In addition, hurdles within the regulatory approval process are discussed. It is clear that various roadblocks to clinical translation of urinary EV biomarkers exist; however, they are addressable by promoting rigor and reproducibility as well as collaboration between basic and clinical scientists, clinicians, industry and regulatory bodies. Moreover, knowledge of obstacles for assay development and regulatory requirements should already be considered when developing a new biomarker to maximize the chance of successful translation. This review presents not only a status quo, but also a roadmap for the further development of the field.

Background Tricuspid valve surgery is recommended for severe isolated tricuspid regurgitation (TR) if symptoms persist despite optimal medical therapy. The definition of optimal therapy for TR is unclear beyond managing underlying conditions. Diuretics are the primary treatment for volume retention in TR, but it is unknown whether a “safe diuretic dose” exists for conservative management. We sought to evaluate the association between diuretic dose and outcomes. Methods Adult patients with ≥moderate–severe isolated TR were retrospectively identified from echocardiographic reports. Clinical and echocardiographic data were extracted from electronic medical records and manually reviewed. The primary end point was all‐cause mortality. Loop diuretic doses were converted to furosemide equivalent and categorized into 4 groups: <40 mg, 40 to 79 mg, 80 to 159 mg, and ≥160 mg daily. Results Of 1302 patients (age 72±13 years, 60% female), 565 (43%) had moderate–severe TR and 737 (57%) had severe TR. Median follow‐up was 8.7 (1.4, 14.0) years. Comorbidities increased with higher diuretic doses. A linear relationship between diuretic dose and mortality was observed in spline‐curve analysis. Hazard ratios (and CIs) for mortality adjusted for age, sex, coronary disease, chronic kidney disease, mild pulmonary hypertension, and New York Heart Association III/IV symptoms were 1.21 (0.96–1.53) ( P =0.12) for <40 mg, 1.50 (1.23–1.82) ( P <0.001) for 40 to 79 mg, 1.86 (1.46–2.37) ( P <0.001) for 80 to 159 mg, and 2.90 (2.18–3.88) ( P <0.001) for ≥160 mg furosemide equivalent. Any diuretic dose was associated with significant symptoms (New York Heart Association III–IV), with more patients experiencing symptoms at higher doses. Conclusion A daily loop diuretic dose ≥40 mg furosemide equivalent is associated with increased mortality and greater symptom severity in patients with TR.

Background Prompt diagnosis of acute central retinal artery occlusion (CRAO) is crucial for therapeutic management and stroke prevention. However, most stroke centers lack onsite ophthalmic expertise before considering fibrinolytic treatment. This study aimed to develop, train, and test a deep learning system to detect hyperacute CRAO on retinal fundus photographs within the critical 4.5‐hour treatment window and up to 24 hours after visual loss to aid in secondary stroke prevention. Methods Our retrospective, cross‐sectional study included 1322 color fundus photographs from 771 patients with acute visual loss due to CRAO, central retinal vein occlusion, nonarteritic anterior ischemic optic neuropathy, and healthy controls. Photographs were collected from 9 expert neuro‐ophthalmology centers in 6 countries, including 3 randomized clinical trials. Training included 1039 photographs (517 patients), followed by testing on 2 data sets: (1) hyperacute CRAO (54 photographs, 54 patients) and (2) CRAO within 24 hours after visual loss (110 photographs, 109 patients). Results The deep learning system achieved an area under the receiver operating characteristic curve of 0.96 (95% confidence interval (CI), 0.95–0.98), a sensitivity of 92.6% (95% CI, 87.0–98.0), and a specificity of 85.0% (95% CI, 81.8–92.8) for detecting CRAO at hyperacute stage, with similar results within 24 hours. The deep learning system outperformed stroke neurologists on a subset of hyperacute testing data set (120 photographs, 120 patients). Conclusions A deep learning system can accurately detect hyperacute CRAO on retinal photographs within a time window compatible with urgent fibrinolysis. If further validated, such systems could improve patient selection for fibrinolytic trials and optimize secondary stroke prevention. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06390579.

