Targeting the chromatin binding of exportin-1 disrupts NFAT and T cell activation.

Exportin-1 (XPO1/CRM1) plays a central role in the nuclear-to-cytoplasmic transport of hundreds of proteins and contributes to other cellular processes, such as centrosome duplication. Small molecules targeting XPO1 induce cytotoxicity, and selinexor was approved by the Food and Drug Administration in 2019 as a cancer chemotherapy for relapsed multiple myeloma. Here, we describe a cell-type-dependent chromatin-binding function for XPO1 that is essential for the chromatin occupancy of NFAT transcription factors and thus the appropriate activation of T cells. Additionally, we establish a class of XPO1-targeting small molecules capable of disrupting the chromatin binding of XPO1 without perturbing nuclear export or inducing cytotoxicity. This work defines a broad transcription regulatory role for XPO1 that is essential for T cell activation as well as a new class of XPO1 modulators to enable therapeutic targeting of XPO1 beyond oncology including in T cell-driven autoimmune disorders.

Post-COVID-19 Condition.

An estimated 10-15% of those infected with SARS-CoV-2 may have post-COVID-19 condition. Common lingering signs and symptoms include shortness of breath, fatigue, high heart rate, and memory and cognitive dysfunction even several months after infection, often impacting survivors' quality of life. The prevalence and duration of individual symptoms remain difficult to ascertain due to the lack of standardized research methods across various studies and limited patient follow-up in clinical studies. Nonetheless, data indicate post-COVID-19 condition may occur independent of acuity of initial infection, hospitalization status, age, or pre-existing comorbidities. Risk factors may include female sex and underlying respiratory or psychiatric disease. Supportive therapies to mitigate symptoms remain the mainstay of treatment. Reassuringly, most patients experience a reduction in symptoms by 1 year. The use of a universal case definition and shared research methods will allow for further clarity regarding the pervasiveness of this entity and its long-term health consequences.

Analysis of Utilization, Cost, and Prescription Trends of Common Immunosuppressive Medications Among Medicare Patients 2013 to 2019.

Immunosuppressive medications are commonly used to manage dermatological conditions, including atopic dermatitis, psoriasis, and bullous diseases. However, cost and adverse effect profile, including increased risk of infections, are important considerations.

Smoking impacts outcomes in transcervical Zenker's diverticulectomy.

PURPOSE: There is sparse literature discussing the impact of smoking on postoperative outcomes following surgical treatment of Zenker's diverticulum. In this study, we seek to characterize differences in the management and outcomes of open Zenker's diverticulectomy based on patient smoking status. METHODS AND MATERIALS: This paper is a retrospective cohort review. The 2005-2018 American College of Surgeons National Surgical Quality Improvement (ACS-NSQIP) database was queried for patients undergoing open Zenker's diverticulectomy. Chi-square and multivariable logistic regression were performed to determine statistical associations between postoperative outcomes and smoking status. RESULTS: Of the 715 identified patients, 70 (9.8 %) were smokers and 645 (91.2 %) were non-smokers. Smokers were younger than non-smokers (mean 63.9 vs. 71.7 years, p < 0.001) and more likely to have a prolonged operative time (20.0 % vs. 11.6 %, p = 0.044). On multivariable regression analysis controlling for demographics and comorbidities, smokers had greater odds than non-smokers for developing overall postoperative complications (OR: 2.776, p = 0.013), surgical infections (OR: 3.194, p = 0.039), medical complications (OR: 3.563, p = 0.011), and medical infections (OR: 1.247, p = 0.016). Smokers also had greater odds for requiring ventilation/intubation (OR: 8.508, p = 0.025) and having a prolonged postoperative stay (OR: 2.425, p = 0.030). CONCLUSION: In a cohort of patients undergoing transcervical Zenker's diverticulectomy, smokers are at increased risk for overall complications, medical complications, medical infections, surgical infections, prolonged postoperative stay, and ventilation/intubation.

