Pediatric cutaneous Crohn disease: A case series of 89 patients and review.

BACKGROUND: Cutaneous (or "Metastatic") Crohn disease (CCD) is a rare and underrecognized disease characterized by cutaneous granulomatous inflammation. We describe patient demographics, clinical characteristics, histology, and treatment of 89 pediatric cases of CCD, including 78 previously reported and 11 new cases seen at four academic institutions. We emphasize the efficacy of biologic mono- and dual therapy. METHODS: PubMed identified cases using keywords including "metastatic Crohn disease" and "cutaneous Crohn disease". Patients were identified by retrospective review of the electronic health record including histopathologic diagnosis consistent with CCD. Chart review collected demographic, clinical, and histologic data. RESULTS: Most pediatric patients with CCD are male 55% (49/89), present with edema (73/89, 82%) and erythema (47/89, 53%) of the genitals (33/49, 67%), and have intestinal Crohn disease (69/89, 78%). Oral corticosteroids (53/75, 71%) and metronidazole (29/75, 39%) are the most frequently prescribed medications. Of the 17 patients treated with tumor necrosis factor (TNF)-blockade, 94% (16/17) had partial or total clearance. Ustekinumab resulted in clearance of cutaneous disease in two patients (2/3, 67%) and partial clearance in one patient (1/3, 33%). Two cases achieved total clearance with the use of dual biologic therapy defined as the use of two biologic therapies with differing mechanisms of action or the use of a biologic therapy and small molecule inhibitor. CONCLUSIONS: TNF blockade is an effective treatment for pediatric CCD, and interleukin-12/23 inhibitors may be similarly effective. Consideration of dual biologic therapy may be useful in pediatric patients requiring discordant therapies for their intestinal and cutaneous CD.

Paradoxical eruptions to targeted therapies in dermatology: A systematic review and analysis.

BACKGROUND: Antibody-based therapies that inhibit proinflammatory cytokine signaling are commonly used in dermatology. Paradoxically, these medications may induce or exacerbate inflammatory disorders. OBJECTIVE: To summarize the spectrum of manifestations, incidence, timing, potential mechanisms of, and general management approaches to paradoxical cutaneous reactions induced by cytokine-targeted antibodies in dermatology. METHODS: We performed a systematic review and analysis of published cases of cutaneous paradoxical reactions (PRs) reported in association with tumor necrosis factor α, interleukin (IL) 12/23 (p40), IL-17A/17R, IL-23 (p19), and IL-4Rα inhibitors. RESULTS: We identified 313 articles reporting 2049 cases of PRs. Tumor necrosis factor α inhibitors resulted in 91.2% (1869/2049) of all cases, followed by IL-17/17R (3.5%), IL-4Rα (2.7%), IL-12/23 (2.4%), and IL-23 (0.01%) inhibitors. Psoriasiform and eczematous eruptions were the most commonly reported, but a wide spectrum of patterns were described. Phenotypically overlapping reaction patterns were common. Time to onset typically ranged from weeks to months but could occur more than a year later. Improvement or resolution upon discontinuation of the inciting drug was common. LIMITATIONS: This was a retrospective analysis. CONCLUSIONS: Familiarity with the clinical features of PRs from cytokine-blocking antibodies may facilitate efficient recognition and management.

Nivolumab-induced localized genital bullous pemphigoid in a 60-year-old male.

A 60-year-old man with metastatic renal cell carcinoma presented with a 6-month history of a pruritic, exquisitely painful genital eruption appearing 3 months after initiation of nivolumab. Examination demonstrated a poorly defined, lichenified scrotal plaque studded with erosions, yellow crust, and tense vesicles. There was no other lesion on the body or mucosae. Histopathology revealed a subepidermal blister with a mixed lymphocytic, neutrophilic, and eosinophilic infiltrate. Direct immunofluorescence of perilesional skin demonstrated subclinical blister and linear/fibrillary patchy IgG and IgA along the dermoepidermal junction. Bullous pemphigoid (BP) serologies revealed normal IgG BP230 antibodies and minimally elevated IgG BP180 antibodies. Indirect immunofluorescence revealed positive IgG at the basement membrane ("epidermal pattern") in human split skin and monkey esophagus substrates; no IgA antibodies were detected. The patient was diagnosed with nivolumab-induced localized genital BP (LGBP). BP is a reported adverse effect of immune checkpoint inhibitors including nivolumab; however, cases are typically generalized. LGBP is a rare BP variant typically presenting in children and females; there are few reports of LGBP in adult males. We report a novel case of nivolumab-induced LGBP with unique histopathologic and clinical challenges. LGBP should be considered in patients on immune checkpoint inhibitor therapy with bullous genital eruptions.

COVID-19 aerosol transmission modeling in support of company HVAC guideline.

