High-speed polarization-independent plasmonic modulator on a silicon waveguide.

The electrical bandwidth of an electro-optic modulator plays a vital role in determining the throughput of an optical communications link. We propose a broadband plasmonic electro-optic modulator operating at telecommunications wavelengths (λ0 ∼ 1550 nm), based on free carrier dispersion in indium tin oxide (ITO). The ITO is driven through its epsilon-near-zero point within the accumulation layers of metal-oxide-semiconductor (MOS) structures. The MOS structures are integrated into a pair of coupled metal-insulator-metal (MIM) waveguides aligned on a planarized silicon waveguide. The coupled MIM waveguides support symmetric and asymmetric plasmonic supermodes, excited adiabatically using mode transformation tapers, by the fundamental TM0 and TE0 modes of the underlying silicon waveguide, respectively, such that the modulator can operate in either mode as selected by the input polarisation to the silicon waveguide. The modulator has an active section 1.5 to 2 µm long, enabling the modulator to operate as a lumped element to bandwidths exceeding 200 GHz (3 dB electrical, RC-limited). The modulators produce an extinction ratio in the range of 3.5 to 6 dB, and an insertion loss in the range of 4 to 7.5 dB including input/output mode conversion losses. The AC drive voltage is ±1.75 V. The devices comprise only inorganic materials and are realisable using standard deposition, etching and nanolithography techniques.

SOI-based compact mode- and polarization-division multiplexer for on-chip optical interconnects: design and simulation.

A compact seven-channel hybrid mode- and polarization-division multiplexer based on a silicon-on-insulator (SOI) waveguide platform is proposed for on-chip optical interconnects. Three independent signals are coupled into the TE0, TM0, and TE1 mode of a three moded waveguide using a taper, a polarization beam splitter, and an asymmetric directional coupler in the first coupler section. In the adiabatically connected second and third sections, two collocated asymmetric directional couplers are used to couple two TE modes (TE2, TE3) and two TM modes (TM1, TM2) to reduce the footprint of the device. A coupling length of ∼44.29µm is achieved with low insertion loss <0.09dB and crosstalk better than -30dB at the designed wavelength of 1.55 µm.

Preservation of Alveolar Ridge using Graft Material after Tooth Extraction: A Clinical Trial.

BACKGROUND: The alveolar process is a tooth-dependent structure, and hence, removal of teeth results in the alteration of alveolar process. To alter bone remodeling after dental extraction, various techniques have been put forward for ridge preservation. AIM: The aim of this study is to evaluate and compare the changes of hard and soft tissues in postextraction socket after the application of bone graft material. MATERIALS AND METHODS: Healthy patients of sample size of 40 were selected who underwent the extraction of anterior tooth irrespective of the arch, from premolar of one side to another, with the exception of incisors in mandible. Twenty patients were randomly selected as the control group and other 20 as the experimental group using an allograft bone material, i.e., beta-tricalcium phosphate to fill the socket. Cone-beam computed tomography (CBCT) was done as baseline preoperative and postoperative at 14 weeks after the extraction. CBCTs data help in recording linear and volumetric measurements which was performed by calibrated examiners to record all the measurements. After measurements, digital planning of dental implants was performed. RESULTS: Forty participants were selected, in which 20 patients each were as the experimental and control groups. No significant difference was found at basal line at any of the cases. At follow-up of 14 weeks, statistical significance was seen in buccal and lingual plate height in the experimental group, and no significant difference was seen in the control group.(P = 0.023). CONCLUSIONS: This study clearly points out that an alveolar ridge preservation technique provides therapeutic benefit by limiting bone resorption in comparison to extraction alone.

Health Care Inequities of Sexual and Gender Minority Patients.

Sexual and gender minority (SGM) individuals include, but are not limited to, those who identify as lesbian, gay, bisexual, transgender, and queer (LGBTQ). LGBTQ individuals are considered a marginalized and at-risk population, facing significant health care inequities when compared with heterosexual and cisgendered (ie, "gender-conforming") populations. They are more likely than heterosexual and cisgendered individuals to experience discrimination, bias, and dissatisfaction with the medical system. This article provides a broad overview of systemic inequalities confronting SGM patients.

Medical and aesthetic procedural dermatology recommendations for transgender patients undergoing transition.

