A Review of Antithrombotic Agents in Dermatologic Surgery and Context for a Practical Approach, With Cardiology and Pharmacologic Input.

Dermatologic surgeons are encountering more patients on antithrombotic agents. There are no established consensus guidelines for managing antithrombotic agents in the perioperative period. We provide an updated overview of antithrombotic agents in dermatologic surgery and management of such agents in the perioperative period with additional unique perspectives from cardiology and pharmacy. A literature search of PubMed and Google Scholar was performed to review the English-language medical literature. The landscape of antithrombotic therapy is changing with a notable rise in the use of direct oral anticoagulants (DOACs.) While no consensus guidelines exist, most studies recommend continuing antithrombotic therapy in the perioperative period with appropriate lab monitoring, when applicable. However, recent data suggest it is safe to hold DOACs in the perioperative period. As antithrombotic therapy evolves, the dermatologic surgeon needs to remain current with the most recent available data. Where data are limited, a multidisciplinary approach to managing these agents in the perioperative period is essential. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.7456.

Primary cutaneous Ewing sarcoma in a young boy.

We report a 10-year-old boy with the challenging presentation of a left toe nodule that failed empiric treatments and was biopsied. Immunohistochemistry and florescence in situ hybridization enabled the diagnosis of Ewing sarcoma (ES). This case emphasizes the importance of including ES on the clinical differential to minimize diagnostic delays.

A Drosophila model for TDP-43 proteinopathy.

Neuropathology involving TAR DNA binding protein-43 (TDP-43) has been identified in a wide spectrum of neurodegenerative diseases collectively named as TDP-43 proteinopathy, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). To test whether increased expression of wide-type human TDP-43 (hTDP-43) may cause neurotoxicity in vivo, we generated transgenic flies expressing hTDP-43 in various neuronal subpopulations. Expression in the fly eyes of the full-length hTDP-43, but not a mutant lacking its amino-terminal domain, led to progressive loss of ommatidia with remarkable signs of neurodegeneration. Expressing hTDP-43 in mushroom bodies (MBs) resulted in dramatic axon losses and neuronal death. Furthermore, hTDP-43 expression in motor neurons led to axon swelling, reduction in axon branches and bouton numbers, and motor neuron loss together with functional deficits. Thus, our transgenic flies expressing hTDP-43 recapitulate important neuropathological and clinical features of human TDP-43 proteinopathy, providing a powerful animal model for this group of devastating diseases. Our study indicates that simply increasing hTDP-43 expression is sufficient to cause neurotoxicity in vivo, suggesting that aberrant regulation of TDP-43 expression or decreased clearance of hTDP-43 may contribute to the pathogenesis of TDP-43 proteinopathy.

GLP-1 receptor agonists modulate blood glucose levels in T2DM by affecting Faecalibacterium prausnitzii abundance in the intestine.

BACKGROUND: Glucagon-like peptide 1 (GLP-1) receptor agonists are a class of medications used to treat type 2 diabetes, including metformin, which is considered first-line therapy for type 2 diabetes. In recent years, GLP-1 receptor agonists (GLP-1 RAs) have been found to alter the composition and structure of gut flora and also promote the production of gut probiotics. However, there have been few clinical studies regarding the effects of GLP-1 RAs on gut flora. In this study, we investigated changes in the abundance of Lactobacillus delbrueckii (L delbrueckii) and Faecalibacterium prausnitzii (F prausnitzii) 1 week after administration of a GLP-1 RA in the clinical treatment of type 2 diabetes. The association with glycemic and body mass index (BMI) correlations was also explored. METHODS: Twelve newly diagnosed patients with type 2 diabetes were examined for changes in the abundance of L delbrueckii and F prausnitzii by Fluorescence in Situ Hybridization 1 week after administration of GLP-1 RAs. Subjects BMI was measured and fasting glucose changes were detected using the glucose oxidase method, and Spearman correlation analysis was performed to explore their relevance. RESULTS: There was no significant change in the abundance of L delbrueckii in the intestine (P = .695) and no significant correlation with BMI and fasting glucose levels (R = 0.134, P = .534) after the use of GLP-1 RA (R = -0.098, P = .647); F prausnitzii on the other hand had a significantly higher abundance (P = .002) and a significant negative correlation with fasting glucose level (R = -0.689, P < .001), but no significant correlation with BMI (R = -0.056, P = .796). CONCLUSION: F prausnitzii may be one of the pathways through which glucose is regulated in the treatment of type 2 diabetes by GLP-1 RAs.

