The public health importance of scabies in community domiciliary care settings: an exploratory cross-sectional survey of health protection teams in England

Scabies is a contagious skin infection commonly occurring in institutions such as care homes. However, a large proportion of vulnerable people in England receive domiciliary care in the community and their experience of scabies has not been described. We undertook a pragmatic cross-sectional survey of Health Protection Teams (HPTs) in England to determine the burden of scabies related to domiciliary care. Fifteen cases or outbreaks were notified to HPTs between January 2013 and December 2017. Although a relatively uncommon event for individual HPTs, they were complex to manage and required the co-ordination of multiple stakeholders. Diagnosis was often delayed and required several clinical consultations. A lack of guidance led to difficulties establishing stakeholder roles and responsibilities and sources of funding for treatment. The stigmatisation of scabies sometimes affected the quality of care provided to patients, such as use of excessive personal protective equipment. Our study demonstrates that scabies is an issue of public health importance for domiciliary care service providers and users, and research is required to better understand the impacts of the disease and to develop evidence-based guidance. More generally, there is a need for simpler treatment regimens and methods of diagnosing scabies

The Physical Properties of the Red Supergiant WOH G64: The Largest Star Known?

WOH G64 is an unusual red supergiant (RSG) in the Large Magellanic Cloud (LMC), with a number of properties that set it apart from the rest of the LMC RSG population, including a thick circumstellar dust torus, an unusually late spectral type, maser activity, and nebular emission lines. Its reported physical properties are also extreme, including the largest radius for any star known and an effective temperature that is much cooler than other RSGs in the LMC, both of which are at variance with stellar evolutionary theory. We fit moderate-resolution optical spectrophotometry of WOH G64 with the MARCS stellar atmosphere models, determining an effective temperature of 3400 +/- 25 K. We obtain a similar result from the star's broadband V - K colors. With this effective temperature, and taking into account the flux contribution from the aysmmetric circumstellar dust envelope, we calculate log(L/L_sun) = 5.45 +/- 0.05 for WOH G64, quite similar to the luminosity reported by Ohnaka and collaborators based on their radiative transfer modeling of the star's dust torus. We determine a radius of R/R_sun = 1540, bringing the size of WOH G64 and its position on the H-R diagram into agreement with the largest known Galactic RSGs, although it is still extreme for the LMC. In addition, we use the Ca II triplet absorption feature to determine a radial velocity of 294 +/- 2 km/s for the star; this is the same radial velocity as the rotating gas in the LMC's disk, which confirms its membership in the LMC and precludes it from being an unusual Galactic halo giant. Finally, we describe the star's unusual nebula emission spectrum; the gas is nitrogen-rich and shock-heated, and displays a radial velocity that is significantly more positive than the star itself by 50 km/s.Comment: 25 pages, 5 figures; accepted for publication in The Astronomical Journa

Visual search for basic emotional expressions in autism: impaired processing of anger, fear and sadness, but a typical happy face advantage

Facial expression recognition was investigated in 20 males with high functioning autism (HFA) or Asperger syndrome (AS), compared to typically developing individuals matched for chronological age (TD CA group) and verbal and non-verbal ability (TD V/NV group). This was the first study to employ a visual search, "face in the crowd" paradigm with a HFA/AS group, which explored responses to numerous facial expressions using real-face stimuli. Results showed slower response times for processing fear, anger and sad expressions in the HFA/AS group, relative to the TD CA group, but not the TD V/NV group. Reponses to happy, disgust and surprise expressions showed no group differences. Results are discussed with reference to the amygdala theory of autism. © 2011 Elsevier Ltd

The Physical Properties of Red Supergiants: Comparing Theory and Observations

Red supergiants (RSGs) are an evolved stage in the life of intermediate massive stars (than than 25 solar masses). For many years, their location in the H-R diagram was at variance with the evolutionary models. Using the MARCS stellar atmospheres, we have determined new effective temperatures and bolometric luminosities for RSGs in the Milky Way, LMC, and SMC, and our work has resulted in much better agreement with the evolutionary models. We have also found evidence of significant visual extinction due to circumstellar dust. Although in the Milky Way the RSGs contribute only a small fraction (than than 1 percent) of the dust to the interstellar medium (ISM), in starburst galaxies or galaxies at large look-back times, we expect that RSGs may be the main dust source. We are in the process of extending this work now to RSGs of higher and lower metallicities using the galaxies M31 and WLM.Comment: Invited review; to appear in Massive Stars as Cosmic Engines, IAU Symp. 250, ed. F. Bresolin, P. A. Crowther, and J. Puls (Cambridge University Press

