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Inhalant misuse and inhalant use disorder are global public health concern that impacts adolescents but can occur throughout life. Toluene is the most commonly misused inhalant. Toluene use leads to significant neuroanatomic, cognitive, and psychiatric deficits. The purpose of this study was to review and summarize the effects of toluene and present a case of a middle-aged patient with an inhalant use disorder. A literature review was conducted to evaluate imaging, neurocognitive, and psychiatric consequences of toluene misuse. The common imaging findings amongst those who misuse toluene were cerebral and cerebellar atrophy, ventricular dilation, loss of gray-white matter differentiation, corpus callosum thinning, and diffuse white matter changes. Concerning cognition, toluene misusers were shown to have deficits in intelligence, attention, memory, visuospatial function, and complex cognition. In addition, toluene users also commonly presented with apathy, flat affect, hallucinations, delusions, anxiety, depression, and insomnia. The neuroanatomical, neurocognitive, and psychiatric effects of toluene misuse are profound. These deficits can make inhalant use disorder difficult to treat. Therefore, evidence-based treatments that recognize and address these domain-specific neurocognitive deficits are needed.

The Enhancing Undergraduate Education and Research in Aging to Eliminate Health Disparities (ENGAGED) program takes advantage of the broad, multidisciplinary research established in the area of aging at Wake Forest University School of Medicine and its partner institutions, Wake Forest University and Winston-Salem State University. The ENGAGED program is designed to provide undergraduate students who are underrepresented in the biomedical sciences an opportunity to participate in educational and research training in aging and health disparities. Funded since August 2019, ENGAGED has provided 73 academic year internships and 46 summer internships, with another 8 internships starting in Fall 2023. A total of 61 students (67% female, 64% African American, 21% Hispanic) have participated in the ENGAGED program, reflecting the fact that 49% participate in more than one session or program offering. To date, 38 of the ENGAGED trainees have graduated (100% with a science, technology, engineering, or math degree), 84% of whom are working or pursuing advanced degrees in the biomedical sciences. Given the unique strengths, existing infrastructure, and long-standing collaborations among the partner institutions, the ENGAGED program is helping advance diversity in aging and health disparities research by creating a pipeline for well-trained underrepresented students interested in biomedical research careers.

Deficiency in the adipose-derived hormone leptin or leptin receptor signaling causes class 3 obesity in individuals with genetic loss-of-function mutations in leptin or its receptor LEPR and metabolic and liver disease in individuals with hypoleptinemia secondary to lipoatrophy such as in individuals with generalized lipodystrophy. Therapies that restore leptin-LEPR signaling may resolve these metabolic sequelae. We developed a fully human monoclonal antibody (mAb), REGN4461 (mibavademab), that activates the human LEPR in the absence or presence of leptin. In obese leptin knockout mice, REGN4461 normalized body weight, food intake, blood glucose, and insulin sensitivity. In a mouse model of generalized lipodystrophy, REGN4461 alleviated hyperphagia, hyperglycemia, insulin resistance, dyslipidemia, and hepatic steatosis. In a phase 1, randomized, double-blind, placebo-controlled two-part study, REGN4461 was well tolerated with an acceptable safety profile. Treatment of individuals with overweight or obesity with REGN4461 decreased body weight over 12 weeks in those with low circulating leptin concentrations (<8 ng/ml) but had no effect on body weight in individuals with higher baseline leptin. Furthermore, compassionate-use treatment of a single patient with atypical partial lipodystrophy and a history of undetectable leptin concentrations associated with neutralizing antibodies to metreleptin was associated with noteable improvements in circulating triglycerides and hepatic steatosis. Collectively, these translational data unveil an agonist LEPR mAb that may provide clinical benefit in disorders associated with relatively low leptin concentrations.

Importance: Scoring systems for Stevens-Johnson syndrome and epidermal necrolysis (EN) only estimate patient prognosis and are weighted toward comorbidities and systemic features; morphologic terminology for EN lesions is inconsistent., Objectives: To establish consensus among expert dermatologists on EN terminology, morphologic progression, and most-affected sites, and to build a framework for developing a skin-directed scoring system for EN., Evidence Review: A Delphi consensus using the RAND/UCLA appropriateness criteria was initiated with a core group from the Society of Dermatology Hospitalists to establish agreement on the optimal design for an EN cutaneous scoring instrument, terminology, morphologic traits, and sites of involvement., Findings: In round 1, the 54 participating dermatology hospitalists reached consensus on all 49 statements (30 appropriate, 3 inappropriate, 16 uncertain). In round 2, they agreed on another 15 statements (8 appropriate, 7 uncertain). There was consistent agreement on the need for a skin-specific instrument; on the most-often affected skin sites (head and neck, chest, upper back, ocular mucosa, oral mucosa); and that blanching erythema, dusky erythema, targetoid erythema, vesicles/bullae, desquamation, and erosions comprise the morphologic traits of EN and can be consistently differentiated., Conclusions and Relevance: This consensus exercise confirmed the need for an EN skin-directed scoring system, nomenclature, and differentiation of specific morphologic traits, and identified the sites most affected. It also established a baseline consensus for a standardized EN instrument with consistent terminology.

Objective: In antiphospholipid antibody (aPL) nephropathy, activation of the mammalian target of rapamycin (mTOR) contributes to endothelial cell proliferation, a key finding of aPL microvascular disease. Here, we examined mTOR activation in the skin of aPL-positive patients with livedo., Methods: Three patient groups with livedo were studied: (1) persistently aPL-positive with systemic lupus erythematosus (SLE); (2) persistently aPL-positive without SLE; and (3) aPL-negative SLE (control). After collecting aPL-related medical history, two 5-mm skin biopsies of livedo were performed on each patient: (1) peripheral (erythematous-violaceous lesion); and (2) central (nonviolaceous area). We stained specimens for phosphorylated protein kinase B (p-AKT) and phosphorylated S6 ribosomal protein (p-S6RP) as mTOR activity markers, CD31 to identify endothelial cells, and Ki-67 to show cellular proliferation. We counted cells in the epidermis and compared mTOR-positive cell counts between peripheral and central samples, and between patient groups, using Freidman test and Wilcoxon signed-rank test., Results: Ten patients with livedo reticularis were enrolled: 4 aPL-positive without SLE (antiphospholipid syndrome [APS] classification met, n = 3), 4 aPL-positive SLE (APS classification met, n = 3), and 2 aPL-negative SLE (control). In all aPL-positive patients, epidermal p-AKT and p-S6RP staining were significantly increased in both peripheral and central skin samples when compared to aPL-negative SLE controls; both were more pronounced in the lower basal layers of epidermis., Conclusion: Our study demonstrates increased mTOR activity in livedoid lesions of aPL-positive patients with or without SLE compared to aPL-negative patients with SLE, with more prominent activity in the lower basal layers of the epidermis. These findings may serve as a basis for further investigating the mTOR pathway in aPL-positive patients., (Copyright © 2022 by the Journal of Rheumatology.)

