Effects of circulating endothelial microvesicles isolated from adults with obesity on endothelial cell inflammation, apoptosis, and nitric oxide production.

Circulating endothelial cell-derived microvesicles (EMVs) have been shown to be elevated with obesity and associated with endothelial dysfunction; however, their direct effect on endothelial cells is unknown. The experimental aim of this study was to determine the effect of EMVs isolated from adults with obesity on endothelial cell inflammation, apoptosis, and nitric oxide (NO) production. EMVs (CD144+ microvesicles) were identified, enumerated, and isolated from plasma by flow cytometry from 24 sedentary adults: 12 normal-weight adults [8 M/4 F; age: 55 ± 6 yr; body mass index (BMI): 24.3 ± 0.7 kg/m2; EMV: 144 ± 53 EMVs/µL] and 12 adults with obesity (6 M/6 F; 59 ± 7 yr; BMI: 31.0 ± 1.1 kg/m2; EMV: 245 ± 89 EMVs/µL). Human umbilical vein endothelial cells were cultured and treated with EMVs from either normal-weight adults or adults with obesity. EMVs from obese adults induced significantly higher release of interleukin (IL)-6 (108.2 ± 7.7 vs. 90.9 ± 10.0 pg/mL) and IL-8 (75.4 ± 9.8 vs. 59.5 ± 11.5 pg/mL) from endothelial cells vs. EMVs from normal-weight adults, concordant with greater intracellular expression of phosphorylated NF-κB p65 (Ser536; active NF-κB) [145.0 ± 34.1 vs. 114.5 ± 30.4 arbitrary units (AU)]. Expression of phosphorylated p38-MAPK (15.4 ± 5.7 vs. 9.2 ± 2.5 AU) and active caspase-3 (168.2 ± 65.5 vs. 107.8 ± 40.5 AU), markers of cell apoptosis, was higher in cells treated with obesity-related EMVs. Phosphorylated endothelial nitric oxide synthase (eNOS) (Ser1177) expression (23.5 ± 7.2 vs. 34.7 ± 9.7 AU) and NO production (6.9 ± 1.4 vs. 8.7 ± 0.7 µmol/L) were significantly lower in the cells treated with EMVs from obese adults. These data indicate that circulating EMVs from adults with obesity promote a proinflammatory, proapoptotic, and NO-compromised endothelial phenotype. Circulating EMVs are a potential mediator of obesity-related endothelial dysfunction.NEW & NOTEWORTHY In the present study, we determined the effect of circulating endothelial cell-derived microvesicles (EMVs) isolated from adults with obesity on endothelial cell inflammation, apoptosis, and nitric oxide (NO) production in vitro. Circulating EMVs harvested from adults with obesity promoted a proinflammatory, proapoptotic, and NO-compromised endothelial phenotype. Elevated circulating EMVs in adults with obesity, independent of other cardiometabolic risk factors, are a potential novel systemic mediator of obesity-related endothelial dysfunction and vascular risk.

Characterizing drug-induced epidermal necrolysis in a pediatric cohort.

This study aims to characterize the timeline and clinical features of onset, progression, and management of drug-induced epidermal necrolysis in pediatric patients. Sixteen pediatric patients were retrospectively identified and selected if under age 18 years at admission with one identified culprit drug exposure. Culprit drugs were antiepileptics (12/16, 75%) and antibiotics (4/16, 25%). Notably, anti-epileptic drugs (AED) had delayed onset and reported dose escalations that precipitated symptom onset; thus, patients prescribed AED with or without planned dose escalations should be monitored for prodromal symptoms longer than the typical onset window.

The Man Who Mistook a Hat for His Wife: Case Report of Aortic Dissection Presenting With Acute Hyperfamiliarity for Faces.

Acute aortic dissection is a challenging diagnosis for emergency physicians because of its high mortality and wide range of clinical presentations. We report a case of a previously healthy man who presented with hyperfamiliarity for faces syndrome as the predominant symptom of a large type A aortic dissection diagnosed by computed tomography angiography in the emergency department. Different elements of his presentation suggested possible other diagnoses, including transient global amnesia and transient ischemic attack. We discuss how evaluating these other diagnostic possibilities led to the correct diagnosis. Given increasing reports of painless aortic dissection, this case demonstrates the need to consider aortic dissection in patients with acute neurological symptoms.

Development of a Hypercoagulable-Hypofibrinolytic State Early After Spinal Cord Injury.

