Anti-IL-17A blockade did not significantly reduce inflammatory lesions in a placebo-controlled pilot study in adult patients with moderate to severe acne.

BACKGROUND: CJM112 is a potent anti-IL-17A monoclonal antibody, whose clinical efficacy in psoriasis was recently documented. This study aimed to assess the effect of IL-17A blockade, using CJM112, in patients with moderate to severe acne. METHODS: A randomized, placebo-controlled, double-blind, parallel-group, proof-of-concept study was conducted on patients with moderate to severe acne. Patients received CJM112 300 mg, 75 mg, or placebo subcutaneously during Treatment Period 1 (0-12 weeks). Patients receiving placebo were re-randomized to receive CJM112 300 mg or 75 mg during Treatment Period 2 (12-24 weeks). The primary endpoint was the number of inflammatory facial lesions at Week 12. RESULTS: As the futility criterion was met during the interim analysis, only 52/75 (69.3%) patients were recruited. In total, 48/52 (92.3%) and 26/41 (63.4%) completed Treatment Periods 1 and 2, respectively. All groups exhibited a reduction in facial inflammatory lesions, with no difference observed between CJM112 and placebo (CJM112 300 mg 27.6 ± 20.7; CJM112 75 mg 30.4 ± 34.8; placebo 23.6 ± 13.6; primary endpoint). Additionally, no differences were observed between groups in other secondary and exploratory endpoints at Week 12. CONCLUSIONS: Anti-IL-17A therapy was not significantly different compared to the placebo in reducing inflammatory lesions in patients with moderate to severe acne.

Author Correction: The balance of metagenomic elements shapes the skin microbiome in acne and health.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Technology-Enabled Clinical Trials: Transforming Medical Evidence Generation.

The complexity and costs associated with traditional randomized, controlled trials have increased exponentially over time, and now threaten to stifle the development of new drugs and devices. Nevertheless, the growing use of electronic health records, mobile applications, and wearable devices offers significant promise for transforming clinical trials, making them more pragmatic and efficient. However, many challenges must be overcome before these innovations can be implemented routinely in randomized, controlled trial operations. In October of 2018, a diverse stakeholder group convened in Washington, DC, to examine how electronic health record, mobile, and wearable technologies could be applied to clinical trials. The group specifically examined how these technologies might streamline the execution of clinical trial components, delineated innovative trial designs facilitated by technological developments, identified barriers to implementation, and determined the optimal frameworks needed for regulatory oversight. The group concluded that the application of novel technologies to clinical trials provided enormous potential, yet these changes needed to be iterative and facilitated by continuous learning and pilot studies.

Using Network Oriented Research Assistant (NORA) Technology to Compare Digital Photographic With In-Person Assessment of Acne Vulgaris.

Importance: Teledermatology has undergone exponential growth in the past 2 decades. Many technological innovations are becoming available without necessarily undergoing validation studies for specific dermatologic applications. Objective: To determine whether patient-taken photographs of acne using Network Oriented Research Assistant (NORA) result in similar lesion counts and Investigator's Global Assessment (IGA) findings compared with in-person examination findings. Design, Setting, and Participants: This pilot reliability study enrolled consecutive patients with acne vulgaris from a single general dermatology practice in Los Angeles, California, who were able to use NORA on an iPhone 6 to take self-photographs. Patients were enrolled from January 1 through March 31, 2016. Each individual underwent in-person and digital evaluation of his or her acne by the same dermatologist. A period of at least 1 week separated the in-person and digital assessments of acne. Interventions: All participants were trained on how to use NORA on the iPhone 6 and take photographs of their face with the rear-facing camera. Main Outcomes and Measures: Reliability of patient-taken photographs with NORA for acne evaluation compared with in-person examination findings. Acne assessment measures included lesion count (total, inflammatory, noninflammatory, and cystic) and IGA for acne severity. Results: A total of 69 patients (37 male [54%] and 32 female [46%]; mean [SD] age, 22.7 [7.7] years) enrolled in the study. The intraclass correlation coefficients of in-person and photograph-based acne evaluations indicated strong agreement. The intraclass correlation coefficient for total lesion count was 0.81; for the IGA, 0.75. Inflammatory lesion count, noninflammatory lesion count, and cyst count had intraclass correlation coefficients of 0.72, 0.72, and 0.82, respectively. Conclusions and Relevance: This study found agreement between acne evaluations performed in person and from self-photographs with NORA. As a reliable telehealth technology for acne, NORA can be used as a teledermatology platform for dermatology research and can increase access to dermatologic care.

