Perspectives of Emergency Medicine Physicians on Hidradenitis Suppurativa Care.

Introduction: Hidradenitis suppurativa (HS) is a chronic skin condition that often requires acute care during periods of flares, with many patients visiting the emergency department over 5 times before receiving a proper diagnosis. However, little is known about emergency medicine (EM) providers' experiences and knowledge of HS management. Methods: In this study, an anonymous survey was distributed to EM providers to identify knowledge and practice gaps in HS care. Results: The results showed that most respondents lacked confidence in HS diagnosis and management, especially in knowing available treatment options and managing patients with moderate to severe HS. Attendings were more confident than non-attendings in diagnosing and managing HS, and providers who saw more HS patients per month were more confident in referring patients to appropriate specialists. Over 80% of respondents referred HS patients to dermatology, which is an important initial step in HS management. Conclusion: The study highlights the importance of educating EM providers in HS recognition, timely referral to dermatology, and initial management to improve quality of life among patients and mitigate disease progression.

Metastasis of cholangiocarcinoma is promoted by extended high-mannose glycans.

Membrane-bound oligosaccharides form the interfacial boundary between the cell and its environment, mediating processes such as adhesion and signaling. These structures can undergo dynamic changes in composition and expression based on cell type, external stimuli, and genetic factors. Glycosylation, therefore, is a promising target of therapeutic interventions for presently incurable forms of advanced cancer. Here, we show that cholangiocarcinoma metastasis is characterized by down-regulation of the Golgi α-mannosidase I coding gene MAN1A1, leading to elevation of extended high-mannose glycans with terminating α-1,2-mannose residues. Subsequent reshaping of the glycome by inhibiting α-mannosidase I resulted in significantly higher migratory and invasive capabilities while masking cell surface mannosylation suppressed metastasis-related phenotypes. Exclusive elucidation of differentially expressed membrane glycoproteins and molecular modeling suggested that extended high-mannose glycosylation at the helical domain of transferrin receptor protein 1 promotes conformational changes that improve noncovalent interaction energies and lead to enhancement of cell migration in metastatic cholangiocarcinoma. The results provide support that α-1,2-mannosylated N-glycans present on cancer cell membrane proteins may serve as therapeutic targets for preventing metastasis.

Micronutrients in Atopic Dermatitis: A Systematic Review.

Objective: The pathophysiology of atopic dermatitis (AD) involves a complex interplay between immune system dysfunction, genetics, and environmental factors. It is well known that nutritional status is essential to a proper functioning immune system, leading to a highly debated question regarding the role of dietary factors in the pathogenesis of AD. Food allergies and elimination diets have been broadly studied in atopy; however, less consideration has been given to how vitamins, minerals, and other micronutrients influence the risk for AD and severity of symptoms. This systematic review discusses evidence on how various micronutrients, including vitamins (C, E, and D) and trace minerals (zinc, selenium, iron, copper, magnesium, and strontium) are associated with AD, and how supplementation influence disease severity. Design: A systematic search was conducted to identify the role that oral micronutrients have on AD. The authors reviewed 49 studies herein. Results: While there are weak associations between vitamins C or E and AD, there is sufficient evidence to suggest that vitamin D supplementation provides benefit in AD patients. Deficiency of selenium and zinc may exacerbate AD. Current reports are not sufficient to confidently discern the role of other vitamins and trace minerals on AD. Conclusions: Though oral micronutrients may play a role in AD, the current literature is limited, and there is a need for more comprehensive randomized controlled trials (RCTs) to truly decipher the role between oral micronutrients and AD.

New and emerging targeted systemic therapies: a new era for atopic dermatitis.

PURPOSE: This is a review of emerging targeted, systemic therapies for atopic dermatitis (AD). The information presented aims to provide dermatologists with updated therapeutic options, stimulate academic interest, and spark future research. MATERIAL AND METHODS: Extensive search of ClinicalTrials.gov, the National Eczema Association, and PubMed was performed for clinical trials examining the effect of emerging targeted, systemic therapies in patients with AD. Results were included if they demonstrated efficacy in reversing AD symptoms. Studies that did not demonstrate clinical benefit were excluded. RESULTS: A number of emerging systemic agents targeting specific mediators involved in the pathogenesis of AD were found. These targets include IL-4, IL-13, IgE, B-cells, IL-5, IL-31, JAK-STAT, SYK, IL-6, PDE-4, IL-12, IL-17, IL-23, IL-22, H4R, NKR1, κOR, TSLP, PPAR-γ, and DGLA. Treatment of AD patients with these therapies has, in many cases, led to statistically significant improvements in clinical severity scores and patient-reported outcomes. CONCLUSIONS: While multiple agents have demonstrated efficacy, only dupilumab is currently approved for adults with AD. Large-scale, randomized, placebo-controlled, double-blind trials, especially in children, are needed. As we enter the dawn of targeted therapy for AD, a comprehensive clinical trial registry is needed to facilitate data pooling and comparison among international registries.

MEK inhibitors and their potential in the treatment of advanced melanoma: the advantages of combination therapy.

The treatment of melanoma has improved markedly over the last several years with the advent of more targeted therapies. Unfortunately, complex compensation mechanisms, such as those of the mitogen-activated protein kinase (MAPK) pathway, have limited the clinical benefit of these treatments. Recently, a better understanding of melanoma resistance mechanisms has given way to intelligently designed multidrug regimes. Herein, we review the extensive pathways of BRAF inhibitor (vemurafenib and dabrafenib) resistance. We also review the advantages of dual therapy, including the addition of an MEK inhibitor (cobimetinib or trametinib), which has proven to increase progression-free survival when compared to BRAF inhibitor monotherapy. Finally, this review touches on future treatment strategies that are being developed for advanced melanoma, including the possibility of triple therapy with immune checkpoint inhibitors and the work on optimizing sequential therapy.

Endothelial ß-Catenin Signaling Is Required for Maintaining Adult Blood-Brain Barrier Integrity and Central Nervous System Homeostasis.

BACKGROUND: The blood-brain barrier (BBB) formed by brain endothelial cells interconnected by tight junctions is essential for the homeostasis of the central nervous system. Although studies have shown the importance of various signaling molecules in BBB formation during development, little is known about the molecular basis regulating the integrity of the adult BBB. METHODS AND RESULTS: Using a mouse model with tamoxifen-inducible endothelial cell-restricted disruption of ctnnb1 (iCKO), we show here that endothelial ß-catenin signaling is essential for maintaining BBB integrity and central nervous system homeostasis in adult mice. The iCKO mice developed severe seizures accompanied by neuronal injury, multiple brain petechial hemorrhages, and central nervous system inflammation, and all had postictal death. Disruption of endothelial ß-catenin induced BBB breakdown and downregulation of the specific tight junction proteins claudin-1 and -3 in adult brain endothelial cells. The clinical relevance of the data is indicated by the observation of decreased expression of claudin-1 and nuclear ß-catenin in brain endothelial cells of hemorrhagic lesions of hemorrhagic stroke patients. CONCLUSIONS: These results demonstrate the prerequisite role of endothelial ß-catenin in maintaining the integrity of adult BBB. The results suggest that BBB dysfunction secondary to defective ß-catenin transcription activity is a key pathogenic factor in hemorrhagic stroke, seizure activity, and central nervous system inflammation.