Apart from autopsy, tissue correlates of coronavirus disease 2019 (COVID-19) clinical stage are lacking. In the current study, cutaneous punch biopsy specimens of 15 individuals with severe/critical COVID-19 and six with mild/moderate COVID-19 were examined. Evidence for arterial and venous microthrombi, deposition of C5b-9 and MASP2 (representative of alternative and lectin complement pathways, respectively), and differential expression of interferon type I-driven antiviral protein MxA (myxovirus resistance A) versus SIN3A, a promoter of interferon type I-based proinflammatory signaling, were assessed. Control subjects included nine patients with sepsis-related acute respiratory distress syndrome (ARDS) and/or acute kidney injury (AKI) pre-COVID-19. Microthrombi were detected in 13 (87%) of 15 patients with severe/critical COVID-19 versus zero of six patients with mild/moderate COVID-19 (P < 0.001) and none of the nine patients with pre-COVID-19 ARDS/AKI (P < 0.001). Cells lining the microvasculature staining for spike protein of severe acute respiratory syndrome coronavirus 2, the etiologic agent of COVID-19, also expressed tissue factor. C5b-9 deposition occurred in 13 (87%) of 15 patients with severe/critical COVID-19 versus zero of six patients with mild/moderate COVID-19 (P < 0.001) and none of the nine patients with pre-COVID-19 ARDS/AKI (P < 0.001). MASP2 deposition was also restricted to severe/critical COVID-19 cases. MxA expression occurred in all six mild/moderate versus two (15%) of 13 severe/critical cases (P < 0.001) of COVID-19. In contrast, SIN3A was restricted to severe/critical COVID-19 cases co-localizing with severe acute respiratory syndrome coronavirus 2 spike protein. SIN3A was also elevated in plasma of patients with severe/critical COVID-19 versus control subjects (P ≤ 0.02). In conclusion, the study identified premortem tissue correlates of COVID-19 clinical stage using skin. If validated in a longitudinal cohort, this approach could identify individuals at risk for disease progression and enable targeted interventions., (Copyright © 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: To determine whether primitive reflexes serve as an indicator of dementia in adults with Down syndrome (DS), we collected neurologic examination data, cognitive and behavioral assessments, and clinical consensus diagnoses of dementia from 92 adults with DS., Methods: In a cross-sectional, observational study of a regional cohort, χ 2 and Fisher exact tests examined individual reflexes across the diagnostic group (no, possible, or probable dementia). In 64 participants with all 8 reflexes assessed, the number of primitive reflexes was assessed as a predictor of diagnosis using age-controlled multinomial logistic regression and of performance on clinical assessments (Brief Praxis Test [BPT], Severe Impairment Battery [SIB], and the Dementia Questionnaire for People with Learning Disabilities [DLD]) using age-adjusted linear regression., Results: Primitive palmomental, grasp, snout, and suck reflexes were more frequent in individuals with probable dementia, but all participants showed at least 1 primitive reflex. Multiple primitive reflexes in combination served as a better indicator of dementia, with each additional abnormal reflex tripling probability of the probable dementia group membership controlling for age. Abnormal reflex count was not associated with direct assessment of cognition and praxis (SIB and BPT) but associated with informant ratings of cognitive and behavioral functioning (DLD)., Discussion: The presence of multiple reflexes serves as an indicator of dementia status in DS as a supplement to direct assessment of cognition and praxis. The reflex examination may serve as a tool in the multimethod evaluation for dementia in DS, as it appears unaffected by intellectual disability and language mastery., (© 2021 American Academy of Neurology.)

Background: Individuals with Down syndrome (DS) are at high risk for dementia, specifically Alzheimer's disease. However, many measures regularly used for the detection of dementia in the general population are not suitable for individuals with DS due in part to floor effects. Some measures, including the Severe Impairment Battery (SIB), Brief Praxis Test (BPT) and Dementia Scale for People with Learning Disabilities (DLD), have been used in clinical trials and other research with this population. Validity research is limited, particularly regarding the use of such tools for detection of prodromal dementia in the DS population. The current project presents baseline cross-sectional SIB, BPT and DLD performance in order to characterise their predictive utility in discriminating normal cognition, possible dementia and probable dementia in adult DS., Method: Baseline SIB, BPT and DLD performances from 100 individuals (no dementia = 68, possible dementia = 16 & probable dementia = 16) were examined from a longitudinal cohort of aging individuals with DS. Receiver operating characteristic curves investigated the accuracy of these measures in relation to consensus dementia diagnoses, diagnoses which demonstrated high percent agreement with the examining neurologist's independent diagnostic impression., Results: The SIB and BPT exhibited fair discrimination ability for differentiating no/possible versus probable dementia [area under the curve (AUC) = 0.61 and 0.66, respectively]. The DLD exhibited good discrimination ability for differentiating no versus possible/probable dementia (AUC = 0.75) and further demonstrated better performance of the DLD Cognitive subscale compared with the DLD Social subscale (AUC = 0.77 and 0.67, respectively)., Conclusions: Results suggest that the SIB, BPT and DLD are able to reasonably discriminate consensus dementia diagnoses in individuals with DS, supporting their continued use in the clinical assessment of dementia in DS. The general performance of these measures suggests that further work in the area of test development is needed to improve on the AUCs for dementia status discrimination in this unique population. At present, however, the current findings suggest that the DLD may be the best option for reliable identification of prodromal dementia in this population, reinforcing the importance of including informant behaviour ratings in assessment of cognition for adults with DS., (© 2021 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), is a single-stranded RNA virus whose sequence is known. COVID-19 is associated with a heterogeneous clinical phenotype ranging from asymptomatic to fatal disease. It appears that access to nasopharyngeal respiratory epithelia expressing angiotensin-converting enzyme (ACE) 2, the receptor for SARS-CoV-2, is followed by viral replication in the pulmonary alveolar septal capillary bed. We have demonstrated in earlier studies that incomplete viral particles, termed pseudovirions, dock to deep subcutaneous and other vascular beds, potentially contributing to the prothrombotic state and systemic complement activation that characterizes severe and critical COVID-19. A variety of skin eruptions have been described in the setting of SARS-CoV-2 infection and more recently, after COVID-19 vaccination. The vaccines deliver a laboratory-synthesized mRNA that encodes a protein that is identical to the spike glycoprotein of SARS-CoV-2, allowing the production of immunogenic spike glycoprotein that will then elicit T cell and B cell adaptive immune responses. In this contribution, we review an array of cutaneous manifestations of COVID-19 that provide an opportunity to study critical pathophysiologic mechanisms that underlie all clinical facets of COVID-19, ranging from asymptomatic/mild to severe and critical COVID-19. We classify cutaneous COVID-19 according to underlying pathophysiologic principles. In this regard we propose three main pathways: (1) complement mediated thrombotic vascular injury syndromes deploying the alternative and mannan binding lectin pathways and resulting in the elaboration of cytokines like interleukin 6 from endothelium in the setting of severe and critical COVID-19 and (2) the robust T cell and type I interferon-driven inflammatory and (3) humoral-driven immune complex mediated vasculitic cutaneous reactions observed with mild and moderate COVID-19. Presented are novel data on cutaneous vaccine reactions that manifest a clinical and morphologic parallel with similar eruptions observed in patients with mild and moderate COVID-19 and in some cases represent systemic eczematoid hypersensitivity reactions to a putative vaccine-based antigen versus unmasking subclinical hypersensitivity due to immune enhancing effects of the vaccine. Finally, we demonstrate for the first time the localization of human synthesized spike glycoprotein after the COVID-19 vaccine to the cutaneous and subcutaneous vasculature confirming the ability of SARS-CoV-2 spike glycoprotein to bind endothelium in the absence of intact virus., (Published by Elsevier Inc.)