A company COVID-19 Heating, Ventilation, and Air Conditioning Guideline was implemented globally, as part of a larger control measure toolset, to minimize the potential for SARS-CoV-2 aerosol transmission. The COVID-19 Heating, Ventilation, and Air Conditioning Guideline informed and provided the process to optimize existing ventilation systems, set occupancy duration limits, and set clearance periods for a given space. Aerosol transmission modeling was used extensively to determine space limitations to reduce the potential for aerosol transmission in various manufacturing, lab, warehouse, aircraft, and administrative workspaces. This paper focuses on the modeling completed for administrative spaces (e.g., offices, conference rooms, restrooms, elevators) due to their lower ventilation rates, higher occupant densities, and greater vocalization levels. A detailed description of how the Guideline was implemented, with examples showing the evaluation and determinations made for specific spaces, is provided. World-wide implementation of this Guideline, as one of the layers of protection, was a key component in the overall strategy to reduce aerosol transmission of the SARS-CoV-2 virus.

Use of portable air purifiers as local exhaust ventilation during COVID-19.

The purpose of this study was to determine if strategic placement of portable air purifiers would improve effectiveness of aerosol reduction in a space as compared to use as a general room air purifier. Two sizes of portable air purifiers were placed in two different positions intended to function similar to either a local exhaust ventilation hood or an air curtain to determine if strategic placement would lead to a reduction of particles in a worker's position at a desk in an office environment. Particle generators were used to introduce particulate into the air and personal aerosol monitors measured particles during each test condition. Results showed that when the medium room portable air purifiers used in this study were set to high, corresponding to 98 CFM, and placed near the breathing zone of each office worker with the unit's filter cover removed, the particle concentration was reduced 35% beyond the reduction that would be expected if the same units were placed on the floor behind the occupant's workstation. Results also indicated that the larger portable air purifier tested, positioned as close as reasonable to each occupant's breathing zone with the largest capture area possible (i.e., removing the unit's filter cover), delivers the best aerosol reduction performance. The authors concluded that as a layer of protection against transmission of airborne infectious organisms for office occupants, installing a portable air purifier, sized and operated similar to the units tested in this study on the desk 12 inches from the breathing zone of the worker, has the potential to reduce airborne particulate to a greater degree than if the same units were placed outside of the breathing zone, in the general cubicle area.

Unilesional granulomatous pigmented purpuric dermatosis in a 7-year-old boy.

Granulomatous pigmented purpuric dermatoses (PPD) are rarely reported. We present a case of granulomatous PPD in a 7-year-old boy, one of only two pediatric cases with reported solitary disease. The pathogenesis of unilesional granulomatous PPD may be different from the more commonly described multifocal/widespread disease variant.

Hispanic/Latinos and Skincare: Disparities in Product Development, Marketing, and Toxicity.

“Hispanic” and “Latino” (also known as Mestizo) describe a diverse racial and ethnic group, with a range of cultures, languages, and biological ancestry. It includes individuals of Mexican, Central-to-South American, and Spanish-Caribbean (eg, Cuban, Puerto Rican, and Dominican) descent.1 Individuals of Hispanic/Latino race and ethnicity represent a heterogenous group of people with different skin tones and Fitzpatrick phototypes. Hispanic/Latinos are the fastest growing population in the United States (US) - projected to increase from 55 million in 2014 to 119 million in 2060, an increase of 115%.2 By 2060, more than one-quarter (29%) of the US is projected to be Hispanic/Latino.2.

Termination of re-entrant atrial tachycardia via optogenetic stimulation with optimized spatial targeting: insights from computational models.

