REL and BHLHE40 Variants Are Associated with IL-12 and IL-10 Responses and Tuberculosis Risk.

The major human genes regulating Mycobacterium tuberculosis-induced immune responses and tuberculosis (TB) susceptibility are poorly understood. Although IL-12 and IL-10 are critical for TB pathogenesis, the genetic factors that regulate their expression in humans are unknown. CNBP, REL, and BHLHE40 are master regulators of IL-12 and IL-10 signaling. We hypothesized that common variants in CNBP, REL, and BHLHE40 were associated with IL-12 and IL-10 production from dendritic cells, and that these variants also influence adaptive immune responses to bacillus Calmette-Guérin (BCG) vaccination and TB susceptibility. We characterized the association between common variants in CNBP, REL, and BHLHE40, innate immune responses in dendritic cells and monocyte-derived macrophages, BCG-specific T cell responses, and susceptibility to pediatric and adult TB in human populations. BHLHE40 single-nucleotide polymorphism (SNP) rs4496464 was associated with increased BHLHE40 expression in monocyte-derived macrophages and increased IL-10 from peripheral blood dendritic cells and monocyte-derived macrophages after LPS and TB whole-cell lysate stimulation. SNP BHLHE40 rs11130215, in linkage disequilibrium with rs4496464, was associated with increased BCG-specific IL-2+CD4+ T cell responses and decreased risk for pediatric TB in South Africa. SNPs REL rs842634 and rs842618 were associated with increased IL-12 production from dendritic cells, and SNP REL rs842618 was associated with increased risk for TB meningitis. In summary, we found that genetic variations in REL and BHLHE40 are associated with IL-12 and IL-10 cytokine responses and TB clinical outcomes. Common human genetic regulation of well-defined intermediate cellular traits provides insights into mechanisms of TB pathogenesis.

One-year follow-up of hospital nurses' work experiences during the COVID-19 pandemic: A qualitative study.

AIM: To follow up on the experiences of Registered Nurses (RNs) working after 1 year of the COVID-19 pandemic in Canadian and American hospitals. DESIGN: Semi-structured interviews were conducted, and transcripts were analysed through a reflexive thematic analysis (RTA). METHODS: RNs (n = 19) first interviewed in the spring of 2020 were re-interviewed 1 year after their original interviews (May 25, 2021-June 25, 2021). Participants consisted of nurses residing in Canada and working in Ontario (n = 12) or American hospitals (n = 7), i.e., both local and cross-border nurses. RESULTS: Five themes were identified: (1) "You call us heroes, but you forgot us": Nurses described experiences of disrespect and stigma from their communities, their government, and their workplaces. (2) "A whole new level of busy": Nurses reported stressors both at home and at work that had increased exponentially throughout the pandemic. (3) "Running on empty": Nurses described burnout and mental health struggles including depression, irritation, and suicidal ideation; they coped using both adaptive and maladaptive strategies. (4) "The job of nursing is painful": Ongoing pandemic issues led nurses to re-evaluate their commitments to their units, their hospitals and the profession itself. (5) "Surviving an un-survivable day": Nurses shared positive moments at work and home that helped give them the strength to carry on. CONCLUSION: Significant investments will be required from hospital organizations and governments to ensure that healthcare systems continue to function safely for patients, their families and nurses. IMPACT: The purpose of this study was to understand and describe nurses' experiences after 1 year of working during the COVID-19 pandemic. Nurses reported feeling disrespected, overwhelmed, and burned out; many were looking to leave the profession. These findings will be of interest to nurses working on the frontline of the pandemic as well as hospital managers and policy makers. NO PATIENT OR PUBLIC CONTRIBUTION: In this investigation, nurses were the participants.

Pevonedistat Inhibits SOX2 Expression and Sphere Formation but Also Drives the Induction of Terminal Differentiation Markers and Apoptosis within Arsenite-Transformed Urothelial Cells.