The balance of metagenomic elements shapes the skin microbiome in acne and health.

Studies have emphasized the importance of disease-associated microorganisms in perturbed communities, however, the protective roles of commensals are largely under recognized and poorly understood. Using acne as a model disease, we investigated the determinants of the overall virulence property of the skin microbiota when disease- and health-associated organisms coexist in the community. By ultra-deep metagenomic shotgun sequencing, we revealed higher relative abundances of propionibacteria and Propionibacterium acnes phage in healthy skin. In acne patients, the microbiome composition at the species level and at P. acnes strain level was more diverse than in healthy individuals, with enriched virulence-associated factors and reduced abundance of metabolic synthesis genes. Based on the abundance profiles of the metagenomic elements, we constructed a quantitative prediction model, which classified the clinical states of the host skin with high accuracy in both our study cohort (85%) and an independent sample set (86%). Our results suggest that the balance between metagenomic elements, not the mere presence of disease-associated strains, shapes the overall virulence property of the skin microbiota. This study provides new insights into the microbial mechanism of acne pathogenesis and suggests probiotic and phage therapies as potential acne treatments to modulate the skin microbiota and to maintain skin health.

The Self-Perception and Usage of Medical Apps amongst Medical Students in the United States: A Cross-Sectional Survey.

Background. Mobile medical software applications (apps) are used for clinical decision-making at the point of care. Objectives. To determine (1) the usage, reliability, and popularity of mobile medical apps and (2) medical students' perceptions of app usage effect on the quality of patient-provider interaction in healthcare settings. Methods. An anonymous web-based survey was distributed to medical students. Frequency of use, type of app used, and perceptions of reliability were assessed via univariate analysis. Results. Seven hundred thirty-one medical students responded, equating to a response rate of 29%. The majority (90%) of participants thought that medical apps enhance clinical knowledge, and 61% said that medical apps are as reliable as textbooks. While students thought that medical apps save time, improve the care of their patients, and improve diagnostic accuracy, 53% of participants believed that mobile device use in front of colleagues and patients makes one appear less competent. Conclusion. While medical students believe in the utility and reliability of medical apps, they were hesitant to use them out of fear of appearing less engaged. Higher levels of training correlated with a greater degree of comfort when using medical apps in front of patients.

Relatively Permanent Pigmented or Vascular Skin Marks for Identification: A Pilot Reliability Study.

In child sexual exploitation offenses, the collected evidence images often show the skin of nonfacial body parts of the criminals and victims. For identification in this scenario, "relatively permanent pigmented or vascular skin marks," abbreviated as RPPVSM, were recently introduced as the basis for a novel biometric trait. This pilot study evaluated the interexaminer variability of RPPVSM identification. Four dermatology physicians were recruited to examine RPPVSM from 75 skin images collected from a total of 51 Caucasian and Asian subjects. The images were separated into 50 reference ("suspect") images and 25 evaluation ("evidence") images. The examiners were asked to perform identification by annotating RPPVSM in each of the 25 evaluation images and matching them with the reference images. The rate of misidentification was 0% while the mean rate at which examiners failed to find a match was 6%, indicating the potential of dermatology physicians performing the role of RPPVSM examiners.

Vitamin B12 modulates the transcriptome of the skin microbiota in acne pathogenesis.