Cutaneous findings have increasingly been reported in patients with coronavirus disease 2019 (COVID-19). This review discusses associated skin findings in patients with COVID-19 in the inpatient setting, ranging from vasculopathy-related lesions associated with high hospitalization rate and poor prognosis to inflammatory vesicular and urticarial eruptions that are rarely associated with prolonged hospitalization. We also discuss other reported COVID-19 cutaneous manifestations such as Sweet's syndrome, purpuric eruptions, and Multisystem Inflammatory Syndrome in Children. Although the relationship between dermatologic changes and COVID-19 disease progression is not fully elucidated, familiarity with cutaneous manifestations is valuable for physicians caring for patients hospitalized with COVID-19 and may help improve disease recognition and care., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Patient outcomes are improved when dermatologists provide inpatient consultations. Inpatient access to dermatologists is limited, illustrating an opportunity to use teledermatology. Little is known about the ability of dermatologists to accurately diagnose disease and manage inpatients with teledermatology, particularly when using nondermatologist-generated clinical data., Methods: This prospective study assessed the ability of teledermatology to diagnose disease and manage 41 dermatology consultations from a large urban tertiary care center, using internal medicine referral documentation and photographs. Twenty-seven dermatology hospitalists were surveyed. Interrater agreement was assessed by the κ statistic., Results: There was substantial agreement between in-person and teledermatology assessment of the diagnosis with differential diagnosis (median κ = 0.83), substantial agreement in laboratory evaluation decisions (median κ = 0.67), almost perfect agreement in imaging decisions (median κ = 1.0), and moderate agreement in biopsy decisions (median κ = 0.43). There was almost perfect agreement in treatment (median κ = 1.0), but no agreement in follow-up planning (median κ = 0.0). There was no association between raw photograph quality and the primary plus differential diagnosis or primary diagnosis alone., Limitations: Selection bias and single-center nature., Conclusions: Teledermatology may be effective in the inpatient setting, with concordant diagnosis, evaluation, and management decisions., (Copyright © 2020. Published by Elsevier Inc.)

Cutaneous manifestations of COVID-19-SARS-CoV-2-are common and varied. Morbilliform, vesicular, and urticarial eruptions may be nonspecific initial features of the disease. Chilblainlike lesions on the fingers or toes typically occur as part of a resolution phase, signifying a milder course, whereas livedoid lesions and retiform purpura are associated with coaguloapthy and more severe disease. Additionally, a severe Kawasaki-like multisystem inflammatory syndrome rarely is seen in children. This diverse range of cutaneous manifestations in COVID-19 reflects a spectrum of host immunologic responses to SARS-CoV-2 and may inform disease pathophysiology.

Background: There are two distinctive acral manifestations of COVID-19 embodying disparate clinical phenotypes. One is perniosis occurring in mildly symptomatic patients, typically children and young adults; the second is the thrombotic retiform purpura of critically ill adults with COVID-19., Objectives: To compare the clinical and pathological profiles of these two different cutaneous manifestations of COVID-19., Methods: We compared the light microscopic, phenotypic, cytokine and SARS-CoV-2 protein and RNA profiles of COVID-19-associated perniosis with that of thrombotic retiform purpura in critical patients with COVID-19., Results: Biopsies of COVID-19-associated perniosis exhibited vasocentric and eccrinotropic T-cell- and monocyte-derived CD11c + , CD14 + and CD123 + dendritic cell infiltrates. Both COVID-associated and idiopathic perniosis showed striking expression of the type I interferon-inducible myxovirus resistance protein A (MXA), an established marker for type I interferon signalling in tissue. SARS-CoV-2 RNA, interleukin-6 and caspase 3 were minimally expressed and confined to mononuclear inflammatory cells. The biopsies from livedo/retiform purpura showed pauci-inflammatory vascular thrombosis without any MXA decoration. Blood vessels exhibited extensive complement deposition with endothelial cell localization of SARS-CoV-2 protein, interleukin-6 and caspase 3; SARS-CoV-2 RNA was not seen., Conclusions: COVID-19-associated perniosis represents a virally triggered exaggerated immune reaction with significant type I interferon signaling. This is important to SARS-CoV-2 eradication and has implications in regards to a more generalized highly inflammatory response. We hypothesize that in the thrombotic retiform purpura of critically ill patients with COVID-19, the vascular thrombosis in the skin and other organ systems is associated with a minimal interferon response. This allows excessive viral replication with release of viral proteins that localize to extrapulmonary endothelium and trigger extensive complement activation., (© 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

