Diversity in pediatric dermatology: A report from the Pediatric Dermatology Research Alliance and a call to action.

BACKGROUND/OBJECTIVES: The Pediatric Dermatology Research Alliance (PeDRA) connects pediatric dermatologists, trainees, basic scientists, allied health professionals, and patient advocates to improve the lives of children with skin disease through research. As a training pipeline for future pediatric dermatologists and steward of research in the field, PeDRA has a responsibility to examine its history and take actionable steps to diversify its membership, grant recipients, study leads, research priorities, and leadership. METHODS: In 2020, PeDRA formed an Equity, Diversity, and Inclusion Task Force to address this need. In an effort to assess PeDRA's past and plan for PeDRA's future, a review of PeDRA's membership, leadership, grant awardees, and research topics was conducted. RESULTS/CONCLUSIONS: Results demonstrated gaps in PeDRA's current operational efforts to diversify the pediatric dermatology workforce and identified areas for improvement. Recommendations are proposed as a call to action for the community.

Acral Changes in pediatric patients during COVID 19 pandemic: Registry report from the COVID 19 response task force of the society of pediatric dermatology (SPD) and pediatric dermatology research alliance (PeDRA).

BACKGROUND/OBJECTIVE: In spring 2020, high numbers of children presented with acral pernio-like skin rashes, concurrent with the coronavirus disease 2019 (COVID-19) pandemic. Understanding their clinical characteristics/ infection status may provide prognostic information and facilitate decisions about management. METHODS: A pediatric-specific dermatology registry was created by the Pediatric Dermatology COVID-19 Response Task Force of the Society for Pediatric Dermatology (SPD) and Pediatric Dermatology Research Alliance (PeDRA) and was managed by Children's Hospital of Philadelphia using REDCap. RESULTS: Data from 378 children 0-18 years entered into the registry between April 13 and July 17, 2020 were analyzed. Data were drawn from a standardized questionnaire completed by clinicians which asked for demographics, description of acral lesions, symptoms before and after acral changes, COVID-19 positive contacts, treatment, duration of skin changes, laboratory testing including SARS-CoV-2 PCR and antibody testing, as well as histopathology. 229 (60.6%) were male with mean age of 13.0 years (± 3.6 years). Six (1.6%) tested positive for SARS-CoV-2. Pedal lesions (often with pruritus and/or pain) were present in 96%. 30% (114/378) had COVID-19 symptoms during the 30 days prior to presentation. Most (69%) had no other symptoms and an uneventful course with complete recovery. CONCLUSIONS AND RELEVANCE: Children with acral pernio-like changes were healthy and all recovered with no short-term sequelae. We believe these acral changes are not just a temporal epiphenomenon of shelter in place during the spring months of the first wave of the COVID-19 pandemic and may be a late phase reaction that needs further study.

Systemic immunosuppressive therapy for inflammatory skin diseases in children: Expert consensus-based guidance for clinical decision-making during the COVID-19 pandemic.

BACKGROUND/OBJECTIVES: The COVID-19 pandemic has raised questions about the approach to management of systemic immunosuppressive therapies for dermatologic indications in children. Change to: Given the absence of data to address concerns related to SARS-CoV-2 infection and systemic immunosuppressive therapies in an evidence-based manner, a Pediatric Dermatology COVID-19 Response Task Force (PDCRTF) was assembled to offer time-sensitive guidance for clinicians. METHODS: A survey was distributed to an expert panel of 37 pediatric dermatologists on the PDCRTF to assess expert opinion and current practice related to three primary domains of systemic therapy: initiation, continuation, and laboratory monitoring. RESULTS: Nearly all respondents (97%) reported that the COVID-19 pandemic had impacted their decision to initiate immunosuppressive medications. The majority of pediatric dermatologists (87%) reported that they were pausing or reducing the frequency of laboratory monitoring for certain immunosuppressive medications. In asymptomatic patients, continuing therapy was the most popular choice across all medications queried. The majority agreed that patients on immunosuppressive medications who have a household exposure to COVID-19 or test positive for new infection should temporarily discontinue systemic and biologic medications, with the exception of systemic steroids, which may require tapering. CONCLUSIONS: The ultimate decision regarding initiation, continuation, and laboratory monitoring of immunosuppressive therapy during the pandemic requires careful deliberation, consideration of the little evidence available, and discussion with families. Consideration of an individual's adherence to COVID-19 preventive measures, risk of exposure, and the potential severity if infected must be weighed against the dermatological disease, medication, and risks to the patient of tapering or discontinuing therapies.