Home Is Where the Match Is: Mentorship and Dermatology Residency Match Trends Before and During the COVID-19 Pandemic.

Dermatology is one of the most competitive residencies for matching among medical school applicants. A strong connection with a residency program through research or clinical rotations may distinguish between similarly qualified applicants. Our previous study of research-mentor relationships among matched dermatology applicants corroborated the importance of program connections.1 However, the 2020-2021 residency match cycle was uniquely affected by the COVID-19 pandemic, which prevented applicants from fostering connections with faculty at outside institutions. Our study objectives were to evaluate research-mentor relationships among matched dermatology applicants in the 2020-2021 pandemic match cycle with comparisons to pre-pandemic match cycles.

Bacterial infections are common among eczema herpeticum inpatients in a cross-sectional analysis of the 2016 Kids' Inpatient Database.

Eczema herpeticum (EH) is a cutaneous infection with herpes simplex virus, typically in the context of atopic dermatitis. Pediatric hospitalizations for EH have increased over the past several decades, yet few studies have investigated comorbidities or epidemiology of pediatric EH inpatients. We searched the 2016 Kids' Inpatient Database and recorded demographics, comorbidities, and associated costs for patients with EH. We found bacterial infections were a common comorbidity which affected nearly half (47.4%) of hospitalized patients, suggesting the importance of regular monitoring of pediatric EH inpatients for bacterial coinfection.

Long-term complications of COVID-19.

SARS-CoV-2 has rapidly spread across the globe and infected hundreds of millions of people worldwide. As our experience with this virus continues to grow, our understanding of both short-term and long-term complications of infection with SARS-CoV-2 continues to grow as well. Just as there is heterogeneity in the acute infectious phase, there is heterogeneity in the long-term complications seen following COVID-19 illness. The purpose of this review article is to present the current literature with regards to the epidemiology, pathophysiology, and proposed management algorithms for the various long-term sequelae that have been observed in each organ system following infection with SARS-CoV-2. We will also consider future directions, with regards to newer variants of the virus and their potential impact on the long-term complications observed.

Clinical and dermoscopic findings of benign longitudinal melanonychia due to melanocytic activation differ by skin type and predict likelihood of nail matrix biopsy.

BACKGROUND: Longitudinal melanonychia (LM) is a common dermatologic finding in clinical practice with a broad differential diagnosis. Melanocytic activation is the most common LM etiology. OBJECTIVE: To investigate clinical and dermoscopic differences of benign LM based on Fitzpatrick skin type and in biopsied versus nonbiopsied patients. METHODS: A 10-year retrospective cohort of 248 benign LM cases at Weill Cornell Dermatology was identified and analyzed. RESULTS: Darker-skinned versus lighter-skinned patients had higher band width percentage (P = .0125), had lower band brightness (P < .001), had more band changes (P = .0071), and received more biopsies (P = .032). Biopsied (n = 47) versus nonbiopsied patients (n = 201) had less multidigit band involvement (P = .0008), higher band width percentage (P = .0213), lower band brightness (P = .0003), and more band changes (P < .0001). Darker skin types more often had brown versus gray coloration on dermoscopy (P = .0232). The mean band width percentage for all biopsied patients was 30.81% (range: 5.80%-100%). LIMITATIONS: Single-center retrospective design. Subungual melanoma and other benign LM etiologies were not analyzed. Only 18.95% of patients received a biopsy. CONCLUSION: Darker versus lighter skin types more often present with darker and wider bands, present with brown versus gray coloration on dermoscopy, and receive more biopsies. Multi-institutional studies on LM are needed to determine nail matrix biopsy criteria in different skin types.

