Deep Learning for Echo Analysis, Tracking, and Evaluation of Mitral Regurgitation (DELINEATE-MR).

BACKGROUND: Artificial intelligence, particularly deep learning (DL), has immense potential to improve the interpretation of transthoracic echocardiography (TTE). Mitral regurgitation (MR) is the most common valvular heart disease and presents unique challenges for DL, including the integration of multiple video-level assessments into a final study-level classification. METHODS: A novel DL system was developed to intake complete TTEs, identify color MR Doppler videos, and determine MR severity on a 4-step ordinal scale (none/trace, mild, moderate, and severe) using the reading cardiologist as a reference standard. This DL system was tested in internal and external test sets with performance assessed by agreement with the reading cardiologist, weighted κ, and area under the receiver-operating characteristic curve for binary classification of both moderate or greater and severe MR. In addition to the primary 4-step model, a 6-step MR assessment model was studied with the addition of the intermediate MR classes of mild-moderate and moderate-severe with performance assessed by both exact agreement and ±1 step agreement with the clinical MR interpretation. RESULTS: A total of 61 689 TTEs were split into train (n=43 811), validation (n=8891), and internal test (n=8987) sets with an additional external test set of 8208 TTEs. The model had high performance in MR classification in internal (exact accuracy, 82%; κ=0.84; area under the receiver-operating characteristic curve, 0.98 for moderate or greater MR) and external test sets (exact accuracy, 79%; κ=0.80; area under the receiver-operating characteristic curve, 0.98 for moderate or greater MR). Most (63% internal and 66% external) misclassification disagreements were between none/trace and mild MR. MR classification accuracy was slightly higher using multiple TTE views (accuracy, 82%) than with only apical 4-chamber views (accuracy, 80%). In subset analyses, the model was accurate in the classification of both primary and secondary MR with slightly lower performance in cases of eccentric MR. In the analysis of the 6-step classification system, the exact accuracy was 80% and 76% with a ±1 step agreement of 99% and 98% in the internal and external test set, respectively. CONCLUSIONS: This end-to-end DL system can intake entire echocardiogram studies to accurately classify MR severity and may be useful in helping clinicians refine MR assessments.

Clinical Outcomes of Additional Below-The-Ankle Intervention Compared to Below-The-Knee Intervention Alone: A Post-Hoc Analysis of a Prospective Multicenter Study.

PURPOSE: To investigate the clinical implication of additional below-the-ankle (BTA) intervention in patients with chronic limb-threatening ischemia (CLTI) undergoing below-the-knee (BTK) intervention. MATERIALS AND METHODS: A sub-analysis was performed using data from the LIBERTY trial (ClinicalTrials.gov identifier NCT01855412), a prospective, observational, core-laboratory adjudicated, multicenter study of endovascular intervention in 1204 patients. Patients with CLTI (Rutherford Classification 4-6) who underwent BTK intervention were included in this sub-analysis. Participants were then stratified into 2 treatment groups according to whether at least one lesion intervened on was BTA (n=66) or not (n=273). The decision on whether and where to intervene was made during the procedure. The main outcome measures included major amputation, target vessel revascularization (TVR), major adverse events (MAE), survival, amputation-free survival, major adverse limb events or peri-operative death (MALE-POD), and all-cause death. Other outcome measures included procedural success, procedural complications, and wound healing rate. RESULTS: There were no differences in procedural success or severe angiographic complications between the 2 groups. At 1-year post-procedure, patients in the BTK group had a higher rate of freedom from major amputation (95.0% vs. 86.9%, respectively; HR: 2.87, 95% CI: 1.17-7.03), a higher rate of freedom from TVR (80.1% vs. 66.9%, respectively; HR: 1.94, 95% CI: 1.14-3.32), a higher rate of freedom from MALE-POD (94.6% vs. 86.9%, respectively; HR: 2.65, 95% CI: 1.10-6.41), and a higher rate of freedom from MAE at both 1 (76.0% vs. 60.1%, respectively; HR: 2.00, 95% CI: 1.24-3.22) and 3 years post procedure (67.5% vs. 55.8%, respectively; HR: 1.69, 95% CI: 1.08-2.65). There was a significantly lower rate of survival in the BTK group at 3 years (74.3% vs. 91.1%, respectively; HR: 0.35, 95% CI: 0.14-0.87). After risk adjustment, there was a higher rate of all-cause death in the BTK group at 3 years (19.4% vs. 9.1%, respectively; p=0.023) post-intervention. CONCLUSION: Patients with disease requiring intervention to BTA lesions have a potential increased amputation rate in the short term, but BTA intervention carries a potential survival benefit in the long term when compared to BTK intervention alone.