Acute intake of B. longum probiotic does not reduce stress, anxiety, or depression in young adults: A pilot study.

BACKGROUND: The gut microbiome communicates bidirectionally with the brain, linking the gut to psychological phenomena such as stress, depression, and anxiety. Probiotics, or ingestible supplements containing billions of mutualistic bacteria, have demonstrated the mechanistic potential to influence mood; however, few studies have experimentally examined the acute effects of these compounds on individuals not recruited for psychopathology or gut dysfunction. The present study hypothesized reductions in stress, anxiety and depression symptoms following an acute, one week dosing period of B. longum intake. METHODS: The efficacy of a one-week period of orally administered B. longum was tested utilizing a double-blind experimental design. Participants were randomly assigned to either placebo or probiotic capsules under double blinded conditions and completed the Perceived Stress Scale (PSS), the Center for Epidemiological Studies Depression scale (CES-D), and the State-Trait Anxiety Inventory (STAI Y2 form) to assess for differences before and after one-week intervention. RESULTS: No significant reduction in symptoms between groups over the one-week period was found. CONCLUSIONS: These findings suggest that 7-days of B. longum does not reduce stress, depressive symptoms, or anxiety in generally healthy young adults.

Factors Influencing Sleep Difficulty and Sleep Quantity in the Citizen Pscientist Psoriatic Cohort.

INTRODUCTION: Sleep is essential for overall health and well-being, yet more than one-third of adults report inadequate sleep. The prevalence is higher among people with psoriasis, with up to 85.4% of the psoriatic population reporting sleep disruption. Poor sleep among psoriasis patients is particularly concerning because psoriasis is independently associated with many of the same comorbidities as sleep dysfunction, including cardiovascular disease, obesity, and depression. Given the high prevalence and serious consequences of disordered sleep in psoriasis, it is vital to understand the nature of sleep disturbance in this population. This study was designed to help meet this need by using survey data from Citizen Pscientist, an online patient portal developed by the National Psoriasis Foundation. METHODS: Our analysis included 3118 participants who identified as having a diagnosis by a physician of psoriasis alone or psoriasis with psoriatic arthritis. Demographic information, psoriasis severity and duration, sleep apnea status, smoking and alcohol consumption, itch timing, and sleep characteristics were included. Two separate multivariate logistic regression models in STATA were used to determine whether the presence of psoriatic arthritis, age, gender, body mass index, comorbid sleep apnea, psoriasis severity, timing of worst itch, smoking status, or high-risk alcohol consumption were associated with sleep difficulty or low sleep quantity, defined by the American Academy of Sleep Medicine as less than 7 h of sleep per night on average. RESULTS: Results from the multivariate logistic regressions found that sleep difficulty was associated with psoriatic arthritis (OR 2.15, 95% CI [1.79-2.58]), female gender (2.03 [1.67-2.46]), obese body mass index (BMI ≥ 30) (1.25 [1.00-1.56]), sleep apnea (1.41 [1.07-1.86]), psoriasis severity of moderate (1.59 [1.30-1.94]) or severe (2.40 [1.87-3.08]), and smoking (1.60 [1.26-2.02]). Low sleep quantity was associated with obese BMI (1.62 [1.29-2.03]), sleep apnea (1.30 [1.01-1.68]), psoriasis severity of moderate (1.41 [1.16-1.72]) or severe (1.40 [1.11-1.76]), and smoking (1.62 [1.31-2.00]). Sleep difficulty and low sleep quantity were not associated with age, alcohol consumption, or timing of worst itch. CONCLUSION: These results are potentially meaningful in several aspects. We identify an important distinction between sleep difficulty and sleep quantity in psoriatic disease, whereby having psoriatic arthritis and being female are each associated with sleep difficulty despite no association with low sleep quantity. Furthermore, there is conflicting evidence from prior studies as to whether psoriasis severity is associated with sleep difficulty, but this well-powered, large study revealed a strong, graded relationship between psoriasis severity and both sleep difficulty and low sleep quantity. Overall, our results show that both sleep difficulty and low sleep quantity were associated with multiple factors in this analysis of a large psoriatic cohort. These findings suggest that dermatologists may gather clinically useful information by screening psoriatic patients for trouble sleeping and low sleep quantity to identify potential comorbidities and to more effectively guide disease management.

