Atopic dermatitis epidemiology and unmet need in the United Kingdom

Atopic dermatitis (AD), also known as atopic eczema, is a chronic inflammatory skin condition associated with a significant health-related and socioeconomic burden, and is characterized by intense itch, disruption of the skin barrier, and upregulation of type 2-mediated immune responses. The United Kingdom (UK) has a high prevalence of AD, affecting 11–20% of children and 5–10% of adults. Approximately 2% of all cases of childhood AD in the UK are severe. Despite this, most AD treatments are performed at home, with little contact with healthcare providers or services. Here, we discuss the course of AD, treatment practices, and unmet need in the UK. Although the underlying etiology of the disease is still emerging, AD is currently attributed to skin barrier dysfunction and altered inflammatory responses. Management of AD focuses on avoiding triggers, improving skin hydration, managing exacerbating factors, and reducing inflammation through topical and systemic immunosuppressants. However, there is a significant unmet need to improve the overall management of AD and help patients gain control of their disease through safe and effective treatments. Approaches that target individual inflammatory pathways (e.g. dupilumab, anti-interleukin (IL)-4 receptor α) are emerging and likely to provide further therapeutic opportunities for patient benefit

Development and validation of an in house multiplex real time PCR for quantification of all four serotypes of dengue virus

Objectives: In order to determine the infecting dengue virus (DENV) serotype and also to quantify the amount of virus in clinical samples and cell cultures, we proceeded to optimize and validate a quantitative real time RT-PCR assay.Methods: WHO reference strains of the four DENV serotypes were cultured on C6/36 cell lines for 7 days. The supernatants were used to determine plaque forming units (pfus) using BHK cell lines, which is indicative of infecting virus particles. cDNA was synthesized from RNA extracted from the virus culture supernatants. A tenfold dilution series (106 to 101 pfu/ml) of the known pfus of the viruses was prepared using the cDNA for standard curves. Data were analyzed using applied biosystems sequence detection systems. The threshold cycle value (Ct) for each reaction was determined by manually setting the threshold limit. Each standard curve was initially generated individually and later was used in a multiplex assay. All experiments were done in triplicate.Results: The optimized multiplex method detected all four DENV serotypes and generated standard curves with correlation coefficients (R2 values) above 0.95, which suggested that the standard curves and dilutions were of acceptable quality. The slope values of the standard curves were between -3.1 and -3.8 for all assays, implying that the PCR reactions were quite efficient.Conclusions: We have optimized and validated a multiplex quantitative real time RT-PCR assay, which can be effectively used to determine the infecting DENV in samples and also quantify the amount of virus

Direct Visualization of Antigen-specific CD8+T Cells during the Primary Immune Response to Epstein-Barr Virus In Vivo

Primary infection with virus can stimulate a vigorous cytotoxic T cell response. The magnitude of the antigen-specific component versus the bystander component of a primary T cell response remains controversial. In this study, we have used tetrameric major histocompatibility complex–peptide complexes to directly visualize antigen-specific cluster of differentration (CD)8+ T cells during the primary immune response to Epstein-Barr virus (EBV) infection in humans. We show that massive expansion of activated, antigen-specific T cells occurs during the primary response to this virus. In one individual, T cells specific for a single EBV epitope comprised 44% of the total CD8+ T cells within peripheral blood. The majority of the antigen-specific cells had an activated/memory phenotype, with expression of human histocompatibility leukocyte antigen (HLA) DR, CD38, and CD45RO, downregulation of CD62 leukocyte (CD62L), and low levels of expression of CD45RA. After recovery from AIM, the frequency of antigen-specific T cells fell in most donors studied, although populations of antigen-specific cells continued to be easily detectable for at least 3 yr

Sphingosine 1-Phosphate in acute dengue infection

Objectives: Many mediators have been implicated in the vascular leak in dengue which is a hallmark of severe dengue. Sphingosine 1-Phosphate (S1P) has been shown to counteract the effects of other mediators that cause increase vascular permeability. Moreover, S1P has been shown to be important in barrier integrity. Therefore, we investigated the role of S1P in acute dengue. This has not been investigated previously.Methods: Serum samples from acute dengue patients were collected 12 hours apart throughout the course of their hospital stay. S1P levels in 32 patients with acute dengue and 12 healthy individuals were assessed using ELISA.Results: S1P levels were significantly lower in patients with acute dengue (p=0.002) and the levels in patients with DHF were significantly lower than those with dengue fever (p=0.005). S1P levels were low throughout the course of illness and S1P levels were < 0.5 μM in 12/23 patients with DHF when compared to 1/9 with dengue fever (DF). Majority of patients with DHF had lower S1P levels especially in the critical phase. Some patients with DF also had quite low levels at certain time points during the course of the illness. The serial S1P levels in patients with both DF and DHF significantly correlated with the serial platelet counts (Spearmans r =0.18, p=0.04).Conclusions: Low levels of S1P in acute dengue infection are likely to contribute to increased vascular permeability. Therefore S1P analogue may have a place in the treatment of acute dengue

Role of natural killer T cells in the pathogenesis of dengue infections

Objectives: The dengue virus exploits cellular lipid metabolism pathways and natural killer T cells (iNKT), which recognize glycolipids have been suggested to play a role in mouse models of acute dengue. Therefore, we set out to determine if iNKT cells play a role in acute dengue infectionMethods: The frequency of iNKT cells (CD3+, Vα24+) was determined in 49 acute dengue and 22 healthy individuals. The functionality and phenotype of iNKT cell subsets were defined only in 19 patients and 10 controls by flow cytometry. Clinical disease severity was determined by the WHO 2011 guidelinesResults: The proportion of iNKTs in patients with acute dengue were significantly higher (P=0.03) compared to healthy individuals. We found that the CD4+ iNKTs, which produce inflammatory cytokines and are less cytotoxic, were significantly expanded (p=0.01) in acute dengue. iNKTs of patients were also significantly (p=0.02) more activated (both CD38+ and HLA-DR+), that iNKT cell activation significantly and positively correlated with dengue-specific IgG antibody titres (Spearmans’ r=0.5018, P=0.03). iNKT of patients were also predominantly of the immature phenotype, as the expression of CD161 was significantly more than in healthy individuals (p=0.01).Conclusions: As the iNKT cell population, especially of the CD4+ T cell subset appears to be highly activated and expanded in acute dengue, iNKT cells could be contributing to the pathogenesis of dengue infection

