Faculty Bibliography

A digital twin is a computational model that provides a virtual representation of a specific physical object, system, or process and predicts its behavior at future time points. These simulation models form computational profiles for new diagnosis and prevention models. The digital twin is a concept borrowed from engineering. However, the rapid evolution of this technology has extended its application across various industries. In recent years, digital twins in healthcare have gained significant traction due to their potential to revolutionize medicine and drug development. In the context of radiology, digital twin technology can be applied in various areas, including optimizing medical device design, improving system performance, facilitating personalized medicine, conducting virtual clinical trials, and educating radiology trainees. Also, radiologic image data is a critical source of patient-specific measures that play a role in generating advanced intelligent digital twins. Generating a practical digital twin faces several challenges, including data availability, computational techniques, validation frameworks, and uncertainty quantification, all of which require collaboration among engineers, healthcare providers, and stakeholders. This review focuses on recent trends in digital twin technology and its intersection with radiology by reviewing applications, technological advancements, and challenges that need to be addressed for successful implementation in the field.

OBJECTIVES/OBJECTIVE:This study aims to evaluate the diagnostic accuracy of an open-source deep learning (DL) model for detecting clinically significant prostate cancer (csPCa) in biparametric MRI (bpMRI). It also aims to outline the necessary components of the model that facilitate effective sharing and external evaluation of PCa detection models. MATERIALS AND METHODS/METHODS:This retrospective diagnostic accuracy study evaluated a publicly available DL model trained to detect PCa on bpMRI. External validation was performed on bpMRI exams from 151 biologically male patients (mean age, 65 ± 8 years). The model's performance was evaluated using patient-level classification of PCa with both radiologist interpretation and histopathology serving as the ground truth. The model processed bpMRI inputs to generate lesion probability maps. Performance was assessed using the area under the receiver operating characteristic curve (AUC) for PI-RADS ≥ 3, PI-RADS ≥ 4, and csPCa (defined as Gleason ≥ 7) at an exam level. RESULTS:The model achieved AUCs of 0.86 (95% CI: 0.80-0.92) and 0.91 (95% CI: 0.85-0.96) for predicting PI-RADS ≥ 3 and ≥ 4 exams, respectively, and 0.78 (95% CI: 0.71-0.86) for csPCa. Sensitivity and specificity for csPCa were 0.87 and 0.53, respectively. Fleiss' kappa for inter-reader agreement was 0.51. CONCLUSION/CONCLUSIONS:The open-source DL model offers high sensitivity to clinically significant prostate cancer. The study underscores the importance of sharing model code and weights to enable effective external validation and further research. KEY POINTS/CONCLUSIONS:Question Inter-reader variability hinders the consistent and accurate detection of clinically significant prostate cancer in MRI. Findings An open-source deep learning model demonstrated reproducible diagnostic accuracy, achieving AUCs of 0.86 for PI-RADS ≥ 3 and 0.78 for CsPCa lesions. Clinical relevance The model's high sensitivity for MRI-positive lesions (PI-RADS ≥ 3) may provide support for radiologists. Its open-source deployment facilitates further development and evaluation across diverse clinical settings, maximizing its potential utility.

RATIONALE/BACKGROUND:Viral lung infections are a major cause of morbidity and mortality worldwide. Despite significant advances in vaccines and antivirals, there remains a tremendous need for broadly applicable treatments that can be utilized across viral infections. Prior to infecting epithelial cells, viruses interact with the epithelial glycocalyx, which contains high molecular weight hyaluronan (HMWHA), a glycosaminoglycan that has beneficial effects in lung injury. OBJECTIVE:To determine the role of HMWHA in viral pneumonia. METHODS:We infected mice with Influenza or SARS-Cov2 and treated with prophylactic or therapeutic doses of HMWHA or saline control. We performed in vitro experiments of infection with viruses of respiratory and non-respiratory human and animal cells and evaluated the effect of HMWHA on infection. We analyzed existing databases for expression of hyaluronan and the transcription factor E2F1. Finally, we performed a clinical trial with HMWHA in patients with severe COVID-19 Measurements and Main Results: Exogenously applied HMWHA improved survival in SARS-CoV2 and influenza infection in mice, by ameliorating inflammation via the inhibition of E2F1. In a clinical study, inhaled HMWHA improved outcomes in patients with severe COVID-19. Furthermore, airway epithelia naturally express HMWHA, which is induced during viral infection and prevents infection via macromolecular crowding of viruses. CONCLUSIONS:Our data provide a mechanistic justification for the use of HMWHA as a broadly effective prophylactic and therapeutic agent in viral airway infection. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND/OBJECTIVES/OBJECTIVE:Vocal fold (VF) muscle atrophy, often associated with neuromuscular disorders and aging, can lead to voice-related disability. Myostatin is well-known to mediate skeletal muscle atrophy via Smad2/3 signaling, whereas TGF-β1, a potent inducer of Smad2/3 signaling, is upregulated following VF injury. However, the impact of Smad2/3 signaling on laryngeal muscles remains unclear. This study provides foundational insight regarding Smad2/3-dependent atrophic responses of VF skeletal muscle cells, to ultimately develop novel therapeutic strategies for VF muscle atrophy. STUDY DESIGN/METHODS:In vitro. METHODS:Myoblasts isolated from the rat thyroarytenoid muscle were differentiated into myotubes in myogenic differentiation medium ±500 ng/mL myostatin or 10 ng/mL TGF-β1, in the presence or absence of an ALK4/5 inhibitor or siRNA targeting Smad2 and Smad3. Myotube formation and activation of Smad2/3 (nuclear localization of Smad2/3) were assessed via immunofluorescence. Transcription related to myotube differentiation and Smad2/3 signaling was quantified by qRT-PCR. RESULTS:Both myostatin and TGF-β1 suppressed myogenic differentiation, increased Smad2/3 nuclear intensity, downregulated Myh2, and upregulated downstream targets of Smad2/3 (Ccn2 and Serpine1) and Fbox32, an atrophy-related gene. These effects were more pronounced with TGF-β1 than with myostatin and were reversed by inhibition of ALK4/5. Furthermore, Smad2/3 knockdown via siRNA promoted myogenic differentiation, further supporting the role of Smad2/3 signaling in the atrophic response in VF myoblasts. CONCLUSIONS:Smad2/3 signaling mediates differentiation of VF myoblasts and TGF-β1, a potent mediator of fibrosis, elicited a more pronounced atrophic response than myostatin. Smad2/3 may be an attractive therapeutic target for VF muscle atrophy. LEVEL OF EVIDENCE/METHODS:NA.