Building a Citizen Pscientist: Advancing Patient-Centered Psoriasis Research by Empowering Patients as Contributors and Analysts.

INTRODUCTION: To design and implement a novel cloud-based digital platform that allows psoriatic patients and researchers to engage in the research process. METHODS: Citizen Pscientist (CP) was created by the National Psoriasis Foundation (NPF) to support and educate the global psoriatic disease community, where patients and researchers have the ability to analyze data. Psoriatic patients were invited to enroll in CP and contribute health data to a cloud database by responding to a 59-question online survey. They were then invited to perform their own analyses of the data using built-in visualization tools allowing for the creation of "discovery charts." These charts were posted on the CP website allowing for further discussion. RESULTS: As of May 2017, 3534 patients have enrolled in CP and have collectively contributed over 200,000 data points on their health status. Patients posted 70 discovery charts, generating 209 discussion comments. CONCLUSION: With the growing influence of the internet and technology in society, medical research can be enhanced by crowdsourcing and online patient portals. Patient discovery charts focused on the topics of psoriatic disease demographics, clinical features, environmental triggers, and quality of life. Patients noted that the CP platform adds to their well-being and allows them to express what research questions matter most to them in a direct and quantifiable way. The implementation of CP is a successful and novel method of allowing patients to engage in research. Thus, CP is an important tool to promote patient-centered psoriatic disease research.

Management of psoriasis in patients with inflammatory bowel disease: From the Medical Board of the National Psoriasis Foundation.

BACKGROUND: There is a significant association between psoriasis and inflammatory bowel disease (IBD). Many treatments for psoriasis and psoriatic arthritis are also used for IBD. OBJECTIVE: To assess therapeutic options for patients with psoriasis and concurrent IBD. METHODS: A systematic literature search was performed for clinical studies of biologic and systemic psoriasis medications in psoriasis, psoriatic arthritis, ulcerative colitis, and Crohn's disease, for the period from January 1, 1947, to February 14, 2017. Randomized, controlled, double-blinded studies were selected if available. If not, the next highest level of available evidence was selected. RESULTS: Of the 2282 articles identified, 132 were selected. Infliximab and adalimumab have demonstrated efficacy in psoriasis, psoriatic arthritis, ulcerative; colitis, and Crohn's disease. Ustekinumab has demonstrated efficacy in psoriasis, psoriatic arthritis, and Crohn's disease. Certolizumab has demonstrated efficacy in psoriatic arthritis and Crohn's disease. Etanercept, secukinumab, brodalumab, and ixekizumab have demonstrated efficacy in psoriasis and psoriatic arthritis but may exacerbate or induce IBD. Guselkumab has demonstrated efficacy in psoriasis. LIMITATIONS: There are no known clinical trials of treatment specifically for concurrent psoriasis and IBD. CONCLUSIONS: Infliximab and adalimumab have demonstrated efficacy in psoriasis, psoriatic arthritis, ulcerative colitis, and Crohn's disease; other agents have demonstrated efficacy for some, but not all, of these indications.

Psoriasis in solid organ transplant patients: best practice recommendations from The Medical Board of the National Psoriasis Foundation.

BACKGROUND: Treatment of solid organ transplant patients who have psoriasis can be a therapeutic challenge. Biologic and systemic drugs used to treat psoriasis can result in an increase in infections or malignancies. OBJECTIVE: We sought to develop a treatment algorithm for organ transplant recipients (OTR) diagnosed with psoriasis vulgaris. METHODS: A systematic literature search for psoriasis treatment in organ transplant patients was performed using MEDLINE and GOOGLE. RESULTS: In mild-to-moderate disease, topical therapy should be a first-line treatment. In moderate-to-severe disease, first-line treatment is acitretin with narrow band ultraviolet light (NBUVB), NBUVB, or acitretin. Second-line treatment is increasing the current antirejection drug dose. Other systemic or biologic therapies should be reserved for more severe or refractory cases. CONCLUSION: No systematic clinical studies have been done to explore psoriasis treatments among affected solid organ transplant patients who have psoriasis, and only a few case reports are available. The algorithm for best practices was developed based on these reports and on the clinical experience and judgment of the Medical Board of the National Psoriasis Foundation. There remains a need for further research on the management of psoriasis in the organ transplant patient population.