The purpose of this study was to examine the deltoid skin biopsy in twenty-three patients with coronavirus disease 2019 (COVID-19), most severely ill, for vascular complement deposition and correlate this with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA and protein localization and ACE2 expression. Deltoid skin microvascular complement screening has been applied to patients with various systemic complement-mediated microvascular syndromes, best exemplified by atypical hemolytic uremic syndrome. In 21 of 23 cases, substantial microvascular deposition of complement components was identified. The two patients without significant complement deposition included one patient with moderate disease and a severely ill patient who although on a ventilator for a day was discharged after 3 days. The dominant microvascular complement immunoreactant identified was the terminal membranolytic attack complex C5b-9. Microvascular complement deposition strongly colocalized in situ with the SARS-CoV-2 viral proteins including spike glycoproteins in the endothelial cells as well as the viral receptor ACE2 in lesional and nonlesional skin; viral RNA was not evident. Microvascular SARS-CoV-2 viral protein, complement, and ACE2 expression was most conspicuous in the subcutaneous fat. Although the samples from severely ill patients with COVID-19 were from grossly normal skin, light microscopically focal microvascular abnormalities were evident that included endothelial cell denudement, basement membrane zone reduplication, and small thrombi. It is concluded that complement activation is common in grossly normal skin, especially in the subcutaneous fat which may provide a link between severe disease and obesity, in people with severe COVID-19, and the strong colocalization with the ACE2 receptor and viral capsid proteins without viral RNA suggests that circulating viral proteins (ie, pseudovirions) may dock onto the endothelial of these microvessels and induce complement activation., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Early detection of dementia symptoms is critical in Down syndrome (DS) but complicated by clinical assessment barriers. The current study aimed to characterize cognitive and behavioral impairment using longitudinal trajectories comparing several measures of cognitive and behavioral functioning., Methods: Measures included global cognitive status (Severe Impairment Battery [SIB]), motor praxis (Brief Praxis Test [BPT]), and clinical dementia informant ratings (Dementia Questionnaire for People with Learning Disabilities [DLD]). One-year reliability was assessed using a two-way mixed effect, consistency, single measurement intraclass correlation among non-demented participants. Longitudinal assessment of SIB, BPT, and DLD was completed using linear mixed effect models., Results: One-year reliability (n = 52; 21 male) was moderate for DLD (0.69 to 0.75) and good for SIB (0.87) and BPT (0.80). Longitudinal analysis (n = 72) revealed significant age by diagnosis interactions for SIB ( F (2, 115.02) = 6.06, P = .003), BPT ( F (2, 85.59) = 4.56, P = .013), and DLD ( F (2, 103.56) = 4.48, P = .014). SIB progression (PR) had a faster decline in performance versus no-dementia (ND) (t(159) = -2.87; P = .013). Dementia had a faster decline in BPT performance versus ND (t(112) = -2.46; P = .041). PR showed quickly progressing scores compared to ND (t(128) = -2.86; P = .014)., Discussion: Current measures demonstrated moderate to good reliability. Longitudinal analysis revealed that SIB, BPT, and DLD changed with age depending on diagnostic progression; no change rates were dependent on baseline cognition, indicating usefulness across a variety of severity levels in DS., Competing Interests: The authors have no conflicts of interest to declare., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Dermatologists treating immune-mediated skin disease must now contend with the uncertainties associated with immunosuppressive use in the context of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Although the risk of infection with many commonly used immunosuppressive agents remains low, direct data evaluating the safety of such agents in coronavirus disease 2019 (COVID-19) are scarce. This article reviews and offers guidance based on currently available safety data and the most recent COVID-19 outcome data in patients with immune-mediated dermatologic disease. The interdisciplinary panel of experts emphasizes a stepwise, shared decision-making approach in the management of immunosuppressive therapy. The goal of this article is to help providers minimize the risk of disease flares while simultaneously minimizing the risk of iatrogenic harm during an evolving pandemic., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Coronavirus disease 2019 (COVID-19) has associated cutaneous manifestations., Objective: To characterize the diversity of cutaneous manifestations of COVID-19 and facilitate understanding of the underlying pathophysiology., Methods: Case series from an international registry from the American Academy of Dermatology and International League of Dermatological Societies., Results: The registry collected 716 cases of new-onset dermatologic symptoms in patients with confirmed/suspected COVID-19. Of the 171 patients in the registry with laboratory-confirmed COVID-19, the most common morphologies were morbilliform (22%), pernio-like (18%), urticarial (16%), macular erythema (13%), vesicular (11%), papulosquamous (9.9%), and retiform purpura (6.4%). Pernio-like lesions were common in patients with mild disease, whereas retiform purpura presented exclusively in ill, hospitalized patients., Limitations: We cannot estimate incidence or prevalence. Confirmation bias is possible., Conclusions: This study highlights the array of cutaneous manifestations associated with COVID-19. Many morphologies were nonspecific, whereas others may provide insight into potential immune or inflammatory pathways in COVID-19 pathophysiology., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Respiratory failure and acute kidney injury (AKI) are associated with high mortality in SARS-CoV-2-associated Coronavirus disease 2019 (COVID-19). These manifestations are linked to a hypercoaguable, pro-inflammatory state with persistent, systemic complement activation. Three critical COVID-19 patients recalcitrant to multiple interventions had skin biopsies documenting deposition of the terminal complement component C5b-9, the lectin complement pathway enzyme MASP2, and C4d in microvascular endothelium. Administration of anti-C5 monoclonal antibody eculizumab led to a marked decline in D-dimers and neutrophil counts in all three cases, and normalization of liver functions and creatinine in two. One patient with severe heart failure and AKI had a complete remission. The other two individuals had partial remissions, one with resolution of his AKI but ultimately succumbing to respiratory failure, and another with a significant decline in FiO 2 requirements, but persistent renal failure. In conclusion, anti-complement therapy may be beneficial in at least some patients with critical COVID-19., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Acute respiratory failure and a systemic coagulopathy are critical aspects of the morbidity and mortality characterizing infection with severe acute respiratory distress syndrome-associated coronavirus-2, the etiologic agent of Coronavirus disease 2019 (COVID-19). We examined skin and lung tissues from 5 patients with severe COVID-19 characterized by respiratory failure (n= 5) and purpuric skin rash (n = 3). COVID-19 pneumonitis was predominantly a pauci-inflammatory septal capillary injury with significant septal capillary mural and luminal fibrin deposition and permeation of the interalveolar septa by neutrophils. No viral cytopathic changes were observed and the diffuse alveolar damage (DAD) with hyaline membranes, inflammation, and type II pneumocyte hyperplasia, hallmarks of classic acute respiratory distress syndrome, were not prominent. These pulmonary findings were accompanied by significant deposits of terminal complement components C5b-9 (membrane attack complex), C4d, and mannose binding lectin (MBL)-associated serine protease (MASP)2, in the microvasculature, consistent with sustained, systemic activation of the complement pathways. The purpuric skin lesions similarly showed a pauci-inflammatory thrombogenic vasculopathy, with deposition of C5b-9 and C4d in both grossly involved and normally-appearing skin. In addition, there was co-localization of COVID-19 spike glycoproteins with C4d and C5b-9 in the interalveolar septa and the cutaneous microvasculature of 2 cases examined. In conclusion, at least a subset of sustained, severe COVID-19 may define a type of catastrophic microvascular injury syndrome mediated by activation of complement pathways and an associated procoagulant state. It provides a foundation for further exploration of the pathophysiologic importance of complement in COVID-19, and could suggest targets for specific intervention., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In this report, we investigated the hexopyranose chemical modification Altriol Nucleic Acid (ANA) within small interfering RNA (siRNA) duplexes that were otherwise fully modified with the 2'-deoxy-2'-fluoro and 2'-O-methyl pentofuranose chemical modifications. The siRNAs were designed to silence the transthyretin (Ttr) gene and were conjugated to a trivalent N-acetylgalactosamine (GalNAc) ligand for targeted delivery to hepatocytes. Sense and antisense strands of the parent duplex were synthesized with single ANA residues at each position on the strand, and the resulting siRNAs were evaluated for their ability to inhibit Ttr mRNA expression in vitro. Although ANA residues were detrimental at the 5' end of the antisense strand, the siRNAs with ANA at position 6 or 7 in the seed region had activity comparable to the parent. The siRNA with ANA at position 7 in the seed region was active in a mouse model. An Oligonucleotide with ANA at the 5' end was more stable in the presence of 5'-exonuclease than an oligonucleotide of the same sequence and chemical composition without the ANA modification. Modeling studies provide insight into the origins of regiospecific changes in potency of siRNAs and the increased protection against 5'-exonuclease degradation afforded by the ANA modification., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Retiform purpura is a specific morphology within the spectrum of reticulate eruptions of vascular origin. It develops when blood vessels serving the skin are compromised resulting in downstream cutaneous ischemia, purpura, and necrosis. Identifying retiform purpura is important particularly in the acutely ill patient. It may elucidate the underlying diagnosis, provide prognostic information, and suggest a treatment approach. The differential diagnosis of retiform purpura is vast, reflecting the myriad conditions that can lead to cutaneous vessel wall damage or lumen occlusion. In this article, we give an overview of the differential diagnosis of this cutaneous morphology, provide an approach to workup, and highlight updates in treatment of some of the more common conditions that manifest as retiform purpura., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

