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Mpox (formerly monkeypox) is a viral illness endemic in certain parts of the world such as Africa. Travel to these endemic areas has increased outbreaks in regions typically unaffected by this poxvirus. Mpox infection is characterized by prodromal symptoms including fever, chills, and lymphadenopathy, followed by a vesiculopustular exanthem. Genital lesions are common especially in vulnerable populations, such as those who engage in high-risk sexual behaviors. We report a 50-year-old man living with HIV who presented for evaluation of multiple painless genital lesions and later tested positive for both mpox and syphilis. With recent outbreaks, clinicians should evaluate genital lesions with a broad sexually transmitted infection differential. Rapid diagnosis and treatment are imperative to prevent more severe disease progression in immunocompromised patients.

Sarecycline is a tetracycline-derived oral antibiotic, specifically designed for acne, and is approved by the Food and Drug Administration (FDA) in 2018 for the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris (AV) in patients 9 years of age and older. It has been decades since a novel systemic antibiotic was approved to treat AV, a disease that affects up to 90% of teenagers and young adults worldwide and lasts well into adulthood. Sarecycline holds promise to yield fewer side effects than other commonly used broad-spectrum tetracyclines, including minocycline and doxycycline. The narrower spectrum of antibacterial activity of sarecycline, which specifically targets C. acnes and some Gram-positive bacteria with little or no activity against Gram-negative bacteria, suggests not only the potential for reduced emergence of antibiotic-resistant bacterial strains but also less disruption of the human gut microflora. Here, we review the key preclinical and clinical evidence on sarecycline.

Sarecycline is a tetracycline-derived oral antibiotic, specifically designed for acne, and is approved by the Food and Drug Administration (FDA) in 2018 for the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris (AV) in patients 9 years of age and older. It has been decades since a novel systemic antibiotic was approved to treat AV, a disease that affects up to 90% of teenagers and young adults worldwide and lasts well into adulthood. Sarecycline holds promise to yield fewer side effects than other commonly used broad-spectrum tetracyclines, including minocycline and doxycycline. The narrower spectrum of antibacterial activity of sarecycline, which specifically targets C. acnes and some Gram-positive bacteria with little or no activity against Gram-negative bacteria, suggests not only the potential for reduced emergence of antibiotic-resistant bacterial strains but also less disruption of the human gut microflora. Here, we review the key preclinical and clinical evidence on sarecycline.

FMX101 4% topical minocycline foam has been shown to be an effective and safe treatment for acne vulgaris (AV).To further evaluate the efficacy and safety of FMX101 4% in treating moderate to severe acne vulgaris.A 12-week, multicenter, randomized (1:1), double-blind, vehicle-controlled study was conducted. Coprimary end points were the absolute change in inflammatory lesion count from baseline and the rate of treatment success (Investigator's Global Assessment score of 0 or 1 with a ≥2-grade improvement).There were 1488 participants in the intent-to-treat population. The FMX101 4% group had significantly greater reductions in the number of inflammatory lesions from baseline (P .0001) and a greater rate of treatment success based on Investigator's Global Assessment (P .0001) versus the foam vehicle group at week 12. FMX101 4% was generally safe and well tolerated.The efficacy and safety of FMX101 4% were not characterized in participants with mild AV.FMX101 4% topical minocycline foam was effective and safe for the treatment of moderate to severe AV.

Truncal acne is common, and the psychosocial burden may be underestimated as patients most often complain of facial acne. The Acne Symptom and Impact Scale (ASIS) is a 17-item patient-reported outcome (PRO) measure designed to assess the signs and impacts of acne vulgaris. ASIS has previously been validated in a prospective, non-interventional study as a reliable PRO instrument for facial acne. In a pilot study, ASIS, and an additional 10 new questions that focused on the concerns of patients (ASIS-C), were given to 10 patients with moderate-to-severe truncal acne vulgaris who received 3 months of monotherapy with oral sarecycline, a narrow-spectrum tetracycline-class antibiotic. ASIS-C questionnaires were also given to 10 acne-free control subjects. Average ASIS-C answers decreased by 4% for Signs, 15% for Impact, and 16% for Concerns in the 10 patients, with greater decreases of 5% for Signs, 20% for Impact, and 19% for Concerns in the 60% of patients whose truncal acne was clear or almost clear after 12 weeks of sarecycline treatment. In this study, sarecycline was effective in reducing the psychosocial burden associated with truncal acne based on the ASIS-C PRO measures.

