The Type I Interferon Signature Reflects Multiple Phenotypic and Activity Measures in Dermatomyositis.

OBJECTIVE: The type 1 interferon (IFN) pathway is up-regulated in dermatomyositis (DM). We sought to define how organ-specific disease activity as well as autoantibodies and other clinical factors are independently associated with systemic type I IFN activity in adult patients with DM. METHODS: RNA sequencing was performed on 355 whole blood samples collected from 202 well-phenotyped DM patients followed up during the course of their clinical care. A previously defined 13-gene type I IFN score was modeled as a function of demographic, serologic, and clinical variables using both cross-sectional and longitudinal data. RESULTS: The pattern of type I IFN-driven transcriptional response was stereotyped across samples with a sequential modular activation pattern strikingly similar to systemic lupus erythematosus. The median type I IFN score was higher or lower in patients with anti-melanoma differentiation-associated protein 5 (anti-MDA-5) or anti-Mi-2 antibodies, respectively, compared to patients without these antibodies. Absolute type I IFN score was independently associated with muscle and skin disease activity, interstitial lung disease, and anti-MDA-5 antibodies. Changes in the type I IFN score over time were significantly associated with changes in skin or muscle disease activity. Stratified analysis accounting for heterogeneity in organ involvement and antibody class revealed high correlation between changes in the type I IFN score and skin disease activity (Spearman's ρ = 0.84-0.95). CONCLUSION: The type I IFN score is independently associated with skin and muscle disease activity as well as certain clinical and serologic features in DM. Accounting for the effect of muscle disease and anti-MDA-5 status revealed that the type I IFN score is strongly correlated with skin disease activity, providing support for type I IFN blockade as a therapeutic strategy for DM.

Localised chronic fibrosing vasculitis versus erythema elevatum diutinum.

A woman in her 70s was referred for a painless plaque on the shin, present for 2 years and progressing in thickness. Examination revealed a large erythematous to violaceous indurated plaque with cobblestone appearance. Biopsy revealed an inflammatory infiltrate of neutrophils with scattered histiocytes, lymphocytes, eosinophils and plasma cells interspersed with areas of lamellar fibrosis and focal areas of vascular damage, suggestive of a localised chronic fibrosing vasculitis of the skin. Localised chronic fibrosing vasculitis is a rare dermatosis, typically presenting as ulcerated violet-red nodules, which can appear histologically similar to erythema elevatum diutinum (EED), which typically presents as red-brown annular plaques. EED may have a predominance of neutrophils and granulomas, while chronic fibrosing vasculitis may have a sparse infiltrate of mixed inflammatory cells without granulomas. While dapsone is a first-line treatment for EED, there are no formal guidelines on the treatment of localised chronic fibrosing vasculitis. Given the neutrophils in this sample and similarities with EED, this patient was treated with oral dapsone, resulting in plaque improvement.

Management of a Child vs an Adult Presenting With Acral Lesions During the COVID-19 Pandemic: A Practical Review.

During the coronavirus disease 2019 (COVID-19) pandemic, there has been a rise in the diagnosis of acral lesions, including chilblains-like lesions, ischemia, and retiform purpura. Understanding the differences in presentation and severity of illness between children and adult patients is important for physicians to understand risk stratification and management of these lesions. We reviewed the literature on the acral lesions seen in children and adults with COVID-19 infection to offer guidelines for diagnosis and treatment.

Phenotypic heterogeneity of neurofibromatosis type 1 in a large international registry.