In this article we focus on updates in select etiologies of retiform purpura. These causes of retiform purpura, in addition to bacterial or fungal sepsis, disseminated intravascular coagulation, purpura fulminans, and catastrophic antiphospholipid syndrome, are important diagnoses with potential for morbidity and mortality. Important aspects in the pathophysiology, patient demographics and risk factors, updates in the diagnostic workup, histopathology, and treatment of these specific conditions are discussed., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Taste impairment is a common radiation-induced toxicity in head and neck cancer (HNC) patients acutely. However, data on the potential for recovery and the time dependent course of late taste impairment are limited., Materials and Methods: As part of an IRB-approved observational prospective study, HNC patients underwent serial surveys including the MD Anderson Symptom Inventory - Head and Neck module (MDASI-HN). For our analysis, we extracted MDASI-HN taste item results from oropharyngeal cancer patients treated with intensity-modulated radiotherapy or volumetric modulated arc therapy and at least two taste assessments after ≥1 year from end of radiotherapy (RT)., Results: 1214 MDASI taste items from 326 patients between 1 and 13 years post-RT were included. Median prescribed dose to the high-dose clinical target volume (CTV1) was 66.0 Gy, with 180 patients (55%) receiving chemotherapy. Taste markedly improved in the first years from end of RT, but plateaued after year 5. In patients with taste assessment in subsequent years, a significant reduction in taste impairment was found from the second to the third year (p = 0.001) and tended towards significance from the third to the fourth year (p = 0.058). Multivariate analysis revealed treatment site as significant factor in the sixth year from RT and CTV1 dose and age in the seventh year., Conclusion: Radiation-induced taste impairment may improve over an extended time interval, but becomes relatively stable from year 5 post-RT. Direct characterization of RT-induced taste impairment and the calculation of normal tissue complication probability should include consideration of the time-dependent course in taste recovery., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)

Purpose: To evaluate 2 published normal tissue complication probability models for radiation-induced hypothyroidism (RHT) on a large cohort of oropharyngeal carcinoma (OPC) patients who were treated with intensity-modulated radiation therapy (IMRT)., Methods and Materials: OPC patients treated with retrievable IMRT Digital Imaging and Communications in Medicine (DICOMs) data and available baseline and follow-up thyroid function tests were included. Mean dose (Dmean) to the thyroid gland (TG) and its volume were calculated. The study outcome was clinical HT at least 6 months after radiation therapy, which was defined as grade ≥2 HT per Common Terminology Criteria for Adverse Events grading system (symptomatic hypothyroidism that required thyroid replacement therapy). Regression analyses and Wilcoxon rank-sum test were used. Receiver operating characteristic curves and area under the curve for the fitted model were calculated., Results: In the study, 360 OPC patients were included. The median age was 58 years. Most tumors (51%) originated from the base of tongue. IMRT-split field was used in 95%, and median radiation therapy dose was 69.96 Gy. In the study, 233 patients (65%) developed clinical RHT that required thyroid replacement therapy. On multivariate analysis higher Dmean and smaller TG volume maintained the statistically significant association with the risk of clinical RHT ( P  < .0001). Dmean was significantly higher in patients with clinical RHT versus those without (50 vs 42 Gy, P  < .0001). Patients with RHT had smaller TG volume compared with those without (11.8 compared with 12.8 mL, P < .0001). AUC of 0.72 and 0.66 were identified for fitted model versus for the applied Boomsma et al and Cella et al models, respectively., Conclusions: Volume and Dmean of the TG are important predictors of clinical RHT and shall be integrated into normal tissue complication probability models for RHT. Dmean and thyroid volume should be considered during the IMRT plan optimization in OPC patients., (© 2019 The Author(s).)