KEY POINTS: Optogenetics has emerged as a potential alternative to electrotherapy for treating heart rhythm disorders, but its applicability for terminating atrial arrhythmias remains largely unexplored. We used computational models reconstructed from clinical MRI scans of fibrotic patient atria to explore the feasibility of optogenetic termination of atrial tachycardia (AT), comparing two different illumination strategies: distributed vs. targeted. We show that targeted optogenetic stimulation based on automated, non-invasive flow-network analysis of patient-specific re-entry morphology may be a reliable approach for identifying the optimal illumination target in each individual (i.e. the critical AT isthmus). The above-described approach yields very high success rates (up to 100%) and requires dramatically less input power than distributed illumination We conclude that simulations in patient-specific models show that targeted light pulses lasting longer than the AT cycle length can efficiently and reliably terminate AT if the human atria can be successfully light-sensitized via gene delivery of ChR2. ABSTRACT: Optogenetics has emerged as a potential alternative to electrotherapy for treating arrhythmia, but feasibility studies have been limited to ventricular defibrillation via epicardial light application. Here, we assess the efficacy of optogenetic atrial tachycardia (AT) termination in human hearts using a strategy that targets for illumination specific regions identified in an automated manner. In three patient-specific models reconstructed from late gadolinium-enhanced MRI scans, we simulated channelrhodopsin-2 (ChR2) expression via gene delivery. In all three models, we attempted to terminate re-entrant AT (induced via rapid pacing) via optogenetic stimulation. We compared two strategies: (1) distributed illumination of the endocardium by multi-optrode grids (number of optrodes, Nopt  = 64, 128, 256) and (2) targeted illumination of the critical isthmus, which was identified via analysis of simulated activation patterns using an algorithm based on flow networks. The illuminated area and input power were smaller for the targeted approach (19-57.8 mm2 ; 0.6-1.8 W) compared to the sparsest distributed arrays (Nopt  = 64; 124.9 ± 6.3 mm2 ; 3.9 ± 0.2 W). AT termination rates for distributed illumination were low, ranging from <5% for short pulses (1/10 ms long) to ∼20% for longer stimuli (100/1000 ms). When we attempted to terminate the same AT episodes with targeted illumination, outcomes were similar for short pulses (1/10 ms long: 0% success) but improved for longer stimuli (100 ms: 54% success; 1000 ms: 90% success). We conclude that simulations in patient-specific models show that light pulses lasting longer than the AT cycle length can efficiently and reliably terminate AT in atria light-sensitized via gene delivery. We show that targeted optogenetic stimulation based on analysis of AT morphology may be a reliable approach for defibrillation and requires less power than distributed illumination.

Insulin resistance is higher in prepubertal girls but switches to become higher in boys at age 16: A Cohort Study (EarlyBird 57).

BACKGROUND: The risk of type 2 diabetes is increasing in teenage girls, and is associated with their greater insulin resistance (IR). HYPOTHESIS: We hypothesized that the adverse metabolic profile of girls (compared with boys) would persist from childhood through adolescence. PATIENTS AND METHODS: Community-based longitudinal cohort of 292 children (147 boys) studied annually from 9 to 16 years. MEASURES: IR (homeostasis-model-assessment-2), high-density lipoprotein-cholesterol (HDL-C), triglycerides, % body-fat (dual-energy x-ray absorptiometry), pubertal stage (age at peak height velocity), physical activity (accelerometry). Multi-level modelling established the age-related trends in IR and lipids and the influence of covariates. RESULTS: Each year from 9 to 15 years, girls had 21% to 63% higher IR than boys (girls mean IR 0.73-1.33, boys 0.51-0.89, P < .005). At 16 years the gender difference was not significant (girls IR 0.60, boys 0.56, P = .45). Girls had lower HDL-C from 9 to 12 years, higher triglycerides from 9 to 14 years, greater adiposity throughout, and earlier puberty, but boys were more active than girls (all P < .05). After adjustment for %-fat, puberty and activity, the gender difference in IR between girls and boys aged 9 to 15 years became non-significant (IR girls 0.66-1.01, boys 0.65-1.04, P > .07). However, after adjustment at 16 years, girls' IR was 25% lower than boys' (girls 0.44, boys 0.63, P = .001), and they had 22% higher HDL-C (P < .001) and 20% lower triglycerides (P = .003). CONCLUSIONS: The higher IR of prepubertal and early pubertal girls diminishes during late puberty, and boys begin to exhibit greater metabolic risk. Despite being leaner and more active, boys at 16 years have higher IR than girls, suggesting future higher risk for diabetes, thus we reject our hypothesis.

Arrhythmia dynamics in computational models of the atria following virtual ablation of re-entrant drivers.

AIMS: Efforts to improve ablation success rates in persistent atrial fibrillation (AF) patients by targeting re-entrant driver (RD) sites have been hindered by weak mechanistic understanding regarding emergent RDs localization following initial fibrotic substrate modification. This study aimed to systematically assess arrhythmia dynamics after virtual ablation of RD sites in computational models. METHODS AND RESULTS: Simulations were conducted in 12 patient-specific atrial models reconstructed from pre-procedure late gadolinium-enhanced magnetic resonance imaging scans. In a previous study involving these same models, we comprehensively characterized pre-ablation RDs in simulations conducted with either 'average human AF'-based electrophysiology (i.e. EPavg) or ±10% action potential duration or conduction velocity (i.e. EPvar). Re-entrant drivers seen under the EPavg condition were virtually ablated and the AF initiation protocol was re-applied. Twenty-one emergent RDs were observed in 9/12 atrial models (1.75 ± 1.35 emergent RDs per model); these dynamically localized to boundary regions between fibrotic and non-fibrotic tissue. Most emergent RD locations (15/21, 71.4%) were within 0.1 cm of sites where RDs were seen pre-ablation in simulations under EPvar conditions. Importantly, this suggests that the level of uncertainty in our models' ability to predict patient-specific ablation targets can be substantially mitigated by running additional simulations that include virtual ablation of RDs. In 7/12 atrial models, at least one episode of macro-reentry around ablation lesion(s) was observed. CONCLUSION: Arrhythmia episodes after virtual RD ablation are perpetuated by both emergent RDs and by macro-reentrant circuits formed around lesions. Custom-tailoring of ablation procedures based on models should take steps to mitigate these sources of AF recurrence.