Sarecycline is a novel, narrow-spectrum, third generation tetracycline class antibiotic approved by the Food and Drug Administration (FDA) for the treatment of moderate-to-severe acne in patients ages nine and older. Recently, focus has increased on whether treatment responses differ in acne in skin of color. Here, we aimed to analyze the efficacy of using sarecycline in Hispanics. We report pooled post hoc analysis of efficacy data on sarecycline in Hispanics with acne from two phase 3, multicenter, randomized, double-blind, placebo-controlled clinical trials, SC1401 and SC1402. Of 2002 patients in the pooled trials with moderate-to-severe acne, 26.9% were Hispanic. Facial inflammatory lesion counts decreased as early as week 3 by 26% (p = 0.0279), with continued reduction by 41% by week 6 (p = 0.0003), by 51% by week 9 (p < 0.0001), and by 55% by week 12 (p < 0.0001). Acne is the most common skin condition diagnosed in Hispanics, and this study illustrates a statistically significant reduction in acne in Hispanic patients with moderate-to-severe acne treated with oral sarecycline. Therefore, oral sarecycline shows promising results as a safe and effective treatment for acne in Hispanics.

Sarecycline is a novel, narrow-spectrum, once-daily tetracycline-derived oral antibiotic that is FDA-approved in the US to be taken with or without food for moderate-to-severe acne vulgaris for ages 9 years of age and older. Sarecycline possesses anti-inflammatory properties and potent activity against Gram-positive bacteria, including activity against multiple strains of Cutibacterium acnes, while exhibiting minimal activity against enteric aerobic Gram-negative bacteria. Unlike many acne studies, sarecycline was investigated for chest and back acne. Significant reduction in inflammatory lesions was seen at week 12 at 1.5 mg/kg/day of sarecycline, with statistically significant improvement seen as early as week 3. No reports of phototoxicity, dizziness, pseudotumor cerebri or lupus but 1.2% nausea and 1.2% vaginal candidiasis was reported in the pivotal Phase III studies.

CLINICAL TRIALS ID: NCT02959970 BACKGROUND: Acne vulgaris in patients aged younger than 12 years is increasingly common and primarily noninflammatory (i.e., comedonal). Dapsone 7.5% gel is indicated for the topical treatment of acne vulgaris in patients nine years of age or older. OBJECTIVE: We sought to evaluate efficacy, safety, tolerability, and pharmacokinetics (PK) of once-daily topical dapsone 7.5% gel. METHODS: This was a Phase IV, multicenter, open-label study in patients with acne aged 9 to 11 years. Patients applied dapsone 7.5% gel once daily to the face and acne-affected areas on the upper chest, upper back, and shoulders for 12 weeks. Patients in the PK cohort applied dapsone 7.5% gel under maximal-use conditions for eight days and a thin layer for the remaining 11 weeks. Lesion counts and proportions of patients with an Investigator’s Global Assessment score of zero points (clear) or one point (almost clear) were assessed. Plasma concentrations of dapsone and metabolites were evaluated after one week in the PK cohort. Safety and dermal tolerability were evaluated. RESULTS: After 12 weeks, facial acne was clear or almost clear in about 47 percent of patients. Inflammatory, noninflammatory, and total lesions decreased from baseline, with a greater reduction apparent in noninflammatory lesions. Systemic exposure to dapsone in PK patients was low. The overall rate of adverse events was low, and dermal tolerability scores indicated no or mild stinging/burning, dryness, scaling, and erythema. CONCLUSION: Once-daily topical dapsone 7.5% gel used for 12 weeks was safe, effective, and well tolerated in preadolescent patients with acne.

