Inflammatory cytokines and biofilm production sustain Staphylococcus aureus outgrowth and persistence: A pivotal interplay in the pathogenesis of Atopic Dermatitis

Individuals with Atopic dermatitis (AD) are highly susceptible to Staphylococcus aureus colonization. However, the mechanisms driving this process as well as the impact of S. aureus in AD pathogenesis are still incompletely understood. In this study, we analysed the role of biofilm in sustaining S. aureus chronic persistence and its impact on AD severity. Further we explored whether key inflammatory cytokines overexpressed in AD might provide a selective advantage to S. aureus. Results show that the strength of biofilm production by S. aureus correlated with the severity of the skin lesion, being significantly higher (P < 0.01) in patients with a more severe form of the disease as compared to those individuals with mild AD. Additionally, interleukin (IL)-β and interferon γ (IFN-γ), but not interleukin (IL)-6, induced a concentration-dependent increase of S. aureus growth. This effect was not observed with coagulase-negative staphylococci isolated from the skin of AD patients. These findings indicate that inflammatory cytokines such as IL1-β and IFN-γ, can selectively promote S. aureus outgrowth, thus subverting the composition of the healthy skin microbiome. Moreover, biofilm production by S. aureus plays a relevant role in further supporting chronic colonization and disease severity, while providing an increased tolerance to antimicrobials

Rapid in situ imaging and whole genome sequencing of biofilm in neonatal feeding tubes: a clinical proof of concept

The bacterial flora of nasogastric feeding tubes and faecal samples were analysed for a low-birth weight (725g) neonate EGA 25 weeks in intensive care. Samples were collected at age 6 and 8 weeks of life. Optical coherence tomography (OCT) was used to visualise bacterial biofilms inside the nasogastric feeding tubes. The biofilm was heterogeneously distributed along the tube lumen wall, and had a depth of up to 500µm. The bacterial biofilm and faecal samples included Enterococcus faecalis and Enterobacter hormaechei. Representative strains, recovered from both feeding tubes and faecal samples, were whole genome sequenced using Illumina, Mi-Seq, which revealed indistinguishable strains, each with less than 28 SNP differences, of E. faecalis and E. hormaechei. The E. faecalis strains were from two sequence types (ST191 and ST211) and encoded for a number of traits related to biofilm formation (BopD), adherence (Epb pili), virulence (cps loci, gelatinase, SprE) and antibiotic resistances (IsaA, tetM). The E. hormaechei were all ST106, and encoded for blaACT-15 β–lactamase and fosfomycin resistance (fosA). This proof of concept study demonstrates that bacterial flora within the neonatal feeding tubes may influence the bacterial colonisation of the intestinal tract and can be visualised nondestructively using OCT

Increase in Ocular Syphilis Cases at Ophthalmologic Reference Center, France, 2012–2015

We describe the frequency, demographic and clinical features, and visual outcomes of ocular syphilis infections observed during 2012–2015 at a tertiary reference center in Paris, France. Twenty-one cases (29 eyes) were identified. The occurrence of ocular syphilis increased from 1 case in 2012 to 5 cases in 2013, 6 cases in 2014, and 9 cases in 2015 (2.22–25.21/1,000 individual patients/year for the period). Among case-patients, an annual 20%–33% were co-infected with HIV. Seventy-six percent of ocular syphilis infections occurred in men who have sex with men. Seventy-five percent of case-patients had a good final visual outcome (best-corrected visual acuity >0.3 logMAR score). Visual outcome was worse for HIV-positive patients than for HIV-negative patients (p = 0.0139). At follow-up, the best visual outcomes were observed in patients whose mean time from first ocular symptom to consultation was 15 days (SD +19 days)

“Working the System”—British American Tobacco's Influence on the European Union Treaty and Its Implications for Policy: An Analysis of Internal Tobacco Industry Documents

Katherine Smith and colleagues investigate the ways in which British American Tobacco influenced the European Union Treaty so that new EU policies advance the interests of major corporations, including those that produce products damaging to health

