Sex-Based Analysis of Workflow and Outcomes in Acute Ischemic Stroke Patients Treated With Alteplase Versus Tenecteplase.

BACKGROUND: Understanding sex differences in stroke care is important in reducing potential disparities. Our objective was to explore sex differences in workflow efficiency, treatment efficacy, and safety in the AcT trial (Alteplase Compared to Tenecteplase). METHODS: AcT was a multicenter, registry-linked randomized noninferiority trial comparing tenecteplase (0.25 mg/kg) with alteplase (0.9 mg/kg) in acute ischemic stroke within 4.5 hours of onset. In this post hoc analysis, baseline characteristics, workflow times, successful reperfusion (extended Thrombolysis in Cerebral Infarction score ≥2b), symptomatic intracerebral hemorrhage, 90-day functional independence (modified Rankin Scale score, 0-1), and 90-day mortality were compared by sex. Mixed-effects regression analysis was used adjusting for age, stroke severity, and occlusion site for outcomes. RESULTS: Of 1577 patients treated with intravenous thrombolysis (2019-2022), 755 (47.9%) were women. Women were older (median, 77 [68-86] years in women versus 70 [59-79] years in men) and had a higher proportion of severe strokes (National Institutes of Health Stroke Scale score >15; 32.4% versus 24.9%) and large vessel occlusions (28.7% versus 21.5%) compared with men. All workflow times were comparable between sexes. Women were less likely to achieve functional independence (31.7% versus 39.8%; unadjusted relative risk, 0.80 [95% CI, 0.70-0.91]) and had higher mortality (17.7% versus 13.3%; unadjusted relative risk, 1.33 [95% CI, 1.06-1.69]). Adjusted analysis showed no difference in outcomes between sexes. CONCLUSIONS: Differences in prognostic factors of age, stroke severity, and occlusion site largely accounted for higher functional dependence and mortality in women. No sex disparities were apparent in workflow quality indicators. Given the integration of the AcT trial into clinical practice, these results provide reassurance that no major sex biases are apparent in acute stroke management throughout participating Canadian centers. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

Mohs Micrographic Surgery for Facial Merkel Cell Carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare malignant cutaneous tumor with frequent metastases. They often appear in the face where cosmetic and functional outcome is critical. Mohs micrographic surgery (MMS) is a controlled intervention that optimizes negative margins without sacrificing tissue. OBJECTIVE: A comprehensive assessment of outcomes of MMS-treated facial MCC will help guide clinicians in surgical and medical management. METHODS & MATERIALS: Retrospective review identified facial MCC cases treated with MMS at a single institution from January 2005 to August 2020. Tumor characteristics and outcomes were recorded and descriptive and predictive analyses were performed. RESULTS: 34 cases were reviewed with a mean followup of 34.4 months. The most common sites were the forehead, cheek-jaw region, and nasal ala. 2 (5.9%) patients had local recurrence by a mean of 4.3 months. No documented variables were significantly associated with local recurrence. 8 (23.5%) patients had progression to metastasis by a mean of 9.4 months. Younger age at biopsy and surgery, male sex, and intraoperative detection of in-transit disease were significantly associated with progression to metastasis. CONCLUSIONS: In summary, the tissue-sparing approach of MMS may be beneficial for MCC in cosmetically and functionally sensitive facial locations as it preserves tissue without compromising outcomes.

Sebaceous Carcinoma of the Face Treated With Mohs Micrographic Surgery.

BACKGROUND: Mohs micrographic surgery (MMS) for sebaceous carcinoma (SC) may reduce local recurrence rates, but published case series have small cohorts and limited follow-up. Mohs micrographic surgery is particularly suitable for sensitive functional and cosmetic locations, such as the face, because it facilitates tissue conservation using complete peripheral and deep margin assessment before reconstruction. Coordinated care between Mohs and oculoplastic surgeons has not been described. OBJECTIVE: To assess rates of local recurrence and metastasis after MMS of facial SC and to describe coordinated care between Mohs and oculoplastic surgeons. MATERIALS AND METHODS: Retrospective review identified facial SC cases treated with MMS at a single institution from January 2005 to August 2020. Tumor characteristics and outcomes were recorded. Descriptive and predictive analyses were performed. RESULTS: Forty-nine cases were reviewed with a mean follow-up of 51 months. The most common sites were periorbital, infraorbital cheek, and nasal ala. No patients experienced regional recurrence after MMS. One patient with Muir-Torre syndrome developed metastatic recurrence (at 82.9 months). All patients underwent 2-stage reconstruction with dermatology-performed MMS and oculoplastic reconstruction. CONCLUSION: Collaboration between Mohs and oculoplastic surgeons with a tissue-sparing approach of MMS can reduce recurrence and optimize cosmesis and function for central facial SC.