OBJECTIVES: To determine whether spinal cord injury (SCI) is associated with adverse changes in coagulation and fibrinolytic factors that underlie thrombogenesis and contribute to atherothrombotic events such as myocardial infarctions (MIs) and strokes. DESIGN: Cross-sectional study. SETTING: Neurorehabilitation hospital and general community. PARTICIPANTS: Thirty young and middle-aged (20-58 years) adults (N=30) were studied: 14 non-injured community dwelling adults. (11M/4F) and 16 with subacute tetraplegic motor complete SCI during initial inpatient rehabilitation (13M/3F; time since injury: 11.8±5.3 wk). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Circulating markers of coagulation [von Willebrand factor (vWf) and factors VII, VIII, and X], the fibrinolytic system [tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) antigen and activity], and fibrin formation (D-dimer) were determined by enzyme immunoassay. RESULTS: Thirty young and middle-aged (20-58 years) adults were studied: 14 non-injured (11M/4F) and 16 with subacute tetraplegic motor complete SCI (13M/3F; time since injury: range 4-25 wk). Circulating levels of coagulation factors VII, VIII, and X were significantly higher (∼20%-45%; P<.05) in the adults with SCI than non-injured adults, whereas vWf was similar between groups. Fibrinolytic markers were adversely disrupted with SCI with t-PA antigen, PAI-1 antigen and PAI-1 activity were markedly higher (∼50%-800%; P<.05) in adults with SCI compared with non-injured adults. The molar concentration ratio of active t-PA to PAI-1 was significantly higher (∼350%) in adults with SCI. Concordant with coagulation cascade activation and fibrinolytic system inhibition, D-dimer concentrations were markedly ∼70% higher (P<.05) in adults with SCI compared with non-injured adults. CONCLUSIONS: Subacute tetraplegic motor complete SCI is associated with a prothrombotic hemostatic profile. Adverse changes in the coagulation cascade and fibrinolytic system appear to occur early after injury and may contribute to the increased atherothrombotic risk in adults living with SCI.

Exploration of biomedical knowledge for recurrent glioblastoma using natural language processing deep learning models.

BACKGROUND: Efficient exploration of knowledge for the treatment of recurrent glioblastoma (GBM) is critical for both clinicians and researchers. However, due to the large number of clinical trials and published articles, searching for this knowledge is very labor-intensive. In the current study, using natural language processing (NLP), we analyzed medical research corpora related to recurrent glioblastoma to find potential targets and treatments. METHODS: We fine-tuned the 'SAPBERT', which was pretrained on biomedical ontologies, to perform question/answering (QA) and name entity recognition (NER) tasks for medical corpora. The model was fine-tuned with the SQUAD2 dataset and multiple NER datasets designed for QA task and NER task, respectively. Corpora were collected by searching the terms "recurrent glioblastoma" and "drug target", published from 2000 to 2020 in the Web of science (N = 288 articles). Also, clinical trial corpora were collected from 'clinicaltrial.gov' using the searching term of 'recurrent glioblastoma" (N = 587 studies). RESULTS: For the QA task, the model showed an F1 score of 0.79. For the NER task, the model showed F1 scores of 0.90 and 0.76 for drug and gene name recognition, respectively. When asked what the molecular targets were promising for recurrent glioblastoma, the model answered that RTK inhibitors or LPA-1 antagonists were promising. From collected clinical trials, the model summarized them in the order of bevacizumab, temozolomide, lomustine, and nivolumab. Based on published articles, the model found the many drug-gene pairs with the NER task, and we presented them with a circus plot and related summarization ( https://github.com/bigwiz83/NLP_rGBM ). CONCLUSION: Using NLP deep learning models, we could explore potential targets and treatments based on medical research and clinical trial corpora. The knowledge found by the models may be used for treating recurrent glioblastoma.

Leveraging the electronic health record to improve dermatologic care delivery: The importance of finding structure in data.

The federal mandate for electronic health record (EHR) keeping for health care providers impacted the burden placed on dermatologists for medical documentation. The hope that EHR would improve care quality and efficiency and reduce health disparities has yet to be fully realized. Despite the significant time and effort spent on documentation, the majority of EHR clinical data remain unstructured and therefore, difficult to process and analyze. Structured data can provide a way for dermatologists and data scientists to make more effective use of clinical data-not only to improve the dermatologist's experience with EHRs, but also to manage technology-related administrative burden, accelerate understanding of disease, and enhance care delivery for patients. Understanding the importance of structured data will allow dermatologists to actively engage in how clinical data will be collected and used to advance patient care.

