Differential expression of CD300a/c on human TH1 and TH17 cells

<p>Abstract</p> <p>Background</p> <p>Human memory CD4⁺T cells can be either CD300a/c⁺or CD300a/c^-and subsequent analyses showed that CD4⁺effector memory T (T_EM) cells are mostly CD300a/c⁺, whereas CD4⁺central memory T (T_CM) cells have similar frequencies of CD300a/c⁺and CD300a/c^-cells.</p> <p>Results</p> <p>Extensive phenotypical and functional characterization showed that in both T_CMand T_EMcells, the CD300a/c⁺subset contained a higher number of T_H1 (IFN-γ producing) cells. Alternatively, T_H17 (IL-17a producing) cells tend to be CD300a/c^-, especially in the T_EMsubset. Further characterization of the IL-17a⁺cells showed that cells that produce only this cytokine are mostly CD300a/c^-, while cells that produce IL-17a in combination with other cytokines, especially IFN-γ, are mostly CD300a/c⁺, indicating that the expression of this receptor is associated with cells that produce IFN-γ. Co-ligation of the TCR and CD300a/c in CD4⁺T cells inhibited Ca²⁺mobilization evoked by TCR ligation alone and modulated IFN-γ production on T_H1 polarized cells.</p> <p>Conclusion</p> <p>We conclude that the CD300a/c receptors are differentially expressed on human T_H1 and T_H17 cells and that their ligation is capable of modulating TCR mediated signals.</p

Abemaciclib in Combination with Single-Agent Options in Patients with Stage IV Non–Small Cell Lung Cancer: A Phase Ib Study

Purpose: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated preclinical activity in non–small cell lung cancer (NSCLC). A multicenter, nonrandomized, open-label phase Ib study was conducted to test safety, MTD, pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies for treatment in patients with metastatic NSCLC. Patients and Methods: An initial dose escalation phase was used to determine the MTD of twice-daily oral abemaciclib (150, 200 mg) plus pemetrexed, gemcitabine, or ramucirumab, followed by an expansion phase for each drug combination. Pemetrexed and gemcitabine were administered according to label. The abemaciclib plus ramucirumab study examined two dosing schedules. Results: The three study parts enrolled 86 patients; all received ≥1 dose of combination therapy. Across arms, the most common treatment-emergent adverse events were fatigue, diarrhea, neutropenia, decreased appetite, and nausea. The trial did not identify an abemaciclib MTD for the combination with pemetrexed or gemcitabine but did so for the combination of abemaciclib with days 1 and 8 ramucirumab (8 mg/kg). Plasma sample analysis showed that abemaciclib did not influence the pharmacokinetics of the combination agents and the combination agents did not affect abemaciclib exposure. The disease control rate was 57% for patients treated with abemaciclib–pemetrexed, 25% for abemaciclib–gemcitabine, and 54% for abemaciclib–ramucirumab. Median progression-free survival was 5.55, 1.58, and 4.83 months, respectively. Conclusions: Abemaciclib demonstrated an acceptable safety profile when dosed on a continuous twice-daily schedule in combination with pemetrexed, gemcitabine, or ramucirumab. Abemaciclib exposures remained consistent with those observed in single-agent studies

Equine Arteritis Virus Elicits a Mucosal Antibody Response in the Reproductive Tract of Persistently Infected Stallions

Equine arteritis virus (EAV) has the ability to establish persistent infection in the reproductive tract of the stallion (carrier) and is continuously shed in its semen. We have recently demonstrated that EAV persists within stromal cells and a subset of lymphocytes in the stallion accessory sex glands in the presence of a significant local inflammatory response. In the present study, we demonstrated that EAV elicits a mucosal antibody response in the reproductive tract during persistent infection with homing of plasma cells into accessory sex glands. The EAV-specific immunoglobulin isotypes in seminal plasma included IgA, IgG1, IgG3/5, and IgG4/7. Interestingly, seminal plasma IgG1 and IgG4/7 possessed virus-neutralizing activity, while seminal plasma IgA and IgG3/5 did not. However, virus-neutralizing IgG1 and IgG4/7 in seminal plasma were not effective in preventing viral infectivity. In addition, the serological response was primarily mediated by virus-specific IgM and IgG1, while virus-specific serum IgA, IgG3/5, IgG4/7, and IgG6 isotype responses were not detected. This is the first report characterizing the immunoglobulin isotypes in equine serum and seminal plasma in response to EAV infection. The findings presented herein suggest that while a broader immunoglobulin isotype diversity is elicited in seminal plasma, EAV has the ability to persist in the reproductive tract, in spite of local mucosal antibody and inflammatory responses. This study provides further evidence that EAV employs complex immune evasion mechanisms during persistence in the reproductive tract that warrant further investigation

