HistoEM: A Pathologist-Guided and Explainable Workflow Using Histogram Embedding for Gland Classification.

Pathologists have, over several decades, developed criteria for diagnosing and grading prostate cancer. However, this knowledge has not, so far, been included in the design of convolutional neural networks (CNN) for prostate cancer detection and grading. Further, it is not known whether the features learned by machine-learning algorithms coincide with diagnostic features used by pathologists. We propose a framework that enforces algorithms to learn the cellular and subcellular differences between benign and cancerous prostate glands in digital slides from hematoxylin and eosin-stained tissue sections. After accurate gland segmentation and exclusion of the stroma, the central component of the pipeline, named HistoEM, utilizes a histogram embedding of features from the latent space of the CNN encoder. Each gland is represented by 128 feature-wise histograms that provide the input into a second network for benign vs cancer classification of the whole gland. Cancer glands are further processed by a U-Net structured network to separate low-grade from high-grade cancer. Our model demonstrates similar performance compared with other state-of-the-art prostate cancer grading models with gland-level resolution. To understand the features learned by HistoEM, we first rank features based on the distance between benign and cancer histograms and visualize the tissue origins of the 2 most important features. A heatmap of pixel activation by each feature is generated using Grad-CAM and overlaid on nuclear segmentation outlines. We conclude that HistoEM, similar to pathologists, uses nuclear features for the detection of prostate cancer. Altogether, this novel approach can be broadly deployed to visualize computer-learned features in histopathology images.

A randomized, double-blinded, placebo-controlled clinical trial of sterile filtered human amniotic fluid for treatment of COVID-19.

IMPORTANCE: Acellular human amniotic fluid (hAF) is an antimicrobial and anti-inflammatory fluid that has been used to treat various pro-inflammatory conditions. In a feasibility study, we have previously demonstrated that hAF could be safely administered to severely ill patients with coronavirus disease-19 (COVID-19). The impact of acellular hAF on markers of systemic inflammation and clinical outcomes during COVID-19 infection remain unknown. OBJECTIVE: To determine the safety and efficacy of acellular, sterile processed intravenously administered hAF on markers of systemic inflammation during COVID-19. DESIGN, SETTINGS AND PARTICIPANTS: This single-center Phase I/II randomized, placebo controlled clinical trial enrolled adult (age ≥ 18 years) patients hospitalized for respiratory symptoms of COVID-19, including hypoxemia, tachypnea or dyspnea. The study was powered for outcomes with an anticipated enrollment of 60 patients. From 09/28/2020 to 02/04/2022 we enrolled and randomized 47 (of an anticipated 60) patients hospitalized due to COVID-19. One patient withdrew consent after randomization but prior to treatment. Safety outcomes to 30 days were collected through hospital discharge and were complete by the end of screening on 6/30/2022. INTERVENTIONS: Intravenous administration of 10 cc sterile processed acellular hAF once daily for up to 5 days vs placebo. MAIN OUTCOME AND MEASURES: Blood biomarkers of inflammation, including C-Reactive protein (CRP), lactate dehydrogenase, D-dimer, and interleukin-6 (IL-6), as well as safety outcomes. RESULTS: Patients who were randomized to hAF (n = 23) were no more likely to have improvements in CRP from baseline to Day 6 than patients who were randomized to placebo (n = 24) hAF: -5.9 [IQR -8.2, -0.6] vs placebo: -5.9 [-9.4, -2.05]; p = 0.6077). There were no significant differences in safety outcomes or adverse events. Secondary measures of inflammation including lactate dehydrogenase, D-dimer and IL-6 were not statistically different from baseline to day 6. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial involving hospitalized patients with COVID-19, the intravenous administration of 10 cc of hAF daily for 5 days did not result in statistically significant differences in either safety or markers of systemic inflammation compared to placebo, though we did not achieve our enrollment target of 60 patients. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov as #NCT04497389 on 04/08/2020.

Measuring the unmet needs of American military Veterans and their caregivers: Survey protocol of the HERO CARE survey.