Examining degenerative disease adjacent to lumbosacral transitional vertebrae: a retrospective cohort study.

OBJECTIVE: Bertolotti syndrome is a clinical diagnosis given to patients with low-back pain arising from a lumbosacral transitional vertebra (LSTV). While biomechanical studies have demonstrated abnormal torques and range of motion occurring at and above this type of LSTV, the long-term effects of these biomechanical changes on the LSTV adjacent segments are not well understood. This study examined degenerative changes at segments superjacent to the LSTV in patients with Bertolotti syndrome. METHODS: This study involved a retrospective comparison of patients between 2010 and 2020 with an LSTV and chronic back pain (Bertolotti syndrome) and control patients with chronic back pain with no LSTV. The presence of an LSTV was confirmed on imaging, and the caudal-most mobile segment above the LSTV was assessed for degenerative changes. Degenerative changes were assessed by grading the intervertebral disc, facets, degree of spinal stenosis, and spondylolisthesis using well documented grading systems. All computations were performed in R, version 4.1.0. All tests were two-sided, and p values < 0.05 was considered statistically significant. Separate logistic regression analyses were run with the associated dependent variables for each aim, with age at MRI and sex included as covariates. Odds ratios and 95% confidence intervals were computed. RESULTS: A total of 172 patients were included, 101 with Bertolotti syndrome and 71 controls. Control patients consisted of patients with low-back pain but no diagnosis of Bertolotti syndrome or an LSTV. Fifty-six Bertolotti (55.4%) and 27 control (38.0%) patients were female, (p = 0.03). After adjusting for age at MRI and sex, Bertolotti patients had pelvic incidence (PI) that was 9.83° greater than control patients (95% CI 5.15°-14.50°, p < 0.001). Sacral slope was not significantly different between the Bertolotti and control groups (beta estimate 3.10°, 95% CI -1.07° to 7.27°; p = 0.14). Bertolotti patients had 2.69 times higher odds of having a high disc grade at L4-5 (3-4 vs 0-2), compared with control patients (OR 2.69, 95% CI 1.28-5.90; p = 0.01). There were no significant differences between Bertolotti patients and controls for spondylolisthesis, facet grade, or spinal stenosis grade. CONCLUSIONS: Patients with Bertolotti syndrome had a significantly higher PI and were more likely to have adjacent-segment disease (ASD; L4-5) compared with control patients. However, after controlling for age and sex, PI and ASD did not appear to have a significant association within the cohort of Bertolotti patients. The altered biomechanics and kinematics in this condition may be a causative factor in this degeneration, although proof of causation is not possible in this study. This association may warrant closer follow-up protocols for patients being treated for Bertolotti syndrome, but further prospective studies are needed to establish if radiographic parameters can serve as an indicator for biomechanical alterations in vivo.

Impact of anemia on acute ischemic stroke outcomes: A systematic review of the literature.

