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.

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.

Delineation of antigen-specific and antigen-nonspecific CD8(+) memory T-cell responses after cytokine-based cancer immunotherapy.

Memory T cells exhibit tremendous antigen specificity within the immune system and accumulate with age. Our studies reveal an antigen-independent expansion of memory, but not naive, CD8(+) T cells after several immunotherapeutic regimens for cancer resulting in a distinctive phenotype. Signaling through T-cell receptors (TCRs) or CD3 in both mouse and human memory CD8(+) T cells markedly up-regulated programmed death-1 (PD-1) and CD25 (IL-2 receptor α chain), and led to antigen-specific tumor cell killing. In contrast, exposure to cytokine alone in vitro or with immunotherapy in vivo did not up-regulate these markers but resulted in expanded memory CD8(+) T cells expressing NKG2D, granzyme B, and possessing broadly lytic capabilities. Blockade of NKG2D in mice also resulted in significantly diminished antitumor effects after immunotherapy. Treatment of TCR-transgenic mice bearing nonantigen expressing tumors with immunotherapy still resulted in significant antitumor effects. Human melanoma tissue biopsies obtained from patients after topically applied immunodulatory treatment resulted in increased numbers of these CD8(+) CD25(-) cells within the tumor site. These findings demonstrate that memory CD8(+) T cells can express differential phenotypes indicative of adaptive or innate effectors based on the nature of the stimuli in a process conserved across species.

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.

Efficacy of synthetic peptides RP-1 and AA-RP-1 against Leishmania species in vitro and in vivo.

Host defense peptides are naturally occurring molecules that play essential roles in innate immunity to infection. Based on prior structure-function knowledge, we tested two synthetic peptides (RP-1 and AA-RP-1) modeled on the conserved, microbicidal α-helical domain of mammalian CXCL4 platelet kinocidins. These peptides were evaluated for efficacy against Leishmania species, the causative agents of the group of diseases known as leishmaniasis. In vitro antileishmanial activity was assessed against three distinct Leishmania strains by measuring proliferation, metabolic activity and parasite viability after exposure to various concentrations of peptides. We demonstrate that micromolar concentrations of RP-1 and AA-RP-1 caused dose-dependent growth inhibition of Leishmania promastigotes. This antileishmanial activity correlated with rapid membrane disruption, as well as with a loss of mitochondrial transmembrane potential. In addition, RP-1 and AA-RP-1 demonstrated distinct and significant in vivo antileishmanial activities in a mouse model of experimental visceral leishmaniasis after intravenous administration. These results establish efficacy of RP-1 lineage synthetic peptides against Leishmania species in vitro and after intravenous administration in vivo and provide further validation of proof of concept for the development of these and related systemic anti-infective peptides targeting pathogens that are resistant to conventional antibiotics.

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.

Characteristic purpura of the ears, vasculitis, and neutropenia--a potential public health epidemic associated with levamisole-adulterated cocaine.

BACKGROUND: Dermatologists at the University of California, San Francisco recently reported two patients in the online Journal of the American Academy of Dermatology with purpura presumably induced by levamisole in contaminated cocaine. Levamisole-induced vasculitis and neutropenia has been reported elsewhere in the United States and Canada. Up to 70% of cocaine in the United States could be contaminated. OBJECTIVE: We sought to describe similar cases of vasculitis associated with cocaine use. METHODS: This is a retrospective case series. RESULTS: We report 6 remarkably similar patients seen over just the past few months with retiform purpura on the body and tender purpuric eruptions, necrosis, and eschars of the ears after cocaine use in New York and California. All of these patients had positive perinuclear antineutrophil cytoplasmic antibody values and 3 of the 6 also had an associated neutropenia. Direct immunofluorescence studies suggested an immune complex-mediated vasculitis. LIMITATIONS: This case series is descriptive in nature and, because testing is not easily performed, we did not test for levamisole in the serum or blood to prove this is the causative agent. CONCLUSION: It appears the use of cocaine is associated with the peculiar clinical findings of ear purpura, retiform purpura of the trunk, and neutropenia. We believe this case series may represent the tip of the iceberg as a looming public health problem caused by levamisole. Although the direct causal relationship may be difficult to establish, the astute dermatologist or primary care physician should be able to recognize the characteristic skin lesions and should be wary of the potential development of agranulocytosis.

Mobile teledermatology: As doctors and patients are increasingly mobile, technology keeps us connected.