National Psoriasis Foundation Priorities for Patient-Centered Research: Proceedings from the 2016 Conference.

The National Psoriasis Foundation (NPF) is developing an agenda for patient-centered research to help patients and their caregivers make more informed health care decisions by engaging psoriasis patients in prioritizing comparative effectiveness research (CER) topics. The NPF has created a novel patient-centered research platform known as Citizen Pscientist (CP), allowing patients with psoriasis and psoriatic arthritis to register and contribute their health data. The CP Governance Council administered an online 23-question CER survey to the CP community and held a structured meeting on December 3, 2016, with patients and researchers to review CER survey results and discuss patient-centered research priorities. Of the 2,945 patients surveyed, 792 patients responded. Three CER topics were deemed to be of high priority for the research agenda: 1) Treat-to-target therapy for psoriasis, 2) Psoriatic arthritis screening questionnaires for early detection and treatment of psoriatic arthritis, and 3) Comparative effectiveness of home-based phototherapy for psoriasis.

Treatment of Inverse/Intertriginous Psoriasis: Updated Guidelines from the Medical Board of the National Psoriasis Foundation.

Inverse or intertriginous psoriasis commonly involves skin fold areas including the axillae, perianal skin, intergluteal cleft, inframammary, genital/inguinal, abdominal, and retroauricular folds. After reviewing the literature for new treatments, a task force was convened to update a consensus on inverse psoriasis therapy. Short-term treatment continues to be low-potency topical steroids. In order to avoid steroid-induced adverse effects, long-term therapy includes topical immunomodulators, calcitriol, and calcipotriene. Second and third-line therapies include antimicrobials, emollients, and tar-based products. Inverse psoriasis resistant to topical therapy has been shown to respond to botulinum toxin injections, excimer laser therapy, and certain systemic agents (such as anti-TNF and anti-IL12/IL23 therapy). Based on promising results from case reports and prior clinical experience, these systemic agents should be strongly considered in inverse psoriasis resistant to topical therapy. However, they need further evidence-based evaluation. The use of randomized trials and objective severity indices may allow for more robust therapeutic data.

J Drugs Dermatol. 2017;16(8):760-766.

Nitric Oxide Regulates Skeletal Muscle Fatigue, Fiber Type, Microtubule Organization, and Mitochondrial ATP Synthesis Efficiency Through cGMP-Dependent Mechanisms.

AIM: Skeletal muscle nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathways are impaired in Duchenne and Becker muscular dystrophy partly because of reduced nNOSµ and soluble guanylate cyclase (GC) activity. However, GC function and the consequences of reduced GC activity in skeletal muscle are unknown. In this study, we explore the functions of GC and NO-cGMP signaling in skeletal muscle. RESULTS: GC1, but not GC2, expression was higher in oxidative than glycolytic muscles. GC1 was found in a complex with nNOSµ and targeted to nNOS compartments at the Golgi complex and neuromuscular junction. Baseline GC activity and GC agonist responsiveness was reduced in the absence of nNOS. Structural analyses revealed aberrant microtubule directionality in GC1-/- muscle. Functional analyses of GC1-/- muscles revealed reduced fatigue resistance and postexercise force recovery that were not due to shifts in type IIA-IIX fiber balance. Force deficits in GC1-/- muscles were also not driven by defects in resting mitochondrial adenosine triphosphate (ATP) synthesis. However, increasing muscle cGMP with sildenafil decreased ATP synthesis efficiency and capacity, without impacting mitochondrial content or ultrastructure. INNOVATION: GC may represent a new target for alleviating muscle fatigue and that NO-cGMP signaling may play important roles in muscle structure, contractility, and bioenergetics. CONCLUSIONS: These findings suggest that GC activity is nNOS dependent and that muscle-specific control of GC expression and differential GC targeting may facilitate NO-cGMP signaling diversity. They suggest that nNOS regulates muscle fiber type, microtubule organization, fatigability, and postexercise force recovery partly through GC1 and suggest that NO-cGMP pathways may modulate mitochondrial ATP synthesis efficiency. Antioxid. Redox Signal. 26, 966-985.