An autoregulatory enhancer controls mammary-specific STAT5 functions.

Signal Transducers and Activators of Transcription (STATs) are principal transcription factors downstream of cytokine receptors. Although STAT5A is expressed in most tissues it remains to be understood why its premier, non-redundant functions are restricted to prolactin-induced mammary gland development and function. We report that the ubiquitously expressed Stat5a/b locus is subject to additional lineage-specific transcriptional control in mammary epithelium. Genome-wide surveys of epigenetic status and transcription factor occupancy uncovered a putative mammary-specific enhancer within the intergenic sequences separating the two Stat5 genes. This region exhibited several hallmarks of genomic enhancers, including DNaseI hypersensitivity, H3K27 acetylation and binding by GR, NFIB, ELF5 and MED1. Mammary-specific STAT5 binding was obtained at two canonical STAT5 binding motifs. CRISPR/Cas9-mediated genome editing was used to delete these sites in mice and determine their biological function. Mutant animals exhibited an 80% reduction of Stat5 levels in mammary epithelium and a concomitant reduction of STAT5-dependent gene expression. Transcriptome analysis identified a class of mammary-restricted genes that was particularly dependent on high STAT5 levels as a result of the intergenic enhancer. Taken together, the mammary-specific enhancer enables a positive feedback circuit that contributes to the remarkable abundance of STAT5 and, in turn, to the efficacy of STAT5-dependent mammary physiology.

The Impact of Telemedicine Visits on the Controlling High Blood Pressure Quality Measure During the COVID-19 Pandemic: Retrospective Cohort Study.

BACKGROUND: Telemedicine visit use vastly expanded during the COVID-19 pandemic, and this has had an uncertain impact on cardiovascular care quality. OBJECTIVE: We sought to examine the association between telemedicine visits and the failure to meet the Controlling High Blood Pressure (BP) quality measure from the Centers for Medicare & Medicaid Services. METHODS: This was a retrospective cohort study of 32,727 adult patients with hypertension who were seen in primary care and cardiology clinics at an urban, academic medical center from February to December 2020. The primary outcome was a failure to meet the Controlling High Blood Pressure quality measure, which was defined as having no BP recorded or having a last recorded BP of ≥140/90 mm Hg (ie, poor BP control). Multivariable logistic regression was used to assess the association between telemedicine visit use during the study period (none, 1 telemedicine visit, or ≥2 telemedicine visits) and poor BP control; we adjusted for demographic and clinical characteristics. RESULTS: During the study period, no BP was recorded for 2.3% (486/20,745) of patients with in-person visits only, 27.1% (1863/6878) of patients with 1 telemedicine visit, and 25% (1277/5104) of patients with ≥2 telemedicine visits. After adjustment, telemedicine use was associated with poor BP control (1 telemedicine visit: odds ratio [OR] 2.06, 95% CI 1.94-2.18; P<.001; ≥2 telemedicine visits: OR 2.49, 95% CI 2.31-2.68; P<.001; reference: in-person visits only). This effect disappeared when the analysis was restricted to patients with at least 1 recorded BP (1 telemedicine visit: OR 0.89, 95% CI 0.83-0.95; P=.001; ≥2 telemedicine visits: OR 0.91, 95% CI 0.83-0.99; P=.03). CONCLUSIONS: Increased telemedicine visit use is associated with poorer performance on the Controlling High Blood Pressure quality measure. However, telemedicine visit use may not negatively impact BP control when BP is recorded.