Biofilms are a diverse and complex collection of microorganisms which are either embedded or attached to a living or nonliving surface. When these biofilms are helpful to the primary organism (i.e., human), then it is considered part of the microbiome. Broad-spectrum antibiotics disrupt the microbiome’s homeostasis, with negative consequences. While antibiotics are ineffective, combination therapies in addition to debridement may be promising at treating biofilms.

Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the BCL11A erythroid-specific enhancer. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same BCL11A enhancer. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.).

After the discoveries of the initial classes of antibiotics in the mid-twentieth century, approximately 40 years passed before a new antibiotic class was discovered. With the rising number of antibiotic-resistant bacteria in the twenty-first century, novel classes of antibiotics and innovative mechanisms of antibiotic delivery have been invented.

BACKGROUND: Photodynamic therapy (PDT) is a well-known treatment modality for actinic keratosis (AK). The largest surface area approved by the FDA is 20cm(2) with 10% 5-aminolevulinic acid hydrochloride gel (10% ALA gel). OBJECTIVE: This retrospective study assessed the tolerability of PDT with 10% ALA gel in areas ranging from 75cm(2) to 300cm(2). METHODS: The medical records of 203 patients with AKs treated with 376 PDT sessions using 10% ALA gel were reviewed. Face and ears were incubated with 10% ALA gel for 60 minutes without occlusion while all other areas were incubated for 90 minutes with plastic wrap occlusion followed by 10J/cm(2) blue light. Patients were given specific post-PDT care directions. Patient outcomes data was collected. RESULTS: Skin irritation was reported in 27 (7%) PDT sessions in 25 patients (12%). These occurred primarily on the face (n=17), hands (n=4,) and scalp (n=3). Of the 349 PDT treatments (93%) without irritation, these subjects reported adherence to a specific post-PDT regimen using zinc oxide and healing creams for 48 hours. LIMITATIONS: This was a retrospective study observing safety and tolerability. Clearance data was not collected. CONCLUSION: Based on this retrospective observational case series, PDT with ALA gel appears to be safe for treating patients with AKs covering surface areas 75 to 300cm(2). Irritation might be mitigated by post-PDT care regimens.

Calcipotriene 0.005% plus betamethasone dipropionate 0.064% (Cal/BD) aerosol foam is a topical agent indicated for the treatment of plaque psoriasis. While topical treatments are typically reserved for milder disease, in clinical trials with Cal/BD foam, the vast majority of patients had beyond-mild psoriasis at baseline, and multiple studies (including subgroup analyses from randomized controlled trials and other small-scale studies) have demonstrated favorable outcomes with the use of Cal/BD foam in this population. The objective of this article is to review existing data on the efficacy, safety, and cost-effectiveness of Cal/BD foam used in patients with beyond-mild psoriasis, either alone as topical monotherapy or as adjunctive therapy. Practical recommendations for managing beyond-mild psoriasis with Cal/BD foam are also provided. J Drugs Dermatol. 2020;19(8): doi:10.36849/JDD.2020.5300.