INTRODUCTION: Anemia has been reported in nearly 40% of acute ischemic stroke (AIS) patients and is linked to significant morbidity and disability. The presence of anemia is associated with worse outcomes in AIS, specifically in the presence of large vessel occlusion (LVO). An optimal hemoglobin (Hb) target specific to this pathology has not yet been established. The goal of this review is to systematically review literature that observes the association that exists between AIS outcomes and hemoglobin (Hb) levels. METHODS: A systematic review was performed in accordance with guidelines for the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) to identify studies from 2008-2022. The following inclusion and exclusion criteria were used: studies of adult patients with AIS; must describe outcomes with regard to Hb levels in AIS (not limited to LVO); must be written in English. The clinical variables extracted included Length of Stay (LOS), modified rankin score (mRS), Hb levels, and mortality. RESULTS: A total of 1,154 studies were gathered, with 116 undergoing full text review. 31 studies were included in this review. The age of patients ranged from 61.4 to 77.8. The presence of anemia in AIS increased LOS by 1.7 days on average and these patients also have a 15.2% higher rate of mortality at one year, on average. DISCUSSION: This data suggests that the contemporary thresholds for treating anemia in AIS patients may be inadequate because anemia is strongly associated with poor outcomes (e.g., mRS>2 or mortality) and increased LOS in AIS patients. The current generalized Hb threshold for transfusion (7 g/dL) is also used in AIS patients, however, a more aggressive transfusion parameter should be further explored based on these findings. Further studies are required to confirm these findings and to determine if a more liberal RBCT threshold will result in clinical benefits.

CT Texture Analysis in Nonalcoholic Fatty Liver Disease (NAFLD).

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease worldwide. There are limited biomarkers that can detect progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The purpose of our study was to utilize CT texture analysis to distinguish steatosis from NASH. Methods: 16 patients with NAFLD (38% male, median (interquartile range): age 57 (48-64) years, BMI 37.5 (35.0-46.8) kg/m2) underwent liver biopsy and abdominal non-contrast CT. CT texture analysis was performed to quantify gray-level tissue summaries (e.g., entropy, kurtosis, skewness, and attenuation) using commercially available software (TexRad, Cambridge England). Logistic regression analyses were performed to quantify the association between steatosis/NASH status and CT texture. ROC curve analysis was performed to determine sensitivity, specificity, AUC, 95% CIs, and cutoff values of texture parameters to differentiate steatosis from NASH. Results: By histology, 6/16 (37%) of patients had simple steatosis and 10/16 (63%) had NASH. Patients with NASH had lower entropy (median, interquartile range (IQR): 4.3 (4.1, 4.8) vs. 5.0 (4.9, 5.2), P = 0.013) and lower mean value of positive pixels (MPP) (34.4 (21.8, 52.2) vs. 66.5 (57.0, 70.7), P = 0.009) than those with simple steatosis. Entropy values below 4.73 predict NASH with 100% (95%CI: 67-100%) specificity and 80% (50-100%) sensitivity, AUC: 0.88. MPP values below 54.0 predict NASH with 100% (67-100%) specificity and 100% (50-100%) sensitivity, AUC 0.90. Conclusion: Our study provides preliminary evidence that CT texture analysis may serve as a novel imaging biomarker for disease activity in NAFLD and the discrimination of steatosis and NASH.

Thrombosis after SARS-CoV2 infection or COVID-19 vaccination: will a nonpathologic anti-PF4 antibody be a solution?-A narrative review.

The coronavirus disease 2019 (COVID-19) pandemic was triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a previously unknown strain of coronavirus. To fully understand the consequences and complications of SARS-CoV-2 infections, we have reviewed current literature on coagulation dysfunctions that are related to the disease and vaccination. While COVID-19 is more commonly considered as a respiratory illness, studies indicate that, in addition to respiratory illness, a coagulation dysfunction may develop in individuals after the initial infection, placing them at the risk of developing thrombotic events. Patients who died of COVID-19 had higher levels of D-dimer, a biomarker for blood clot formation and breakdown. Effective treatments for coagulation dysfunctions are critically needed to improve patient survival. On the other hand, antibodies against platelet factor 4 (PF4)/heparin may be found in patients with rare instances of vaccine-induced immunological thrombotic thrombocytopenia (VITT) following vaccination with adenovirus-based vaccines. VITT is characterized by atypical thrombosis and thrombocytopenia, similar to immune-mediated heparin-induced thrombocytopenia (HIT), but with no need for heparin to trigger the immune response. Although both adenovirus-based and mRNA-based vaccines express the Spike protein of SARS-CoV-2, VITT is exclusively related to adenovirus-based vaccines. Due to the resemblance with HIT, the use of heparin is highly discouraged against treating patients with thrombotic thrombocytopenia after SARS-CoV-2 infection or with VITT after vaccination. Intravenous immunoglobulin therapy coupled with anticoagulation is recommended instead. The well-studied anti-PF4 monoclonal antibody RTO, which does not induce pathologic immune complexes in the presence of heparin and has been humanized for a potential treatment modality for HIT, may provide a nonanticoagulant HIT-specific solution to the problem of increased blood coagulation after SARS-CoV-2 infection or the VITT after immunization.