Urothelial cancer (UC) is a common malignancy and its development is associated with arsenic exposure. Around 25% of diagnosed UC cases are muscle invasive (MIUC) and are frequently associated with squamous differentiation. These patients commonly develop cisplatin (CIS) resistance and have poor prognosis. SOX2 expression is correlated to reduced overall and disease-free survival in UC. SOX2 drives malignant stemness and proliferation in UC cells and is associated with development of CIS resistance. Using quantitative proteomics, we identified that SOX2 was overexpressed in three arsenite (As3+)-transformed UROtsa cell lines. We hypothesized that inhibition of SOX2 would reduce stemness and increase sensitivity to CIS in the As3+-transformed cells. Pevonedistat (PVD) is a neddylation inhibitor and is a potent inhibitor of SOX2. We treated non-transformed parent and As3+-transformed cells with PVD, CIS, or in combination and monitored cell growth, sphere forming abilities, apoptosis, and gene/protein expression. PVD treatment alone caused morphological changes, reduced cell growth, attenuated sphere formation, induced apoptosis, and elevated the expression of terminal differentiation markers. However, the combined treatment of PVD with CIS significantly elevated the expression of terminal differentiation markers and eventually led to more cell death than either solo treatment. Aside from a reduced proliferation rate, these effects were not seen in the parent. Further research is needed to explore the potential use of PVD with CIS as a differentiation therapy or alternative treatment for MIUC tumors that may have become resistant to CIS.

Topical opioid use in dermatologic disease: A systematic review.

Topical opioid formulations offer a potential solution to manage pain and decrease the use of systemic opioids. Synthesis of use and efficacy of topical opioids in dermatological conditions has not been well characterized. We conducted a systematic search of the PubMed, Embase, and Cochrane databases from 1980 to February 2021. This study analyzed data from 14 articles and 263 patients on the use of topical opioids for pain related to chronic ulcers, burns, oral lichen planus, photodynamic therapy, and split-thickness skin grafts. Topical opioids included in this review were topical morphine and diamorphine. Common formulations consisted of 0.2-10 mg of opioid compounded with hydrogel or IntraSite gel. Topical opioids were variably effective in the use for pain control related to chronic ulcers and other dermatologic conditions. For example, the use of topical opioids appears to be effective in the reduction of pain related to pressure ulcers. Topical opioids were generally well tolerated. Insufficient data exist to adequately evaluate the efficacy and safety of topical opioid use in the context of nonpressure ulcers, burns, oral lichen planus, photodynamic therapy, and split-thickness skin grafts.

ARTICLE: Advances in Oral Isotretinoin Therapy.

Since its approval in 1982, oral isotretinoin has revolutionized acne therapy. However, oral isotretinoin use has long been associated with challenges of variable bioavailability and food dependence. It is recommended to ingest oral isotretinoin with a high-fat meal in order to maximize absorption, but many patients fail to adhere to this recommendation. This may lead to inadequate isotretinoin absorption levels. Patients who fail to achieve isotretinoin target cumulative dose are more likely to experience symptom relapse. To address the challenge of traditional isotretinoin variable bioavailability, subsequent isotretinoin formulations have attempted to improve its absorption abilities. In 2014, an isotretinoin formulation utilizing Lidose technology, known as Absorica, showed significant improvements in absorption levels compared to traditional oral isotretinoin in the fasted state. In 2019, isotretinoin absorption levels were further advanced in a new formulation approved by the FDA known as Absorica LD. Utilizing advanced micronization technology that physically reduces the size of the drug molecule, Absorica LD exhibits twice the absorption levels of Absorica under fasting conditions. In the fed state, Absorica LD achieves similar plasma levels to Absorica with a 20 percent lower dose. Absorica LD also produces consistent serum isotretinoin levels irrespective of gastrointestinal contents. By eliminating the “food effect” seen in traditional oral isotretinoin, Absorica LD has the potential to improve patient adherence and long-term patient outcomes. J Drugs Dermatol. 20:5(Suppl):s5-11.

Differences in acne therapy prescribing patterns between dermatologists and pediatricians: A population-based study.