The translation of AI-generated brain metastases (BM) segmentation into clinical practice relies heavily on diverse, high-quality annotated medical imaging datasets. The BraTS-METS 2023 challenge has gained momentum for testing and benchmarking algorithms using rigorously annotated internationally compiled real-world datasets. This study presents the results of the segmentation challenge and characterizes the challenging cases that impacted the performance of the winning algorithms. Untreated brain metastases on standard anatomic MRI sequences (T1, T2, FLAIR, T1PG) from eight contributed international datasets were annotated in stepwise method: published UNET algorithms, student, neuroradiologist, final approver neuroradiologist. Segmentations were ranked based on lesion-wise Dice and Hausdorff distance (HD95) scores. False positives (FP) and false negatives (FN) were rigorously penalized, receiving a score of 0 for Dice and a fixed penalty of 374 for HD95. The mean scores for the teams were calculated. Eight datasets comprising 1303 studies were annotated, with 402 studies (3076 lesions) released on Synapse as publicly available datasets to challenge competitors. Additionally, 31 studies (139 lesions) were held out for validation, and 59 studies (218 lesions) were used for testing. Segmentation accuracy was measured as rank across subjects, with the winning team achieving a LesionWise mean score of 7.9. The Dice score for the winning team was 0.65 ± 0.25. Common errors among the leading teams included false negatives for small lesions and misregistration of masks in space. The Dice scores and lesion detection rates of all algorithms diminished with decreasing tumor size, particularly for tumors smaller than 100 mm3. In conclusion, algorithms for BM segmentation require further refinement to balance high sensitivity in lesion detection with the minimization of false positives and negatives. The BraTS-METS 2023 challenge successfully curated well- annotated, diverse datasets and identified common errors, facilitating the translation of BM segmentation across varied environments and providing the tools for future development of personalized volumetric reports to patients undergoing BM treatment.

Abstract We conducted this systematic review to evaluate outcomes of thrombolysis followed by anticoagulation vs anticoagulation alone in pediatric patients with venous thromboembolism (VTE). This systematic review addresses mortality, VTE resolution, recurrence, bleeding, and organ-specific outcomes in 5 PICO (population, intervention, comparison, outcomes) questions on thrombolysis across pulmonary embolism (PE), extremity deep vein thrombosis (DVT), right atrial thrombosis (RAT), cerebral sinus venous thrombosis (CSVT), and renal vein thrombosis (RVT). Meta-analysis reported risk ratios or differences (95% confidence intervals [CIs]), and absolute effects per 1000 patients. Certainty of evidence was assessed using GRADE (Grading of recommendation, assessment, Development, and Evaluation) guidelines. Thirteen nonrandomized studies were included and no randomized clinical trials addressed these questions. Thrombolysis might be associated with a higher risk of major bleeding, clinically relevant nonmajor bleeding, or unspecified bleeding with risk differences of 0.09 (95% CI, −0.06 to 0.23), 0.06 (95% CI, −0.11 to 0.22), and 0.09 (95% CI, −0.04 to 0.23), respectively. In PE with hemodynamic compromise, thrombolysis might be associated with a lower risk of mortality but conclusions on PE progression were uncertain in submassive PE. In DVT, thrombolysis may have little to no effect on mortality or thrombus resolution but might be associated with lower risk of postthrombotic syndrome. In RAT, thrombolysis might have little to no effect on thrombus resolution but a higher risk of major bleeding and mortality. For CSVT and RVT, the evidence was very limited. These findings were based on very-low-certainty evidence because of confounding and imprecision from small sample sizes. This systematic review highlights key challenges in developing recommendations for thrombolysis in children with VTE.

OBJECTIVE In many individuals, type 2 diabetes (T2D) remains poorly controlled despite taking multiple glucose-lowering therapies. Several studies have demonstrated that endogenous hypercortisolism is prevalent among these individuals. We tested whether cortisol-directed therapy improves their glycemic control. RESEARCH DESIGN AND METHODS In this prospective, multicenter, double-blind study, 136 individuals with T2D (hemoglobin A1c [HbA1c] 7.5%–11.5% [58–102 mmol/mol] on multiple medications) and hypercortisolism (by dexamethasone suppression test) were randomized 2:1 to the glucocorticoid receptor antagonist mifepristone (300–900 mg once daily; n = 91) or placebo (n = 45) for 24 weeks, with stratification by presence/absence of an adrenal imaging abnormality. The primary end point was the change in HbA1c. Secondary end points included changes in glucose-lowering medications, weight, and waist circumference and safety. RESULTS Mean baseline HbA1c in the study cohort was 8.55% (69.9 mmol/mol). At 24 weeks, the least squares mean (LSM) difference from placebo in HbA1c was −1.32% (95% CI −1.81 to −0.83; P &lt; 0.001). Participants receiving mifepristone experienced reductions in body weight and waist circumference (placebo-adjusted LSM differences of −5.12 kg [95% CI −8.20 to −2.03] and −5.1 cm [−8.23 to −1.99], respectively). Of participants on mifepristone, 46% discontinued therapy, compared with 18% on placebo. Adverse events with mifepristone (&gt;10% of participants) included hypokalemia, fatigue, nausea, vomiting, headache, peripheral edema, diarrhea, and dizziness, consistent with mifepristone’s known tolerability profile. Increases in blood pressure also occurred. CONCLUSIONS In individuals with inadequately controlled T2D and hypercortisolism, cortisol-directed medical therapy with mifepristone reduced HbA1c, with a manageable tolerability profile.