Using a Pericentromeric Interspersed Repeat to Recapitulate the Phylogeny and Expansion of Human Centromeric Segmental Duplications

Despite considerable advances in sequencing of the human genome over the past few years, the organization and evolution of human pericentromeric regions have been difficult to resolve. This is due, in part, to the presence of large, complex blocks of duplicated genomic sequence at the boundary between centromeric satellite and unique euchromatic DNA. Here, we report the identification and characterization of an approximately 49-kb repeat sequence that exists in more than 40 copies within the human genome. This repeat is specific to highly duplicated pericentromeric regions with multiple copies distributed in an interspersed fashion among a subset of human chromosomes. Using this interspersed repeat (termed PIR4) as a marker of pericentromeric DNA, we recovered and sequence-tagged 3 Mb of pericentromeric DNA from a variety of human chromosomes as well as nonhuman primate genomes. A global evolutionary reconstruction of the dispersal of PIR4 sequence and analysis of flanking sequence supports a model in which pericentromeric duplications initiated before the separation of the great ape species (>12 MYA). Further, analyses of this duplication and associated flanking duplications narrow the major burst of pericentromeric duplication activity to a time just before the divergence of the African great ape and human species (5 to 7 MYA). These recent duplication exchange events substantially restructured the pericentromeric regions of hominoid chromosomes and created an architecture where large blocks of sequence are shared among nonhomologous chromosomes. This report provides the first global view of the series of historical events that have reshaped human pericentromeric regions over recent evolutionary time

National identity predicts public health support during a global pandemic

Changing collective behaviour and supporting non-pharmaceutical interventions is an important component in mitigating virus transmission during a pandemic. In a large international collaboration (Study 1, N = 49,968 across 67 countries), we investigated self-reported factors associated with public health behaviours (e.g., spatial distancing and stricter hygiene) and endorsed public policy interventions (e.g., closing bars and restaurants) during the early stage of the COVID-19 pandemic (April-May 2020). Respondents who reported identifying more strongly with their nation consistently reported greater engagement in public health behaviours and support for public health policies. Results were similar for representative and non-representative national samples. Study 2 (N = 42 countries) conceptually replicated the central finding using aggregate indices of national identity (obtained using the World Values Survey) and a measure of actual behaviour change during the pandemic (obtained from Google mobility reports). Higher levels of national identification prior to the pandemic predicted lower mobility during the early stage of the pandemic (r = −0.40). We discuss the potential implications of links between national identity, leadership, and public health for managing COVID-19 and future pandemics

Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative

We aimed to develop evidence-based multinational recommendations for the diagnosis and management of gout. Using a formal voting process, a panel of 78 international rheumatologists developed 10 key clinical questions pertinent to the diagnosis and management of gout. Each question was investigated with a systematic literature review. Medline, Embase, Cochrane CENTRAL and abstracts from 2010-2011 European League Against Rheumatism and American College of Rheumatology meetings were searched in each review. Relevant studies were independently reviewed by two individuals for data extraction and synthesis and risk of bias assessment. Using this evidence, rheumatologists from 14 countries (Europe, South America and Australasia) developed national recommendations. After rounds of discussion and voting, multinational recommendations were formulated. Each recommendation was graded according to the level of evidence. Agreement and potential impact on clinical practice were assessed. Combining evidence and clinical expertise, 10 recommendations were produced. One recommendation referred to the diagnosis of gout, two referred to cardiovascular and renal comorbidities, six focused on different aspects of the management of gout (including drug treatment and monitoring), and the last recommendation referred to the management of asymptomatic hyperuricaemia. the level of agreement with the recommendations ranged from 8.1 to 9.2 (mean 8.7) on a 1-10 scale, with 10 representing full agreement. Ten recommendations on the diagnosis and management of gout were established. They are evidence-based and supported by a large panel of rheumatologists from 14 countries, enhancing their utility in clinical practice.AbbVieAustralian National Health and Medical Research Council (NHMRC)Hosp Gen Univ Elda, Dept Reumatol, Elda 03600, SpainHosp Gen Univ Alicante, Dept Reumatol, Alicante, SpainUniv Camilo Jose Cela, Fac Ciencias Salud, Madrid, SpainUniv British Columbia, Div Rheumatol, Vancouver, BC V5Z 1M9, CanadaRoyal Melbourne Hosp, Parkville, Vic 3050, AustraliaUniv Hosp Southampton NHS Fdn Trust, Southampton, Hants, EnglandNIHR Wellcome Trust Clin Res Facil, Southampton, Hants, EnglandCtr Hosp Univ Liege, Liege, BelgiumMaastricht Univ, Med Ctr, Dept Internal Med Rheumatol, Maastricht, NetherlandsAtrium Med Ctr, Heerlen, NetherlandsUniv Toronto, Div Rheumatol, Toronto, ON, CanadaRepatriat Gen Hosp, Rheumatol Res Unit, Adelaide, SA, AustraliaFlinders Univ S Australia, Adelaide, SA 5001, AustraliaMed Univ Vienna, Dept Internal Med 3, Div Rheumatol, Vienna, AustriaUniv Toronto, Dept Hlth Policy Management & Evaluat, Toronto, ON, CanadaMt Sinai Hosp, Univ Hlth Network, Toronto Gen Res Inst, Div Clin Decis Making & Hlth Care, Toronto, ON M5G 1X5, CanadaCabrini Hosp, Monash Dept Clin Epidemiol, Malvern, Vic, AustraliaMonash Univ, Dept Epidemiol & Prevent Med, Malvern, Vic, AustraliaUniv Amsterdam, Acad Med Ctr, Dept Clin Immunol & Rheumatol, NL-1105 AZ Amsterdam, NetherlandsUniv Med Ctr Utrecht, Dept Rheumatol & Clin Immunol, Utrecht, NetherlandsUniv Nova Lisboa, Fac Ciencias Med, CEDOC, P-1200 Lisbon, PortugalEPE Hosp Egas Moniz, CHLO, Dept Rheumatol, Lisbon, PortugalHosp Gen Mexico City, Rheumatol Unit, Mexico City, DF, MexicoKarolinska Univ Hosp, Dept Rheumatol, Stockholm, SwedenKarolinska Inst, Stockholm, SwedenGhent Univ Hosp, Dept Rheumatol, Ghent, BelgiumUniversidade Federal de São Paulo, Div Rheumatol, São Paulo, BrazilSt Georges Healthcare NHS Trust, Dept Rheumatol, London, EnglandState Hosp Stockerau, Ctr Rheumatol, Lower Austria, Stockerau, AustriaUniv Pavia, IRCCS Policlin S Matteo, Cattedra Reumatol, I-27100 Pavia, ItalyUniv Giessen, Kerckhoff Klin, Dept Rheumatol & Clin Immunol, Bad Nauheim, GermanyCopenhagen Univ Hosp, Ctr Rheumatol & Spine Dis, Copenhagen Ctr Arthrit Res, Glostrup, DenmarkMenzies Res Inst Tasmania, Hobart, Tas, AustraliaColumbia Univ, Med Ctr, New York, NY USALeiden Univ, Med Ctr, Leiden, NetherlandsUniversidade Federal de São Paulo, Div Rheumatol, São Paulo, BrazilWeb of Scienc

The importance of myo-inositol and D-chiro-inositol to support fertility and reproduction

This review details the physiologic roles of two insulin sensitizers, myo-inositol (MI) and D-chiro-inositol (DCI). In the human ovary, MI is a second messenger of follicle stimulating hormone (FSH) and DCI is an aromatase inhibitor. These activities allow a treatment for polycystic ovary syndrome (PCOS) to be defined based on the combined administration of MI and DCI, where the best MI:DCI ratio is 40:1. In addition, MI plays a pivotal role in the physiology of reproduction, and has beneficial effects on the development of oocytes, spermatozoa, and embryos. By contrast, DCI has little effect on spermatozoa, but high concentrations in the ovary can negatively affect the quality of oocytes and the blastocyst. Overall, the evidence in the literature supports the beneficial effects of MI in both female and male reproduction, warranting clinical use of MI in assisted reproductive treatment (ART).Cette revue détaille les rôles physiologiques de deux sensibilisateurs à l'insuline, le myo-inositol (MI) et le D-chiro-inositol (DCI). Dans l'ovaire humain, le MI est un second messager de l'hormone folliculostimulante (FSH) et le DCI est un inhibiteur de l'aromatase. Ces activités permettent de définir un traitement du syndrome des ovaires polykystiques (SOPK) basé sur l'administration combinée de MI et de DCI, où le meilleur rapport MI:DCI est de 40:1. En outre, le MI joue un rôle essentiel dans la physiologie de la reproduction et a des effets bénéfiques sur le développement des ovocytes, des spermatozoïdes et des embryons. En revanche, le DCI a peu d'effet sur les spermatozoïdes, mais des concentrations élevées dans l'ovaire peuvent avoir un effet négatif sur la qualité des ovocytes et du blastocyste. Dans l'ensemble, les données de la littérature confirment les effets bénéfiques du MI dans la reproduction féminine et masculine, ce qui justifie l'utilisation clinique du MI dans l'assistance médicale à la procréation