Gaps and Disparities in Primary Prevention Statin Prescription During Outpatient Care.

The 2018 American College of Cardiology/American Heart Association Guideline on the Management of Blood Cholesterol recommends statin therapy for eligible patients to reduce the risk of atherosclerotic cardiovascular disease (ASCVD). We extracted electronic health record data for patients with at least one primary care or cardiology visit between October 2018 and January 2020 at an urban, academic medical center in New York City. Clinical and demographic data were used to identify patients eligible for primary prevention statin therapy. Statin prescription status was extracted from the electronic health record, and multivariate logistic regression was used to assess the association between statin prescription and age, gender, race, ethnicity, and other clinical and demographic covariables. In 7,550 patients eligible for primary prevention statin therapy, 3,994 (52.9%) were prescribed statins on at least 1 visit. Statin prescription was highest in patients with diabetes mellitus (73.6%) and with a 10-year ASCVD risk ≥20% (60.6%) and was lowest for those with a 10-year ASCVD risk between 5% and 7.5% (18.7%). Compared with those never prescribed statins, patients prescribed statins were less likely to be women, mainly driven by lower statin prescription rates for women with diabetes. In a fully adjusted model, women remained less likely to be prescribed statin therapy (adjusted odds ratios 0.79, 95% confidence interval 0.71 to 0.88). In conclusion, primary prevention statin therapy remains underutilized.

Spine Trauma From Personal Watercraft Usage.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To identify patient characteristics and associated injuries in those sustaining a spine fracture from personal watercraft (PWC) usage. SUMMARY OF BACKGROUND DATA: There are few studies regarding PWC use and injuries, and even more scarce are studies evaluating PWC usage and spine injuries. Identifying high-risk actions and individuals can help to effectively treat them, reduce mortality, and possibly avoid certain spine fractures. METHODS: Retrospective analysis of 142 patients admitted from the emergency department with PWC-related injuries at a single-level I trauma center from January 1, 2004 to May 1, 2017. Twenty-six (18.3%) sustained a spine fracture, totaling 71 fractures. Statistical analysis was used to investigate the patient characteristics, specific mechanisms of injury, injury severity score (ISS), and associated injuries. Patients expiring (12) had incomplete evaluations and were excluded from most reported results. RESULTS: Spine fractures were not associated with age, race, or sex, but were associated with a higher ISS, intensive care unit length, in-patient length of stay, cerebral injury, and abdominal/genitourinary (GU) injury. There were 8 cervical fractures, 22 thoracic fractures, 33 lumbar, and 8 sacral fractures. Axial load injuries were associated with vertebral body fractures and specifically burst fractures. Being a driver or passenger did not influence likelihood of a spine fracture, but did correlate with abdominal/GU injury. Five (19.2%) of patients with spine fractures required eight spine surgeries during admission. Mortality was associated with females, severe systemic injuries (ISS ≥ 15), direct collision mechanism of injury, and the spring season. CONCLUSION: PWC usage may result in spine fractures with a moderate percentage requiring orthopedic surgery. Additional studies should examine how hull or seat modifications can lessen the risk of axial loads leading to spine fractures. PWC patients with spine fractures should also be evaluated for abdominal/GU and cerebral injuries at presentation. LEVEL OF EVIDENCE: 4.

Microphysiologic Human Tissue Constructs Reproduce Autologous Age-Specific BCG and HBV Primary Immunization in vitro.