A systematic review of periungual eccrine neoplasms.

Eccrine tumors are a rare cutaneous adnexal neoplasm originating from the sweat glands. The periungual region represents an uncommon localization for these neoplasms. We analyzed all published demographic, clinical, and treatment data on periungual eccrine tumors. A systematic review following PRISMA guidelines was performed of articles published prior to March 2021. Articles were included in the review if a full-text English version was available. Of the surveyed literature, 27 full-text case reports were included in the final analysis. Benign eccrine poroma and porocarcinoma were the most common tumor subtypes (nine and eight cases, respectively). Males were only affected by poroma and porocarcinoma, while females were affected by all tumor subtypes. The first toe was the most common lower extremity affected. Misdiagnosis led to delayed treatment in 25% of cases. As such, while periungual eccrine neoplasms are rare diagnoses, the nonspecific presentations of these growths raise concerns about misdiagnosis and delayed treatment. Further research is needed related to sex-differences in the epidemiology of these growths and into the prevalence of the first toe as a location. These tumors should be considered in the differential diagnosis for nail unit afflictions.

Cancer cell mechanobiology: a new frontier for cancer research.

The study of physical and mechanical features of cancer cells, or cancer cell mechanobiology, is a new frontier in cancer research. Such studies may enhance our understanding of the disease process, especially mechanisms associated with cancer cell invasion and metastasis, and may help the effort of developing diagnostic biomarkers and therapeutic drug targets. Cancer cell mechanobiological changes are associated with the complex interplay of activation/inactivation of multiple signaling pathways, which can occur at both the genetic and epigenetic levels, and the interactions with the cancer microenvironment. It has been shown that metastatic tumor cells are more compliant than morphologically similar benign cells in actual human samples. Subsequent studies from us and others further demonstrated that cell mechanical properties are strongly associated with cancer cell invasive and metastatic potential, and thus may serve as a diagnostic marker of detecting cancer cells in human body fluid samples. In this review, we provide a brief narrative of the molecular mechanisms underlying cancer cell mechanobiology, the technological platforms utilized to study cancer cell mechanobiology, the status of cancer cell mechanobiological studies in various cancer types, and the potential clinical applications of cancer cell mechanobiological study in cancer early detection, diagnosis, and treatment.

Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis.

Mutations in the gene encoding TDP-43-the major protein component of neuronal aggregates characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusion bodies-have been linked to familial forms of both disorders. Aggregates of TDP-43 in cortical and spinal motorneurons in ALS, or in neurons of the frontal and temporal cortices in FTLD, are closely linked to neuron loss and atrophy in these areas. However, the mechanism by which TDP-43 mutations lead to neurodegeneration is unclear. To investigate the pathogenic role of TDP-43 mutations, we established a model of TDP-43 proteinopathies by expressing fluorescently tagged wild-type and mutant TDP-43 in primary rat cortical neurons. Expression of mutant TDP-43 was toxic to neurons, and mutant-specific toxicity was associated with increased cytoplasmic mislocalization of TDP-43. Inclusion bodies were not necessary for the toxicity and did not affect the risk of cell death. Cellular survival was unaffected by the total amount of exogenous TDP-43 in the nucleus, but the amount of cytoplasmic TDP-43 was a strong and independent predictor of neuronal death. These results suggest that mutant TDP-43 is mislocalized to the cytoplasm, where it exhibits a toxic gain-of-function and induces cell death.