Various diseases have been linked to the human microbiota, but the underlying molecular mechanisms of the microbiota in disease pathogenesis are often poorly understood. Using acne as a disease model, we aimed to understand the molecular response of the skin microbiota to host metabolite signaling in disease pathogenesis. Metatranscriptomic analysis revealed that the transcriptional profiles of the skin microbiota separated acne patients from healthy individuals. The vitamin B12 biosynthesis pathway in the skin bacterium Propionibacterium acnes was significantly down-regulated in acne patients. We hypothesized that host vitamin B12 modulates the activities of the skin microbiota and contributes to acne pathogenesis. To test this hypothesis, we analyzed the skin microbiota in healthy subjects supplemented with vitamin B12. We found that the supplementation repressed the expression of vitamin B12 biosynthesis genes in P. acnes and altered the transcriptome of the skin microbiota. One of the 10 subjects studied developed acne 1 week after vitamin B12 supplementation. To further understand the molecular mechanism, we revealed that vitamin B12 supplementation in P. acnes cultures promoted the production of porphyrins, which have been shown to induce inflammation in acne. Our findings suggest a new bacterial pathogenesis pathway in acne and provide one molecular explanation for the long-standing clinical observation that vitamin B12 supplementation leads to acne development in a subset of individuals. Our study discovered that vitamin B12, an essential nutrient in humans, modulates the transcriptional activities of skin bacteria, and provided evidence that metabolite-mediated interactions between the host and the skin microbiota play essential roles in disease development.

The diversity and host interactions of Propionibacterium acnes bacteriophages on human skin.

The viral population, including bacteriophages, is an important component of the human microbiota, yet is poorly understood. We aim to determine whether bacteriophages modulate the composition of the bacterial populations, thus potentially playing a role in health or disease. We investigated the diversity and host interactions of the bacteriophages of Propionibacterium acnes, a major human skin commensal implicated in acne pathogenesis. By sequencing 48 P. acnes phages isolated from acne patients and healthy individuals and by analyzing the P. acnes phage populations in healthy skin metagenomes, we revealed that P. acnes phage populations in the skin microbial community are often dominated by one strain. We also found phage strains shared among both related and unrelated individuals, suggesting that a pool of common phages exists in the human population and that transmission of phages may occur between individuals. To better understand the bacterium-phage interactions in the skin microbiota, we determined the outcomes of 74 genetically defined Propionibacterium strains challenged by 15 sequenced phages. Depending on the Propionibacterium lineage, phage infection can result in lysis, pseudolysogeny, or resistance. In type II P. acnes strains, we found that encoding matching clustered regularly interspaced short palindromic repeat spacers is insufficient to confer phage resistance. Overall, our findings suggest that the prey-predator relationship between bacteria and phages may have a role in modulating the composition of the microbiota. Our study also suggests that the microbiome structure of an individual may be an important factor in the design of phage-based therapy.

Training pattern recognition of skin lesion morphology, configuration, and distribution.

BACKGROUND: The ability to reliably recognize and classify a range of skin signs and symptoms remains a necessary skill across most clinical disciplines but one that is traditionally mastered via nonsystematic experience over long periods. OBJECTIVE: We investigated whether online Perceptual and Adaptive Learning Modules (PALMs) could efficiently train preclerkship medical students to identify and discriminate primary skin lesion morphologies, configurations, and anatomic distributions. METHODS: Medical students completed an online skin lesion morphology PALM voluntarily in year 1 and by requirement, along with configuration and anatomic distribution PALMs, in year 2. In controlled before-and-after studies, multiple-choice pretests and posttests using previously unused images, assessed PALM-induced learning. In prospective cohort studies, differences in year-2 performance between students who had and had not completed the morphology PALM in year 1 were also assessed. RESULTS: Multiple-choice tests, used to evaluate PALM effectiveness, demonstrated large (effect sizes of 1.1 [±0.1 SE] to 2.2 [±0.1 SE]) and statistically significant (P < .0001) improvements after PALM training, with learning retention when tested after 1 year. LIMITATIONS: Results are from self-selected groups and a single class at 1 institution. CONCLUSION: PALMs are a useful tool for efficient development of the core clinical skills of pattern recognition and classification of skin lesion characteristics.

Draft Genome Sequences of Propionibacterium acnes Type Strain ATCC6919 and Antibiotic-Resistant Strain HL411PA1.

Propionibacterium acnes is a major skin commensal and is associated with acne vulgaris, the most common skin disease. Here we report the draft genome sequences of two P. acnes strains, the type strain ATCC6919 and an antibiotic-resistant strain, HL411PA1.

Topical resiquimod protects against visceral infection with Leishmania infantum chagasi in mice.