Transgender individuals may transition to their identified gender through social, hormonal, and procedural methods by using a multidisciplinary team of health care providers, including dermatologists. In this review, we discuss the medical and aesthetic dermatologic needs related to the transitioning of transgender patients and provide therapeutic and procedural recommendations. In addition to routine cutaneous conditions, dermatologists may need to treat hormonal therapy-related complications. Acumen for genital dermatology and familiarity with gender reassignment surgery is important for the dermatologist caring for a transgender patient. From a structural standpoint, transgender beauty poses a unique aesthetic task. We identify key differences in the facial structure and physique of males versus those of females. Dermatologists may have a tremendous impact on the lives of transgender individuals who seek to realize their gender identity.

Contact Sensitization to Allergens in Nail Cosmetics.

Ingredients found in the nail cosmetic industry, including but not limited to methacrylate and acrylate monomers, formaldehyde, and toluene sulfonamide-formaldehyde resin, can incite allergic contact dermatitis. An eczematous outbreak presents on areas surrounding the nail plate and may spread through contact transfer of the allergen, commonly to the face and neck. Even components that were originally deemed nonsensitizing, such as the ubiquitous cyanoacrylate adhesive family, have been found to be allergenic. They do not, however, cross-react with methacrylates and acrylates. Alternative options for individuals with allergic contact dermatitis reactions to these ingredients can be avoidance of these procedures or use of products that are "3, 4, 5 free" in which the common allergens dibutyl phthalate, toluene, and formaldehyde are absent. In cases where strengthening of the nail is the sole purpose, nail wraps or preformed nails can be applied for non-cyanoacrylate-sensitive individuals.

An Integrated Model of Atopic Dermatitis Biomarkers Highlights the Systemic Nature of the Disease.

Current atopic dermatitis (AD) models link epidermal abnormalities in lesional skin to cytokine activation. However, there is evolving evidence of systemic immune activation and detectable abnormalities in nonlesional skin. Because some of the best single correlations with severity (Scoring of AD, or SCORAD) are detected not only in lesional but also nonlesional skin and blood, more complex biomarker models of AD are needed. We thus performed extensive biomarker measures in these compartments using univariate and multivariate approaches to correlate disease biomarkers with SCORAD and with a combined hyperplasia score [thickness and keratin 16 (K16) mRNA] at baseline and after cyclosporine A treatment in 25 moderate to severe AD patients. Increases in serum cytokines and chemokines (IL-13, IL-22, CCL17) were found in AD versus healthy individuals and were reduced with treatment. SCORAD correlated with immune (IL-13, IL-22) and epidermal (thickness, K16) measures in lesional and, even more strongly, in nonlesional AD. Serum cytokines also had higher correlations with nonlesional markers at baseline and with treatment. Multivariate U statistics improved baseline and treatment-response SCORAD correlations. Nonlesional models showed the strongest correlations, with further improvement upon integration of serum markers. Even better correlations were obtained between biomarkers and the hyperplasia score. Larger cohorts are needed to confirm these preliminary data.

Petrolatum: Barrier repair and antimicrobial responses underlying this "inert" moisturizer.

BACKGROUND: Petrolatum is a common moisturizer often used in the prevention of skin infections after ambulatory surgeries and as a maintenance therapy of atopic dermatitis (AD). However, the molecular responses induced by petrolatum in the skin have never been assessed. OBJECTIVE: We sought to define the cutaneous molecular and structural effects induced by petrolatum. METHODS: Thirty-six healthy subjects and 13 patients with moderate AD (mean SCORAD score, 39) were studied by using RT-PCR, gene arrays, immunohistochemistry, and immunofluorescence performed on control skin, petrolatum-occluded skin, and skin occluded with a Finn chamber only. RESULTS: Significant upregulations of antimicrobial peptides (S100A8/fold change [FCH], 13.04; S100A9/FCH, 11.28; CCL20/FCH, 8.36; PI3 [elafin]/FCH, 15.40; lipocalin 2/FCH, 6.94, human ß-defensin 2 [DEFB4A]/FCH, 4.96; P < .001 for all) and innate immune genes (IL6, IL8, and IL1B; P < .01) were observed in petrolatum-occluded skin compared with expression in both control and occluded-only skin. Application of petrolatum also induced expression of key barrier differentiation markers (filaggrin and loricrin), increased stratum corneum thickness, and significantly reduced T-cell infiltrates in the setting of "normal-appearing" or nonlesional AD skin, which is known to harbor barrier and immune defects. CONCLUSIONS: Petrolatum robustly modulates antimicrobials and epidermal differentiation barrier measures. These data shed light on the beneficial molecular responses of petrolatum in barrier-defective states, such as AD and postoperative wound care.