High speed ink aggregates are ejected from tattoos during Q-switched Nd:YAG laser treatments.

INTRODUCTION: Dark material has been observed embedded within glass slides following Q-switched Nd:YAG laser treatment of tattoos. It appears that these fragments are ejected at high speed from the skin during the treatment. METHOD: Light microscopic analysis of the slides reveals aggregates of dark fragmented material, presumably tattoo ink, with evidence of fractured/melted glass. Photomicrographs reveal that the sizes of these aggregates are in the range 12 µm to 0.5 mm. RESULTS: Tattoo ink fragments were clearly observed on the surface and embedded within glass slides. Surface aggregates were observed as a fine dust and were easily washed off while deeper fragments remained in situ. The embedded fragments were not visible to the unaided eye. Some fragments appeared to have melted yielding an "insect-like" appearance. These were found to be located between approximately 0.2 and 1 mm deep in the glass. CONCLUSION: Given the particle masses and kinetic energies attained by some of these aggregates their velocities, when leaving the skin, may be hundreds to thousands of metres per second. However, the masses of the aggregates are minuscule meaning that laser operators may be subjected to these high-speed aggregates without their knowledge. These high-speed fragments of ink may pose a contamination risk to laser operators. Lasers Surg. Med. 9999:1-7, 2018. © 2018 Wiley Periodicals, Inc.

Educational Gaps in Molecular Diagnostics, Genomics, and Personalized Medicine in Dermatopathology Training: A Survey of U.S. Dermatopathology Fellowship Program Directors.

BACKGROUND: Molecular technologies offer clinicians the tools to provide high-quality, cost-effective patient care. We evaluated education focused on molecular diagnostics, genomics, and personalized medicine in dermatopathology fellowship training. DESIGN: A 20-question online survey was emailed to all (n = 53) Accreditation Council for Graduate Medical Education (ACGME)-accredited dermatopathology training programs in the United States. RESULTS: Thirty-one of 53 program directors responded (response rate = 58%). Molecular training is undertaken in 74% of responding dermatopathology fellowships, with levels of instruction varying among dermatology-based and pathology-based programs. Education differed for dermatology- and pathology-trained fellows in approximately one-fifth (19%) of programs. Almost half (48%) of responding program directors believe that fellows are not currently receiving adequate molecular education, although the majority (97%) expect to incorporate additional instruction in the next 2-5 years. Factors influencing the incorporation of relevant education include perceived clinical utility and Accreditation Council for Graduate Medical Education/residency review committee (RRC) requirements. Potential benefits of molecular education include increased medical knowledge, improved patient care, and promotion of effective communication with other healthcare professionals. More than two-thirds (68%) of responding program directors believe that instruction in molecular technologies should be required in dermatopathology fellowship training. CONCLUSIONS: Although all responding dermatopathology fellowship program directors agreed that molecular education is important, only a little over half of survey participants believe that their fellows receive adequate instruction. This represents an important educational gap. Discussion among those who oversee fellow education is necessary to best integrate and evaluate teaching of molecular dermatopathology.

Guest Programmable Multistep Spin Crossover in a Porous 2-D Hofmann-Type Material.

The spin crossover (SCO) phenomenon defines an elegant class of switchable materials that can show cooperative transitions when long-range elastic interactions are present. Such materials can show multistepped transitions, targeted both fundamentally and for expanded data storage applications, when antagonistic interactions (i.e., competing ferro- and antiferro-elastic interactions) drive concerted lattice distortions. To this end, a new SCO framework scaffold, [FeII(bztrz)2(PdII(CN)4)]·n(guest) (bztrz = (E)-1-phenyl-N-(1,2,4-triazol-4-yl)methanimine, 1·n(guest)), has been prepared that supports a variety of antagonistic solid state interactions alongside a distinct dual guest pore system. In this 2-D Hofmann-type material we find that inbuilt competition between ferro- and antiferro-elastic interactions provides a SCO behavior that is intrinsically frustrated. This frustration is harnessed by guest exchange to yield a very broad array of spin transition characters in the one framework lattice (one- (1·(H2O,EtOH)), two- (1·3H2O) and three-stepped (1·âˆ¼2H2O) transitions and SCO-deactivation (1)). This variety of behaviors illustrates that the degree of elastic frustration can be manipulated by molecular guests, which suggests that the structural features that contribute to multistep switching may be more subtle than previously anticipated.