E-Consults in Dermatology: A Retrospective Analysis.

Dermatology electronic consultations (e-consults) placed by primary care providers (PCPs) can increase access to specialty care while reducing wait times and providing accurate clinical outcomes. These e-consults also may reduce barriers for underserved patients who historically have limited access to dermatologic care. Our retrospective chart review examines patient outcomes from a dermatology e-consult program at a tertiary care medical center. E-consults effectively increased access to dermatology care while shortening wait times and reducing health care expenditures.

Integration of ζ-deficient CARs into the CD3ζ gene conveys potent cytotoxicity in T and NK cells.

ABSTRACT: Chimeric antigen receptor (CAR)-redirected immune cells hold significant therapeutic potential for oncology, autoimmune diseases, transplant medicine, and infections. All approved CAR-T therapies rely on personalized manufacturing using undirected viral gene transfer, which results in nonphysiological regulation of CAR-signaling and limits their accessibility due to logistical challenges, high costs and biosafety requirements. Random gene transfer modalities pose a risk of malignant transformation by insertional mutagenesis. Here, we propose a novel approach utilizing CRISPR-Cas gene editing to redirect T cells and natural killer (NK) cells with CARs. By transferring shorter, truncated CAR-transgenes lacking a main activation domain into the human CD3ζ (CD247) gene, functional CAR fusion-genes are generated that exploit the endogenous CD3ζ gene as the CAR's activation domain. Repurposing this T/NK-cell lineage gene facilitated physiological regulation of CAR expression and redirection of various immune cell types, including conventional T cells, TCRγ/δ T cells, regulatory T cells, and NK cells. In T cells, CD3ζ in-frame fusion eliminated TCR surface expression, reducing the risk of graft-versus-host disease in allogeneic off-the-shelf settings. CD3ζ-CD19-CAR-T cells exhibited comparable leukemia control to TCRα chain constant (TRAC)-replaced and lentivirus-transduced CAR-T cells in vivo. Tuning of CD3ζ-CAR-expression levels significantly improved the in vivo efficacy. Notably, CD3ζ gene editing enabled redirection of NK cells without impairing their canonical functions. Thus, CD3ζ gene editing is a promising platform for the development of allogeneic off-the-shelf cell therapies using redirected killer lymphocytes.

A spatial cell atlas of neuroblastoma reveals developmental, epigenetic and spatial axis of tumor heterogeneity.

Neuroblastoma is a pediatric cancer arising from the developing sympathoadrenal lineage with complex inter- and intra-tumoral heterogeneity. To chart this complexity, we generated a comprehensive cell atlas of 55 neuroblastoma patient tumors, collected from two pediatric cancer institutions, spanning a range of clinical, genetic, and histologic features. Our atlas combines single-cell/nucleus RNA-seq (sc/scRNA-seq), bulk RNA-seq, whole exome sequencing, DNA methylation profiling, spatial transcriptomics, and two spatial proteomic methods. Sc/snRNA-seq revealed three malignant cell states with features of sympathoadrenal lineage development. All of the neuroblastomas had malignant cells that resembled sympathoblasts and the more differentiated adrenergic cells. A subset of tumors had malignant cells in a mesenchymal cell state with molecular features of Schwann cell precursors. DNA methylation profiles defined four groupings of patients, which differ in the degree of malignant cell heterogeneity and clinical outcomes. Using spatial proteomics, we found that neuroblastomas are spatially compartmentalized, with malignant tumor cells sequestered away from immune cells. Finally, we identify spatially restricted signaling patterns in immune cells from spatial transcriptomics. To facilitate the visualization and analysis of our atlas as a resource for further research in neuroblastoma, single cell, and spatial-omics, all data are shared through the Human Tumor Atlas Network Data Commons at www.humantumoratlas.org.

Integration of ζ-deficient CARs into the CD3-zeta gene conveys potent cytotoxicity in T and NK cells.

