Citations

BACKGROUND: Left atrial (LA) diverticula are focal outpouchings of the LA wall and may increase ischemic stroke risk. We studied recurrent ischemic stroke in patients with acute ischemic stroke and LA diverticula detected on cardiac computed tomography. METHODS: We used data from a prospective cohort study of patients with acute ischemic stroke undergoing cardiac computed tomography acquired during the acute stroke imaging protocol. Cardiac radiologists systematically assessed the presence and characteristics of LA diverticula, defined as LA wall outpouchings with a length/ostium width ratio >0.5 and length ≥3 mm. We compared recurrent ischemic stroke and functional outcome (modified Rankin Scale) after 2 years between patients with and without LA diverticula, adjusting for age, history of atrial fibrillation and ischemic stroke, and anticoagulation use. RESULTS: Of 447 included patients (median age 72 [interquartile range (IQR), 62–81], 59% male), 126 (28%) had LA diverticula: median length 6 mm (IQR, 4–8), width 5 mm (IQR, 4–7), and volume 113 mm 3 (IQR, 52–254). There was no statistically significant difference in age (median 70 [IQR, 58–79] versus 73 [IQR, 63–81]; P =0.06), sex (64% versus 57% male; P =0.28), history of ischemic stroke (21% versus 17%; P =0.48), atrial fibrillation (11% versus 19%; P =0.09), or baseline National Institutes of Health Stroke Scale score (median 5 [IQR, 2–14] versus 5 [IQR, 3–14]; P =0.54) between patients with and without LA diverticula, respectively. Recurrent ischemic stroke was more common in patients with LA diverticula (18/124 [15%] versus 24/314 [8%], adjusted hazard ratio, 2.01 [95% CI, 1.08–3.77]), and recurrence risk increased with diverticulum volume (adjusted hazard ratio, 1.02 [95% CI, 1.01–1.03] per 10 mm 3 ). Functional outcome was better in patients with diverticula (median modified Rankin Scale score of 2 [IQR, 1–3] versus 3 [IQR, 1–6], adjusted common odds ratio, 0.62, [95% CI, 0.42–0.92]). CONCLUSIONS: LA diverticula are a common finding on cardiac computed tomography in patients with acute ischemic stroke, and the risk of recurrent ischemic stroke was increased in these patients, particularly in those with larger diverticula. Atrial diverticula may be a risk factor for recurrent ischemic stroke. REGISTRATION: URL: https://www.onderzoekmetmensen.nl/nl/trial/50352 ; Unique identifier: NL6413901818.

PURPOSE Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy is used commonly for pediatric Hodgkin lymphoma (pHL) in low- and middle-income countries. The role of radiotherapy (RT) after ABVD in pHL is uncertain. MATERIALS AND METHODS We conducted a systematic review to explore the use of ABVD with or without RT in pHL. Key clinical questions included the number of cycles of ABVD, indications for and dose of RT, and outcomes by risk group. A search was performed in PubMed. Articles reporting survival outcomes by risk group were included. RESULTS Of 97 articles identified in the literature search, nine met inclusion criteria. Chemotherapy consisted of four to six cycles in limited disease and mostly six cycles in advanced disease. Three studies used RT for all patients within a specified risk group. Six studies dictated an adapted RT approach, with 3%-43% of the patients receiving RT for bulky adenopathy, slow early response (SER), and/or incomplete response. Radiation doses ranged between 20 and 36 Gy. The progression-free survival and overall survival at 4-10 years ranged from 84% to 100% and 93%-100% in limited disease and 50%-84.4% and 75%-95.3% in advanced disease, respectively. Studies did not directly assess the impact of certain chemotherapy or RT strategies. Recommendations were made after reviewing outcomes with particular approaches. CONCLUSION Four cycles of ABVD are recommended for limited disease, and six cycles of ABVD are recommended for advanced disease. In both limited and advanced diseases, RT is recommended with a dose of 20-21 Gy only to sites of bulky and/or SER, with a boost of up to 36 Gy to sites of incomplete response. This approach could spare radiation for at least half of the patients with limited disease and one third of advanced disease.

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 Purpose: TRK-950 is a first-in-class humanized antibody targeting cytoplasmic activation/proliferation-associated protein-1, which is strongly expressed on the cell membrane surface in or on most solid tumors but not in or on normal tissues. This first-in-human study investigated the safety profile, pharmacokinetics (PK), and preliminary antitumor activity. Patients and Methods: Patients with treatment-refractory, locally advanced, or metastatic solid tumors were enrolled in a dose escalation/expansion study. TRK-950 was administered intravenously weekly for 3 weeks in a 28-day cycle, with doses ranging from 3 to 30 mg/kg. Dose expansion included 10 mg/kg weekly and 30 mg/kg biweekly for colorectal cancer and 10 mg/kg weekly for cholangiocarcinoma. The primary objective of this study was to determine its safety, tolerability, and maximum tolerated dose. The secondary objectives were PK, preliminary antitumor activity, and identification of potential biomarkers. Results: Thirty-six patients received at least one dose of TRK-950. In the dose escalation cohort, the maximum tolerated dose was not reached, and no dose-limiting toxicities were observed up to 30 mg/kg. Common adverse events included abdominal pain, fatigue, constipation, back pain, nausea, and decreased appetite. TRK-950 exhibited a PK profile similar to that of other IgG subclass 1 therapeutic antibodies, with linear PK parameters over the 3 to 30 mg/kg dose range. The best response was stable disease. Notably, one patient with cholangiocarcinoma showed signs of cavitation after approximately 8 months, suggesting potential antitumor activity. Conclusions: TRK-950 is safe and well tolerated, has a favorable PK profile, and should be further investigated as a monotherapy and in combination with standard treatment for various types of solid tumors. Significance: TRK-950, a humanized antibody targeting CAPRIN-1, demonstrated good tolerability, no dose-limiting toxicities, a favorable PK profile, and potential antitumor activity in this first-in-human study. Currently, TRK-950 is undergoing Phase Ib and II trials for various cancers, showing promising development potential.