From the Medical Board of the National Psoriasis Foundation: Treatment targets for plaque psoriasis.

BACKGROUND: An urgent need exists in the United States to establish treatment goals in psoriasis. OBJECTIVE: We aim to establish defined treatment targets toward which clinicians and patients with psoriasis can strive to inform treatment decisions, reduce disease burden, and improve outcomes in practice. METHODS: The National Psoriasis Foundation conducted a consensus-building study among psoriasis experts using the Delphi method. The process consisted of: (1) literature review, (2) pre-Delphi question selection and input from general dermatologists and patients, and (3) 4 Delphi rounds. RESULTS: A total of 25 psoriasis experts participated in the Delphi process. The most preferred instrument was body surface area (BSA). The most preferred time for evaluating patient response after starting new therapies was at 3 months. The acceptable response at 3 months postinitiation was either BSA 3% or less or BSA improvement 75% or more from baseline. The target response at 3 months postinitiation was BSA 1% or less. During the maintenance period, evaluation every 6 months was most preferred. The target response at every 6 months maintenance evaluation is BSA 1% or less. LIMITATIONS: Although BSA is feasible in practice, it does not encompass health-related quality of life, costs, and risks of side effects. CONCLUSION: With defined treatment targets, clinicians and patients can regularly evaluate treatment responses and perform benefit-risk assessments of therapeutic options individualized to the patient.

Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice.

Mitochondrial dysfunction plays a key pathogenic role in aging skeletal muscle resulting in significant healthcare costs in the developed world. However, there is no pharmacologic treatment to rapidly reverse mitochondrial deficits in the elderly. Here, we demonstrate that a single treatment with the mitochondrial-targeted peptide SS-31 restores in vivo mitochondrial energetics to young levels in aged mice after only one hour. Young (5 month old) and old (27 month old) mice were injected intraperitoneally with either saline or 3 mg kg(-1) of SS-31. Skeletal muscle mitochondrial energetics were measured in vivo one hour after injection using a unique combination of optical and (31) P magnetic resonance spectroscopy. Age-related declines in resting and maximal mitochondrial ATP production, coupling of oxidative phosphorylation (P/O), and cell energy state (PCr/ATP) were rapidly reversed after SS-31 treatment, while SS-31 had no observable effect on young muscle. These effects of SS-31 on mitochondrial energetics in aged muscle were also associated with a more reduced glutathione redox status and lower mitochondrial H2 O2 emission. Skeletal muscle of aged mice was more fatigue resistant in situ one hour after SS-31 treatment, and eight days of SS-31 treatment led to increased whole-animal endurance capacity. These data demonstrate that SS-31 represents a new strategy for reversing age-related deficits in skeletal muscle with potential for translation into human use.

Defects in mitochondrial localization and ATP synthesis in the mdx mouse model of Duchenne muscular dystrophy are not alleviated by PDE5 inhibition.

Given the crucial roles for mitochondria in ATP energy supply, Ca(2+) handling and cell death, mitochondrial dysfunction has long been suspected to be an important pathogenic feature in Duchenne muscular dystrophy (DMD). Despite this foresight, mitochondrial function in dystrophin-deficient muscles has remained poorly defined and unknown in vivo. Here, we used the mdx mouse model of DMD and non-invasive spectroscopy to determine the impact of dystrophin-deficiency on skeletal muscle mitochondrial localization and oxidative phosphorylation function in vivo. Mdx mitochondria exhibited significant uncoupling of oxidative phosphorylation (reduced P/O) and a reduction in maximal ATP synthesis capacity that together decreased intramuscular ATP levels. Uncoupling was not driven by increased UCP3 or ANT1 expression. Dystrophin was required to maintain subsarcolemmal mitochondria (SSM) pool density, implicating it in the spatial control of mitochondrial localization. Given that nitric oxide-cGMP pathways regulate mitochondria and that sildenafil-mediated phosphodiesterase 5 inhibition ameliorates dystrophic pathology, we tested whether sildenafil's benefits result from decreased mitochondrial dysfunction in mdx mice. Unexpectedly, sildenafil treatment did not affect mitochondrial content or oxidative phosphorylation defects in mdx mice. Rather, PDE5 inhibition decreased resting levels of ATP, phosphocreatine and myoglobin, suggesting that sildenafil improves dystrophic pathology through other mechanisms. Overall, these data indicate that dystrophin-deficiency disrupts SSM localization, promotes mitochondrial inefficiency and restricts maximal mitochondrial ATP-generating capacity. Together these defects decrease intramuscular ATP and the ability of mdx muscle mitochondria to meet ATP demand. These findings further understanding of how mitochondrial bioenergetic dysfunction contributes to disease pathogenesis in dystrophin-deficient skeletal muscle in vivo.