Background: Readmissions for skin disease, particularly for the same diagnosis and over time, have not been well studied., Objective: To characterize hospital readmissions for skin disease., Methods: A cross-sectional observational study examined the Nationwide Readmissions Database from 2010 to 2014, a national sample of hospital discharges in the United States., Results: Of the patients in 3,602,599 dermatologic hospitalizations from 2010 to 2014, 9.8% were readmitted for any cause, 3.3% were admitted for the same diagnosis within 30 days, and 7.8% were readmitted for the same diagnosis within the calendar year (CY). The cost of all CY same-cause readmissions was $508 million per year. Mycosis fungoides had the highest 30-day all-cause readmission rate (32%), vascular hamartomas and dermatomyositis had the highest 30-day same-cause readmission rates (21% and 18%, respectively), and dermatomyositis and systemic lupus erythematosus had the highest CY same-cause readmission rates (31% and 24%, respectively). Readmission rates stayed stable from 2010 to 2014. Readmission for the same diagnosis was strongly associated with Medicaid and morbid obesity., Limitations: This study is a broad description of hospitalizations for skin disease. Conclusions for individual diseases are not intended., Conclusion: The rates and costs of readmissions for skin diseases remained high from 2010 to 2014. This study identifies diseases associated with high risk of hospital readmission, but disease-specific studies are needed. The diseases and risk factors presented should guide additional studies focused on strategies to reduce readmissions in specific skin diseases., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

The mechanism by which potassium ions are transported through ion channels is currently being investigated by several groups using many different techniques. Clarification of the location of water molecules during transport is central to understanding how these integral membrane proteins function. Neutrons have a unique sensitivity to both hydrogen and potassium, rendering neutron crystallography capable of distinguishing waters from K + ions. Here, the collection of a complete neutron data set from a potassium ion channel to a resolution of 3.55 Å using the Macromolecular Neutron Diffractometer (MaNDi) is reported. A room-temperature X-ray data set was also collected from the same crystal to a resolution of 2.50 Å. Upon further refinement, these results will help to further clarify the ion/water population within the selectivity filter of potassium ion channels.

The cutaneous manifestations of Crohn's disease are myriad. A 15-year-old girl presented with recurrent lip swelling and eventual development of diarrhea and targetoid macules on the palms, feet, and back. She was finally diagnosed with Crohn's disease in the setting of a clinical presentation and histopathology consistent with orofacial granulomatosis and erythema multiforme. We review the literature and summarize reported occurrences of these cutaneous diseases in children with Crohn's disease., (© 2018 Wiley Periodicals, Inc.)

Regenerative medicine is a novel discipline that both excites undergraduates and may be used as a vehicle to expose students to scientific concepts and opportunities. The goal of this article is to describe the implementation of a National Science Foundation-funded Targeted Infusion Project in which underrepresented minority undergraduates are exposed to laboratory-bench skills and summer research opportunities that they may not have encountered otherwise. A 3-wk infusion of laboratory-bench and data presentation skills, in the context of a regenerative medicine/bioengineering project, aimed to engage students and expose them to opportunities as summer researchers and teaching assistants. The infusion aimed to assess the extent to which students improved 1) attitudes toward laboratory-bench-based techniques, using attitudes toward science as a proxy; 2) perceptions of scientific inquiry; 3) intentions to engage in undergraduate research; and 4) intentions to persist in science, technology, engineering, and mathematics (STEM)-related fields. Results indicate that the 3-wk infusion had no effect on science attitudes, but transcribed responses to structured interviews administered after the summer research experience indicated that students who completed summer research projects had positive experiences. Differences in intentions to engage in research were detected between groups of students in different STEM majors, in addition to differences in intentions to pursue a career in science. We describe the implementation of the infusion and briefly discuss quantitative outcomes. We conclude that infusion of laboratory-bench modules in the context of a regenerative medicine/bioengineering project may play a small but important role in increasing (minority) participation and persistence in the STEM pipeline.

We designed novel 4'-modified 2'-deoxy-2'-fluorouridine (2'-F U) analogues with the aim to improve nuclease resistance and potency of therapeutic siRNAs by introducing 4'-C-methoxy (4'-OMe) as the alpha (C4'α) or beta (C4'β) epimers. The C4'α epimer was synthesized by a stereoselective route in six steps; however, both α and β epimers could be obtained by a nonstereoselective approach starting from 2'-F U. 1 H NMR analysis and computational investigation of the α-epimer revealed that the 4'-OMe imparts a conformational bias toward the North-East sugar pucker, due to intramolecular hydrogen bonding and hyperconjugation effects. The α-epimer generally conceded similar thermal stability as unmodified nucleotides, whereas the β-epimer led to significant destabilization. Both 4'-OMe epimers conferred increased nuclease resistance, which can be explained by the close proximity between 4'-OMe substituent and the vicinal 5'- and 3'-phosphate group, as seen in the X-ray crystal structure of modified RNA. siRNAs containing several C4'α-epimer monomers in the sense or antisense strands triggered RNAi-mediated gene silencing with efficiencies comparable to that of 2'-F U.

Tepsin is currently the only accessory trafficking protein identified in adaptor-related protein 4 (AP4)-coated vesicles originating at the trans-Golgi network (TGN). The molecular basis for interactions between AP4 subunits and motifs in the tepsin C-terminus have been characterized, but the biological role of tepsin remains unknown. We determined X-ray crystal structures of the tepsin epsin N-terminal homology (ENTH) and VHS/ENTH-like domains. Our data reveal unexpected structural features that suggest key functional differences between these and similar domains in other trafficking proteins. The tepsin ENTH domain lacks helix0, helix8 and a lipid binding pocket found in epsin1/2/3. These results explain why tepsin requires AP4 for its membrane recruitment and further suggest ENTH domains cannot be defined solely as lipid binding modules. The VHS domain lacks helix8 and thus contains fewer helices than other VHS domains. Structural data explain biochemical and biophysical evidence that tepsin VHS does not mediate known VHS functions, including recognition of dileucine-based cargo motifs or ubiquitin. Structural comparisons indicate the domains are very similar to each other, and phylogenetic analysis reveals their evolutionary pattern within the domain superfamily. Phylogenetics and comparative genomics further show tepsin within a monophyletic clade that diverged away from epsins early in evolutionary history (~1500 million years ago). Together, these data provide the first detailed molecular view of tepsin and suggest tepsin structure and function diverged away from other epsins. More broadly, these data highlight the challenges inherent in classifying and understanding protein function based only on sequence and structure., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Here we report the investigation of glycol nucleic acid (GNA), an acyclic nucleic acid analogue, as a modification of siRNA duplexes. We evaluated the impact of (S)- or (R)-GNA nucleotide incorporation on RNA duplex structure by determining three individual crystal structures. These structures indicate that the (S)-nucleotide backbone adopts a conformation that has little impact on the overall duplex structure, while the (R)-nucleotide disrupts the phosphate backbone and hydrogen bonding of an adjacent base pair. In addition, the GNA-T nucleobase adopts a rotated conformation in which the 5-methyl group points into the minor groove, rather than the major groove as in a normal Watson-Crick base pair. This observation of reverse Watson-Crick base pairing is further supported by thermal melting analysis of GNA-C and GNA-G containing duplexes where it was demonstrated that a higher thermal stability was associated with isoguanine and isocytosine base pairing, respectively, over the canonical nucleobases. Furthermore, it was also shown that GNA nucleotide or dinucleotide incorporation increases resistance against snake venom phosphodiesterase. Consistent with the structural data, modification of an siRNA with (S)-GNA resulted in greater in vitro potencies over identical sequences containing (R)-GNA. A walk of (S)-GNA along the guide and passenger strands of a GalNAc conjugate duplex targeting mouse transthyretin (TTR) indicated that GNA is well tolerated in the seed region of both strands in vitro, resulting in an approximate 2-fold improvement in potency. Finally, these conjugate duplexes modified with GNA were capable of maintaining in vivo potency when subcutaneously injected into mice.