Long-Term Outcomes of Melanoma In Situ Treated With Topical 5% Imiquimod Cream: A Retrospective Review.

BACKGROUND: Melanoma in situ (MIS) is a noninvasive form of melanoma for which nonsurgical therapeutic options continue to be explored. The off-label use of topical 5% imiquimod cream in the management of MIS has shown potential but reported recurrence rates vary considerably between 0% and 40%. Furthermore, the long-term efficacy of imiquimod is not well established. OBJECTIVE: To determine the recurrence rate of MIS among patients treated with topical 5% imiquimod cream at Dartmouth-Hitchcock Medical Center with at least 1 year of follow-up. METHODS: A retrospective chart review identified 12 patients with MIS who have been treated with topical 5% imiquimod cream for 6 to 12 weeks. Patients who underwent surgical treatment for MIS were excluded from analysis. RESULTS: Of 12 patients with histologically confirmed MIS treated with topical 5% imiquimod cream, there were 2 recurrences (17%) during a median follow-up time of 5.5 years. CONCLUSION: Although surgery is still considered the gold standard for the treatment of MIS, imiquimod may represent a potentially effective noninvasive treatment option for patient who are not surgical candidates.

Lawrence Transfer Factor: Transference of Specific Immune Memory by Dialyzable Leukocyte Extract from a CD8+ T Cell Line.

Lawrence transfer factor (TF) is defined as dialyzable leukocyte extract (DLE) that can transfer antigen-specific cell-mediated immunity from a person testing positive for the antigen in a delayed type hypersensitivity skin test manner to a person negative for the same antigen. A recent article by Myles et al1 has identified a DLE isolated from an established CD8+ T cell line capable of transferring antigen-specific immunity. The DLE contains a portion of the beta chain of the T cell receptor and additional nucleotide and protein factors that are being subjected to further modern biochemical analysis. After months of study that included interviews of TF physician-scientists, we conclude that an antigen-specific TF exists for most, if not all, antigens. By working from a CD8+ T cell line with modern biochemical technology, it should be possible to identify and patent products capable of treating infectious diseases, antigen-responsive cancers, and autoimmune disorders.

Simplifying Forehead Reconstruction: A Review of More Than 200 Cases.

The forehead is a unique facial region with distinct boundaries and variability in shape from patient to patient. When reconstructing the forehead, it is critical to take into account the regional boundaries as their distortion may result in noticeable facial asymmetry. We propose subdividing the forehead into newly defined zones and put forth a rational algorithm for forehead repair based on these divisions. We retrospectively reviewed a single surgeon's (F. H. S.) experience with Mohs excision and immediate reconstruction of the forehead over a 3-year period. A total of 227 consecutive post-Mohs forehead reconstructions were identified, and the reconstructive technique for a given defect size and location and postoperative complications were recorded. The average patient age was 69 years and 114 (50%) patients were female. Reconstructive techniques varied based on defect size and location within the five distinct forehead zones. Primary closure was the favored technique when appropriate, with variation in orientation based on forehead zone. Modified Burow's advancement flap was the most commonly utilized reconstruction for defects of midlateral forehead and suprabrow area, accounting for 51.7 and 62.5% of repairs, respectively. Other techniques included A-to-T flaps, rotation flaps, and full-thickness skin grafting. Using our defined zones, most common repair techniques, and final outcomes, a reconstructive algorithm for post-Mohs excisions on the forehead was derived. Consideration of the five distinct forehead zones and application of an algorithm to guide technique selection for post-Mohs forehead defect repair can lead to consistent results.

Fibroblast growth factor-2 is required for vasa vasorum plexus stability in hypercholesterolemic mice.