BACKGROUND/OBJECTIVES: Acne is a common skin condition that may be treated by both dermatologists and pediatricians. However, the treatments provided by dermatologists and pediatricians may differ. We aimed to describe acne therapy prescribing patterns of dermatologists and pediatricians. METHODS: We performed a population-based, cross-sectional analysis using data from the National Ambulatory Medical Care Survey from 2006 to 2016 for pediatric patients (age ≤ 18 years). RESULTS: There were approximately 30.5 million (weighted) outpatient acne visits between 2006 and 2016 for pediatric patients; 52% of visits were conducted by dermatologists, 29% by pediatricians, and 19% by other providers. Compared to pediatricians, dermatologists saw older patients (mean age 15.5 ± 0.12 vs 13.5 ± 0.35; P < .001), as well as a higher proportion of white patients (92.5% vs 76.3%; P < .001), non-Hispanic patients (89.5% vs 81.6%; P < .001), and patients with private insurance (84.6% vs 67.8%; P < .001). Compared to patients seen by dermatologists, patients seen by pediatricians were 68% less likely to receive topical retinoids (aOR 0.32, 95% CI 0.22-0.46), 38% less likely to receive topical antibiotics (aOR 0.62, 95% CI 0.41-0.95), and 48% less likely to receive oral antibiotics (adjusted aOR 0.52, 95% CI 0.36-0.75). CONCLUSIONS: Our findings demonstrate that pediatricians prescribe topical retinoids, topical antibiotics, and oral antibiotics less frequently compared to dermatologists. It is important to understand these differences in prescribing patterns for acne and to identify potential educational gaps.

Mental health outcomes in White patients versus patients with skin of color with psoriasis.

OBJECTIVE: To evaluate the relationship between psoriasis and mental health in patients from different racial backgrounds. METHODS: We performed a nationwide, cross-sectional study evaluating 7,519,662 (weighted) patients, comparing White patients versus patients with skin of color (SOC), using the 2004-2017 Medical Expenditure Panel Survey (MEPS). RESULTS: Psychological distress (measured by Kessler 6-Item Psychological Distress Scale) was similar between White and SOC patients (4.132 [95% CI,3.679-4.586] and 3.710 [95% CI,2.932-4.488], P=0.407). Depression (measured by Patient Health Questionnaire 2) was similar between White and SOC patients (0.886 [95% CI,0.744-1.027] and 0.748 [95% CI,0.506-0.989], P=0.385). Overall mental health (measured by Mental Component Summary) was similar between White and SOC patients (49.959 [95% CI,48.979-50.939] and 50.257 [95% CI,48.449-52.065], P=0.789). Perceived mental health state (measured by Perceived Mental Health Status) was similar between White and SOC patients (2.159 [95% CI,2.065-2.253] and 2.103 [95% CI,1.911-2.294], P=0.603). CONCLUSION: There were no significant differences in mental health outcome scores between White and SOC patients with psoriasis. Clinicians should screen for and manage mental health comorbidities in psoriasis patients of all racial backgrounds.

Unique Transcriptional Programs Identify Subtypes of AKI.

Two metrics, a rise in serum creatinine concentration and a decrease in urine output, are considered tantamount to the injury of the kidney tubule and the epithelial cells thereof (AKI). Yet neither criterion emphasizes the etiology or the pathogenetic heterogeneity of acute decreases in kidney excretory function. In fact, whether decreased excretory function due to contraction of the extracellular fluid volume (vAKI) or due to intrinsic kidney injury (iAKI) actually share pathogenesis and should be aggregated in the same diagnostic group remains an open question. To examine this possibility, we created mouse models of iAKI and vAKI that induced a similar increase in serum creatinine concentration. Using laser microdissection to isolate specific domains of the kidney, followed by RNA sequencing, we found that thousands of genes responded specifically to iAKI or to vAKI, but very few responded to both stimuli. In fact, the activated gene sets comprised different, functionally unrelated signal transduction pathways and were expressed in different regions of the kidney. Moreover, we identified distinctive gene expression patterns in human urine as potential biomarkers of either iAKI or vAKI, but not both. Hence, iAKI and vAKI are biologically unrelated, suggesting that molecular analysis should clarify our current definitions of acute changes in kidney excretory function.

A Novel Experimental Approach to Understand the Transport of Nanodrugs.

