Amylin Pharmaceuticals (AstraZeneca).

Aging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-and-dysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early as middle age and progresses to the end of the life span. Gain-of-function and loss-of-function manipulations show that this BBB dysfunction triggers hyperactivation of transforming growth factor–β (TGFβ) signaling in astrocytes, which is necessary and sufficient to cause neural dysfunction and age-related pathology in rodents. Specifically, infusion of the serum protein albumin into the young rodent brain (mimicking BBB leakiness) induced astrocytic TGFβ signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGFβ receptors or pharmacological inhibition of TGFβ signaling reversed these symptomatic outcomes in aged mice. Last, we found that this same signaling pathway is activated in aging human subjects with BBB dysfunction. Our study identifies dysfunction in the neurovascular unit as one of the earliest triggers of neurological aging and demonstrates that the aging brain may retain considerable latent capacity, which can be revitalized by therapeutic inhibition of TGFβ signaling.

Knowledge of the normal and abnormal imaging appearances of the thyroid gland is essential for appropriate identification and diagnosis of thyroid lesions. Thyroid nodules are often detected incidentally at computed tomography, magnetic resonance imaging, and positron emission tomography; however, ultrasonography (US) is the most commonly used imaging modality for characterization of these nodules. US characteristics that increase the likelihood of malignancy in a thyroid nodule include microcalcifications, solid composition, and central vascularity. Nuclear scintigraphy is commonly used for evaluation of physiologic thyroid function and for identification of metabolically active and inactive nodules. When fine-needle aspiration biopsy (FNAB) of a lesion is indicated based on clinical and radiologic features, appropriate US-guided biopsy technique and careful cytologic analysis are crucial for making the diagnosis. FNAB and core biopsy are the two percutaneous techniques used to obtain a specimen, with the latter technique being indicated following nondiagnostic or indeterminate FNAB. Specimen adequacy and diagnostic accuracy vary due to several factors, including location of aspiration and biopsy technique used. The radiologist must have a basic knowledge of thyroid disease, be familiar with specimen processing, and recognize the cytologic and radiologic appearances of thyroid lesions, all of which will facilitate the management of these lesions. Online supplemental material is available for this article.

The cardiovascular outcomes challenge examined the predictive accuracy of 10 diabetes models in estimating hard outcomes in 2 recent cardiovascular outcomes trials (CVOTs) and whether recalibration can be used to improve replication. Methods: Participating groups were asked to reproduce the results of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program. Calibration was performed and additional analyses assessed model ability to replicate absolute event rates, hazard ratios (HRs), and the generalizability of calibration across CVOTs within a drug class. Results: Ten groups submitted results. Models underestimated treatment effects (ie, HRs) using uncalibrated models for both trials. Calibration to the placebo arm of EMPA-REG OUTCOME greatly improved the prediction of event rates in the placebo, but less so in the active comparator arm. Calibrating to both arms of EMPA-REG OUTCOME individually enabled replication of the observed outcomes. Using EMPA-REG OUTCOME-calibrated models to predict CANVAS Program outcomes was an improvement over uncalibrated models but failed to capture treatment effects adequately. Applying canagliflozin HRs directly provided the best fit. Conclusions: The Ninth Mount Hood Diabetes Challenge demonstrated that commonly used risk equations were generally unable to capture recent CVOT treatment effects but that calibration of the risk equations can improve predictive accuracy. Although calibration serves as a practical approach to improve predictive accuracy for CVOT outcomes, it does not extrapolate generally to other settings, time horizons, and comparators. New methods and/or new risk equations for capturing these CV benefits are needed.