Red Supergiants in the Andromeda Galaxy (M31)

Red supergiants are a short-lived stage in the evolution of moderately massive stars (10-25Mo), and as such their location in the H-R diagram provides an exacting test of stellar evolutionary models. Since massive star evolution is strongly affected by the amount of mass-loss a star suffers, and since the mass-loss rates depend upon metallicity, it is highly desirable to study the physical properties of these stars in galaxies of various metallicities. Here we identify a sample of red supergiants in M31 (the most metal-rich of the Local Group galaxies) and derive their physical properties by fitting MARCS atmosphere models to moderate resolution optical spectroscopy, and from V-K photometry.Comment: Accepted for publication in the Astrophysical Journa

IRF5 promotes influenza-induced inflammatory responses in human iPSC-derived myeloid cells and murine models.

Recognition of Influenza A virus (IAV) by the innate immune system triggers pathways that restrict viral replication, activates innate immune cells, and regulates adaptive immunity. However, excessive innate immune activation can exaggerate disease. The pathways promoting excessive activation are incompletely understood, with limited experimental models to investigate mechanisms driving influenza-induced inflammation in humans. Interferon regulatory factor (IRF5) is a transcription factor that plays important roles in induction of cytokines after viral sensing. In an in vivo model of IAV infection, IRF5 deficiency reduced IAV-driven immune pathology and associated inflammatory cytokine production, specifically reducing cytokine-producing myeloid cell populations in Irf5-/- mice, but not impacting type 1 IFN production or virus replication. Using cytometry by time-of-flight (CyTOF), we identified that human lung IRF5 expression was highest in cells of the myeloid lineage. To investigate the role of IRF5 in mediating human inflammatory responses by myeloid cells to IAV, we employed human induced pluripotent stem cells (hIPSCs) with biallelic mutations in IRF5, demonstrating for the first time iPS-derived dendritic cells (iPS-DCs) with biallelic mutations can be used to investigate regulation of human virus-induced immune responses. Using this technology, we reveal that IRF5 deficiency in human DCs, or macrophages, corresponded with reduced virus-induced inflammatory cytokine production, with IRF5 acting downstream of TLR7 and, possibly, RIG-I after viral sensing. Thus, IRF5 acts as a regulator of myeloid cell inflammatory cytokine production during IAV infection in mice and humans, and drives immune-mediated viral pathogenesis independently of type 1 IFN and virus replication.ImportanceThe inflammatory response to Influenza A virus (IAV) participates in infection control but contributes to disease severity. After viral detection intracellular pathways are activated, initiating cytokine production, but these pathways are incompletely understood. We show that interferon regulatory factor 5 (IRF5) mediates IAV-induced inflammation and, in mice, drives pathology. This was independent of antiviral type 1 IFN and virus replication, implying that IRF5 could be specifically targeted to treat influenza-induced inflammation. We show for the first time that human iPSC technology can be exploited in genetic studies of virus-induced immune responses. Using this technology, we deleted IRF5 in human myeloid cells. These IRF5-deficient cells exhibited impaired influenza-induced cytokine production and revealed that IRF5 acts downstream of Toll-like receptor 7 and possibly retinoic acid-inducible gene-I. Our data demonstrate the importance of IRF5 in influenza-induced inflammation, suggesting genetic variation in the IRF5 gene may influence host susceptibility to viral diseases.This work was supported by The Wellcome Trust. This work was funded by a Wellcome 641 Trust Senior Research Fellowship to Ian Humphreys (207503/Z/17/Z); Medical Research 642 Council, United Kingdom (MR/L018942/1 and MRC Human Immunology Unit Core); 643 Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences 644 (CIFMS), China (grant number: 2018-I2M-2-002). The Wellcome Trust Sanger Institute was 645 the source of the Kolf2 human induced pluripotent cell line which was generated under the 646 Human Induced Pluripotent Stem Cell Initiative funded by a grant from the Wellcome Trust Downloaded from http://jvi.asm.org/ on March 2, 2020 at CAMBRIDGE UNIV27 and Medical Research Council, supported 647 by the Wellcome Trust (WT098051) and the 648 NIHR/Wellcome Trust Clinical Research Facility, and Life Science Technologies 649 Corporation provided Cytotune for reprogramming. We thank the Wellcome Trust Sanger Institute Gene editing pipeline for generation of IRF5-/- 650 iPSCs and the Mass spectrometry 651 Facility at the Weatherall Institute of Molecular Medicine for help with CyTOF experiments