A Preliminary Study of Deep-Learning Algorithm for Analyzing Multiplex Immunofluorescence Biomarkers in Body Fluid Cytology Specimens.

INTRODUCTION: Multiplex biomarker analysis of cytological body fluid specimens is often used to assist cytologists in distiguishing metastatic cancer cells from reactive mesothelial cells. However, evaluating biomarker expression visually may be challenging, especially when the cells of interest are scant. Deep-learning algorithms (DLAs) may be able to assist cytologists in analyzing multiple biomarker expression at the single cell level in the multiplex fluorescence imaging (MFI) setting. This preliminary study was performed to test the feasibility of using DLAs to identify immunofluorescence-stained metastatic adenocarcinoma cells in body fluid cytology samples. METHODS: A DLA was developed to analyze MFI-stained cells in body fluid cytological samples. A total of 41 pleural fluid samples, comprising of 20 positives and 21 negatives, were retrospectively collected. Multiplex immunofluorescence labeling for MOC31, BerEP4, and calretinin, were performed on cell block sections, and results were analyzed by manual analysis (manual MFI) and DLA analysis (MFI-DLA) independently. RESULTS: All cases with positive original cytological diagnoses showed positive results either by manual MFI or MFI-DLA, but 2 of the 14 (14.3%) original cytologically negative cases had rare cells with positive MOC31 and/or BerEP4 staining in addition to calretinin. Manual MFI analysis and MFI-DLA showed 100% concordance. CONCLUSION: MFI combined with DLA provides a potential tool to assist in cytological diagnosis of metastatic malignancy in body fluid samples. Larger studies are warranted to test the clinical validity of the approach.

Effects of Open-Label, Adjunctive Ganaxolone on Persistent Depression Despite Adequate Antidepressant Treatment in Postmenopausal Women: A Pilot Study.

OBJECTIVE: The neuroactive steroid metabolite of progesterone, allopregnanolone, is a positive allosteric modulator of γ-aminobutyric acid-A (GABAA) receptors and a putative treatment for mood disorders. This pilot study was performed to determine whether an oral allopregnanolone analog (ganaxolone) may be effective adjunctive therapy for persistent depression despite adequate antidepressant treatment in postmenopausal women. METHOD: Ten postmenopausal women (mean ± SD age: 62.8 ± 6.3 years; range, 53-69 years) with persistent depression despite adequate antidepressant treatment (current DSM-IV-TR major depressive episode per the Structured Clinical Interview for DSM-IV-TR, Montgomery-Asberg Depression Rating Scale [MADRS] score ≥ 16, and treated with an adequately dosed antidepressant for ≥ 6 weeks) were studied from December 2016 to April 2018. Open-label ganaxolone (225 mg twice daily, increased to 450 mg twice daily if tolerated) was administered for 8 weeks, followed by a 2-week taper. RESULTS: Mean ± SEM total MADRS score (primary endpoint) decreased by 8 weeks (24.4 ± 1.6 to 12.8 ± 2.9, P = .015), and the decrease persisted over the 2-week taper (P = .019); of the 9 subjects who completed the full 8-week treatment period, 44% (4/9) experienced response (MADRS score decrease ≥ 50%) and remission (final MADRS score < 10), which persisted in 100% and 50% of subjects at 10 weeks, respectively. Secondary endpoints showed significant improvement, including Inventory of Depressive Symptomatology-Self-Report score (P = .003), MADRS reduced sleep subscale score (P < .001), total Symptoms of Depression Questionnaire (SDQ) score (P = .012), and scores on SDQ subscales for disruptions in sleep quality (P = .003) and changes in appetite and weight (P = .009) over 8 weeks. No significant effects were observed on quality of life or sexual function. All subjects experienced sleepiness and fatigue; 60% experienced dizziness. CONCLUSIONS: In this open-label, uncontrolled pilot study, adjunctive ganaxolone appears to exert antidepressant effects but produces sedation with twice-daily dosing. Ganaxolone may also improve sleep, which may be useful in patients with depression and insomnia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02900092.