Nanoparticle-based drugs offer attractive advantages like targeted delivery to the diseased site and size and shape-controlled properties. Therefore, understanding the particulate flow of the nanodrugs is important for effective delivery, accurate prediction of required dosage, and developing efficient drug delivery platforms for nanodrugs. In this study, the transport of nanodrugs including flow velocity and deposition is investigated using three model metal oxide nanodrugs of different sizes including iron oxide, zinc oxide, and combined Cu-Zn-Fe oxide synthesized via a modified polyol approach. The hydrodynamic size, size, morphology, chemical composition, crystal phase, and surface functional groups of the water-soluble nanodrugs were characterized via dynamic light scattering, transmission electron microscopy, scanning electron microscopy-energy dispersive X-ray, X-ray diffraction, and fourier transform infrared spectroscopy, respectively. Two different biomimetic flow channels with customized surfaces are developed via 3D printing to experimentally monitor the velocity and deposition of the different nanodrugs. A diffusion dominated mechanism of flow is seen in size ranges 92 nm to 110 nm of the nanodrugs, from the experimental velocity and mass loss profiles. The flow velocity analysis also shows that the transport of nanodrugs is controlled by sedimentation processes in the larger size ranges of 110-302 nm. However, the combined overview from experimental mass loss and velocity trends indicates presence of both diffusive and sedimentation forces in the 110-302 nm size ranges. It is also discovered that the nanodrugs with higher positive surface charges are transported faster through the two test channels, which also leads to lower deposition of these nanodrugs on the walls of the flow channels. The results from this study will be valuable in realizing reliable and cost-effective in vitro experimental approaches that can support in vivo methods to predict the flow of new nanodrugs.

Size Exclusion Chromatography for Separating Extracellular Vesicles from Conditioned Cell Culture Media.

Extracellular vesicles (EVs) are nano-sized lipid-membrane bound structures that are released from all cells, are present in all biofluids, and contain proteins, nucleic acids, and lipids that are reflective of the parent cell from which they are derived. Proper separation of EVs from other components in a sample allows for characterization of their associated cargo and lends insight into their potential as intercellular communicators and non-invasive biomarkers for numerous diseases. In the current study, oligodendrocyte derived EVs were isolated from cell culture media using a combination of state-of-the-art techniques, including ultrafiltration and size exclusion chromatography (SEC) to separate EVs from other extracellular proteins and protein complexes. Using commercially available SEC columns, EVs were separated from extracellular proteins released from human oligodendroglioma cells under both control and endoplasmic reticulum (ER) stress conditions. The canonical EV markers CD9, CD63, and CD81 were observed in fractions 1-4, but not in fractions 5-8. GM130, a protein of the Golgi apparatus, and calnexin, an integral protein of the ER, were used as negative EV markers, and were not observed in any fraction. Further, when pooling and concentrating fractions 1-4 as the EV fraction, and fractions 5-8 as the protein fraction, expression of CD63, CD81, and CD9 in the EV fraction was observed. The expression of GM130 or calnexin was not observed in either of the fraction types. The pooled fractions from both control and ER stress conditions were visualized with transmission electron microscopy and vesicles were observed in the EV fractions, but not in the protein fractions. Particles in the EV and protein fractions from both conditions were also quantified with nanoparticle tracking analysis. Together, these data demonstrate that SEC is an effective method for separating EVs from conditioned cell culture media.

Are we contributing to the opioid epidemic? A systematic review on systemic opioid use in dermatology.

BACKGROUND: Although dermatologists treat many painful skin conditions and perform procedures that may require analgesic use, there is a lack of evidence synthesis on opioid use in dermatology. OBJECTIVE: To conduct a systematic review of the evidence on the use of opioid analgesics in dermatology. METHODS: We applied the PRISMA guidelines and systematically reviewed literature that examined opioid use in dermatology published between 1980 and 2020 in the PubMed, EMBASE, and Cochrane databases. This review was registered with PROSPERO (CRD42020204864). RESULTS: We identified 24 studies that analyzed 52,705,201 patients and 13,099 dermatologists. Between 34% and 87.5% of patients received opioids following dermatologic procedures; however, many did not use the entirety of their prescriptions, and 35-69% did not use any of their prescription. Top opioid prescribers were more likely to be Mohs surgeons, male, and practice in the South. Variability exists in the current evidence for opioid prescribing for nonprocedural dermatologic disease. CONCLUSION: While opioid prescribing in dermatology is low compared with other specialties, patients are not utilizing the entirety of their prescriptions. Opioid prescribing for nonprocedural dermatologic disease varies; treatments focused on targeting the pathogenesis of these diseases is important to minimize opioid use. Dermatologists should consider limiting opioid prescribing and utilizing nonnarcotic analgesics.