Neurofibromatosis type 1 (NF1) is a rare genetic disorder, characterized by the development of benign and malignant nerve tumors. Although all individuals with NF1 harbor genetic alterations in the same gene, the clinical manifestations of NF1 are extremely heterogeneous even among individuals who carry identical genetic defects. In order to deepen the understanding of phenotypic manifestations in NF1, we comprehensively characterized the prevalence of 18 phenotypic traits in 2051 adults with NF1 from the Children's Tumor Foundation's NF1 registry. We further investigated the coassociation of traits and found positive correlations between spinal neurofibromas and pain, spinal neurofibromas and scoliosis, spinal neurofibromas and optic gliomas, and optic gliomas and sphenoid wing dysplasia. Furthermore, with increasing numbers of cutaneous neurofibromas, the odds ratio of malignant peripheral nerve sheath tumor increased. Phenotypic clustering revealed 6 phenotypic patient cluster subtypes: mild, freckling predominant, neurofibroma predominant, skeletal predominant, late-onset neural severe, and early-onset neural severe, highlighting potential phenotypic subtypes within NF1. Together, our results support potential shared molecular pathogenesis for certain clinical manifestations and illustrate the utility of disease registries for understanding rare diseases.

Differentiation syndrome during ivosidenib treatment with immunohistochemistry showing isocitrate dehydrogenase R132H mutation.

We report a case of differentiation syndrome in a patient receiving the IDH1 inhibitor ivosidenib, with skin biopsy showing isocitrate dehydrogenase (IDH) R132H-mutated leukemia cutis. A 72-year-old man with IDH1-mutated acute myeloid leukemia (AML), status-post allogeneic cell transplantation, on ivosidenib for 6 months, was admitted for culture-negative neutropenic fever, pink and purpuric plaques and patches on the legs, abdomen and back, edema, hypotension, and shortness of breath. Skin biopsy revealed an infiltrate of atypical, immature, myeloperoxidase-positive mononuclear cells compatible with leukemia cutis or Sweet syndrome. Although dermal edema and interstitial neutrophilic infiltrate with karyorrhexis characteristic of Sweet syndrome were not seen, the atypical cells lacked expression of CD117 and CD34, which were expressed in the original leukemia. Additional immunohistochemical staining of suspected blasts was strongly positive for IDH1 R132H, suggesting a diagnosis of leukemia cutis. As the immunophenotype of blasts in skin infiltrates can significantly differ from the immunophenotype seen in blood and bone marrow, this case shows that mutation-specific antibodies such as anti-IDH1 R132H may be useful to help distinguish malignant from non-malignant infiltrates in the skin. Furthermore, differentiation syndrome may show histopathologic features of leukemia cutis on skin biopsy.

Gamification improves melanoma visual identification among high school students: Results from a randomized study.

Identification of melanoma or worrisome moles is often taught as an important part of routine skin checks. We sought to evaluate the efficacy of gamified education vs. traditional ABCDEs education on melanoma identification and self-confidence in identifying worrisome moles. We report that in our cohort (n = 271), participants randomized to the gamified intervention were more likely to correctly identify melanoma and non-melanoma skin lesions than those randomized to the ABCDE control cohort (74.2% vs 63.5% correct, P < .0001) and perceived confidence in self-identifying worrisome lesions was slightly higher in the gamified group than the traditional group, though the trend was not significant. These novel findings have significant implications on improved ways to educate young patients on the visual identification of melanoma and worrisome moles.

Periorbital dermatitis in patients receiving docetaxel in combination chemotherapy.

Recognition of new cutaneous side effects of combination chemotherapy can help prevent unnecessary cessation or reduction of cancer therapy. Periorbital rash has not been found with docetaxel alone, but here, we report it as a result of combination chemotherapy. A series of three patients who received docetaxel in combination with other chemotherapies developed clinically near-identical, distinctive periorbital rashes. Rashes resolved by resolving underlying docetaxel-induced epiphora in conjunction with ophthalmological consultation, topical skin-directed care, and in some cases, chemotherapy dose reduction. It is important for dermatologists and oncologists to recognise the increased severity of cutaneous reactions when docetaxel is used in combination chemotherapy.

Pityriasis rubra pilaris-like graft-vs-host disease following allogeneic stem cell transplant in two patients.

Chronic cutaneous graft-vs-host disease (GVHD) has several atypical variants. We describe two cases of GVHD with clinical and histopathologic features of pityriasis rubra pilaris (PRP), which responded to additional immunosuppression. Recognition of this newly described PRP-like clinical presentation of GVHD may prompt early consideration of additional steroid-sparing therapies.