Patients with atopic dermatitis have attenuated and distinct contact hypersensitivity responses to common allergens in skin.

BACKGROUND: Atopic dermatitis (AD) is the most common inflammatory disease. The prevalence of allergic contact dermatitis to allergens (eg, fragrance) is higher in patients with AD, despite a trend toward weaker clinical allergic contact dermatitis reactions. The role of the AD skin phenotype in modulating allergic sensitization to common sensitizers has not been evaluated. OBJECTIVE: We sought to investigate whether patients with AD have altered tissue immune responses on allergen challenge. METHODS: Gene expression and immunohistochemistry studies were performed on biopsy specimens from 10 patients with AD and 14 patients without AD patch tested with common contact allergens (nickel, fragrance, and rubber). RESULTS: Although 1085 differentially expressed genes (DEGs) were commonly modulated in patch-tested skin from patients with AD and patients without AD versus control skin, 1185 DEGs were uniquely altered in skin from patients without AD, and only 246 DEGs were altered in skin from patients with AD. Although many inflammatory products (ie, matrix metalloproteinase 12/matrix metalloproteinase 1/S100A9) were upregulated in both groups, higher-magnitude changes and upregulation of interferon responses were evident only in the non-AD group. Stratification by allergen showed decreased expression of immune, TH1-subset, and TH2-subset genes in nickel-related AD responses, with increased TH17/IL-23 skewing. Rubber/fragrance showed similar trends of lesser magnitude. Negative regulators showed higher expression in patients with AD. CONCLUSIONS: Through contact sensitization, our study offers new insights into AD. Allergic immune reactions were globally attenuated and differentially polarized in patients with AD, with significant decreases in levels of TH1 products, some increases in levels of TH17 products, and inconsistent upregulation in levels of TH2 products. The overall hyporesponsiveness in skin from patients with background AD might be explained by baseline immune abnormalities, such as increased TH2, TH17, and negative regulator levels compared with those seen in non-AD skin.

Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis.

BACKGROUND: Severe atopic dermatitis (AD) has a high unmet need for effective and safe therapeutics. In early-phase trials, dupilumab, a fully human mAb targeting IL-4 receptor α, markedly improved disease activity, but the effect of IL-4/IL-13 blockade on AD at the molecular level has not been characterized. OBJECTIVES: We sought to evaluate dupilumab modulation of the AD molecular signature. METHODS: We performed transcriptomic analyses of pretreatment and posttreatment skin biopsy specimens from patients with moderate-to-severe AD treated weekly with 150 or 300 mg of dupilumab or placebo. RESULTS: Exacerbation of the AD transcriptome was observed in placebo-treated patients. Dupilumab improved the AD signature in a dose-dependent manner. Expression of genes upregulated in AD lesions decreased in patients treated with dupilumab by 26% (95% CI, 21% to 32%) and 65% (95% CI, 60% to 71%) for treatment with 150 and 300 mg, respectively. Genes downregulated in AD lesions increased by 21% (95% CI, 16% to 27%) and 32% (95% CI, 26% to 37%) with dupilumab (150 and 300 mg, respectively). The molecular changes paralleled improvements in clinical scores. A dupilumab treatment signature of 821 probes (>2-fold change, P < .05) significantly modulated in the 300-mg dupilumab group at week 4 compared with baseline was identified in this sample set. Significant (P < .05) decreases in mRNA expression of genes related to hyperplasia (K16 and MKI67), T cells, and dendritic cells (CD1b and CD1c) and potent inhibition of TH2-associated chemokines (CCL17, CCL18, CCL22, and CCL26) were noted without significant modulation of TH1-associated genes (IFNG). CONCLUSIONS: This is the first report showing rapid improvement of the AD molecular signature with targeted anti-IL-4 receptor α therapy. These data suggest that IL-4 and IL-13 drive a complex, TH2-centered inflammatory axis in patients with AD.