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This prospective, parallel-group, randomized, double-blind, multicenter study compared the efficacy and safety of FV-100 with valacyclovir for reducing pain associated with acute herpes zoster (HZ). Patients, ≥50 years of age, diagnosed with HZ within 72 h of lesion appearance who had HZ-associated pain, were randomized 1:1:1 to a 7-day course of either FV-100 200 mg QD (n = 117), FV-100 400 mg QD (n = 116), or valacyclovir 1000 mg TID (n =117). Efficacy was evaluated on the basis of the burden of illness (BOI; Zoster Brief Pain Inventory scores); incidence and duration of clinically significant pain (CSP); pain scores; incidence and severity of post-herpetic neuralgia (PHN); and times to full lesion crusting and to lesion healing. Safety was evaluated on the basis of adverse event (AE)/SAE profiles, changes in laboratory and vital signs values, and results of electrocardiograms. The burden of illness scores for pain through 30 days were 114.5, 110.3, and 118.0 for FV-100 200 mg, FV-100 400 mg, and valacyclovir 3000 mg, respectively. The incidences of PHN at 90 days for FV-100 200 mg, FV-100 400 mg, and valacyclovir 3000 mg were 17.8%, 12.4%, and 20.2%, respectively. Adverse event and SAE profiles of the two FV-100 and the valacyclovir groups were similar and no untoward signals or trends were evident. These results demonstrate a potential for FV-100 as an antiviral for the treatment of shingles that could both reduce the pain burden of the acute episode and reduce the incidence of PHN compared with available treatments.

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This corrects the article DOI: 10.1038/nature24265.

X chromosome inactivation (XCI) silences the transcription from one of the two X chromosomes in mammalian female cells to balance expression dosage between XX females and XY males. XCI is, however, characteristically incomplete in humans: up to one third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of “escape” from inactivation varying between genes and individuals1,2 (Fig. 1). However, the extent to which XCI is shared between cells and tissues remains poorly characterized3,4, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression5 and phenotypic traits6. Here we report a systematic survey of XCI using a combination of over 5,500 transcriptomes from 449 individuals spanning 29 tissues, and 940 single-cell transcriptomes, integrated with genomic sequence data (Fig. 1). By combining information across these data types we show that XCI at the 683 X-chromosomal genes assessed is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven new escape genes supported by multiple lines of evidence, and demonstrate that escape from XCI results in sex biases in gene expression, thus establishing incomplete XCI as a likely mechanism introducing phenotypic diversity6,7. Overall, this updated catalogue of XCI across human tissues informs our understanding of the extent and impact of the incompleteness in the maintenance of XCI.

Rosacea is a chronic inflammatory dermatologic condition that can often be disfiguring with significant negative impact on patients' quality of life. Sanrosa (brimonidine tartate) is a novel therapeutic agent targeting the facial flushing and erythema of rosacea through its α₂ adrenergic receptor agonist activity. The goal of this article is to discuss current treatment options for rosacea and the properties of brimonidine tartate as well as the evidence surrounding its efficacy and safety profile.

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P-type ATPases comprise a superfamily of proteins that play vital roles in the human body and can cause severe diseases if their functions are impaired. P₄-ATPases or type 4 of P-type ATPases are implicated in the ATP-dependent flipping of phospholipids across cell membranes. This generates and maintains transverse phospholipid asymmetry, a property important for biological processes including vesicle trafficking. ATP9A is a P₄-ATPase that remains poorly characterized despite its high expression in brain and testis. Interestingly, loss of Neo1p, the yeast ortholog of ATP9A, is lethal. The first part of this study investigates the functional properties and cellular localization of ATP9A. Human ATP9A was expressed in HEK293T cells and characterized using biochemical and cell-based approaches. ATP9A exhibited little if any phospholipid-dependent ATPase activity, but underwent hydroxylamine-sensitive phosphorylation, a characteristic feature of the P-type ATPase reaction cycle. A monoclonal antibody to ATP9A was generated for analysis of ATP9A in cells and brain tissues by western blotting and immunofluorescence microscopy. In transfected HEK293T cells ATP9A localized to perinuclear and peripheral punctate structures possibly related to the endocytic pathway. Our findings suggest that ATP9A undergoes autophosphorylation, but fails to dephosphorylate, possibly due to lack of an accessory protein or a specific substrate. Further studies on endogenous ATP9A should provide further insight into its physiological function and possible role in human disease. On the other hand, Na⁺/K⁺-ATPase (NKA) belongs to type 2C of P-type ATPases and establishes Na⁺ and K⁺ gradients across cell membranes. NKA has been shown to interact with retinoschisin (RS1), an adhesion protein essential for normal retinal structure and function. Mutations in the gene encoding RS1 cause a macular degeneration disorder called X-linked retinoschisis (XLRS). RS1 is thought to be anchored to the membranes of photoreceptor and bipolar cells through interaction with the α3 and β2 isoforms of NKA. The second part aims to characterize the RS1-NKA complex by generating monoclonal antibodies specific for the components. Indeed, immunoaffinity purification of NKAβ2 from bovine retinal membranes co-immunoprecipitated the α3 subunit and RS1. Tandem affinity purification of the native protein complexes should enhance understanding of the molecular and cellular mechanisms underlying XLRS.