Updates in Cerebral Venous Thrombosis.

PURPOSE OF REVIEW: Cerebral venous thrombosis (CVT) is a rare cause of stroke that most commonly affects younger women. Here, we review new literature relevant to the management and prognosis of individuals with CVT and ongoing areas of uncertainty. RECENT FINDINGS: Direct-acting oral anticoagulants (DOACs) are being increasingly integrated into routine care but are not yet recommended by guidelines. Recent randomized clinical trials and available case series offer reassuring safety data. Routine use of endovascular therapy is not associated with improved outcomes. The relationship between recanalization and prognosis is uncertain. The evidence base for management of CVT continues to improve. Ongoing areas of uncertainty include duration of therapy and whether certain subgroups of patients may benefit from neurointervention or personalized approaches to antithrombotic strategy. The state of knowledge will continue to benefit from large collaborative international efforts, and integration of patient partnerships to identify research priorities.

Orbital and periorbital dermoid cysts: a retrospective analysis of 270 lesions.

PURPOSE: To report the clinical characteristics and intraoperative findings of periorbital and orbital dermoid cysts and their relationship to location and rupture. METHODS: Retrospective review of 270 cases with orbital or periorbital dermoid cysts that presented over a period of 11 years. Patients were included if diagnosis of dermoid cyst was made by histopathologic analysis. Clinical characteristics and operative outcomes were recorded and analyzed with Chi-squared analyses or univariate regression. Multivariate binary logistic regression was performed to assess predictors of location and rupture. RESULTS: Dermoids frequently occurred unilaterally and were more frequently described as mobile (61.5%), followed by fixed (30.8%), and partially fixed (7.7%). Dermoid rigidity was most commonly described as firm (75.5%), followed by cystic, soft, and rubbery. The most common dermoid location was superotemporal (60.4%). On Chi-squared analysis, superotemporal lesions were less likely to have orbital extension than non-superotemporal lesions (OR 0.28, 95% CI: 0.11-0.70, p = .01), less likely to undergo CT (OR 0.16, 95% CI: 0.06-0.41, p < .01) or MRI (OR 0.23, 95% CI: 0.13-0.41, p < .01), more likely to be described as mobile (OR 2.91, 95% CI: 1.32-6.43, p = .01), and less likely to rupture intraoperatively (OR 0.28, 95% CI: 0.11-0.73, p = .01). No variables were associated with rupture in multivariate analysis. CONCLUSION: Superotemporal dermoid cysts are common in the pediatric population, less likely to have orbital extension, undergo imaging, and have intraoperative rupture when compared to other locations in the orbit.

Clinical and electrophysiological properties of atrial tachycardia after pediatric heart transplantation.

BACKGROUND: Pediatric heart transplant recipients are at an elevated risk for development of atrial tachycardia (AT); however, the underlying mechanisms and long-term outcomes are unclear. OBJECTIVE: We hypothesized that occurrence of AT in pediatric heart transplant recipients would be associated with a higher frequency of adverse events during follow-up. METHODS: A single-center retrospective review of all pediatric heart transplant recipients with suspected AT between 1997 and 2017 was performed. Unaffected controls were matched with cases for age and transplant era. Clinical characteristics and long-term outcomes were compared between groups. RESULTS: Of 294 heart transplant recipients, 13 with AT at electrophysiology study (4.4%) were identified and compared with 29 controls. The most common mechanism was focal (11), followed by atrial flutter (two), and electrical reconnection of a surgical atrial anastomosis (two). Focal AT was only observed in the right atrium or atrial septum, and was frequently found on or near the crista terminalis. Relative to controls, cases exhibited more frequent clinical evidence of rejection (9/13 vs 10/29, P  =  0.037). For patients with AT, there was a higher rate of death/retransplant among cases (log-rank P  =  0.022), which remained significant in multivariate analysis. CONCLUSION: In this cohort, the most common form of AT after pediatric heart transplantation was focal, with predilection for sites near the crista terminalis. Transplant patients with AT experienced a higher rate of clinical rejection and the composite end-point of retransplantation or death relative to unaffected controls.

Individual variation in ACTH-induced cortisol levels in females of a livebearing fish at different gestational stages.