Trials

OBJECTIVES: To assess the efficacy of several repurposed drugs to prevent hospitalisation or death in patients aged 65 or more with recent symptomatic SARS-CoV-2 infection (COVID-19) and no criteria for hospitalisation. TRIAL DESIGN: Phase III, multi-arm (5) and multi-stage (MAMS), randomized, open-label controlled superiority trial. Participants will be randomly allocated 1:1:1:1:1 to the following strategies: Arm 1: Control arm Arms 2 to 5: Experimental treatment arms Planned interim analyses will be conducted at regular intervals. Their results will be reviewed by an Independent Data and Safety Monitoring Board. Experimental arms may be terminated for futility, efficacy or toxicity before the end of the trial. New experimental arms may be added if new evidence suggests that other treatments should be tested. A feasibility and acceptability substudy as well as an immunological substudy will be conducted alongside the trial. PARTICIPANTS: Inclusion criteria are: 65-year-old or more; Positive test for SARS-CoV-2 on a nasopharyngeal swab; Symptoms onset within 3 days before diagnosis; No hospitalisation criteria; Signed informed consent; Health insurance. Exclusion criteria are: Inability to make an informed decision to participate (e.g.: dementia, guardianship); Rockwood Clinical Frailty Scale ≥7; Long QT syndrome; QTc interval > 500 ms; Heart rate 5.5 mmol/L or <3.5 mmol/L; Ongoing treatment with piperaquine, halofantrine, dasatinib, nilotinib, hydroxyzine, domperidone, citalopram, escitalopram, potent inhibitors or inducers of cytochrome P450 CYP3A4 isoenzyme, repaglinide, azathioprine, 6-mercaptopurine, theophylline, pyrazinamide, warfarin; Known hypersensitivity to any of the trial drugs or to chloroquine and other 4-aminoquinolines, amodiaquine, mefloquine, glafenine, floctafenine, antrafenine, ARB; Hepatic porphyria; Liver failure (Child-Pugh stage ≥B); Stage 4 or 5 chronic kidney disease (GFR <30 mL/min/1.73 m²); Dialysis; Hypersentivity to lactose; Lactase deficiency; Abnormalities in galactose metabolism; Malabsorption syndrome; Glucose-6-phosphate dehydrogenase deficiency; Symptomatic hyperuricemia; Ileus; Colitis; Enterocolitis; Chronic hepatitis B virus disease. The trial is being conducted in France in the Bordeaux, Corse, Dijon, Nancy, Paris and Toulouse areas as well as in the Grand Duchy of Luxembourg. Participants are recruited either at home, nursing homes, general practices, primary care centres or hospital outpatient consultations. INTERVENTION AND COMPARATOR: The four experimental treatments planned in protocol version 1.2 (April 8(th), 2020) are: (1) Hydroxychloroquine 200 mg, 2 tablets BID on day 0, 2 tablets QD from day 1 to 9; (2) Imatinib 400 mg, 1 tablet QD from day 0 to 9; (3) Favipiravir 200 mg, 12 tablets BID on day 0, 6 tablets BID from day 1 to 9; (4) Telmisartan 20 mg, 1 tablet QD from day 0 to 9. The comparator is a complex of vitamins and trace elements (AZINC Forme et Vitalité®), 1 capsule BID for 10 days, for which there is no reason to believe that they are active on the virus. In protocol version 1.2 (April 8th, 2020): People in the control arm will receive a combination of vitamins and trace elements; people in the experimental arms will receive hydroxychloroquine, or favipiravir, or imatinib, or telmisartan. MAIN OUTCOME: The primary outcome is the proportion of participants with an incidence of hospitalisation and/or death between inclusion and day 14 in each arm. RANDOMISATION: Participants are randomized in a 1:1:1:1:1 ratio to each arm using a web-based randomisation tool. Participants not treated with an ARB or ACEI prior to enrolment are randomized to receive the comparator or one of the four experimental drugs. Participants already treated with an ARB or ACEI are randomized to receive the comparator or one of the experimental drugs except telmisartan (i.e.: hydroxychloroquine, imatinib, or favipiravir). Randomisation is stratified on ACEI or ARBs treatment at inclusion and on the type of residence (personal home vs. nursing home). BLINDING (MASKING): This is an open-label trial. Participants, caregivers, investigators and statisticians are not blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 1057 participants will be enrolled if all arms are maintained until the final analysis and no additional arm is added. Three successive futility interim analyses are planned, when the number of participants reaches 30, 60 and 102 in the control arm. Two efficacy analyses (interim n°3 and final) will be performed successively. TRIAL STATUS: This describes the Version 1.2 (April 8(th), 2020) of the COVERAGE protocol that was approved by the French regulatory authority and ethics committee. The trial was opened for enrolment on April 15(th), 2020 in the Nouvelle Aquitaine region (South-West France). Given the current decline of the COVID-19 pandemic in France and its unforeseeable dynamic in the coming months, new trial sites in 5 other French regions and in Luxembourg are currently being opened. A revised version of the protocol was submitted to the regulatory authority and ethics committee on June 15(th), 2020. It contains the following amendments: (i) Inclusion criteria: age ≥65 replaced by age ≥60; time since first symptoms <3 days replaced by time since first symptoms <5 days; (ii) Withdrawal of the hydroxychloroquine arm (due to external data); (iii) increase in the number of trial sites. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on April 22(nd), 2020 (Identifier: NCT04356495): and on EudraCT on April 10(th), 2020 (Identifier: 2020-001435-27). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2)

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men