SummaryConstitutive heterochromatin is traditionally viewed as the static form of heterochromatin that silences pericentromeric and telomeric repeats in a cell cycle- and differentiation-independent manner. Here, we show that, in the mouse olfactory epithelium, olfactory receptor (OR) genes are marked in a highly dynamic fashion with the molecular hallmarks of constitutive heterochromatin, H3K9me3 and H4K20me3. The cell type and developmentally dependent deposition of these marks along the OR clusters are, most likely, reversed during the process of OR choice to allow for monogenic and monoallelic OR expression. In contrast to the current view of OR choice, our data suggest that OR silencing takes place before OR expression, indicating that it is not the product of an OR-elicited feedback signal. Our findings suggest that chromatin-mediated silencing lays a molecular foundation upon which singular and stochastic selection for gene expression can be applied.

not available. Disclosures: Study sponsored by Mayne Pharma. Copyright 2018 SKIN

Angela Y Moore, Blakely S RichardsonArlington Center for Dermatology, Arlington, Texas, USAAbstract: Psoriasis is a chronic T-cell-mediated inflammatory disease that primarily affects the skin and joints. Patients with moderate to severe psoriasis constitute about 30% of the psoriasis population. Treatment of this group is challenging due to the long-term side effects, toxicities and inconvenience of conventional treatments such as phototherapy, methotrexate and cyclosporine. However, recent advances in our understanding of the pathogenesis of psoriasis have led to the popular use of biologics, which offer a safer, more convenient and effective targeted therapy. Adalimumab was originally approved for treating rheumatoid arthritis. Currently, adalimumab is also approved for treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy or when other systemic therapies are medically less appropriate. Since the onset of the use of biologics, there have been concerns over safety and efficacy when used as long-term therapy. This paper reviews all publications, posters and abstracts reporting original data on the efficacy and/or safety of adalimumab in patients treated for chronic plaque psoriasis for more than 1 year.Keywords: psoriasis, adalimumab, biologics

Nature 550, 244–248 (2017); doi:10.1038/nature24265 In this Letter, the Source Data associated with Fig. 2a and d were incorrect. This was due to an error during manuscript preparation, when transformed data instead of the raw values plotted in the figure were included in the Source Data file. The figure panels are correct and remain unchanged, and these errors do not affect the results or conclusions of the Letter.

We investigated the aberrant promoter methylation status of 12 genes in skin lesions, both malignant (basal cell carcinomas (BCCs), n=68 and squamous cell carcinomas (SCCs), n=35) and non-malignant (tags, n=58) skin lesions and compared the results of lesions from sun exposed (SE) and sun protected (SP) regions. Methylation was studied using a methylation specific PCR (MSP) and methylation of CDH1 was also measured using a semi-quantitative fluorescence based real-time MSP method. The methylation index (MI) was calculated as the methylated fraction of the genes examined. In this report, we found high frequencies of methylation of several known or suspected tumor suppressor genes in tags and skin cancers. Among the 12 genes, for the cadherin genes CDH1 and CDH3 and for two of the laminin 5 encoding genes LAMA3 and LAMC2 methylation frequencies greater than 30% were noted in one or more specimen types. We investigated whether methylation was tumor related. Surprisingly, the differences in the methylation profile of genes among the three specimen types were modest, and the MI, indicators of overall methylation frequencies, was nearly identical. However, significant differences were noted in the frequencies of methylation among the three specimen types for the genes RASSF1A (P=0.002), CDH1 (P=0.007) and one or more of three CAD genes (P=0.02). Methylation was highly significantly related to sun exposure, and sun protected specimens had little or no methylation. As methylation of CDH1 was completely SE specific we analyzed all the skin samples using a semi-quantitative real-time PCR assay for the CDH1 gene. The concordance between standard MSP and real-time MSP for all the samples (n=161) was 75% (P