New prevention and treatment strategies are needed for visceral leishmaniasis, particularly ones that can be deployed simply and inexpensively in areas where leishmaniasis is endemic. Synthetic molecules that activate Toll-like receptor 7 and 8 (TLR7/8) pathways have previously been demonstrated to enhance protection against cutaneous leishmaniasis. We initially sought to determine whether the TLR7/8-activating molecule resiquimod might serve as an effective vaccine adjuvant targeting visceral leishmaniasis caused by infection with Leishmania infantum chagasi. Resiquimod was topically applied to the skin of mice either prior to or after systemic infection with L. infantum chagasi, and parasite burdens were assessed. Surprisingly, topical resiquimod application alone, in the absence of vaccination, conferred robust resistance to mice against future intravenous challenge with virulent L. infantum chagasi. This protection against L. infantum chagasi infection persisted as long as 8 weeks after the final topical resiquimod treatment. In addition, in mice with existing infections, therapeutic treatment with topical resiquimod led to significantly lower visceral parasite loads. Resiquimod increased trafficking of leukocytes, including B cells, CD4(+) and CD8(+) T cells, dendritic cells, macrophages, and granulocytes, in livers and spleens, which are the key target organs of visceralizing infection. We conclude that topical resiquimod leads to systemic immune modulation and confers durable protection against visceralizing L. infantum chagasi infection, in both prophylactic and therapeutic settings. These studies support continued studies of TLR-modulating agents to determine mechanisms of protection and also provide a rationale for translational development of a critically needed, novel class of topical, preventative, and therapeutic agents for these lethal infections.

Propionibacterium acnes strain populations in the human skin microbiome associated with acne.

The human skin microbiome has important roles in skin health and disease. However, bacterial population structure and diversity at the strain level is poorly understood. We compared the skin microbiome at the strain level and genome level of Propionibacterium acnes, a dominant skin commensal, between 49 acne patients and 52 healthy individuals by sampling the pilosebaceous units on their noses. Metagenomic analysis demonstrated that although the relative abundances of P. acnes were similar, the strain population structures were significantly different in the two cohorts. Certain strains were highly associated with acne, and other strains were enriched in healthy skin. By sequencing 66 previously unreported P. acnes strains and comparing 71 P. acnes genomes, we identified potential genetic determinants of various P. acnes strains in association with acne or health. Our analysis suggests that acquired DNA sequences and bacterial immune elements may have roles in determining virulence properties of P. acnes strains, and some could be future targets for therapeutic interventions. This study demonstrates a previously unreported paradigm of commensal strain populations that could explain the pathogenesis of human diseases. It underscores the importance of strain-level analysis of the human microbiome to define the role of commensals in health and disease.

Transcriptome patterns from primary cutaneous Leishmania braziliensis infections associate with eventual development of mucosal disease in humans.

INTRODUCTION: Localized Cutaneous Leishmaniasis (LCL) and Mucosal Leishmaniasis (ML) are two extreme clinical forms of American Tegumentary Leishmaniasis that usually begin as solitary primary cutaneous lesions. Host and parasite factors that influence the progression of LCL to ML are not completely understood. In this manuscript, we compare the gene expression profiles of primary cutaneous lesions from patients who eventually developed ML to those that did not. METHODS: Using RNA-seq, we analyzed both the human and Leishmania transcriptomes in primary cutaneous lesions. RESULTS: Limited number of reads mapping to Leishmania transcripts were obtained. For human transcripts, compared to ML patients, lesions from LCL patients displayed a general multi-polarization of the adaptive immune response and showed up-regulation of genes involved in chemoattraction of innate immune cells and in antigen presentation. We also identified a potential transcriptional signature in the primary lesions that may predict long-term disease outcome. CONCLUSIONS: We were able to simultaneously sequence both human and Leishmania mRNA transcripts in primary cutaneous leishmaniasis lesions. Our results suggest an intrinsic difference in the immune capacity of LCL and ML patients. The findings correlate the complete cure of L. braziliensis infection with a controlled inflammatory response and a balanced activation of innate and adaptive immunity.

Possible links between sickle cell crisis and pentavalent antimony.