The impact of COVID-19-related mental health effects on health behaviors among people living with HIV (PLWH) remains unknown. Our qualitative study explored the relationship between the mental health consequences of the COVID-19 pandemic and self-management of HIV and cardiovascular disease (CVD) among PLWH in the United States. Twenty-four PLWH enrolled in a multicenter, cardiovascular, clinical trial completed one-on-one semistructured interviews to assess changes in mood, health behaviors, and comorbid CVD management during the COVID-19 pandemic. The majority of participants (ages 43-70 years) were male (n = 17, 70.8%) and Black (n = 19, 79.2%). Participants reported increased mental distress during the COVID-19 pandemic, which they perceived to negatively affect heart-healthy behaviors. Despite mental health stressors, this population continued to adhere to medications, including antiretroviral therapy. Future initiatives should focus on improving mental health outcomes and promotion of healthy lifestyle choices among PLWH to mitigate adverse CVD outcomes.

BACKGROUND:Foot process effacement (FPE), a marker of podocyte injury observable via electron microscopy (EM), plays a key role in the pathophysiology of albuminuria and kidney disease progression. Whether FPE, as reported on kidney biopsies, is associated with histopathologic lesions and adverse clinical outcomes across a range of kidney diseases has not yet been explored. METHODS:We developed semi-quantitative scores from free text pathologists' descriptions of FPE severity, using EM reports from 813 participants in the Boston Kidney Biopsy Cohort (BKBC), a prospective cohort study of individuals with biopsy-confirmed kidney disease. Logistic regression and accelerated failure time models were used to assess the associations of FPE severity with pathologist-adjudicated histopathologic lesions and progression to kidney failure, respectively. In exploratory analysis, we employed mediation analysis to decompose the total effect of FPE severity on kidney failure, exploring the role of measured albuminuria as a mediator in this pathway. RESULTS:Fifty-six % of BKBC participants had no or mild FPE and 44% had moderate or severe FPE. After multivariable adjustment for age, race, sex, and eGFR, more severe mesangial expansion (OR 1.91, 95% CI 1.26 to 2.88, p=0.002) and more severe interstitial fibrosis/tubular atrophy (OR 1.60, 95% CI 1.09 to 2.33, p=0.015) were significantly associated with moderate or severe FPE. In the fully adjusted model, moderate or severe FPE was associated with a 2.7-fold higher hazard of progression to kidney failure compared to none or mild FPE (HR=2.66 (95% CI 1.91, 3.71, p<0.001). Mediation analysis showed that FPE affected kidney failure survival times through both direct effects and indirect (mediated) effects via albuminuria. CONCLUSIONS:FPE is associated not only with glomerular but also tubulointerstitial patterns of injury and may serve as a prognostic tool for assessing the risk of kidney disease progression.

OBJECTIVES/OBJECTIVE:There is a limited number of studies comparing paediatric to adult antiphospholipid syndrome (APS) patients. Our objective was to analyse the characteristics of patients presenting with antiphospholipid antibody (aPL)-related clinical manifestations during childhood versus adulthood. METHODS:We retrieved baseline characteristics from an international registry of persistently aPL-positive adult patients. Clinical events were grouped as vascular and non-vascular. We compared the frequency of and the timeline between vascular and non-vascular events for different age groups at the time of their first aPL-related manifestations: a) paediatric- (0-17 years) versus adult-onset (18-75 years); and b) based on narrower age intervals. Secondly, we analysed the timeline between the first aPL-related clinical event and first aPL positivity. RESULTS:Of 787 patients, 447 (57%) had only vascular events, 108 (14%) only non-vascular events, and 232 (29%) both. Compared to adult-onset patients (n=742), paediatric-onset patients (n=45) presented more commonly with a non-vascular event (49% vs. 19%, p=0.0001). The percentage of patients presenting with a non-vascular event mostly decreased with each increasing age group. Timeline analysis demonstrated 317 (40%) patients had a positive aPL test within the same calendar year (c-y) of the first clinical event, 207 (26%) within 1 to 3 c-y, and 263 (33%) more than 3 c-y. CONCLUSIONS:Our analysis of an international registry for persistently aPL-positive patients demonstrates that patients with paediatric-onset aPL-related manifestations more commonly present with non-vascular events. These results highlight the importance of understanding the clinical differences between paediatric and adult APS patients, which have diagnostic, therapeutic, and research implications.