Impaired adaptability of in vivo mitochondrial energetics to acute oxidative insult in aged skeletal muscle.

Periods of elevated reactive oxygen species (ROS) production are a normal part of mitochondrial physiology. However, little is known about age-related changes in the mitochondrial response to elevated ROS in vivo. Significantly, ROS-induced uncoupling of oxidative phosphorylation has received attention as a negative feedback mechanism to reduce mitochondrial superoxide production. Here we use a novel in vivo spectroscopy system to test the hypothesis that ROS-induced uncoupling is diminished in aged mitochondria. This system simultaneously acquires (31)P magnetic resonance and near-infrared optical spectra to non-invasively measure phosphometabolite and O(2) concentrations in mouse skeletal muscle. Using low dose paraquat to elevate intracellular ROS we assess in vivo mitochondrial function in young, middle aged, and old mice. Oxidative phosphorylation was uncoupled to the same degree in response to ROS at each age, but this uncoupling was associated with loss of phosphorylation capacity and total ATP in old mice only. Using mice lacking UCP3 we demonstrate that this in vivo uncoupling is independent of this putative uncoupler of skeletal muscle mitochondria. These data indicate that ROS-induced uncoupling persists throughout life, but that oxidative stress leads to mitochondrial deficits and loss of ATP in aged organisms that may contribute to impaired function and degeneration.

Reduced coupling of oxidative phosphorylation in vivo precedes electron transport chain defects due to mild oxidative stress in mice.

Oxidative stress and mitochondrial function are at the core of many degenerative conditions. However, the interaction between oxidative stress and in vivo mitochondrial function is unclear. We used both pharmacological (2 week paraquat (PQ) treatment of wild type mice) and transgenic (mice lacking Cu, Zn-superoxide dismutase (SOD1(-/-))) models to test the effect of oxidative stress on in vivo mitochondrial function in skeletal muscle. Magnetic resonance and optical spectroscopy were used to measure mitochondrial ATP and oxygen fluxes and cell energetic state. In both models of oxidative stress, coupling of oxidative phosphorylation was significantly lower (lower P/O) at rest in vivo in skeletal muscle and was dose-dependent in the PQ model. Despite this reduction in efficiency, in vivo mitochondrial phosphorylation capacity (ATPmax) was maintained in both models, and ex vivo mitochondrial respiration in permeabilized muscle fibers was unchanged following PQ treatment. In association with the reduced P/O, PQ treatment led to a dose-dependent reduction in PCr/ATP ratio and increased phosphorylation of AMPK. These results indicate that oxidative stress uncouples oxidative phosphorylation in vivo and results in energetic stress in the absence of defects in the mitochondrial electron transport chain.

Assessment of blood supply in superficial tissue by polarization-gated elastic light-scattering spectroscopy.

We report the feasibility of monitoring both hemoglobin oxygen saturation and hemoglobin concentration in the superficial layer of tissue using polarization-gated elastic light-scattering spectroscopy. We detail our analysis technique, the experimental validation of our analysis, and the detection of an early increase in blood supply to the superficial layer of colon tissue in human patients with colonic adenomas as well as in an animal model of colon carcinogenesis. To the best of our knowledge, this study represents the first evidence that polarization gating can be used as a spectroscopic tool to quantify hemoglobin concentration as well as oxygen saturation in the uppermost tissue layer.