Complete Genome Sequences of Microbacterium Phages Clayda5 and Gshelby23 and Gordonia Phages Wrigley and Santhid.

Bacteriophages Clayda5, Gshelby23, Wrigley, and Santhid were isolated from soil samples collected in Iowa, with genomes typical of actinobacteriophages from clusters EB, EM, CY, and DY, respectively. Wrigley and Santhid were isolated on Gordonia terrae and are likely to be temperate. Clayda5 and Gshelby23 were isolated on Microbacterium foliorum.

Bullous Dermatoses and Depression: A Systematic Review.

IMPORTANCE: There is a lack of evidence synthesis on the association between bullous skin disease and depression. OBJECTIVE: To synthesize and interpret the current evidence on the association between bullous skin disease and depression. EVIDENCE REVIEW: This review was conducted according to PRISMA guidelines and reviewed literature related to bullous skin disease and depression in the PubMed, Embase, PsycInfo, and Cochrane databases published between 1945 and February 2021. The quality of each included article was assessed via the Newcastle-Ottawa Scale. This review was registered with PROSPERO (CRD42021230750). FINDINGS: A total of 17 articles were identified that analyzed a total of 83 910 patients (55.2% female; specifically, 6951 patients with bullous pemphigoid, 1669 patients with pemphigus, and 79 patients with epidermolysis bullosa were analyzed). The prevalence of depressive symptoms among patients with bullous dermatoses ranged from 40% to 80%. The prevalence of depression diagnosis among patients with bullous dermatoses ranged from 11.4% to 28%. CONCLUSIONS AND RELEVANCE: In this systematic review, high rates of depression and depressive symptoms existed among patients with bullous skin disease. Adequate treatment of bullous dermatoses may be associated with a decrease in mental health burden on patients.

The Use of Biologics During the COVID-19 Pandemic.

During the coronavirus disease 2019 (COVID-19) pandemic, there has been considerable discussion regarding the use of biologics in patients with inflammatory skin conditions, such as psoriasis, hidradenitis suppurativa, and atopic dermatitis. This article discusses clinical trial data, real-world evidence, and guidelines and recommendations for biologics that inhibit tumor necrosis factor, interleukin (IL)-12/23, IL-17, IL-23, and IL-4/13 during the COVID-19 pandemic. Across these inflammatory skin conditions, existing data generally suggest that biologics do not seem to increase the risk of COVID-19 infection or worsen COVID-19 outcomes. The impact of biologics on COVID-19 is an area of active exploration.

Implementation of a Student-Developed, Service-Based Internship for Pharmacy Students.

PURPOSE: This article describes the development, implementation, and impact of a student-created pharmacy internship program with aspects of service-learning, professional development, and ambulatory care pharmacy practice. PROGRAM DESCRIPTION: As the pharmacy profession continues to evolve, pharmacy internships present valuable opportunities for student pharmacists to explore career pathways and develop personal and professional skills. While internships in clinical and industry settings support interns' professional development, service-based internships provide additional benefits to student pharmacists by promoting cultural awareness, community engagement, and commitment to serving underserved patients. Student leaders from the Student Health Action Coalition (SHAC) at the University of North Carolina Eshelman School of Pharmacy created a service-learning, ambulatory carefocused pharmacy internship for fellow student pharmacists. Two rising third-year students were selected to participate in the internship in the summer of 2018. Over the two-month program, the interns participated in various program components including direct patient care activities, faculty-led workshops and topic discussions, and quality improvement projects. In addition to supporting the interns' academic and professional growth, this program also furthered the mission of SHAC to promote positive health outcomes for underserved populations. SUMMARY: The SHAC Ambulatory Care in Underserved Populations Internship represents an innovative initiative by pharmacy student leaders to develop a service-focused internship for fellow student pharmacists. Participation in the internship provides unique opportunities not often available in conventional pharmacy curricula, including engagement with underserved patient populations and exploration of strategies to mitigate health disparities. Crafted by students for fellow students, this internship provides opportunities for personal and professional growth for both student developers and interns to carry into their future pharmacy careers.