Chimeric antigen receptor (CAR)-reprogrammed immune cells hold significant therapeutic potential for oncology, autoimmune diseases, transplant medicine, and infections. All approved CAR-T therapies rely on personalized manufacturing using undirected viral gene transfer, which results in non-physiological regulation of CAR-signaling and limits their accessibility due to logistical challenges, high costs and biosafety requirements. Here, we propose a novel approach utilizing CRISPR-Cas gene editing to redirect T cells and natural killer (NK) cells with CARs. By transferring shorter, truncated CAR-transgenes lacking a main activation domain into the human CD3 ζ (CD247) gene, functional CAR fusion-genes are generated that exploit the endogenous CD3 ζ gene as the CAR's activation domain. Repurposing this T/NK-cell lineage gene facilitated physiological regulation of CAR-expression and reprogramming of various immune cell types, including conventional T cells, TCRγ/δ T cells, regulatory T cells, and NK cells. In T cells, CD3 ζ in-frame fusion eliminated TCR surface expression, reducing the risk of graft-versus-host disease in allogeneic off-the-shelf settings. CD3 ζ-CD19-CAR-T cells exhibited comparable leukemia control to T cell receptor alpha constant ( TRAC )-replaced and lentivirus-transduced CAR-T cells in vivo . Tuning of CD3 ζ-CAR-expression levels significantly improved the in vivo efficacy. Compared to TRAC -edited CAR-T cells, integration of a Her2-CAR into CD3 ζ conveyed similar in vitro tumor lysis but reduced susceptibility to activation-induced cell death and differentiation, presumably due to lower CAR-expression levels. Notably, CD3 ζ gene editing enabled reprogramming of NK cells without impairing their canonical functions. Thus, CD3 ζ gene editing is a promising platform for the development of allogeneic off-the-shelf cell therapies using redirected killer lymphocytes. Key points: Integration of ζ-deficient CARs into CD3 ζ gene allows generation of functional TCR-ablated CAR-T cells for allogeneic off-the-shelf use CD3 ζ-editing platform allows CAR reprogramming of NK cells without affecting their canonical functions.

Ultralow-dose binary oncolytic/helper-dependent adenovirus promotes antitumor activity in preclinical and clinical studies.

We show that a binary oncolytic/helper-dependent adenovirus (CAdVEC) that both lyses tumor cells and locally expresses the proinflammatory cytokine IL-12 and PD-L1 blocking antibody has potent antitumor activity in humanized mouse models. On the basis of these preclinical studies, we treated four patients with a single intratumoral injection of an ultralow dose of CAdVEC (NCT03740256), representing a dose of oncolytic adenovirus more than 100-fold lower than used in previous trials. While CAdVEC caused no significant toxicities, it repolarized the tumor microenvironment with increased infiltration of CD8 T cells. A single administration of CAdVEC was associated with both locoregional and abscopal effects on metastases and, in combination with systemic administration of immune checkpoint antibodies, induced sustained antitumor responses, including one complete and two partial responses. Hence, in both preclinical and clinical studies, CAdVEC is safe and even at extremely low doses is sufficiently potent to induce significant tumor control through oncolysis and immune repolarization.

Bromhidrosis treatment modalities: A literature review.

BACKGROUND: Treatment options for Bromhidrosis include botulinum toxin therapy, microwave-based therapy, laser therapy, and surgical intervention. Limited studies compare their efficacies. OBJECTIVE: The purpose of this literature review is to compare the efficacy and safety of these treatments for bromhidrosis. METHODS: A PubMed search included terms bromhidrosis and bromhidrosis AND treatment. RESULTS: A total of 25 articles were reviewed. Botulinum toxin therapy shows consistent benefit but requires repeated therapies. Microwave therapies have shown promising results but require larger cohort sizes with bromhidrosis. Similarly, laser therapy has shown promise with biopsy-proven results, but long-lasting effects remain unknown. Surgery has the best long-term prognosis, but the ideal surgical method remains unknown. LIMITATIONS: Each study varied in their treatment interval and method of assessing bromhidrosis, making direct comparisons difficult. CONCLUSIONS: Managing bromhidrosis requires shared decision making with the patient. Mild-to-moderate symptoms may be treated initially with botulinum toxin therapy. In cases that are refractory, laser therapy should be considered, as it is better studied than microwave therapy currently. Lastly, if the condition is severe and refractory to other options, surgery can be considered, although the ideal method remains unknown.

Understanding eligibility creep in psoriasis assessments: a survey study.