Docking of competitive inhibitors to the P2X7 receptor family reveals key differences responsible for changes in response between rat and human

The P2X7 receptor is a calcium permeable cationic channel activated by extracellular ATP, playing a role in chronic pain, osteoporosis and arthritis. A number of potential lead compounds are inactive against the rat isoform, despite good activity against the human homologue, making animal model studies problematic. Here we have produced P2X7 models and docked three structurally distinct inhibitors using in silico approaches and show they have a similar mode of binding in which Phe95 plays a key role by forming pi-stacking interactions. Importantly this residue is replaced by Leu in the rat P2X7 receptor resulting in a significantly reduced binding affinity. This work provides new insights into binding of P2X7 inhibitors and shows the structural difference in human and rat P2X7 receptors which results in a difference in affinity. Such information is useful both for the rational design of inhibitors based on these scaffolds and also the way in which these compounds are tested in animal models

Reviewing essential public health functions in the Eastern Mediterranean Region post COVID-19 pandemic: a foundation for system resilience.

The COVID-19 pandemic exposed vulnerabilities in many health systems worldwide with profound implications for health and society. The public health challenges experienced during the pandemic have highlighted the importance of resilient health systems, that can adapt and transform to meet the population's evolving health needs. Essential public health functions (EPHFs) offer a holistic, integrated and sustainable approach to public health by contributing to achieving several health priorities and goals. In recent years, there has been a focused effort to conceptualise and define the EPHFs. In this paper, we describe the collaborative approach undertaken by the WHO Eastern Mediterranean Region (EMR) and UK Health Security Agency and present the findings and results of the revised EPHFs, in view of lessons learnt from the COVID-19 pandemic and the current priorities for countries across the EMR. This included conducting a desktop review, a gap and bottleneck analysis and stakeholder consultation to arrive at the revised EPHF model including four enablers and nine core functions, including a new function: public health services. The EPHFs will offer countries a complementary and synergistic approach to strengthen health systems and public health capacities and contribute to the region's ability to effectively respond to future health challenges and emergencies. By focusing on the EPHFs, countries can work towards ensuring health security as an integral goal for the health system besides universal health coverage, thus strengthening and building more resilient and equitable health systems

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

A Daphnane Diterpenoid Isolated from Wikstroemia polyantha Induces an Inflammatory Response and Modulates miRNA Activity

MicroRNAs (miRNAs) are endogenously expressed single-stranded ∼21–23 nucleotide RNAs that inhibit gene expression post-transcriptionally by binding imperfectly to elements usually within the 3′untranslated region (3′UTR) of mRNAs. Small interfering RNAs (siRNAs) mediate site-specific cleavage by binding with perfect complementarity to RNA. Here, a cell-based miRNA reporter system was developed to screen for compounds from marine and plant extracts that inhibit miRNA or siRNA activity. The daphnane diterpenoid genkwanine M (GENK) isolated from the plant Wikstroemia polyantha induces an early inflammatory response and can moderately inhibit miR-122 activity in the liver Huh-7 cell line. GENK does not alter miR-122 levels nor does it directly inhibit siRNA activity in an in vitro cleavage assay. Finally, we demonstrate that GENK can inhibit HCV infection in Huh-7 cells. In summary, the development of the cell-based miRNA sensor system should prove useful in identifying compounds that affect miRNA/siRNA activity