OBJECTIVE: Vasa vasorum are angiogenic in advanced stages of human atherosclerosis and hypercholesterolemic mouse models. Fibroblast growth factor-2 (FGF-2) is the predominant angiogenic growth factor in the adventitia and plaque of hypercholesterolemic low-density lipoprotein receptor-deficient/apolipoprotein B(100/100) mice (DKO). FGF-2 seems to play a role in the formation of a distinct vasa vasorum network. This study examined the vasa vasorum structure and its relationship to FGF-2. METHODS AND RESULTS: DKO mice treated with saline, antiangiogenic recombinant plasminogen activator inhibitor-1(23) (rPAI-1(23)), or soluble FGF receptor 1 were perfused with fluorescein-labeled Lycopersicon esculentum lectin. Confocal images of FGF-2-probed descending aorta adventitia show that angiogenic vasa vasorum form a plexus-like network in saline-treated DKO similar to the FGF-2 pattern of distribution. Mice treated with rPAI-1(23) and soluble FGF receptor 1 lack a plexus; FGF-2 and vasa vasorum density and area are significantly reduced. A perlecan/FGF-2 complex is critical for plexus stability. Excess plasmin produced in rPAI-1(23)-treated DKO mice degrades perlecan and destabilizes the plexus. Plasmin activity and plaque size measured in DKO and DKO/plasminogen activator inhibitor-1(-)(/-) mice demonstrate that elevated plasmin activity contributes to reduced plaque size. CONCLUSIONS: An FGF-2/perlecan complex is required for vasa vasorum plexus stability. Elevated plasmin activity plays a significant inhibitory role in vasa vasorum plexus and plaque development.

Differential Expression of Vascular-Related MicroRNA in Circulating Endothelial Microvesicles in Adults With Spinal Cord Injury: A Pilot Study.

Background: Spinal cord injury (SCI) is associated with an increased risk and prevalence of cardiopulmonary and cerebrovascular disease-related morbidity and mortality. The factors that initiate, promote, and accelerate vascular diseases and events in SCI are poorly understood. Clinical interest in circulating endothelial cell-derived microvesicles (EMVs) and their microRNA (miRNA) cargo has intensified due to their involvement in endothelial dysfunction, atherosclerosis, and cerebrovascular events. Objectives: The aim of this study was to determine whether a subset of vascular-related miRNAs is differentially expressed in EMVs isolated from adults with SCI. Methods: We assessed eight adults with tetraplegia (7 male/1 female; age: 46±4 years; time since injury: 26±5 years) and eight uninjured (6 male/2 female; age: 39±3 years). Circulating EMVs were isolated, enumerated, and collected from plasma by flow cytometry. The expression of vascular-related miRNAs in EMVs was assessed by RT-PCR. Results: Circulating EMV levels were significantly higher (~130%) in adults with SCI compared with uninjured adults. The expression profile of miRNAs in EMVs from adults with SCI were significantly different than uninjured adults and were pathologic in nature. Expression of miR-126, miR-132, and miR-Let-7a were lower (~100-150%; p < .05), whereas miR-30a, miR-145, miR-155, and miR-216 were higher (~125-450%; p < .05) in EMVs from adults with SCI. Conclusion: This study is the first examination of EMV miRNA cargo in adults with SCI. The cargo signature of vascular-related miRNAs studied reflects a pathogenic EMV phenotype prone to induce inflammation, atherosclerosis, and vascular dysfunction. EMVs and their miRNA cargo represent a novel biomarker of vascular risk and a potential target for intervention to alleviate vascular-related disease after SCI.

Circulating Immune Cell and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma.

PURPOSE: PD-L1 is upregulated in glioblastoma and supports immunosuppression. We evaluated PD-L1 blockade with durvalumab among glioblastoma cohorts and investigated potential biomarkers. PATIENTS AND METHODS: MGMT unmethylated newly diagnosed patients received radiotherapy plus durvalumab (cohort A; n = 40). Bevacizumab-naïve, recurrent patients received durvalumab alone (cohort B; n = 31) or in combination with standard bevacizumab (cohort B2; n = 33) or low-dose bevacizumab (cohort B3; n = 33). Bevacizumab-refractory patients received durvalumab plus bevacizumab (cohort C; n = 22). Primary endpoints were: OS-12 (A), PFS-6 (B, B2, B3), and OS-6 (C). Exploratory biomarkers included: a systematic, quantitative, and phenotypic evaluation of circulating immune cells; tumor mutational burden (TMB); and tumor immune activation signature (IAS). RESULTS: No cohort achieved the primary efficacy endpoint. Outcome was comparable among recurrent, bevacizumab-naïve cohorts. No unexpected toxicities were observed. A widespread reduction of effector immune cell subsets was noted among recurrent patients compared with newly diagnosed patients that was partially due to dexamethasone use. A trend of increased CD8+Ki67+ T cells at day 15 was noted among patients who achieved the primary endpoint and were not on dexamethasone. Neither TMB nor IAS predicted outcome. CONCLUSIONS: Patients with recurrent glioblastoma have markedly lower baseline levels of multiple circulating immune cell subsets compared with newly diagnosed patients. An early increase in systemic Ki67+CD8+ cells may warrant further evaluation as a potential biomarker of therapeutic benefit among patients with glioblastoma undergoing checkpoint therapy. Dexamethasone decreased immune cell subsets. PD-L1 blockade and combination with standard or reduced dose bevacizumab was ineffective.