Psoriasis severity assessments for clinical trial entry may be unintentionally overestimated, especially if trial eligibility is chiefly dependent on rating of disease severity. When this results in patients with less severe phenotypes joining clinical trials it is referred to as eligibility creep. We investigated the potential impact of psychosocial incentives on psoriasis lesion severity grading. A survey was constructed and disseminated through Amazon Mechanical Turk. Participants completed two vignette-style questions prompted with a randomly allocated psychosocial incentive. Questions required participants to grade and select psoriasis lesion pictures for a fictional trial. Participants also decided whether or not to schedule re-evaluation of patients deemed ineligible at initial visit. There were 646 participants. There was no significant difference in number of total lesions selected for study inclusion between incentive groups (Kruskal-Wallis, P=0.30). In general, participants completing empathy and professional uncertainty incentives selected the most and least number of lesion pictures for trial inclusion, respectively. Participants prompted with empathy incentives had significantly greater rates of choosing to schedule a follow-up visit for ineligible patients compared to participants prompted with other incentives (69.7% versus 59.1%, Chi square P=0.046). Situations evoking empathy may contribute to eligibility creep.

Unmet Needs in Psoriasis Patients.

BACKGROUND: Psoriasis can greatly impact patients' quality of life. The introduction of new treatments has improved treatment outcomes, but treatment gaps may still exist. OBJECTIVE: Identify unmet treatment needs in patients with psoriasis. METHODS: Participants aged 18 years or older, with an Amazon Mechanical Turk account, who reported diagnosis of psoriasis and correctly answered an attention check question were included. Results were analyzed using descriptive and inferential statistics. RESULTS: Of the 417 participants who met study inclusion criteria, 51.1% were female, and 39.3% were 31-40 years of age; 61.2% reported mild, 25.4% moderate, and 13.4% severe psoriasis. Most (74.8%) were currently under treatment; half (51.6%) were mostly or completely satisfied with treatment, while 24.5% were slightly or not at all satisfied. Respondents were most satisfied with topical (59.5%), followed by oral (46%), and injectable treatments (19.9%). Most (78.7%) slightly or strongly felt there should be more cost-effective options. Gaps in current psoriasis treatment options included more affordable topical and oral treatments that work faster and require less frequent use. LIMITATIONS: The use of an English survey and Amazon Mechanical Turk precludes certain populations from this study. Participants were not asked to provide their current form of psoriasis treatment. CONCLUSIONS: Despite advances in psoriasis treatment, there remains a desire for more effective, faster, longer acting, and less costly, more accessible treatments. J Drugs Dermatol. 2022;21(8):839-844. doi:10.36849/JDD.6589.

Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy.

Neoadjuvant immune checkpoint blockade has shown promising clinical activity. Here, we characterized early kinetics in tumor-infiltrating and circulating immune cells in oral cancer patients treated with neoadjuvant anti-PD-1 or anti-PD-1/CTLA-4 in a clinical trial (NCT02919683). Tumor-infiltrating CD8 T cells that clonally expanded during immunotherapy expressed elevated tissue-resident memory and cytotoxicity programs, which were already active prior to therapy, supporting the capacity for rapid response. Systematic target discovery revealed that treatment-expanded tumor T cell clones in responding patients recognized several self-antigens, including the cancer-specific antigen MAGEA1. Treatment also induced a systemic immune response characterized by expansion of activated T cells enriched for tumor-infiltrating T cell clonotypes, including both pre-existing and emergent clonotypes undetectable prior to therapy. The frequency of activated blood CD8 T cells, notably pre-treatment PD-1-positive KLRG1-negative T cells, was strongly associated with intra-tumoral pathological response. These results demonstrate how neoadjuvant checkpoint blockade induces local and systemic tumor immunity.

Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and treatment-refractory cancer. Molecular stratification in pancreatic cancer remains rudimentary and does not yet inform clinical management or therapeutic development. Here, we construct a high-resolution molecular landscape of the cellular subtypes and spatial communities that compose PDAC using single-nucleus RNA sequencing and whole-transcriptome digital spatial profiling (DSP) of 43 primary PDAC tumor specimens that either received neoadjuvant therapy or were treatment naive. We uncovered recurrent expression programs across malignant cells and fibroblasts, including a newly identified neural-like progenitor malignant cell program that was enriched after chemotherapy and radiotherapy and associated with poor prognosis in independent cohorts. Integrating spatial and cellular profiles revealed three multicellular communities with distinct contributions from malignant, fibroblast and immune subtypes: classical, squamoid-basaloid and treatment enriched. Our refined molecular and cellular taxonomy can provide a framework for stratification in clinical trials and serve as a roadmap for therapeutic targeting of specific cellular phenotypes and multicellular interactions.

Mouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade.

Fetal growth restriction (FGR) affects 5-10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicate KIR and HLA genes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map. Here, we demonstrate that the interaction between the maternal KIR2DL1, expressed on uterine natural killer (NK) cells, and the paternally inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanized mouse model. We show that the KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and modulation of uterine NK cell function. This initial effect cascades to altered transcriptional expression and intercellular communication at the maternal-fetal interface. These findings provide mechanistic insight into specific FGR risk alleles, and provide avenues of prevention and treatment.

HydrAd: A Helper-Dependent Adenovirus Targeting Multiple Immune Pathways for Cancer Immunotherapy.

For decades, Adenoviruses (Ads) have been staple cancer gene therapy vectors. Ads are highly immunogenic, making them effective adjuvants. These viruses have well characterized genomes, allowing for substantial modifications including capsid chimerism and therapeutic transgene insertion. Multiple generations of Ad vectors have been generated with reduced or enhanced immunogenicity, depending on their intended purpose, and with increased transgene capacity. The latest-generation Ad vector is the Helper-dependent Ad (HDAd), in which all viral coding sequences are removed from the genome, leaving only the cis-acting ITRs and packaging sequences, providing up to 34 kb of transgene capacity. Although HDAds are replication incompetent, their innate immunogenicity remains intact. Therefore, the HDAd is an ideal cancer gene therapy vector as its infection results in anti-viral immune stimulation that can be enhanced or redirected towards the tumor via transgene expression. Co-infection of tumor cells with an oncolytic Ad and an HDAd results in tumor cell lysis and amplification of HDAd-encoded transgene expression. Here, we describe an HDAd-based cancer gene therapy expressing multiple classes of immunomodulatory molecules to simultaneously stimulate multiple axes of immune pathways: the HydrAd. Overall, the HydrAd platform represents a promising cancer immunotherapy agent against complex solid tumors.

A Case of Late-Onset Alopecia Areata.

Alopecia areata (AA) is a condition characterized by nonscarring hair loss. Cases of alopecia areata are most commonly seen in patients under age 30 and are frequently idiopathic. In this report, we discuss a woman in her 50s who developed AA shortly after receiving the Tdap vaccine and after one year of guselkumab therapy.

Review of the holistic management of pediatric atopic dermatitis.

Atopic Dermatitis (AD) is a chronic inflammatory skin disease that is broadly characterized by eczematous lesions and pruritus. This condition is detrimental in a multitude of ways, including patient quality of life (QOL), family QOL, economic burden, and psychosocial afflictions. Current management needs to incorporate a holistic approach which considers the financial, emotional, and physical limitations of both the treatments and the provider. A non-systematic search was conducted on the holistic management of pediatric AD. Various search queries were used such as the key terms of "atopic dermatitis," "pediatric," "eczema," "management," and more to encompass treatments, adherence, and comorbidities. There is an association with AD and depression in children, and its prevalence should be screened for routinely in children with AD. Collaboration with other specialties may prove to be prudent in addressing this comorbidity. Objective quality of life scores can open the door to much needed conversation with patients to get them the help they need. In expanding our scope, we find the extended consequences of AD have a ripple effect on families of pediatric patients. Lastly, we introduce a model for improving treatment adherence. CONCLUSION: Patient quality-of-life can be negatively affected by the symptoms, expense, stigma, and time commitment, and inconvenience imposed by complicated treatment regimens. To ensure proper, holistic management of pediatric AD, multiple factors must be considered; seasonal changes, lifestyle modifications, and the psychosocial impact are just a couple of factors that require monitoring. WHAT IS KNOWN: • Atopic dermatitis impacts patients and their families in quality of life, economically, and psychosocially. • Current treatment revolves largely around treating physical manifestation of disease with first line measures such as topical steroids. WHAT IS NEW: • The holistic management of AD incorporates a good physician-patient relationship, frequent follow-up, and providing structured written plans. • We introduce the house building model for improving treatment adherence. KEY POINTS: Pediatric AD can be managed in a more holistic manner which incorporates several factors from the lives of patients and their families. Pediatric patients suffer from many physical and mental comorbidities which should be screened for. Adherence with treatment may be improved by following a model which emphasizes establishing a good physician-patient relationship, frequent follow-up, and providing structured written plans.