Hydralazine-induced small vessel vasculitis is a rare entity with a limited number of cases reported in the dermatologic literature. A characteristic pattern of acral pseudoembolic vesiculopustules with necrosis and ulceration has been suggested along with involvement of the aerodigestive tract, indicating mucosal involvement is an important feature of this disease. We report the case of a patient with hydralazine-induced vasculitis who exemplified this characteristic presentation associated with severe involvement of the aerodigestive tract and gastrointestinal tract bleeding. In addition to the distinctive clinical presentation, the patient's workup revealed the characteristic antineutrophil cytoplasmic antibody (ANCA)-positive serologic profile. Increased recognition of the clinical and serological features of hydralazine-induced small vessel vasculitis may lead to earlier recognition of this disease and decreased time to discontinuation of hydralazine when appropriate. Drug withdrawal is the cornerstone of therapy, and depending on the severity of symptoms, additional immunosuppressive treatment such as corticosteroids may be necessary.

Genetic disruption or pharmacologic inhibition of glucagon signaling effectively lowers blood glucose but results in compensatory glucagon hypersecretion involving expansion of pancreatic α-cell mass. Ben-Zvi et al. recently reported that angiopoietin-like protein 4 (Angptl4) links glucagon receptor inhibition to hyperglucagonemia and α-cell proliferation [Ben-Zvi et al. (2015) Proc Natl Acad Sci USA 112:15498-15503]. Angptl4 is a secreted protein and inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. We report that Angptl4 -/- mice treated with an anti-glucagon receptor monoclonal antibody undergo elevation of plasma glucagon levels and α-cell expansion similar to wild-type mice. Overexpression of Angptl4 in liver of mice caused a 8.6-fold elevation in plasma triglyceride levels, but did not alter plasma glucagon levels or α-cell mass. Furthermore, administration of glucagon receptor-blocking antibody to healthy individuals increased plasma glucagon and amino acid levels, but did not change circulating Angptl4 concentration. These data show that Angptl4 does not link glucagon receptor inhibition to compensatory hyperglucagonemia or expansion of α-cell mass, and that it cannot be given to induce such secretion and growth. The reduction of plasma triglyceride levels in Angptl4 -/- mice and increase following Angptl4 overexpression suggest that changes in plasma triglyceride metabolism do not regulate α-cells in the pancreas. Our findings corroborate recent data showing that increased plasma amino acids and their transport into α-cells link glucagon receptor blockage to α-cell hyperplasia.

Objective: To present a heuristic model of a symptom attribution and classification algorithm (SACA) for mild traumatic brain injury (mTBI)., Setting: VA Polytrauma sites., Participants: 422 Veterans., Design: Cross-sectional., Main Measures: SACA, Comprehensive TBI Evaluation (CTBIE), Structured TBI Diagnostic Interview, Minnesota Multiphasic Personality Inventory (MMPI-2-RF), Letter Memory Test, Validity-10., Results: SACA and CTBIE diagnoses differ significantly (P < .01). The CTBIE, compared with SACA, attributes 16% to 500% more symptoms to mTBI, behavioral health (BH), mTBI + BH and symptom resolution. Altering SACA criteria indicate that (1) CTBIE determination of cognitive impairment yields 27% to 110% more mTBI, mTBI + BH and symptom resolution diagnoses, (2) ignoring timing of symptom onset yields 32% to 76% more mTBI, mTBI + BH and Other Condition diagnoses, (3) Proportion of sample having questionably valid profiles using structured TBI diagnostic interview and MMPI-2-RF and Letter Memory Test is 26% whereas with CTBIE item number 23 and Validity-10 is 6% to 26%, (4) MMPI-2-RF F-scale is the only measure identifying Veterans with posttraumatic amnesia for more than 24 hours as having questionably valid profiles., Conclusions: Symptom attribution-based diagnoses differ when using status quo versus the SACA. The MMPI-2-RF F-scale, compared with the Validity-10 and Letter Memory Test, may be more precise in identifying questionably valid profiles for mTBI + BH. The SACA provides a framework to inform clinical practice, resource allocation, and future research.

Hyperglycaemia is commonly observed on admission and during hospitalization for medical illness, traumatic injury, burn and surgical intervention. This transient hyperglycaemia is referred to as stress-induced hyperglycaemia (SIH) and frequently occurs in individuals without a history of diabetes. SIH has many of the same underlying hormonal disturbances as diabetes mellitus, specifically absolute or relative insulin deficiency and glucagon excess. SIH has the added features of elevated blood levels of catecholamines and cortisol, which are not typically present in people with diabetes who are not acutely ill. The seriousness of SIH is highlighted by its greater morbidity and mortality rates compared with those of hospitalized patients with normal glucose levels, and this increased risk is particularly high in those without pre-existing diabetes. Insulin is the treatment standard for SIH, but new therapies that reduce glucose variability and hypoglycaemia are desired. In the present review, we focus on the key role of glucagon in SIH and discuss the potential use of glucagon receptor blockers and glucagon-like peptide-1 receptor agonists in SIH to achieve target glucose control., (© 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Although judicious use of chemical modifications has contributed to the success of nucleic acid therapeutics, poor systemic stability remains a major hurdle. The introduction of functional groups around the phosphate backbone can enhance the nuclease resistance of oligonucleotides (ONs). Here, we report the synthesis of enantiomerically pure (R)- and (S)-5'-C-methyl (C5'-Me) substituted nucleosides and their incorporation into ONs. These modifications generally resulted in a decrease in thermal stability of oligonucleotide (ON) duplexes in a manner dependent on the stereoconfiguration at C5' with greater destabilization characteristic of (R)-epimers. Enhanced stability against snake venom phosphodiesterase resulted from modification of the 3'-end of an ON with either (R)- or (S)-C5'-Me nucleotides. The (S)-isomers with different 2'-substituents provided greater resistance against 3'-exonucleases than the corresponding (R)-isomers. Crystal structure analyses of RNA octamers with (R)- or (S)-5'-C-methyl-2'-deoxy-2'-fluorouridine [(R)- or (S)-C5'-Me-2'-FU, respectively] revealed that the stereochemical orientation of the C5'-Me and the steric effects that emanate from the alkyl substitution are the dominant determinants of thermal stability and are likely molecular origins of resistance against nucleases. X-ray and NMR structural analyses showed that the (S)-C5'-Me epimers are spatially and structurally more similar to their natural 5' nonmethylated counterparts than the corresponding (R)-epimers.