We present the case of a 31-year-old patient who developed widespread mycetoma across her back and shoulders caused by Cladophialophora bantiana 16 years after injury to those sites from tornado debris. The patient also had a history of systemic lupus erythematosus treated with systemic steroids. Systemic antifungal treatment with fluconazole and itraconazole proved ineffective, and surgical debridement was required. Nine other culture-confirmed cases of cutaneous infection with this organism have been reported worldwide. This type of infection can occur in immunocompromised or immunocompetent patients, and may respond to systemic antifungals or surgery.

A subset of individuals with Lynch syndrome (LS) has a variant called Muir-Torre syndrome (MTS) where patients develop multiple sebaceous neoplasms. Absence of gene expression and microsatellite instability (MSI) have been welldocumented in LS neoplasms. It is unclear whether the presence of these abnormalities in isolated sebaceous neoplasms would indicate the likely presence of otherwise unsuspected LS or MTS. 164 specimens of sporadic cutaneous sebaceous neoplasms were obtained. IHC was performed for expression of the DNA mismatch repair (MMR) genes MSH2 and MLH1. A 5-marker mononucleotide repeat microsatellite panel was analyzed to detect MSI, and two or more mutated markers were required for MSI. 164 sebaceous neoplasms were obtained from 162 patients. IHC data was successfully obtained from 162 samples and MSI data was obtained from 138 samples. 50/162 (31 %) had abnormal IHC with loss of staining for either MSH2 (37/162, 23 %), MLH1 (9/162, 5 %) or both (4/162, 2 %). 37 % (52/138) of the tumors had MSI. 82 % (111/136) of those with both IHC and MSI results correlated as expected. 18 % (25/136) showed discordance between IHC and MSI. 69/163 (42 %) had either abnormal IHC or MSI, indicating deficient DNA MMR activity. Given the substantial proportion of DNA MMR deficiency in these sebaceous neoplasms, screening for DNA MMR defects in sebaceous neoplasms would not appear to be an effective way to distinguish patients with LS or MTS from those with sporadic skin lesions and an ordinary risk of cancer.

Epigenomic data sets provide critical information about the dynamic role of chromatin states in gene regulation, but a key question of how chromatin state segmentations vary under different conditions across the genome has remained unaddressed. Here we present ChromDiff, a group-wise chromatin state comparison method that generates an information-theoretic representation of epigenomes and corrects for external covariate factors to better isolate relevant chromatin state changes. By applying ChromDiff to the 127 epigenomes from the Roadmap Epigenomics and ENCODE projects, we provide novel group-wise comparative analyses across sex, tissue type, state and developmental age. Remarkably, we find that distinct sets of epigenomic features are maximally discriminative for different group-wise comparisons, in each case revealing distinct enriched pathways, many of which do not show gene expression differences. Our methodology should be broadly applicable for epigenomic comparisons and provides a powerful new tool for studying chromatin state differences at the genome scale., National Science Foundation (U.S.). Graduate Research Fellowship, National Institutes of Health (U.S.) (U54 HG006991), National Institutes of Health (U.S.) (U41 HG007000), National Institutes of Health (U.S.) (5U01ES017156), National Institutes of Health (U.S.) (RC1-HG005334), National Institutes of Health (U.S.) (HG004570), National Institutes of Health (U.S.) (HG006911), National Institutes of Health (U.S.) (R01 HG004037)