Individuals vary in their baseline levels of stress hormones (predictive homeostasis) and in their stress responses (reactive homeostasis). Variation in normal reactive scope, both predictive and reactive homeostasis, may be important for understanding how endocrine traits respond to selection. Reactive homeostasis is the increase in glucocorticoid (GCs) hormones above baseline. Individuals at different life history stages, such as gestation in females, may show variation in normal reactive scope. We performed an adrenocorticotropic hormone (ACTH) challenge and measured changes in circulating GCs to estimate the reactive scope of female sailfin mollies (Poecilia latipinna) at different gestational states. We measured cortisol, primary GC in teleost fishes, to obtain baseline release rates prior to injection with either ACTH or saline control. Using water-borne hormones, we measured cortisol release rates at four time intervals post-injection. Females were then sacrificed to determine the developmental stage of embryos, if present, and the number of developing embryos or mature ova. We found that ACTH-injected females had significant increases in cortisol releases rates, whereas cortisol release rates of control females did not change during the 4 h post-injection period. We found high repeatability in predictive homeostasis of cortisol and moderate repeatability in reactive homeostasis and a phenotypic correlation between predictive and reactive homeostasis. Gestational state did not affect female predictive or reactive homeostasis. We applied the reactive scope model to P. latipinna and gained a further understanding of how among- and within-individual variation in both predictive and reactive homeostasis are partitioned and how these traits vary under certain life-history conditions.

Pharmacologic Management for Heart Failure and Emerging Therapies.

PURPOSE OF REVIEW: This review aims to summarize the growing body of literature of HF with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) with a focus on recent pharmacologics. RECENT FINDINGS: HFrEF continues to be more widely investigated than HFpEF. Ivabradine and combinatorial treatment with sacubitril and valsartan are promising newly approved therapies. Other experimental therapies have emerged, which include Serelaxin, Empagliflozin, Neuregulin, and Omecamtive mecarbil, among others. These drugs need to continue to be investigated for safety and efficacy. We predict ivabradine and combinatorial treatment with sacubitril-valsartan to develop as a widespread therapy. New therapies should be aimed at treating HFpEF or target the cardiomyocyte itself.

Electrocardiogram voltage discordance: Interpretation of low QRS voltage only in the precordial leads.

OBJECTIVES: To define clinical correlates of low voltage isolated to precordial leads on the surface electrocardiogram (ECG). INTRODUCTION: Low voltage (V) on the ECG is defined as QRS V<5mm in all limb leads and <10mm in all precordial leads. The diagnostic use of ECGs with low voltage isolated to the precordial leads with normal limb lead voltages is unclear. METHODS: Twelve-lead ECGs with QRS V>5mm in one or more limb leads and <10mm in all precordial leads were collected. Associated clinical conditions were determined from clinical data, echocardiograms, and chest radiographs. RESULTS: Low precordial voltage was found in 256 of 150,000 ECGs (~0.2%). 50.4% of patients had discordant ECGs that correlated with classic etiologies, with a higher incidence of LV dilation in those with classic etiologies than those without. CONCLUSION: Low precordial voltage is associated with classic etiologies and LV dilation.

Single-Center Experience Using Selexipag in a Pediatric Population.

Pulmonary arterial hypertension (PAH) is a rare and progressive disorder. Current treatment in the pediatric population includes phosphodiesterase 5 inhibitors (PDE-5i), endothelin receptor antagonists (ERA), and both inhaled and intravenous prostacyclin pathway agonists. As of December 22, 2015 the first oral prostacyclin pathway agonist, selexipag (Uptravi®), was FDA approved in the US. In this case series, we discuss our single-center experience using selexipag in a pediatric population, composed of both patients with idiopathic PAH, and patients with congenital heart disease and PAH.

An event-based account of conformity.

People often change their behavior and beliefs when confronted with deviating behavior and beliefs of others, but the mechanisms underlying such phenomena of conformity are not well understood. Here we suggest that people cognitively represent their own actions and others' actions in comparable ways (theory of event coding), so that they may fail to distinguish these two categories of actions. If so, other people's actions that have no social meaning should induce conformity effects, especially if those actions are similar to one's own actions. We found that female participants adjusted their manual judgments of the beauty of female faces in the direction consistent with distracting information without any social meaning (numbers falling within the range of the judgment scale) and that this effect was enhanced when the distracting information was presented in movies showing the actual manual decision-making acts. These results confirm that similarity between an observed action and one's own action matters. We also found that the magnitude of the standard conformity effect was statistically equivalent to the movie-induced effect.

Risk Factors for Chalazion Diagnosis and Subsequent Surgical Excision.