For over 60 years, pentavalent antimony (Sb(v)) has been the first-line treatment of leishmaniasis. Sickle cell anemia is a disease caused by a defect in red blood cells, which among other things can cause vasooclusive crisis. We report the case of a 6-year-old child with leishmaniasis who during treatment with meglumine antimoniate developed a sickle cell crisis (SCC). No previous reports describing the relationship between antimonial drugs and sickle cell disease were found. Reviews of both the pathophysiology of SCC and the mechanism of action of Sb(v) revealed that a common pathway (glutathione) may have resulted in the SCC. ChemoText, a novel database created to predict chemical-protein-disease interactions, was used to perform a more expansive and systematic review that was able to support the association between glutathione, Sb(v), and SCC. Although suggestive evidence to support the hypothesis, additional research at the bench would be needed to prove Sb(v) caused the SCC.

Regulatory T cells in the pathogenesis and healing of chronic human dermal leishmaniasis caused by Leishmania (Viannia) species.

BACKGROUND: The inflammatory response is prominent in the pathogenesis of dermal leishmaniasis. We hypothesized that regulatory T cells (Tregs) may be diminished in chronic dermal leishmaniasis (CDL) and contribute to healing during treatment. METHODOLOGY/PRINCIPAL FINDINGS: The frequency and functional capacity of Tregs were evaluated at diagnosis and following treatment of CDL patients having lesions of ≥6 months duration and asymptomatically infected residents of endemic foci. The frequency of CD4(+)CD25(hi) cells expressing Foxp3 or GITR or lacking expression of CD127 in peripheral blood was determined by flow cytometry. The capacity of CD4(+)CD25(+) cells to inhibit Leishmania-specific responses was determined by co-culture with effector CD4(+)CD25(-) cells. The expression of FOXP3, IFNG, IL10 and IDO was determined in lesion and leishmanin skin test site biopsies by qRT-PCR. Although CDL patients presented higher frequency of CD4(+)CD25(hi)Foxp3(+) cells in peripheral blood and higher expression of FOXP3 at leishmanin skin test sites, their CD4(+)CD25(+) cells were significantly less capable of suppressing antigen specific-IFN-γ secretion by effector cells compared with asymptomatically infected individuals. At the end of treatment, both the frequency of CD4(+)CD25(hi)CD127(-) cells and their capacity to inhibit proliferation and IFN-γ secretion increased and coincided with healing of cutaneous lesions. IDO was downregulated during healing of lesions and its expression was positively correlated with IFNG but not FOXP3. CONCLUSIONS/SIGNIFICANCE: The disparity between CD25(hi)Foxp3(+) CD4 T cell frequency in peripheral blood, Foxp3 expression at the site of cutaneous responses to leishmanin, and suppressive capacity provides evidence of impaired Treg function in the pathogenesis of CDL. Moreover, the concurrence of increased Leishmania-specific suppressive capacity with induction of a CD25(hi)CD127(-) subset of CD4 T cells during healing supports the participation of Tregs in the resolution of chronic dermal lesions. Treg subsets may therefore be relevant in designing immunotherapeutic strategies for recalcitrant dermal leishmaniasis caused by Leishmania (Viannia) species.

Dermatologic care in the homeless and underserved populations: observations from the Venice Family Clinic.

Dermatologic care in the homeless and impoverished urban underserved populations is rarely described despite the wide prevalence of skin concerns in this population. Because the homeless population may be subject to increased sun exposure compared to the nonhomeless population, they also may be at increased risk for skin cancer. We sought to describe the spectrum of dermatologic diseases seen in a free clinic in Venice, California--the Venice Family Clinic (VFC)--as well as the differences in diagnoses between the homeless and nonhomeless patients seen at this clinic. A retrospective chart review was performed of dermatology patients (N = 82) seen at VFC throughout the 2006 calendar year. The homeless population (n = 22) was found to have more diagnoses of malignant/premalignant growths (25% [16/64] of all homeless diagnoses) compared to their nonhomeless (n = 60) counterparts (6.1% [8/132] of all nonhomeless diagnoses; P < .0001). This difference was sustained when ethnicity was controlled, with 29.6% [16/54] of diagnoses in the homeless white group consisting of malignant/ premalignant growths compared to 8.9% [4/45] of diagnoses in the nonhomeless white cohort (P < .005). Homeless patients may have a higher incidence of skin cancers and precancerous skin lesions due to increased sun exposure and/or limited access to dermatologic care.