Paraneoplastic granulomatous dermatitis in a patient with Hodgkin's disease: a diagnostic pitfall.

The association of malignant lymphomas with non-necrotic epithelioid granulomas has been reported rarely since 1977. Hodgkin's disease-associated widespread cutaneous granuloma annulare (GA) has been reported in only eight patients. We report the second case of subcutaneous GA associated with Hodgkin's disease. A 73-year-old man with Epstein-Barr virus-associated Hodgkin's lymphoma and paraneoplastic subcutaneous GA, presented 3 months after the diagnosis of malignancy. Examination revealed a large, broad erythematous, indurated, subcutaneous plaque spanning the majority of the left lower back and flank with no associated symptoms. Initial biopsy was suggestive of morphea. Prompted by positron emission tomography (PET) findings of increased fluorodeoxyglucose (FDG) uptake, a second, deeper biopsy was performed, revealing subcutaneous palisaded granulomatous dermatitis. After complete workup, the diagnosis most strongly suggested subcutaneous GA. This case highlights the importance of deep incisional biopsies, the fluorodeoxyglucose - positron emission tomography (FDG-PET) findings in GA and the rare association of GA with Hodgkin's disease which may signal the presence of malignancy.

A Novel Approach to Improving Fat Delivery in Neonatal Enteral Feeding.

Continuous infusion systems used for enteral nutrition support in the neonatal intensive care unit deliver as little as 60% of the fat in human milk to the neonate. This study determined the effect of mixing common feedings for preterm infants in the feeding bag and tubing on fat losses during enteral feeding. Laboratory models were developed to assess the contribution of various mixing techniques to delivered fat content. Fat content was measured periodically during feeding and compared to baseline measurements. A multistage approach incorporating a feeding bag inverter and a tubing circulation loop delivered >90% of milk fat when used in conjunction with a commercial continuous infusion system. With unfortified human milk, this approach delivered 91.9% ± 1.5% of fat content over a one hour feed, significantly greater (p < 0.01) than 77.5% ± 2.2% delivered by continuous infusion controls (Mean ± SEM). With fortified human milk, this approach delivered 92.1% ± 2.4% of fat content, significantly greater (p < 0.01) than 79.4% ± 1.0% delivered by a non-adapted infusion system (Mean ± SEM). Mixing human milk during continuous infusion improves fat delivery, which may improve nutrition and growth outcomes in low birth weight neonates.

Chemical Makeup and Hydrophilic Behavior of Graphene Oxide Nanoribbons after Low-Temperature Fluorination.

Here we investigated the fluorination of graphene oxide nanoribbons (GONRs) using H2 and F2 gases at low temperature, below 200 °C, with the purpose of elucidating their structure and predicting a fluorination mechanism. The importance of this study is the understanding of how fluorine functional groups are incorporated in complex structures, such as GONRs, as a function of temperature. The insight provided herein can potentially help engineer application-oriented materials for several research and industrial sectors. Direct (13)C pulse magic angle spinning (MAS) nuclear magnetic resonance (NMR) confirmed the presence of epoxy, hydroxyl, ester and ketone carbonyl, tertiary alkyl fluorides, as well as graphitic sp(2)-hybridized carbon. Moreover, (19)F-(13)C cross-polarization MAS NMR with (1)H and (19)F decoupling confirmed the presence of secondary alkyl fluoride (CF2) groups in the fluorinated graphene oxide nanoribbon (FGONR) structures fluorinated above 50 °C. First-principles density functional theory calculations gained insight into the atomic arrangement of the most dominant chemical groups. The fluorinated GONRs present atomic fluorine percentages in the range of 6-35. Interestingly, the FGONRs synthesized up to 100 °C, with 6-19% of atomic fluorine, exhibit colloidal similar stability in aqueous environments when compared to GONRs. This colloidal stability is important because it is not common for materials with up to 19% fluorine to have a high degree of hydrophilicity.

Fortifier and cream improve fat delivery in continuous enteral infant feeding of breast milk.