A possible role for IL-17A in establishing Th2 inflammation in murine models of atopic dermatitis.

Atopic dermatitis (AD) is associated with the effects of T helper type 2 (Th2) and Th22 cytokines. Recent studies, however, have also implicated Th17 in acute AD. Functional studies of Th2 and Th22 cytokines revealed their roles in generating molecular changes during AD; IL-17A's role, however, has yet to be defined. The report by Nakajima et al. (this issue) begins to define that role by demonstrating IL-17A's ability to induce Th2 inflammation in acute disease.

Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology.

BACKGROUND: Atopic dermatitis (AD) is the most common inflammatory disease. Evolving disease models link changes in epidermal growth and differentiation to T(H)2/T(H)22 cytokine activation. However, these models have not been tested by in vivo suppression of T-cell cytokines. Cyclosporine (CsA) is an immunosuppressant that is highly effective for severe disease, but its mechanism in AD skin lesions has not been studied. OBJECTIVE: We sought to establish the ability of a systemic immunosuppressant to modulate immune and epidermal alterations that form the pathogenic disease phenotype and to correlate changes with clinical improvement. METHODS: CsA's effects on AD skin pathology were evaluated by using gene expression and immunohistochemistry studies in baseline, week 2, and week 12 lesional and nonlesional biopsy specimens from 19 patients treated with 5 mg/kg/d CsA for 12 weeks. RESULTS: After 2 and 12 weeks of treatment, we observed significant reductions of 51% and 72%, respectively, in SCORAD scores. Clinical improvements were associated with significant gene expression changes in lesional but also nonlesional skin, particularly reductions in levels of T(H)2-, T(H)22-, and some T(H)17-related molecules (ie, IL-13, IL-22, CCL17, S100As, and elafin/peptidase inhibitor 3), and modulation of epidermal hyperplasia and differentiation measures. CONCLUSIONS: This is the first study that establishes a relationship between cytokine activation and molecular epidermal alterations, as well as correlations between disease biomarkers in the skin and clinical improvement. The reversal of the molecular phenotype with CsA and the associated biomarkers can serve as a reference for the successful modulation of tissue inflammation with specific immune antagonists in future studies, contributing to the understanding of the specific cytokines involved in epidermal pathology.

Molecular profiling of contact dermatitis skin identifies allergen-dependent differences in immune response.

BACKGROUND: Allergic contact dermatitis (ACD) is the most common occupational disease. Although murine contact hypersensitivity provides a framework for understanding ACD, it carries important differences from its human counterpart. Unlike the contact hypersensitivity model, which is induced by potent sensitizers (ie, dinitrofluorobenzene), human ACD is induced by weak-to-moderate sensitizers (ie, nickel), which cannot induce reactions in mice. Distinct hapten-specific immune-polarizing responses to potent inducers were suggested in mice, with unclear relevance to human ACD. OBJECTIVE: We explored the possibility of distinct T-cell polarization responses in skin to common clinically relevant ACD allergens. METHODS: Gene-expression and cellular studies were performed on common allergens (ie, nickel, fragrance, and rubber) compared with petrolatum-occluded skin, using RT-PCR, gene arrays, and immunohistochemistry. RESULTS: Despite similar clinical reactions in all allergen groups, distinct immune polarizations characterized different allergens. Although the common ACD transcriptome consisted of 149 differentially expressed genes across all allergens versus petrolatum, a much larger gene set was uniquely altered by individual allergens. Nickel demonstrated the highest immune activation, with potent inductions of innate immunity, TH1/TH17 and a TH22 component. Fragrance, and to a lesser extent rubber, demonstrated a strong TH2 bias, some TH22 polarization, and smaller TH1/TH17 contributions. CONCLUSIONS: Our study offers new insights into the pathogenesis of ACD, expanding the understanding of T-cell activation and associated cytokines in allergen-reactive tissues. It is the first study that defines the common transcriptome of clinically relevant sensitizers in human skin and identifies unique pathways preferentially activated by different allergens, suggesting that ACD cannot be considered a single entity.

Mechanisms of contact sensitization offer insights into the role of barrier defects vs. intrinsic immune abnormalities as drivers of atopic dermatitis.

