Citations

Accurate prediction of progression in subjects at risk of Alzheimer's disease is crucial for enrolling the right subjects in clinical trials. However, a prospective comparison of state-of-the-art algorithms for predicting disease onset and progression is currently lacking. We present the findings of "The Alzheimer's Disease Prediction Of Longitudinal Evolution" (TADPOLE) Challenge, which compared the performance of 92 algorithms from 33 international teams at predicting the future trajectory of 219 individuals at risk of Alzheimer's disease. Challenge participants were required to make a prediction, for each month of a 5-year future time period, of three key outcomes: clinical diagnosis, Alzheimer's Disease Assessment Scale Cognitive Subdomain (ADAS-Cog13), and total volume of the ventricles. The methods used by challenge participants included multivariate linear regression, machine learning methods such as support vector machines and deep neural networks, as well as disease progression models. No single submission was best at predicting all three outcomes. For clinical diagnosis and ventricle volume prediction, the best algorithms strongly outperform simple baselines in predictive ability. However, for ADAS-Cog13 no single submitted prediction method was significantly better than random guesswork. Two ensemble methods based on taking the mean and median over all predictions, obtained top scores on almost all tasks. Better than average performance at diagnosis prediction was generally associated with the additional inclusion of features from cerebrospinal fluid (CSF) samples and diffusion tensor imaging (DTI). On the other hand, better performance at ventricle volume prediction was associated with inclusion of summary statistics, such as the slope or maxima/minima of patient-specific biomarkers. On a limited, cross-sectional subset of the data emulating clinical trials, performance of the best algorithms at predicting clinical diagnosis decreased only slightly (2 percentage points) compared to the full longitudinal dataset. The submission system remains open via the website https://tadpole.grand-challenge.org, while TADPOLE SHARE (https://tadpole-share.github.io/) collates code for submissions. TADPOLE's unique results suggest that current prediction algorithms provide sufficient accuracy to exploit biomarkers related to clinical diagnosis and ventricle volume, for cohort refinement in clinical trials for Alzheimer's disease. However, results call into question the usage of cognitive test scores for patient selection and as a primary endpoint in clinical trials.

Abstract Introduction During the early phase of the coronavirus disease 2019 (COVID‐19), remdesivir was only approved for hospitalized patients. Our institution developed hospital‐based, outpatient infusion centers for selected hospitalized patients with COVID‐19 who had clinical improvement to allow for early dismissal. The outcomes of patients who transitioned to complete remdesivir in the outpatient setting were examined. Methods Retrospective study of all hospitalized adult patients with COVID‐19 who received at least one dose of remdesivir from November 6, 2020, to November 5, 2021, at one of the Mayo Clinic hospitals. Results Among 3029 hospitalized patients who received treatment with remdesivir for COVID‐19, the majority (89.5%) completed the recommended 5‐day course. Among them, 2169 (80%) patients completed treatment during hospitalization, whereas 542 (20.0%) patients were dismissed to complete remdesivir in outpatient infusion centers. Patients who completed the treatment in the outpatient setting had lower odds of death within 28 days (aOR 0.14, 95% CI 0.06–0.32, p < 0.001). However, their rate of subsequent hospital encounters within 30 days was higher (aHR 1.88, 95% CI 1.27–2.79, p = 0.002). Among patients treated with remdesivir only in the inpatient setting, the adjusted odds of death within 28 days were significantly higher among those who did not complete the 5‐day course of remdesivir (aOR 2.07, 95% CI 1.45–2.95, p < 0.001). Conclusions This study describes the clinical outcomes of a strategy of transitioning remdesivir therapy from inpatient to outpatient among selected patients. Mortality was lower among patients who completed the 5‐day course of remdesivir.

Background Hereditary and acquired thrombophilia are risk factors for venous thromboembolism (VTE). Whether testing helps guide management decisions is controversial. Objective These evidence-based guidelines from the American Society of Hematology (ASH) intend to support decision making about thrombophilia testing. Methods ASH formed a multidisciplinary guideline panel covering clinical and methodological expertise and minimizing bias from conflicts of interest. The McMaster University GRADE Centre provided logistical support, performed systematic reviews, and created evidence profiles and evidence-to-decision tables. The Grading of Recommendations Assessment, Development, and Evaluation approach (GRADE) was used. Recommendations were subject to public comment. Results The panel agreed on 23 recommendations regarding thrombophilia testing and associated management. Nearly all recommendations are based on very low certainty in the evidence due to modeling assumptions. Conclusions The panel issued a strong recommendation against testing the general population before starting combined oral contraceptives (COCs) and conditional recommendations for thrombophilia testing in the following scenarios: (a) patients with VTE associated with nonsurgical major transient or hormonal risk factors; (b) patients with cerebral or splanchnic venous thrombosis, in settings where anticoagulation would otherwise be discontinued; (c) individuals with a family history of antithrombin, protein C, or protein S deficiency when considering thromboprophylaxis for minor provoking risk factors and for guidance to avoid COCs/hormone replacement therapy; (d) pregnant women with a family history of high-risk thrombophilia types; and (e) patients with cancer at low or intermediate risk of thrombosis and with a family history of VTE. For all other questions, the panel provided conditional recommendations against testing for thrombophilia.