With advancements in electronics and health informatics, telemedicine has emerged as a cost-effective tool capable of increasing care to remote regions, facilitating specialist consults, supporting self-management by patients, and sharing knowledge over great distances. In this review, the authors discuss existing telemedicine modalities, highlight examples of mobile systems documented in the literature to date, and emphasize the data supporting the feasibility of telecommunication technologies to deliver dermatology services and education remotely. While many studies have suggested the potential for teledermatology to increase access to care in developing countries with few dermatologists, the authors share some of the most recent developments, including the use of diagnostic decision support software. The authors encourage a thriving and open network that will enhance the ongoing research and development of innovative and useful products. This network will also connect dermatologists willing to volunteer their consultation to health care workers in remote areas lacking specialists.

Diagnostic accuracy in patients admitted to hospitals with cellulitis.

Misdiagnosis of non-infectious conditions such as cellulitis is a common error and can result in unnecessary hospitalization and antibiotic use. We sought to prospectively determine the misdiagnosis rate of cellulitis among hospitalized patients and to determine if a visually-based computerized diagnostic decision support system (VCDDSS, also named VisualDx) could generate an improved differential diagnosis (DDx) for misdiagnosed patients. In two separate institutions, attending dermatologists or infectious disease specialists evaluated all consecutive patients hospitalized for "cellulitis" by the emergency department. Among 145 subjects enrolled, misdiagnosis occurred in 41 (28%) patients. The diagnosis most commonly mistaken as cellulitis was stasis dermatitis (37%). At one center, in cases that were misdiagnosed by the emergency department, the VCDDSS included the correct diagnosis in the DDx more frequently than the admitting team (18/28 cases (64%) compared to 4/28 cases (14%), p=0.0003). These results demonstrate the capability of this VCDDSS to assist primary care physicians with generating a more accurate DDx when confronted with patients presenting with possible skin infections. Misdiagnoses may result in a significant source of healthcare costs and misdiagnosis-related patient harm. Inclusion of decision support tools early in the diagnostic workflow may reduce misdiagnosis and result in more efficient healthcare management.

Disseminated Strongyloides stercoralis: hyperinfection during medical immunosuppression.

Hyperinfection caused by Strongyloides stercoralis in iatrogenically immunosuppressed patients is becoming more frequently observed. Here, we review the relevant literature and present a recent case of hyperinfection syndrome of S stercoralis in a patient chronically treated with systemic corticosteroids and methotrexate for dermatomyositis. The patient was born in Guatemala but no history of Strongyloides infection was documented. Disseminated Strongyloides is often associated with the immunocompromised state and is commonly seen with cutaneous lesions, respiratory failure, and sepsis. In this patient, a protracted course of progressive muscle weakness and multiple hospital stays for respiratory distress led to acute respiratory failure, septic shock, and rapid physical decline. A few days preceding his death, the patient developed petechiae and multiple purpuric macules and patches over the abdomen and thighs. Histologic review of skin biopsy specimens demonstrated multiple intravascular and interstitial filariform larvae. Dermatologists should be aware of patient populations at risk for infection with S stercoralis and be able to make this diagnosis to initiate earlier treatment of hyperinfection and dissemination.

Mucocutaneous leishmaniasis masquerading as Wegener granulomatosis.

A 43-year-old Brazilian female presented in 2001 with nasal stuffiness and sinusitis. A biopsy was consistent with limited Wegener's granulomatosis although antineutrophil cytoplasmic antibodies were negative. Her nasal inflammation progressed despite trials of prednisone, methotrexate, and azathioprine. A septal perforation developed and a repeat biopsy showed granulomatous inflammation. In 2006 the patient was referred to Division of Rheumatology, University of California, Los Angeles. The nose was grossly erythematous and a magnetic resonance imaging revealed nasal destruction and sinusitis. Palatine biopsies showed chronic inflammation. Cyclophosphamide at 150 mg/d resulted in markedly improved mucocutaneous lesions. The patient developed a leg and arm rash in 2007. A skin biopsy was positive for Leishmania braziliensis. The cyclophosphamide was discontinued and amphotericin B was initiated with transient benefit. Remission was achieved with pentavalent antimony. Despite multiple nasopharyngeal biopsies, for a 6-year span, mucocutaneous leishmaniasis masqueraded as Wegener's granulomatosis. Cyclophosphamide not only resulted in clinical improvement, due to reduced inflammatory response, but also allowed widespread cutaneous dissemination.