Atopic dermatitis (AD) is a common inflammatory skin disease characterized by wet, oozing, erythematous, pruritic lesions in the acute stage and xerotic, lichenified plaques in the chronic stage. It frequently coexists with asthma and allergic rhinitis, sharing some mechanistic features with these diseases as part of the "atopic march." Controversy exists as to whether immune abnormalities, epidermal barrier defects, or both are the primary factors responsible for disease pathogenesis. In AD patients, there is often a coexisting irritant contact dermatitis (ICD) or allergic contact dermatitis (ACD) that is sometimes clinically difficult to distinguish from AD. ACD shares molecular mechanisms with AD, including increased cellular infiltrates and cytokine activation (Gittler et al., 2013). In this issue, Newell et al. (2013) used an experimental contact sensitization model with dinitrochlorobenzene (DNCB) to gain insight into the unique immune phenotype of AD patients.

Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is classified as extrinsic and intrinsic, representing approximately 80% and 20% of patients with the disease, respectively. Although sharing a similar clinical phenotype, only extrinsic AD is characterized by high serum IgE levels. Because most patients with AD exhibit high IgE levels, an "allergic"/IgE-mediated disease pathogenesis was hypothesized. However, current models associate AD with T-cell activation, particularly TH2/TH22 polarization, and epidermal barrier defects. OBJECTIVE: We sought to define whether both variants share a common pathogenesis. METHODS: We stratified 51 patients with severe AD into extrinsic AD (n = 42) and intrinsic AD (n = 9) groups (with similar mean disease activity/SCORAD scores) and analyzed the molecular and cellular skin pathology of lesional and nonlesional intrinsic AD and extrinsic AD by using gene expression (real-time PCR) and immunohistochemistry. RESULTS: A significant correlation between IgE levels and SCORAD scores (r = 0.76, P < 10(-5)) was found only in patients with extrinsic AD. Marked infiltrates of T cells and dendritic cells and corresponding epidermal alterations (keratin 16, Mki67, and S100A7/A8/A9) defined lesional skin of patients with both variants. However, higher activation of all inflammatory axes (including TH2) was detected in patients with intrinsic AD, particularly TH17 and TH22 cytokines. Positive correlations between TH17-related molecules and SCORAD scores were only found in patients with intrinsic AD, whereas only patients with extrinsic AD showed positive correlations between SCORAD scores and TH2 cytokine (IL-4 and IL-5) levels and negative correlations with differentiation products (loricrin and periplakin). CONCLUSIONS: Although differences in TH17 and TH22 activation exist between patients with intrinsic AD and those with extrinsic AD, we identified common disease-defining features of T-cell activation, production of polarized cytokines, and keratinocyte responses to immune products. Our data indicate that a TH2 bias is not the sole cause of high IgE levels in patients with extrinsic AD, with important implications for similar therapeutic interventions.

New era of biologic therapeutics in atopic dermatitis.

INTRODUCTION: Atopic dermatitis (AD) is a common inflammatory skin disease regulated by genetic and environmental factors. Both skin barrier defects and aberrant immune responses are believed to drive cutaneous inflammation in AD. Existing therapies rely largely on allergen avoidance, emollients and topical and systemic immune-suppressants, some with significant toxicity and transient efficacy; no specific targeted therapies are in clinical use today. As our specific understanding of the immune and molecular pathways that cause different subsets of AD increases, a variety of experimental agents, particularly biologic agents that target pathogenic molecules bring the promise of safe and effective therapeutics for long-term use. AREAS COVERED: This paper discusses the molecular pathways characterizing AD, the contributions of barrier and immune abnormalities to its pathogenesis, and development of new treatments that target key molecules in these pathways. In this review, we will discuss a variety of biologic therapies that are in development or in clinical trials for AD, perhaps revolutionizing treatment of this disease. EXPERT OPINION: Biologic agents in moderate to severe AD offer promise for controlling a disease that currently lacks good and safe therapeutics posing a large unmet need. Unfortunately, existing treatments for AD aim to decrease cutaneous inflammation, but are not specific for the pathways driving this disease. An increasing understanding of the immune mechanisms underlying AD brings the promise of narrow targeted therapies as has occurred for psoriasis, another inflammatory skin disease, for which specific biologic agents have been demonstrated to both control the disease and prevent occurrence of new skin lesions. Although no biologic is yet approved for AD, these are exciting times for active therapeutic development in AD that might lead to revolutionary therapeutics for this disease.