Predictors of time to definitive surgery and survival in Merkel cell carcinoma: analysis of the US National Cancer Database.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive cancer, and it has been suggested that earlier treatment would allow for better patient outcomes. However, the causes of delays in the initiation of treatment and the effects of delayed treatment on survival of patients have not fully been explored, and the effects of treatment delays for MCC are not yet fully understood. AIM: To determine the effect of time to treatment initiation (TTI) on mortality in MCC and to determine the predictors of TTI itself. METHODS: This was a retrospective cohort analysis of the US National Cancer Database (NCDB) for cases of MCC from 2004 to 2016, excluding individuals with Stage IV MCC, as surgery is not the preferred treatment for this group. The time difference between initial biopsy of MCC and definitive surgery (TTI) was stratified into five groups by 30-day intervals. RESULTS: In total, 12 157 patients [7491 (61.6%) men, 4666 (38.4%) women; mean ± SD age 74.4 ± 10.9 years] were included in the study. A risk for longer TTI was seen in black individuals (OR = 1.7, 95% CI 1.2-2.6) and in elderly individuals aged > 70 years (OR = 1.7, 95% CI 1.2-2.5). Kaplan-Meier survival analysis showed that individuals with TTI < 30 days had a significantly longer overall survival than those with TTI > 120 days (6.1 vs. 4.8 years, P < 0.001). However, after controlling for clinical and tumour factors in Cox multivariable analysis, no difference in survival was noted for TTI < 30 days and TTI > 120 days [hazard ratio (HR) = 0.9, 95% CI 0.8-1.1). Worse outcomes were also associated with increasing age (HR = 2.0, 95% CI 1.7-2.5), male sex (HR = 1.2, 95% CI 1.2-1.3), higher Charlson-Deyo comorbidity score (HR = 1.4, 95% CI 1.3-1.5), lack of radiation therapy (HR = 0.8, 95% CI 0.8-0.9), lack of private insurance (HR = 0.7, 95% CI 0.6-1.0), and use of surgical technique other than Mohs micrographic surgery or wide local excision (HR = 1.2, 95% CI 1.2-1.3). CONCLUSION: Although TTI is a useful prognostic metric in isolated survival analysis, its utility declines when other factors are controlled for in the analysis. Age, radiotherapy, type of surgery performed, comorbidities, tumour size and lymph node involvement may be important predictors of survival.

Assessing Patient Satisfaction Following Blepharoplasty Using Social Media Reviews.

BACKGROUND: Because patient satisfaction is a significant qualitative consideration in measuring aesthetic surgery outcome, it is important to characterize the individual factors that shape the patient perspective about blepharoplasty. OBJECTIVES: This study analyzed reviews by blepharoplasty patients on the aesthetic surgery social media platform RealSelf.com to determine which aspects of the surgical process have the most significant impact on patient satisfaction. METHODS: Blepharoplasty reviews were gathered from RealSelf.com with an automated web crawler. These reviews were characterized as positive or negative, then given a specific category that more specifically defined the theme of the review. Additional variables, including the specialty of the reviewed physician and any patient self-reported ratings, were documented. RESULTS: A total of 1991 reviews pertaining to blepharoplasty were collected. Among reviews with self-reported "worth it" ratings, 93.5% were positive. Following categorization of all reviews, 1865 (93.7%) were positive and 126 (6.3%) were negative. Of the positive reviews, the most common overall themes were bedside manner (n = 899, 48.2%), aesthetic result (n = 859, 46.1%), and overall comfort (n = 58, 3.1%). Among negative reviews, most pertained to aesthetic result (n = 100, 79.4%), and bedside manner (n = 14, 11.1%). The most frequently encountered physician specialties performing blepharoplasty were plastic surgery (n = 1101, 55.3%), ophthalmology (n = 634, 31.8%), and otolaryngology (n = 69, 3.5%). CONCLUSIONS: The majority of reviews were positive. The most prominent factor driving positive reviews was bedside manner, followed by aesthetic results. Negative reviews were most frequently attributed to suboptimal aesthetic results. Most blepharoplasties in our study cohort were performed by plastic and oculoplastic surgeons.

Inhibition of 15-PGDH Protects Mice from Immune-Mediated Bone Marrow Failure.