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.

Immunosensitization with a Bcl-2 small molecule inhibitor.

Several tumor immunotherapy approaches result in a low percentage of durable responses in selected cancers. We hypothesized that the insensitivity of cancer cells to immunotherapy may be related to an anti-apoptotic cancer cell milieu, which could be pharmacologically reverted through the inhibition of antiapoptotic Bcl-2 family proteins in cancer cells. ABT-737, a small molecule inhibitor of the antiapoptotic proteins Bcl-2, Bcl-w and Bcl-x(L), was tested for the ability to increase antitumor immune responses in two tumor immunotherapy animal models. The addition of systemic therapy with ABT-737 to the immunization of BALB/c mice with tumor antigen peptide-pulsed dendritic cells (DC) resulted in a significant delay in CT26 murine colon carcinoma tumor growth and improvement in survival. However, the addition of ABT-737 to either a vaccine strategy involving priming with TRP-2 melanoma antigen peptide-pulsed DC and boosting with recombinant Listeria monocytogenes expressing the same melanoma antigen, or the adoptive transfer of TCR transgenic cells, did not result in superior antitumor activity against B16 murine melanoma. In vitro studies failed to demonstrate increased cytotoxic lytic activity when testing the combination of ABT-737 with lymphokine activated killer (LAK) cells, or the death receptor agonists Fas, TRAIL-ligand or TNF-alpha against the CT26 and B16 cell lines. In conclusion, the Bcl-2 inhibitor ABT-737 sensitized cancer cells to the antitumor effect of antigen-specific immunotherapy in a vaccine model for the CT26 colon carcinoma in vivo but not in two immunotherapy strategies against B16 melanoma.

Cutaneous and mucocutaneous leishmaniasis.

Leishmaniasis is a cluster of diseases caused by protozoa in the genus Leishmania. There are three basic clinical forms: cutaneous, mucocutaneous, and visceral leishmaniasis. The present review focuses on the diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis. Characteristics of both the human host and the parasite species influence the clinical disease manifestations that range from asymptomatic exposure, to self-healing skin ulcers, to life-threatening widespread destructive ulcerations. Whether through medical treatment or through spontaneous resolution, skin ulcerations generally result in disfiguring scars with significant social and economic impact. Tests to confirm the diagnosis should be performed on patients who have recently visited endemic areas and have skin or mucosal manifestations consistent with leishmaniasis. Treatment depends on the species of Leishmania and the risk of widespread or disfiguring disease. Because of increasing trends in global travel, educating health care providers to recognize and treat leishmaniasis in both endemic and non-endemic countries is imperative.

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.

Listeria as a vaccine vector.

The immunostimulatory characteristics and intracellular niche of Listeria monocytogenes make it uniquely suitable for use as a live bacterial vaccine vector. Preclinical results supporting this idea, and current strategies to induce beneficial cell-mediated immunity to both infectious diseases and cancer with this vector, are discussed in this review.

Cutaneous signs of child abuse.

UNLABELLED: Maltreatment of children is a major public health crisis, and it is estimated that each year more than 3 million children are victims of abuse. Safeguarding the welfare of children is a priority, and it is the moral and ethical responsibility of healthcare professionals to detect cases of abuse and intervene appropriately to prevent further harm. Clinicians are often challenged to differentiate signs of child abuse from skin conditions that mimic maltreatment. Because cutaneous injury represents the most recognizable and common form of abuse, dermatologists are often called upon to help distinguish signs of intentional injury from skin conditions that mimic maltreatment. However, few resources specific to dermatologic signs of abuse exist to aid in diagnosis. A review of the literature will provide an educational resource to assist dermatologists and other clinicians in differentiating cutaneous signs of child abuse, including physical and sexual abuse, from mimickers of inflicted injury. LEARNING OBJECTIVE: After completing this learning activity, participants should be able to distinguish signs of intentional injury from skin conditions that mimic maltreatment and understand the clinician's role in the diagnosis and reporting of cases of suspected child abuse.

Adult-onset tufted angioma: a case report and review of the literature.

Tufted angiomas (TAs) are benign vascular tumors, primarily occurring on the trunk and extremities of children younger than 5 years. Few cases occurring on the oral mucosa and in adults have been reported. Although they are typically isolated lesions, TA has been associated with port-wine stains. We describe a case of adult-onset TA on the lower lip mucosa.

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.