Premature and high-risk infants require accurate delivery of nutrients to promote appropriate growth. Continuous enteral feeding methods may result in significant fat and micronutrient loss. This study evaluated fat loss in enteral nutrition using current strategies for providing high-risk infants fortified human milk (HM). The fat content of HM was measured by IR analyzer in a simulated feeding system using the Kangaroo epumpTM and the MedFusionTM 2010 pump. Comparisons in fat loss were made between HM, HM supplemented with donor HM-derived fortifier Prolacta+H2MFTM (H2MF), and HM supplemented with H2MF and donor HM-derived cream ProlactCRTM (cream). When using the Kangaroo epumpTM, the addition of H2MF and cream to HM increased fat delivery efficiency from 75.0%±1.2% to 83.7%±1.0% (p<0.0001). When using the MedFusionTM 2010 pump, the addition of H2MF to HM increased fat delivery efficiency from 83.2%±2.8% to 88.8%±0.8% (p<0.05), and the addition of H2MF and cream increased fat delivery efficiency to 92.0%±0.3% (p<0.01). The addition of H2MF and cream to HM provides both the benefits of bioactive elements from mother's milk and increased fat delivery, making the addition of H2MF and cream an appropriate method to improve infant weight gain.

Evaluation of effectiveness of prophylactic cerclage of a short cervix according to interleukin-8 in cervical mucus.

OBJECTIVE: This study was undertaken to compare rates of preterm delivery according to cervical mucus interleukin-8 (IL-8) among women who underwent cerclage because of a short cervix. STUDY DESIGN: This retrospective study included 16,508 patients whose cervical length and cervical mucus IL-8 concentrations were measured between 20 and 24 weeks. A short cervix was defined by a length of 25 mm or less, whereas IL-8 concentrations exceeding 360 ng/mL were considered high. Whether to perform cerclage was decided by clinicians without consideration of IL-8 concentrations. RESULTS: Among all subjects, a significantly smaller percentage of subjects avoided delivery before 37 weeks when cervical mucus IL-8 was elevated (P = .0302) or the cervix was short (P < .0001). Among patients with a short cervix, preterm delivery was more likely when cervical mucus IL-8 was elevated. Overall, risk of preterm delivery in patients with a short cervix did not differ between those undergoing and not undergoing cerclage. However, among patients with a short cervix, those with normal IL-8 concentrations in cervical mucus were less likely to have preterm delivery if they underwent cerclage (before 37 weeks, 33% vs 54.5%, P = .01; before 34 weeks, 4% vs 13.6%, P = .03). In contrast, when cervical mucus IL-8 was high, delivery before 37 weeks was more likely with than without cerclage (78% vs 54.1%, P = .03). CONCLUSION: With normal cervical mucus IL-8, cerclage treatment for cervical shortening may reduce the rate of preterm delivery, but with elevated cervical mucus IL-8 cerclage may be harmful.

Relationship between cervical mucus interleukin-8 concentrations and vaginal bacteria in pregnancy.

PROBLEM: High interleukin (IL)-8 concentration in cervical mucus in the second trimester is a risk factor for premature birth. We investigated the relationship between vaginal pathogens and IL-8 in cervical mucus. METHOD OF STUDY: In 501 women with single pregnancy, vaginal secretions were cultured for bacteria and cervical mucus IL-8 concentrations were measured between 20 and 24 gestational weeks. RESULTS: Lactobacillus species were detected in 56.0% of 84 subjects with high IL-8 (> or =377 ng/mL), significantly less often than in 417 subjects with IL-8 below 377 ng/mL (84.7%; P < 0.0001). Anaerobic pathogens were detected in 83.3% of high IL-8 subjects, significantly more often than in normal IL-8 subjects (43.9%; P < 0.0001). By multivariate analysis, cervical IL-8 was significantly high only in subjects without Lactobacillus species; they showed a significantly higher prematurity rate than Lactobacillus-positive subjects. CONCLUSIONS: Absence of vaginal Lactobacilli was associated with increased cervical IL-8 and increased risk of premature delivery.