AbstractObjectiveThe aim of this study was to determine the effect of age of obesity onset on senescence‐related markers in abdominal (AB) and femoral (FEM) subcutaneous adipose tissue (SAT) before and after moderate (~10%) weight loss.MethodsAB and FEM SAT were collected from human females with childhood‐onset obesity (CO) or adult‐onset obesity (AO) before and after diet‐ and exercise‐induced weight loss. Immunofluorescence analysis of γH2AX/RAD51 (DNA damage/repair markers) and p53/p21 (senescence markers) was conducted in cultured preadipocytes, and senescence‐associated β‐galactosidase (SA‐β‐gal) activity was measured in SAT.ResultsCO had proportionately more AB and FEM preadipocytes with DNA damage (γH2AX+) and senescence markers (p53+ and/or p21+) than AO at baseline. The proportion of γH2AX+ FEM preadipocytes declined with weight loss in CO and was similar between groups after weight loss. The number of γH2AX foci in γH2AX+ preadipocytes decreased similarly between groups and regions with weight loss in parallel with an increase in RAD51. The proportion of p53+ and p21+ preadipocytes and SA‐β‐gal+ cells in SAT did not change with weight loss, but the total p21 intensity in p53+/p21+ FEM preadipocytes declined in AO.ConclusionsThese results provide preliminary evidence that females with CO have an accelerated preadipocyte aging state that improves with weight loss in terms of DNA damage but not senescence.

Abstract Context Childhood papillary thyroid carcinoma (CPTC), despite bilateral thyroidectomy, nodal dissection and radioiodine remnant ablation (RRA), recurs within neck nodal metastases (NNM) in 33% within 20 postoperative years. These NNM are usually treated with reoperation or further radioiodine. Ethanol ablation (EA) may be considered when numbers of NNM are limited. Objective We studied the long-term results of EA in 14 patients presenting with CPTC during 1978 to 2013 and having EA for NNM during 2000 to 2018. Methods Cytologic diagnoses of 20 NNM (median diameter 9 mm; median volume 203 mm3) were biopsy proven. EA was performed during 2 outpatient sessions under local anesthesia; total volume injected ranged from 0.1 to 2.8 cc (median 0.7). All were followed regularly by sonography and underwent volume recalculation and intranodal Doppler flow measurements. Successful ablation required reduction both in NNM volume and vascularity. Results Post EA, patients were followed for 5 to 20 years (median 16). There were no complications, including postprocedure hoarseness. All 20 NNM shrank (mean by 87%) and Doppler flow eliminated in 19 of 20. After EA, 11 NNM (55%) disappeared on sonography; 8 of 11 before 20 months. Nine ablated foci were still identifiable after a median of 147 months; only one identifiable 5-mm NNM retained flow. Median serum Tg post EA was 0.6 ng/mL. Only one patient had an increase in Tg attributed to lung metastases. Conclusion EA of NNM in CPTC is effective and safe. Our results suggest that for CPTC patients who do not wish further surgery and are uncomfortable with active surveillance of NNM, EA represents a minimally invasive outpatient management option.

Introduction: An 82-year-old female presented to the emergency department with presyncope and was found to be bradycardic with proptosis and ophthalmoparesis. MRI revealed an extra-axial enhancing mass compressing the medulla and bilateral enhancing retro-orbital masses. Case Description: Imaging, including nuclear medicine bone scan, PET CT, and cardiac MRI raised the suspicion for a histiocytic neoplasm. These findings, along with a fibrohistiocytic infiltrate on bone biopsy and a BRAF V600E oncogenic mutation on plasma cell-free DNA confirmed a diagnosis of Erdheim-Chester disease. Discussion: These enhancing masses invoke a broad differential, including a histiocytic or granulomatous process, fungal infection, amyloidosis, IgG4 disease, and lymphoma. Systematic laboratory, radiologic, pathology, and genetic testing yielded a diagnosis of this rare histiocytic disorder with frequent neurologic involvement.