PURPOSE: To identify factors associated with chalazion diagnosis and surgical excision. METHODS: Patients with an incident chalazion diagnosis from 2002 to 2019 were compared 1:5 with matched controls. Multivariable logistic regression was performed to identify variables associated with diagnosis and surgical excision. RESULTS: Chalazion patients (n = 134,959) and controls (678,160) were analyzed. Risk factors for diagnosis included female sex, non-white race, northeast location, conditions affecting periocular skin and tear film (blepharitis, meibomian gland dysfunction, rosacea, pterygium), non-ocular inflammatory conditions (gastritis, inflammatory bowel disease, sarcoidosis, seborrheic dermatitis, Graves' disease), and smoking (p < .001 for all comparisons). Thirteen percent of patients with chalazion underwent subsequent surgical excision. Diabetes and systemic sclerosis diagnoses decreased odds of diagnosis (p < .001). Male sex, rosacea diagnosis, Black and Hispanic race, antibiotic use, and doxycycline use increased odds of surgery (p < .001). CONCLUSION: Female sex, non-white race, conditions affecting periocular skin and the tear film, several non-ocular inflammatory conditions, and smoking were risk factors for chalazion diagnosis. Male sex, rosacea diagnosis, Black and Hispanic race, antibiotic use, and doxycycline use were risk factors for surgical intervention for chalazion. Our results prompt further study of these variables and their relationship to chalazion diagnosis to understand physiology and improve clinical outcomes. Furthermore, the results of this study suggest early recognition and treatment of concomitant rosacea may serve an important role in the management of chalazion and in the prevention of surgical intervention.

Cavernous sinus thrombosis with bilateral orbital vein involvement and diffuse ischemic retinopathy.

A 53-year-old man with a 3-day history of periorbital swelling and vision loss in the left eye was found to have septic cavernous sinus thrombosis with bilateral orbital vein involvement causing congestive orbitopathy. He was treated with an emergent canthotomy and cantholysis, intraocular pressure-lowering drops, antibiotics, anticoagulation, and serial examinations. Optical coherence tomography ultimately revealed diffuse ischemic destruction of both layers of the retina, which suggested occlusion of the ophthalmic artery or the short posterior ciliary arteries and central retinal artery without intracavernous internal carotid artery involvement. The patient remained without light perception in the left eye after treatment.

Teaching NeuroImage: Rapidly Changing Symptoms With Multistep Migration of Clot in the Posterior Circulation After Tenecteplase for Acute Ischemic Stroke.

A 70-year-old man presented with acute vertigo and ataxia. CT angiogram revealed left V3 segment vertebral artery occlusion (Figure 1, A and B). He received tenecteplase (0.25 mg/kg IV bolus) and was transferred to our comprehensive stroke center due to the risk of early neurologic deterioration from clot migration that would necessitate thrombectomy. Repeat CT angiogram revealed migration to V4 segment with posterior inferior cerebellar artery reopacification and improving symptoms (Figure 1, C and D). Two hours post-tenecteplase, he developed aphasia, right hemianopia, and sensorimotor symptoms (National Institutes of Health Stroke Scale 15). Angiogram showed a left P1 posterior cerebral artery thrombus. Attempted thrombectomy resulted in further migration to P2. MRI demonstrated multiple infarcts (Figure 2), representing stepwise ischemia from dynamic clot movement. Clot reformation from hypercoagulability or re-embolization seemed unlikely, given short time course and exclusive posterior circulation involvement.

Sox17 mediates adult arterial endothelial cell adaptation to hemodynamics.

Sox17 is a critical regulator of arterial identity during early embryonic vascular development. However, its role in adult endothelial cells (ECs) are not fully understood. Sox17 is highly expressed in arterial ECs but not in venous ECs throughout embryonic development to adulthood suggesting that it may play a functional role in adult arteries. Here, we investigated Sox17 mediated phenotypical changes in adult ECs. To precisely control the temporal expression level of Sox17, we designed a tetracycline-inducible lentiviral gene expression system to express Sox17 selectively in cultured venous ECs. We confirmed that Sox17-induced ECs exhibit a gene profile favoring arterial and tip cell identity. Furthermore, in comparison to control ECs, Sox17-activated ECs under shear leads to greater expression of arterial markers and suppression of venous identity. These data suggest that Sox17 enables greater hemodynamic adaptability of ECs in response to fluid shear stress. Here, we also demonstrate key morphogenic behaviors of Sox17-mediated ECs. In both vasculogenic and angiogenic 3D fibrin gel studies, Sox17-mediated ECs prefer to form cohesive vessels with one another while interfering the vessel formation of the control ECs. Sox17-mediated ECs elicit hyper-sprouting behavior in the presence of pericytes but not fibroblasts, suggesting Sox17 mediated sprouting frequency is dependent on supporting cell type. Using a microfluidic chip, we also show that Sox17-mediated ECs maintain thinner diameter vessels that do not widen under interstitial flow like the control ECs. Taken together, these data showed that Sox17 mediated EC gene expression and phenotypical changes are highly modulated in the context of biomechanical stimuli, suggesting Sox17 plays a role in regulating the arterial ECs adaptability under arterial hemodynamics as well as tip cells behavior during angiogenesis and vasculogenesis. The results from this study may be valuable in improving vein graft adaptation to arterial hemodynamics and bioengineering microvasculature for tissue engineering applications.