Preexposure Prophylaxis for Human Immunodeficiency Virus Infection for Men Who Have Sex with Men and Transgender Persons:: What Dermatologists Need to Know.

HIV remains an important public health concern in the United States, particularly for men who have sex with men (MSM) and transgender persons. With HIV preexposure prophylaxis (PrEP), persons who are HIV-uninfected take antiretroviral medications to prevent HIV infection. The most common PrEP regimen involves taking a single pill daily and is very effective in reducing risk of HIV infection, with few adverse effects. Barriers to PrEP access exist for MSM and transgender persons. Dermatologists can help combat the ongoing HIV epidemic among MSM, transgender persons, and others by understanding why, when, and how PrEP should be considered as an HIV prevention approach.

Noncontrast MRI with advanced diffusion weighted imaging for breast cancer detection in a lactating woman.

Magnetic resonance imaging (MRI) is used for preoperative evaluation, high-risk screening, and other select indications for breast cancer. However, the interpretation of breast MR images in pregnant and lactating women is complicated by physiologic changes of the breast that may result in marked background enhancement. Breast MRI with contrast administration is contraindicated in pregnancy. Restriction spectrum imaging (RSI) is an advanced diffusion-weighted (DW)-MRI method that theoretically reflects signal from cells with high nuclear-to-cytoplasm ratio without gadolinium-based contrast. This report describes a case in which RSI notably increased tumor conspicuity in a lactating woman, compared to contrast-enhanced (CE)-MRI and conventional DW-MRI.

Machine Learning Model to Predict Pseudoprogression Versus Progression in Glioblastoma Using MRI: A Multi-Institutional Study (KROG 18-07).

Some patients with glioblastoma show a worsening presentation in imaging after concurrent chemoradiation, even when they receive gross total resection. Previously, we showed the feasibility of a machine learning model to predict pseudoprogression (PsPD) versus progressive disease (PD) in glioblastoma patients. The previous model was based on the dataset from two institutions (termed as the Seoul National University Hospital (SNUH) dataset, N = 78). To test this model in a larger dataset, we collected cases from multiple institutions that raised the problem of PsPD vs. PD diagnosis in clinics (Korean Radiation Oncology Group (KROG) dataset, N = 104). The dataset was composed of brain MR images and clinical information. We tested the previous model in the KROG dataset; however, that model showed limited performance. After hyperparameter optimization, we developed a deep learning model based on the whole dataset (N = 182). The 10-fold cross validation revealed that the micro-average area under the precision-recall curve (AUPRC) was 0.86. The calibration model was constructed to estimate the interpretable probability directly from the model output. After calibration, the final model offers clinical probability in a web-user interface.

Prophylactic treatment of osteoporosis after SCI: promising research, but not yet indicated.

In persons with spinal cord injury (SCI), osteoporosis and associated fragility fractures are a prevalent phenomenon with clinically meaningful morbidity and mortality. Prevention of osteoporosis utilizing both physical modalities and pharmacological therapies is an area of high-clinical importance. In our perspective, the current body of research cannot provide clear guidance on prophylactic interventions to prevent osteoporosis specifically to stratify SCI subjects to their risk for fragility fractures. Without this critical research, clinicians cannot weigh the risk versus benefits of interventions, such as bisphosphonates, which is not a benign treatment. Other treatments such as physical modalities provide little risk and have other therapeutic benefit. This perspective is an argument that the current research does not indicate prophylactic pharmacological intervention to prevent osteoporosis in the SCI population.

Information technologies in health care delivery and policy: giant steps and missteps.

The influences of information technology have touched almost all aspects of our lives, and health care delivery has been no exception. Law, policy, and regulation have driven the adoption of electronic medical records, particularly over the past decade, driving fundamental changes to the practice of medicine in general and dermatology in particular. This article reviews the history of these changes, the regulations that drove these changes, the intended and unintended consequences of these initiatives, and our insights into the appropriate roles for policy and regulation to drive positive change.