Current vaccine development disregards human immune ontogeny, relying on animal models to select vaccine candidates targeting human infants, who are at greatest risk of infection worldwide, and receive the largest number of vaccines. To help accelerate and de-risk development of early-life effective immunization, we engineered a human age-specific microphysiologic vascular-interstitial interphase, suitable for pre-clinical modeling of distinct age-targeted immunity in vitro. Our Tissue Constructs (TCs) enable autonomous extravasation of monocytes that undergo rapid self-directed differentiation into migratory Dendritic Cells (DCs) in response to adjuvants and licensed vaccines such as Bacille Calmette-Guérin (BCG) or Hepatitis B virus Vaccine (HBV). TCs contain a confluent human endothelium grown atop a tri-dimensional human extracellular matrix substrate, employ human age-specific monocytes and autologous non heat-treated plasma, and avoid the use of xenogenic materials and exogenous cytokines. Vaccine-pulsed TCs autonomously generated DCs that induced single-antigen recall responses from autologous naïve and memory CD4+ T lymphocytes, matching study participant immune-status, including BCG responses paralleling donor PPD status, BCG-induced adenosine deaminase (ADA) activity paralleling infant cohorts in vivo, and multi-dose HBV antigen-specific responses as demonstrated by lymphoproliferation and TCR sequencing. Overall, our microphysiologic culture method reproduced age- and antigen-specific recall responses to BCG and HBV immunization, closely resembling those observed after a birth immunization of human cohorts in vivo, offering for the first time a new approach to early pre-clinical selection of effective age-targeted vaccine candidates.

Toll like receptors TLR1/2, TLR6 and MUC5B as binding interaction partners with cytostatic proline rich polypeptide 1 in human chondrosarcoma.

Metastatic chondrosarcoma is a bone malignancy not responsive to conventional therapies; new approaches and therapies are urgently needed. We have previously reported that mTORC1 inhibitor, antitumorigenic cytostatic proline rich polypeptide 1 (PRP-1), galarmin caused a significant upregulation of tumor suppressors including TET1/2 and SOCS3 (known to be involved in inflammatory processes), downregulation of oncoproteins and embryonic stem cell marker miR-302C and its targets Nanog, c-Myc and Bmi-1 in human chondrosarcoma. To understand better the mechanism of PRP-1 action it was very important to identify the receptor it binds to. Nuclear pathway receptor and GPCR assays indicated that PRP-1 receptors are not G protein coupled, neither do they belong to family of nuclear or orphan receptors. In the present study, we have demonstrated that PRP-1 binding interacting partners belong to innate immunity pattern recognition toll like receptors TLR1/2 and TLR6 and gel forming secreted mucin MUC5B. MUC5B was identified as PRP-1 receptor in human chondrosarcoma JJ012 cell line using Ligand-receptor capture technology. Toll like receptors TLR1/2 and TLR6 were identified as binding interaction partners with PRP-1 by western blot analysis in human chondrosarcoma JJ012 cell line lysates. Immunocytochemistry experiments confirmed the finding and indicated the localization of PRP-1 receptors in the tumor nucleus predominantly. TLR1/2, TLR6 and MUC5B were downregulated in human chondrosarcoma and upregulated in dose-response manner upon PRP-1 treatment. Experimental data indicated that in this cellular context the mentioned receptors had tumor suppressive function.

Hierarchy within the mammary STAT5-driven Wap super-enhancer.

Super-enhancers comprise dense transcription factor platforms highly enriched for active chromatin marks. A paucity of functional data led us to investigate the role of super-enhancers in the mammary gland, an organ characterized by exceptional gene regulatory dynamics during pregnancy. ChIP-seq analysis for the master regulator STAT5A, the glucocorticoid receptor, H3K27ac and MED1 identified 440 mammary-specific super-enhancers, half of which were associated with genes activated during pregnancy. We interrogated the Wap super-enhancer, generating mice carrying mutations in STAT5-binding sites within its constituent enhancers. Individually, the most distal site displayed the greatest enhancer activity. However, combinatorial mutation analysis showed that the 1,000-fold induction in gene expression during pregnancy relied on all enhancers. Disabling the binding sites of STAT5, NFIB and ELF5 in the proximal enhancer incapacitated the entire super-enhancer. Altogether, these data suggest a temporal and functional enhancer hierarchy. The identification of mammary-specific super-enhancers and the mechanistic exploration of the Wap locus provide insights into the regulation of cell-type-specific expression of hormone-sensing genes.