Increased energy demand from anabolic-catabolic processes drives ß-lactam antibiotic lethality.

ß-Lactam antibiotics disrupt the assembly of peptidoglycan (PG) within the bacterial cell wall by inhibiting the enzymatic activity of penicillin-binding proteins (PBPs). It was recently shown that ß-lactam treatment initializes a futile cycle of PG synthesis and degradation, highlighting major gaps in our understanding of the lethal effects of PBP inhibition by ß-lactam antibiotics. Here, we assess the downstream metabolic consequences of treatment of Escherichia coli with the ß-lactam mecillinam and show that lethality from PBP2 inhibition is a specific consequence of toxic metabolic shifts induced by energy demand from multiple catabolic and anabolic processes, including accelerated protein synthesis downstream of PG futile cycling. Resource allocation into these processes is coincident with alterations in ATP synthesis and utilization, as well as a broadly dysregulated cellular redox environment. These results indicate that the disruption of normal anabolic-catabolic homeostasis by PBP inhibition is an essential factor for ß-lactam antibiotic lethality.

Abametapir for the Treatment of Head Lice: A Drug Review.

OBJECTIVE: This article reviews the pharmacology, safety, efficacy, and clinical importance of abametapir 0.74% (Xeglyze) for the treatment of head lice. DATA SOURCES: From 2020 to May 2021, a systematic review of the MEDLINE and EMBASE databases was conducted using the terms abametapir, Xeglyze, Ha44, and head lice. Bibliographies, Food and Drug Administration (FDA) drug package inserts, and ClinicalTrials.gov were searched for further information. STUDY SELECTION AND DATA EXTRACTION: All relevant full-text articles in English were considered for inclusion, with a final article date range of 1999 to 2020. DATA SYNTHESIS: Abametapir chelates heavy metal cations and inhibits metalloproteinases critical to louse ova development, hatching, and adult survival. In phase II, abametapir had direct ovicidal activity inhibiting 100% of treated louse eggs from hatching, compared with 64% in the vehicle-treated group. In two identical phase III clinical trials, subjects treated with a single 10-minute application of abametapir had greater treatment success compared with vehicle-treated subjects, with 81.1% success versus 50.9% in study 1 (P = 0.001) and 81.8% versus 47.2% in study 2 (P < 0.001). Abametapir was well tolerated, with only mild adverse effects. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Abametapir is a newly FDA-approved, single-application treatment for head lice in patients aged 6 months and older. This review highlights the safety and efficacy of abametapir in the treatment of head lice. CONCLUSIONS: In the wake of increasing widespread resistance to first-line treatment options, abametapir offers a safe and effective new treatment option for head lice infestations.

Factors Influencing Patient Preferences for Phototherapy: A Survey Study.

There is limited literature regarding patient preferences for phototherapy. Patients may consider different forms of phototherapy depending on a multitude of factors important to them, including safety, cost, efficacy, insurance issues, and convenience. This study aimed to determine which form of phototherapy-in-office UVB, at-home UVB, home tanning, salon tanning, and sunbathing-was preferred by survey participants and the reasons for their preferences. Additionally, participants were asked which forms of phototherapy they considered safest and most efficacious, cost-effective, and convenient.

Tumid lupus erythematosus and systemic lupus erythematosus: a rare coexistence.

A patient diagnosed with tumid lupus erythematosus (TLE) was subsequently found to have systemic lupus erythematosus (SLE) after presenting to a tertiary care medical centre with shortness of breath and oedema. In this commentary, we discuss this patient's presentation and the association between TLE and SLE.