Recanalization and outcomes after cerebral venous thrombosis: a systematic review and meta-analysis.

Background: Recanalization in cerebral venous thrombosis (CVT) can begin as early as 1 week after initiating therapeutic anticoagulation. The clinical significance of recanalization remains uncertain. Objectives: We aimed to investigate the association between recanalization and functional outcomes and explored predictors of recanalization. Methods: A systematic literature search was conducted (EMBASE, MEDLINE, Cochrane library) to identify: (1) patients with CVT aged ≥18 years treated with anticoagulation only; (2) case series, cohort, or randomized controlled trial studies; and (3) reported recanalization rates and functional outcomes using either a modified Rankin Scale (mRS) or sequelae of CVT at last follow-up. Meta-analysis was performed using pooled odds ratios (ORs) with exploration of sex and age effects using meta-regression. Results: Twenty-three studies were eligible with 1418 individual patients in total. Timing of reimaging and clinical reassessment was variable. Absence of recanalization was associated with increased odds of an unfavorable functional outcome (mRS 2-6 versus 0-1; OR, 3.66; 95% CI, 1.73-7.74; p = 0.001), CVT recurrence (OR, 8.81; 95% CI, 1.63-47.7; p = 0.01), and chronic headache (OR, 2.78; 95% CI, 1.16-6.70; p = 0.02). On meta-regression, the relationship between recanalization and mRS differed by the proportion of female patients, where lower proportions of women were associated with higher likelihood of a worse outcome, but not by mean participant age. There was no incremental benefit of full compared with partial recanalization with respect to favorable mRS or recurrence, but odds of chronic headache were higher with partial versus full recanalization (OR, 3.80; 95% CI, 1.43-10.11; p = 0.008). Epilepsy and visual sequelae were not associated with recanalization. Conclusions: Absence of recanalization was associated with worse functional outcomes, CVT recurrence, and headache, but outcomes were modified by sex. The degree of recanalization was significant in relation to headache outcomes, where partial compared with complete recanalization resulted in a greater likelihood of residual headache. Prospective studies with common timing of repeat clinical-neuroimaging assessments will help to better ascertain the relationship and directionality between the degree of recanalization and outcomes.

Cryptophthalmos: associated syndromes and genetic disorders.

PURPOSE: Cryptophthalmos is a rare congenital condition caused by anomalous eyelid development where the eyelid folds do not develop or fail to separate. Cryptophthalmos can be unilateral or bilateral and can occur in isolation or as part of an underlying syndrome. We aim to identify genetic syndromes associated with cryptophthalmos to facilitate genetic diagnosis. METHODS: We performed a retrospective medical record review of all patients diagnosed with cryptophthalmos followed at a single center between 2000 and 2020. The analysis included medical history, clinical examination findings, and genetic testing results. RESULTS: Thirteen patients were included, 10 (77%) males, mean age of 2.4 years. Eight (61%) had bilateral cryptophthalmos, and 4 (31%) had complete cryptophthalmos. Associated ocular abnormalities included corneal opacities (13/13, 100%), upper eyelid colobomas (12/13, 92%), and microphthalmia/clinical anophthalmia (3/13, 23%). All cases of complete cryptophthalmos had bilateral disease. An underlying clinical or molecular diagnosis was identified in 10/13 (77%) cases, including Fraser syndrome (n = 5), amniotic band syndrome (n = 1), FREM1-related disease (n = 1), Goldenhar versus Schimmelpenning syndrome (n = 1), MOTA syndrome (n = 1), and CELSR2-related disease (n = 1). CONCLUSION: This is the first report of a possible association between cryptophthalmos and biallelic CELSR2 variants. Children with cryptophthalmos, especially those with extra-ocular involvement, should be referred for comprehensive genetic evaluation.