Antagonizing glucagon action represents an attractive therapeutic option for reducing hepatic glucose production in settings of hyperglycemia where glucagon excess plays a key pathophysiological role. We therefore generated REGN1193, a fully human monoclonal antibody that binds and inhibits glucagon receptor (GCGR) signaling in vitro. REGN1193 administration to diabetic ob/ob and diet-induced obese mice lowered blood glucose to levels observed in GCGR-deficient mice. In diet-induced obese mice, REGN1193 reduced food intake, adipose tissue mass, and body weight. REGN1193 increased circulating levels of glucagon and glucagon-like peptide 1 and was associated with reversible expansion of pancreatic α-cell area. Hyperglucagonemia and α-cell hyperplasia was observed in fibroblast growth factor 21-deficient mice treated with REGN1193. Single administration of REGN1193 to diabetic cynomolgus monkeys normalized fasting blood glucose and glucose tolerance and increased circulating levels of glucagon and amino acids. Finally, administration of REGN1193 for 8 weeks to normoglycemic cynomolgus monkeys did not cause hypoglycemia or increase pancreatic α-cell area. In summary, the GCGR-blocking antibody REGN1193 normalizes blood glucose in diabetic mice and monkeys but does not produce hypoglycemia in normoglycemic monkeys. Thus, REGN1193 provides a potential therapeutic modality for diabetes mellitus and acute hyperglycemic conditions.

Objective: The aim of this study was to describe the association between mild traumatic brain injury (mTBI) and persisting postconcussive symptoms according to symptom category, number, and severity., Design: The study design was observational., Participants: The study sample comprised veterans (≥18 years of age) deployed in Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) conflicts who had not received any treatment for mTBI in the 30 days preceding study enrollment., Methods: Veterans were interviewed and completed testing in a single day. The Standard TBI Diagnostic Interview and the Clinician-Administered PTSD Scale were used. Testing included the Neurobehavioral Symptom Inventory and a full neuropsychological battery. Gold standard classification methods were utilized to determine presence/absence of mTBI. For each of the 5 symptom outcomes, an adjusted multiple linear regression model (negative binomial count models) accounting for effects of socio-demographic variables and behavioral health conditions was used., Main Outcome Measures: Self-report of neurobehavioral symptoms categorized as affective, cognitive, somatic, and vestibular symptoms, in addition to the instruments specified above., Results: OEF/OIF veterans with mTBI, relative to veterans with no mTBI, were observed to have 30% more symptoms overall (P < .001), 34% more somatic symptoms (P < .001), 22% more cognitive symptoms (P = .008), 15% more affective symptoms (P = .017), and 59% more vestibular symptoms (P < .001). For adjusted models, variables significantly related to number of symptoms across all 4 symptom categories were anxiety (all P < .001) and insomnia (all P < .001). For the adjusted models, variables significantly related to symptom severity across all 4 symptom categories were insomnia (all P < .001), depression (P < .001-.05) and anxiety (all, P < .001)., Conclusions: OEF/OIF veterans with mTBI, relative to veterans with no mTBI, have significantly more and significantly more severe persisting symptoms, with vestibular symptoms reported with the greatest frequency. After accounting for behavioral health conditions and socio-demographic factors, OEF/OIF veterans with mTBI compared to veterans without mTBI had significantly more cognitive, affective, vestibular, and somatic symptoms persisting 4.8 years after the mTBI event(s)., (Copyright © 2015 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.)

The initiation of antiretroviral treatment for individuals with HIV may be accompanied by a paradoxical flare of underlying inflammatory diseases, the recurrence of dormant infections, or worsening of prior treated opportunistic infections, termed the immune reconstitution inflammatory syndrome (IRIS). Cutaneous manifestations of IRIS are common. Pyoderma gangrenosum is a neutrophilic dermatosis postulated to reflect disrupted innate immune regulation causing altered neutrophil chemotaxis. It is uncommonly reported in association with HIV. In this case series, we present three cases of IRIS manifesting with pyoderma gangrenosum in individuals with HIV from India and the United States to raise awareness of this previously undescribed presentation and discuss the treatment challenges in the management of these patients.

Importance: Cutaneous granulomas without an identifiable infectious etiology are a rare manifestation of primary immunodeficiency (ID). These cutaneous lesions can be misdiagnosed, often as sarcoidosis, when the skin findings precede the diagnosis of immunodeficiency., Objective: We present four cases from our institution and review the literature in order to emphasize the clinical relevance of this association, discuss the histologic and immunohistochemical features, and explore possible pathogenic mechanisms of granuloma formation., Evidence Review: We retrospectively reviewed case reports of all patients presenting with cutaneous granulomas in the setting of primary immunodeficiency. Cases with insufficient information to confirm an immunodeficiency state were excluded. Four patients from our clinic were included, for 54 total cases., Findings: The majority of cutaneous granulomas are seen in three types of immunodeficiencies: ataxia-telangiectasia, severe combined immunodeficiency, and combined variable immunodeficiency. Twenty-six percent of patients developed cutaneous granulomas prior to their immunodeficiency diagnosis. Histologically, various granulomatous patterns have been described. Immunohistochemistry revealed a CD4+/CD8+ lymphocyte ratio of less than or equal to 1 in our four patients, which may help differentiate cutaneous granulomas in primary ID from sarcoidal granulomas that typically show a CD4+ predominance., Conclusions and Relevance: Cutaneous granulomas are a rare manifestation of primary ID and occur predominantly in immunodeficiencies that affect T and B cell compartments., (© 2015 The International Society of Dermatology.)