Low-Dose Testosterone Augmentation for Antidepressant-Resistant Major Depressive Disorder in Women: An 8-Week Randomized Placebo-Controlled Study.

OBJECTIVE: Low-dose testosterone has been shown to improve depression symptom severity, fatigue, and sexual function in small studies in women not formally diagnosed with major depressive disorder. The authors sought to determine whether adjunctive low-dose transdermal testosterone improves depression symptom severity, fatigue, and sexual function in women with antidepressant-resistant major depression. A functional MRI (fMRI) substudy examined effects on activity in the anterior cingulate cortex (ACC), a brain region important in mood regulation. METHODS: The authors conducted an 8-week randomized double-blind placebo-controlled trial of adjunctive testosterone cream in 101 women, ages 21-70, with antidepressant-resistant major depression. The primary outcome measure was depression symptom severity as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary endpoints included fatigue, sexual function, and safety measures. The primary outcome of the fMRI substudy (N=20) was change in ACC activity. RESULTS: The participants' mean age was 47 years (SD=14) and their mean baseline MADRS score was 26.6 (SD=5.9). Eighty-seven (86%) participants completed 8 weeks of treatment. MADRS scores decreased in both study arms from baseline to week 8 (testosterone arm: from 26.8 [SD=6.3] to 15.3 [SD=9.6]; placebo arm: from 26.3 [SD=5.4] to 14.4 [SD=9.3]), with no significant difference between groups. Improvement in fatigue and sexual function did not differ between groups, nor did side effects. fMRI results showed a relationship between ACC activation and androgen levels before treatment but no difference in ACC activation with testosterone compared with placebo. CONCLUSIONS: Adjunctive transdermal testosterone, although well tolerated, was not more effective than placebo in improving symptoms of depression, fatigue, or sexual dysfunction. Imaging in a subset of participants demonstrated that testosterone did not result in greater activation of the ACC.

Plasma Free Cortisol in States of Normal and Altered Binding Globulins: Implications for Adrenal Insufficiency Diagnosis.

CONTEXT: Accurate diagnosis of adrenal insufficiency is critical because there are risks associated with overdiagnosis and underdiagnosis. Data using liquid chromatography tandem mass spectrometry (LC/MS/MS) free cortisol (FC) assays in states of high or low cortisol-binding globulin (CBG) levels, including cirrhosis, critical illness, and oral estrogen use, are needed. DESIGN: Cross-sectional. OBJECTIVE: Determine the relationship between CBG and albumin as well as total cortisol (TC) and FC in states of normal and abnormal CBG. Establish the FC level by LC/MS/MS that best predicts TC of <18 µg/dL (497 nmol/L) (standard adrenal insufficiency diagnostic cutoff) in healthy individuals. SUBJECTS: This study included a total of 338 subjects in four groups: healthy control (HC) subjects (n = 243), patients with cirrhosis (n = 38), intensive care unit patients (ICU) (n = 26), and oral contraceptive (OCP) users (n = 31). MAIN OUTCOME MEASURE(S): FC and TC by LC/MS/MS, albumin by spectrophotometry, and CBG by ELISA. RESULTS: TC correlated with FC in the ICU (R = 0.91), HC (R = 0.90), cirrhosis (R = 0.86), and OCP (R = 0.70) groups (all P < 0.0001). In receiver operator curve analysis in the HC group, FC of 0.9 µg/dL (24.8 nmol/L) predicted TC of <18 µg/dL (497 nmol/L; 98% sensitivity, 91% specificity; AUC, 0.98; P < 0.0001). Decreasing the cutoff to 0.7 µg/dL led to a small decrease in sensitivity (92%) with similar specificity (91%). CONCLUSIONS: A cutoff FC of <0.9 µg/dL (25 nmol/L) in this LC/MS/MS assay predicts TC of <18 µg/dL (497 nmol/L) with excellent sensitivity and specificity. This FC cutoff may be helpful in ruling out adrenal insufficiency in patients with binding globulin derangements.