BACKGROUND: Empowering Veterans to age in place is a Department of Veterans Affairs priority. Family or unpaid caregivers play an important role in supporting Veterans to achieve this goal. Effectively meeting the needs of Veterans and caregivers requires identifying unmet needs and relevant gaps in resources to address those needs. METHODS: Using a modified Socio-Ecological Model, we developed a prospective longitudinal panel design survey. We randomly selected 20,000 community-dwelling Veterans enrolled in the Veterans Health Administration (VHA), across five VHA sites. We oversampled Veterans with a higher predicted 2-year long-term institutional care (LTIC) risk. Veterans were mailed a packet containing a Veteran survey and a caregiver survey, to be answered by their caregiver if they had one. The Veteran survey assessed the following health-related domains: physical, mental, social determinants of health, and caregiver assistance. Caregivers completed questions regarding their demographic factors, caregiving activities, impact of caregiving, use of VA and non-VA services, and caregiver support resources. Follow-up surveys will be repeated twice at 12-month intervals for the same respondents. This article describes the HERO CARE survey protocol, content, and response rates. RESULTS: We received responses from 8,056 Veterans and 3,579 caregivers between July 2021 and January 2022, with 95.6% being received via mail. Veteran respondents were mostly males (96.5%), over 65 years of age (94.9%), married (55.0%), Non-Hispanic White (75.2%), and residing in urban areas (80.7%). CONCLUSIONS: This longitudinal survey is unique in its comprehensive assessment of domains relevant to older Veterans stratified by LTIC risk and their caregivers, focusing on social determinants, caregiver support, and the use of caregiver support resources. Survey data will be linked to Centers for Medicare & Medicaid Services and VA data. The results of this study will inform better planning of non-institutional care services and policy for Veterans and their caregivers.

Mifepristone for miscarriage treatment in Utah: A survey of clinician knowledge and assessment of an educational video on future use.

Objectives: We aimed to: (a) describe current use of mifepristone for early pregnancy loss (EPL) management in Utah, (b) identify predictors of knowledge pre- and posteducational video, and (c) explore postvideo impacts on the likelihood to use mifepristone. Mifepristone is subject to the Food and Drug Administration's (FDA) Risk Evaluation and Mitigation Strategy (REMS) requirements. Methods: Between September 2020 and March 2021 we surveyed Utah clinicians from six specialties caring for people experiencing EPL, recruited through professional organizations and hospital listservs. Participants viewed a 3.5-minute educational video on mifepristone for EPL and completed pre- and postvideo questionnaires. We evaluated predictors of high prevideo and improved postvideo knowledge using random forest regression conditional importance measures and partial dependency plots. We described current mifepristone use and video effects on likelihood to use mifepristone. Results: Of 506 participants, most specialize in emergency medicine (172, 34%) and practice in private settings (253, 51%). Two-thirds had heard of mifepristone (328/471, 70%). Of 176/471 (37%) attempting provision of mifepristone, actual provision occurred for 59% (104/176). Baseline knowledge scores were low (mean 4.81/13 [37%] correct). Predictors of high prevideo knowledge include provision or attempted provision of mifepristone, having heard of mifepristone, providing EPL management expectantly or via medication, and specialty type. Mean postvideo knowledge scores improved by 3.27 points (68% improvement, paired t-test; 95% confidence interval 2.82-3.72, p < 0.0001). Postvideo, 66% (242/364) stated they are much more or somewhat more likely to use mifepristone, with compliance with FDA requirements cited as a barrier to utilization. Conclusions: Among Utah providers, baseline mifepristone knowledge and use for EPL management are low. An educational video improved knowledge and likelihood of use, but FDA REMS requirements continue to be a barrier to including mifepristone in medication management of EPL.

High value care education in general surgery residency programs: A multi-institutional needs assessment.

BACKGROUND: The ACGME mandates that residency programs provide training related to high value care (HVC). The purpose of this study was to explore HVC education in general surgery residency programs. METHODS: An electronic survey was distributed to general surgery residents in geographically diverse programs. RESULTS: The response rate was 29% (181/619). Residents reported various HVC components in their curricula. Less than half felt HVC is very important for their future practice (44%) and only 15% felt confident they could lead a QI initiative in practice. Only 20% of residents reported participating in a root cause analysis and less than one-third of residents (30%) were frequently exposed to cost considerations. CONCLUSION: Few residents feel prepared to lead quality improvement initiatives, have participated in patient safety processes, or are aware of patients' costs of care. This underscores the need for improved scope and quality of HVC education and establishment of formal curricula.