Aplastic anemia (AA) is a human immune-mediated bone marrow failure syndrome that is treated by stem cell transplantation for patients who have a matched related donor and by immunosuppressive therapy (IST) for those who do not. Responses to IST are variable, with patients still at risk for prolonged neutropenia, transfusion dependence, immune suppression, and severe opportunistic infections. Therefore, additional therapies are needed to accelerate hematologic recovery in patients receiving front-line IST. We have shown that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) with the small molecule SW033291 (PGDHi) increases bone marrow (BM) prostaglandin E2 levels, expands hematopoietic stem cell (HSC) numbers, and accelerates hematologic reconstitution following murine BM transplantation. We now report that in a murine model of immune-mediated BM failure, PGDHi therapy mitigated cytopenias, increased BM HSC and progenitor cell numbers, and significantly extended survival compared with vehicle-treated mice. PGDHi protection was not immune-mediated, as serum IFN-γ levels and BM CD8+ T lymphocyte frequencies were not impacted. Moreover, dual administration of PGDHi plus low-dose IST enhanced total white blood cell, neutrophil, and platelet recovery, achieving responses similar to those seen with maximal-dose IST with lower toxicity. Taken together, these data demonstrate that PGDHi can complement IST to accelerate hematologic recovery and reduce morbidity in severe AA.

Management of Arrhythmias Associated with COVID-19.

PURPOSE OF REVIEW: Cardiac arrhythmias are known complications in patients with COVID-19 infection that may persist even after recovery from infection. A review of the spectrum of cardiac arrhythmias due to COVID-19 infection and current guidelines and assessment or risk and benefit of management considerations is necessary as the population of patients infected and covering from COVID-19 continues to grow. RECENT FINDINGS: Cardiac arrhythmias such as atrial fibrillation, supraventricular tachycardia, complete heart block, and ventricular tachycardia occur in patients infected, recovering and recovered from COVID-19. Personalized care while balancing risk/benefit of medical or invasive therapy is necessary to improve care of patients with arrhythmias. Providers must provide thorough follow-up care and use necessary precaution while caring for COVID-19 patients.

A second-generation 15-PGDH inhibitor promotes bone marrow transplant recovery independently of age, transplant dose and granulocyte colony-stimulating factor support.

Hematopoietic stem cell transplantation following myeloablative chemotherapy is a curative treatment for many hematopoietic malignancies. However, profound granulocytopenia during the interval between transplantation and marrow recovery exposes recipients to risks of fatal infection, a significant source of transplant-associated morbidity and mortality. We have previously described the discovery of a small molecule, SW033291, that potently inhibits the prostaglandin degrading enzyme 15-PGDH, increases bone marrow prostaglandin E2, and accelerates hematopoietic recovery following murine transplant. Here we describe the efficacy of (+)-SW209415, a second-generation 15-PGDH inhibitor, in an expanded range of models relevant to human transplantation. (+)-SW209415 is 10,000-fold more soluble, providing the potential for intravenous delivery, while maintaining potency in inhibiting 15-PGDH, increasing in vivo prostaglandin E2, and accelerating hematopoietic regeneration following transplantation. In additional models, (+)-SW209415: (i) demonstrated synergy with granulocyte colony-stimulating factor, the current standard of care; (ii) maintained efficacy as transplant cell dose was escalated; (iii) maintained efficacy when transplant donors and recipients were aged; and (iv) potentiated homing in xenotransplants using human hematopoietic stem cells. (+)-SW209415 showed no adverse effects, no potentiation of in vivo growth of human myeloma and leukemia xenografts, and, on chronic high-dose administration, no toxicity as assessed by weight, blood counts and serum chemistry. These studies provide independent chemical confirmation of the activity of 15-PGDH inhibitors in potentiating hematopoietic recovery, extend the range of models in which inhibiting 15-PGDH demonstrates activity, allay concerns regarding potential for adverse effects from increasing prostaglandin E2, and thereby, advance 15-PGDH as a therapeutic target for potentiating hematopoietic stem cell transplantation.