Genomic and epidemiological analysis of SARS-CoV-2 viruses in Sri Lanka

Background: In order to understand the molecular epidemiology of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Sri Lanka, since March 2020, we carried out genomic sequencing overlaid on available epidemiological data until April 2021. Methods: Whole genome sequencing was carried out on diagnostic sputum or nasopharyngeal swabs from 373 patients with COVID-19. Molecular clock phylogenetic analysis was undertaken to further explore dominant lineages. Results: The B.1.411 lineage was most prevalent, which was established in Sri Lanka and caused outbreaks throughout the country until March 2021. The estimated time of the most recent common ancestor (tMRCA) of this lineage was June 1, 2020 (with 95% lower and upper bounds March 30 to July 27) suggesting cryptic transmission may have occurred, prior to a large epidemic starting in October 2020. Returning travellers were identified with infections caused by lineage B.1.258, as well as the more transmissible B.1.1.7 lineage, which has replaced B.1.411 to fuel the ongoing large outbreak in the country. Conclusions: The large outbreak that started in early October, is due to spread of a single virus lineage, B.1.411 until the end of March 2021, when B.1.1.7 emerged and became the dominant lineage

Production and Decay of D_1(2420)^0 and D_2^*(2460)^0

We have investigated $D^{+}\pi^{-}$ and $D^{*+}\pi^{-}$ final states and observed the two established $L=1$ charmed mesons, the $D_1(2420)^0$ with mass $2421^{+1+2}_{-2-2}$ MeV/c$^{2}$ and width $20^{+6+3}_{-5-3}$ MeV/c$^{2}$ and the $D_2^*(2460)^0$ with mass $2465 \pm 3 \pm 3$ MeV/c$^{2}$ and width $28^{+8+6}_{-7-6}$ MeV/c$^{2}$. Properties of these final states, including their decay angular distributions and spin-parity assignments, have been studied. We identify these two mesons as the $j_{light}=3/2$ doublet predicted by HQET. We also obtain constraints on {\footnotesize $\Gamma_S/(\Gamma_S + \Gamma_D)$} as a function of the cosine of the relative phase of the two amplitudes in the $D_1(2420)^0$ decay.Comment: 15 pages in REVTEX format. hardcopies with figures can be obtained by sending mail to: [email protected]

Measurement of the branching fraction for Υ(1S)→τ+τ−\Upsilon (1S) \to \tau^+ \tau^-

We have studied the leptonic decay of the $\Upsilon (1S)$ resonance into tau pairs using the CLEO II detector. A clean sample of tau pair events is identified via events containing two charged particles where exactly one of the particles is an identified electron. We find $B(\Upsilon(1S) \to \tau^+ \tau^-) = (2.61~\pm~0.12~{+0.09\atop{-0.13}})$. The result is consistent with expectations from lepton universality.Comment: 9 pages, RevTeX, two Postscript figures available upon request, CLNS 94/1297, CLEO 94-20 (submitted to Physics Letters B

Measurement of the Decay Asymmetry Parameters in Λc+→Λπ+\Lambda_c^+ \to \Lambda\pi^+ and Λc+→Σ+π0\Lambda_c^+ \to \Sigma^+\pi^0

We have measured the weak decay asymmetry parameters (\aLC ) for two \LC\ decay modes. Our measurements are \aLC = -0.94^{+0.21+0.12}_{-0.06-0.06} for the decay mode $\Lambda_c^+ \to \Lambda\pi^+$ and \aLC = -0.45\pm 0.31 \pm 0.06 for the decay mode $\Lambda_c \to \Sigma^+\pi^0$. By combining these measurements with the previously measured decay rates, we have extracted the parity-violating and parity-conserving amplitudes. These amplitudes are used to test models of nonleptonic charmed baryon decay.Comment: 11 pages including the figures. Uses REVTEX and psfig macros. Figures as uuencoded postscript. Also available as http://w4.lns.cornell.edu/public/CLNS/1995/CLNS95-1319.p

Study of the B^0 Semileptonic Decay Spectrum at the Upsilon(4S) Resonance

We have made a first measurement of the lepton momentum spectrum in a sample of events enriched in neutral B's through a partial reconstruction of B0 --> D*- l+ nu. This spectrum, measured with 2.38 fb**-1 of data collected at the Upsilon(4S) resonance by the CLEO II detector, is compared directly to the inclusive lepton spectrum from all Upsilon(4S) events in the same data set. These two spectra are consistent with having the same shape above 1.5 GeV/c. From the two spectra and two other CLEO measurements, we obtain the B0 and B+ semileptonic branching fractions, b0 and b+, their ratio, and the production ratio f+-/f00 of B+ and B0 pairs at the Upsilon(4S). We report b+/b0=0.950 (+0.117-0.080) +- 0.091, b0 = (10.78 +- 0.60 +- 0.69)%, and b+ = (10.25 +- 0.57 +- 0.65)%. b+/b0 is equivalent to the ratio of charged to neutral B lifetimes, tau+/tau0.Comment: 14 page, postscript file also available at http://w4.lns.cornell.edu/public/CLN