Context.— Complexity of ordering and transfusing blood is particularly evident in the pediatric population. Simplification, clarification, and standardization of blood orders can decrease complexity and improve patient safety. Objective.— To improve patient safety by optimizing electronic ordering of blood components in pediatrics through a collaborative process improvement initiative. Design.— A multidisciplinary working group, formed as part of a value stream analysis to improve transfusion safety at Children’s Healthcare of Atlanta (Atlanta, Georgia), focused on decreasing variability and providing clarity when ordering, preparing, and transfusing blood using the electronic health record. Through benchmarking with other pediatric institutions and a collaborative design process with multiple local stakeholders, an extensive redesign in the existing orders and order sets occurred. Metrics were collected to determine if a change was an improvement. Results.— Nurse and laboratory informaticists, a pathology informaticist, and a transfusion medicine specialist built the new orders based on the design. The new orders focused on the following changes: standardization, introduction of logic, naming conventions, clarifying definitions, adding calculations, improving transparency of history and laboratory data, removing aliquots, clarifying communication, and implementing additional modules to inform the provider of necessary information about the patient. Metrics included a decrease in the number of orders changed within an hour, decreased calls from the blood bank to the provider to clarify the order, and an absence of overtransfusions and transfusion-related serious safety events for a year following implementation. Conclusions.— This collaborative initiative, using standard process improvement tools, resulted in standardized blood orders improving transfusion safety.

Introduction Differentiated thyroid cancer (DTC) is the most common endocrine malignancy, with a high 5-year survival rate of approximately 98%. Despite advances in diagnosis and treatment, up to 20% of patients experience recurrence, adversely affecting their quality of life. Predictive models have been developed to assess recurrence risk and guide clinical decision-making, but these models often face limitations such as retrospective design, lack of diversity in study populations and absence of external validation. The primary aim is to externally validate existing predictive models for DTC recurrence using prospective data from a diverse Latin American cohort. The secondary aim is to explore opportunities for model recalibration to improve their performance in our population. Methods and analysis The CaTaLiNA study is a multicentre prospective observational study conducted across 10 hospitals in five Latin American countries, including Ecuador, Peru, Uruguay and Mexico. Patients aged 18 years or older receiving treatment for DTC, such as the first thyroid surgery, active surveillance or radiofrequency ablation will be included. Recruitment will occur from November 2023 to June 2025, with follow-up extending until June 2028. Data collection will include baseline clinical, surgical and histological characteristics, treatment details and follow-up outcomes. Statistical analysis will follow the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis guidelines, using imputation strategies for missing data and evaluating calibration and discrimination of the prediction models. Calibration measures include the ratio of expected and observed events, calibration slope and calibration plot, while discrimination will be assessed using the C-index and area under the receiver operating characteristic curve. Ethics and dissemination This study protocol was approved by Comité de Ética de Investigación en Seres Humanos de la Universidad San Francisco de Quito USFQ ‘CEISH-USFQ’ APO-010–2023-CEIHS-USFQ Oficio No. 161-2023-CA-23030M-CEISH-USFQ. Results will be disseminated via peer-reviewed publications.

Objective To assess the association between educational level and cardiovascular age acceleration metric derived from ECG, and to determine whether this association is mediated by established cardiovascular disease (CVD) risk factors. Design Prospective population-based cohort study (the Tromsø Study). Setting General population of the Tromsø municipality, Norway. Participants The study sample consisted of 4367 participants of the Tromsø Study, who took part in both Tromsø6 (2007–2008) and Tromsø7 (2015–2016), had a 12-lead ECG obtained at Tromsø7 and did not report a history of heart attack, stroke or atrial fibrillation. Primary outcome measures δ-age, a biomarker of cardiovascular ageing, is defined as the difference (in years) between an individual’s ECG-predicted heart age and their chronological age. ECG-predicted heart age was estimated using a previously validated deep neural network. Results Our findings indicate an inverse association between education and δ-age, with a regression coefficient per increment increase in education of −0.24 (95% CI −0.41 to –0.07) in the overall sample, −0.38 (95% CI −0.59 to –0.16) for women and −0.04 (95% CI −0.31 to 0.23) for men. Participants with the highest level of education (university/college for 4 or more years) had the lowest estimated δ-age with a regression coefficient of −0.69 years (95% CI −1.23 to –0.16) compared with the group with primary education for the overall sample, −1.05 years (95% CI −1.73 to –0.37) for women and −0.15 years (95% CI −1.03 to 0.73) for men. CVD risk factors mediated up to 75% of the association between overall education and δ-age, and 80% of the association among those with the highest education level (university/college for 4 or more years). Among women, 50% of the effect of overall education on δ-age was mediated by CVD risk factors, rising to 53% in the category with the highest level of education. However, in the subsample of men, there was no significant association between education and δ-age, and the mediation analysis produced natural direct and indirect effects pointing in opposite directions. Conclusions Cardiovascular ageing is inversely associated with educational level, an effect that appears to be largely mediated through established risk factors.

Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

Background: Despite the association of insulin resistance (IR) in the pathophysiology of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), few studies have evaluated the utility of acanthosis nigricans (AN) as a clinical predictor for this condition. Thus, we aimed to determine the role of AN as a risk factor and clinical predictor of MASLD. Methods: This cross-sectional study conducted a comprehensive clinical history and physical examination. The presence of acanthosis nigricans was assessed in the neck, elbows, axillae, and knuckles. Liver biochemical parameters were measured, hepatic fat was analyzed using the controlled attenuation parameter (CAP), while hepatic stiffness was evaluated in kilopascals (kPA) with the FibrosScan 530 Compact and Smart Exam software. Multiple analyses were performed to determine the relationship between acanthosis nigricans and MASLD. Results: We recruited 251 adult participants. The mean BMI was 29.9 ± 7.3 kg/m 2 , including 40.2% of participants with obesity and 63.7% with AN. Transient elastography evaluation resulted in 65.7% and 6% participants with hepatic steatosis (S3, 48.6%) and fibrosis, respectively. A non-adjusted (OR 2.63, 95% CI 1.57-4.52) and adjusted model (OR 1.97, 95% CI 0.95-4.12) were determined for AN as a risk factor for liver steatosis. Furthermore, the presence of AN in knuckles resulted in an association to predict liver steatosis (OR 2.09, 95% CI 1.01-4.35), while a multivariate analysis indicated that AN predicts a higher steatosis grade (S2 OR = 6.58, CI 95% 1.18-36.53; S3 OR = 2.36, CI 95% 1.04-5.3). Conclusions: Acanthosis nigricans demonstrated to predict a higher steatosis grade in adults with overweight and obesity. Our study supports the clinical applicability of AN as a screening tool for MASLD to identify high-risk subjects in resource-limited settings. Additional studies are needed to define alternative diagnostic tools for the early identification of metabolic risk factors in populations with specific clinical or demographic characteristics.

ABSTRACT Background Despite the classic Kraepelinian dichotomy between bipolar disorder (BD) and schizophrenia (SZ), contemporary evidence suggests shared antecedent risk factors and similarities in the early course. This study aimed to identify distinct trajectories leading to first‐episode mania (FEM) and first‐episode psychosis (FEP) by examining antecedent psychopathology, including psychiatric diagnoses, symptoms, substance use, and psychotropic medication exposure. Methods Individuals born after 1985 who resided in Olmsted County, Minnesota, USA, and had FEM/FEP were identified through the Rochester Epidemiology Project. Latent class analysis (LCA) was used to identify subgroups based on antecedent psychopathology incorporating 57 dichotomous antecedent measures before FEM/FEP. Results A total of 202 individuals ( BD n = 73, SZ n = 129; 26.7% female, mean age 20.8 ± 3.7 years) were included. A 3‐class LCA model optimally fits the data. Class 1 (Neurodevelopmental, 29.7%) had a high prevalence of neurodevelopmental disorders, behavioral symptoms, and ADHD medication use. Class 2 (Depressive‐Anxious, 31.2%) included depressive and anxiety disorders, mood‐related symptoms, and SSRI / SNRI use. Class 3 (Minimal Psychiatric Morbidity, 39.1%) had a low prevalence of antecedent diagnoses and symptoms, with comparable substance use to other classes. There were significant diagnostic differences, with SZ being more common in the Neurodevelopmental (71.7%) and Minimal Psychiatric Morbidity (70.9%) classes, while BD was more common in the Depressive‐Anxious class ( p = 0.007). Neurodevelopmental and Minimal Psychiatric Morbidity classes had higher proportions of males (85.0% and 82.3%, respectively) compared to the Depressive‐Anxious class (50.8%, p < 0.001). The Neurodevelopmental class showed an earlier age at first mental health visit (9.5 ± 5.5 years) and a longer antecedent illness duration (10.8 ± 6.1 years) than the other classes ( p < 0.001). Conclusion This study identified three distinct pathways to FEM and FEP, offering a transdiagnostic perspective on the antecedent illness trajectories of BD and SZ. Future research should validate these categories that are more inclusive than the classic BD versus SZ dichotomy and explore their potential for predicting illness course and guiding personalized early interventions.