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Rationale and design of the hip fracture accelerated surgical treatment and care track (hip attack) trial : A protocol for an international randomised controlled trial evaluating early surgery for hip fracture patients

Introduction Annually, millions of adults suffer hip fractures. The mortality rate post a hip fracture is 7%-10% at 30 days and 10%-20% at 90 days. Observational data suggest that early surgery can improve these outcomes in hip fracture patients. We designed a clinical trial - HIP fracture Accelerated surgical TreaTment And Care tracK (HIP ATTACK) to determine the effect of accelerated surgery compared with standard care on the 90-day risk of all-cause mortality and major perioperative complications. Methods and analysis HIP ATTACK is a multicentre, international, parallel group randomised controlled trial (RCT) that will include patients ≥45 years of age and diagnosed with a hip fracture from a low-energy mechanism requiring surgery. Patients are randomised to accelerated medical assessment and surgical repair (goal within 6 h) or standard care. The co-primary outcomes are (1) all-cause mortality and (2) a composite of major perioperative complications (ie, mortality and non-fatal myocardial infarction, pulmonary embolism, pneumonia, sepsis, stroke, and life-threatening and major bleeding) at 90 days after randomisation. All patients will be followed up for a period of 1 year. We will enrol 3000 patients. Ethics and dissemination All centres had ethics approval before randomising patients. Written informed consent is required for all patients before randomisation. HIP ATTACK is the first large international trial designed to examine whether accelerated surgery can improve outcomes in patients with a hip fracture. The dissemination plan includes publishing the results in a policy-influencing journal, conference presentations, engagement of influential medical organisations, and providing public awareness through multimedia resources. Trial registration number NCT02027896; Pre-results

Overview: On the transport and transformation of pollutants in the outflow of major population centres – observational data from the EMeRGe European intensive operational period in summer 2017

Megacities and other major population centres (MPCs) worldwide are major sources of air pollution, both locally as well as downwind. The overall assessment and prediction of the impact of MPC pollution on tropospheric chemistry are challenging. The present work provides an overview of the highlights of a major new contribution to the understanding of this issue based on the data and analysis of the EMeRGe (Effect of Megacities on the transport and transformation of pollutants on the Regional to Global scales) international project. EMeRGe focuses on atmospheric chemistry, dynamics, and transport of local and regional pollution originating in MPCs. Airborne measurements, taking advantage of the long range capabilities of the High Altitude and LOng Range Research Aircraft (HALO, https://www.halo-spp.de, last access: 22 March 2022), are a central part of the project. The synergistic use and consistent interpretation of observational data sets of different spatial and temporal resolution (e.g. from ground-based networks, airborne campaigns, and satellite measurements) supported by modelling within EMeRGe provide unique insight to test the current understanding of MPC pollution outflows. In order to obtain an adequate set of measurements at different spatial scales, two field experiments were positioned in time and space to contrast situations when the photochemical transformation of plumes emerging from MPCs is large. These experiments were conducted in summer 2017 over Europe and in the inter-monsoon period over Asia in spring 2018. The intensive observational periods (IOPs) involved HALO airborne measurements of ozone and its precursors, volatile organic compounds, aerosol particles, and related species as well as coordinated ground-based ancillary observations at different sites. Perfluorocarbon (PFC) tracer releases and model forecasts supported the flight planning, the identification of pollution plumes, and the analysis of chemical transformations during transport. This paper describes the experimental deployment and scientific questions of the IOP in Europe. The MPC targets – London (United Kingdom; UK), the Benelux/Ruhr area (Belgium, the Netherlands, Luxembourg and Germany), Paris (France), Rome and the Po Valley (Italy), and Madrid and Barcelona (Spain) – were investigated during seven HALO research flights with an aircraft base in Germany for a total of 53 flight hours. An in-flight comparison of HALO with the collaborating UK-airborne platform Facility for Airborne Atmospheric Measurements (FAAM) took place to assure accuracy and comparability of the instrumentation on board. Overall, EMeRGe unites measurements of near- and far-field emissions and hence deals with complex air masses of local and distant sources. Regional transport of several European MPC outflows was successfully identified and measured. Chemical processing of the MPC emissions was inferred from airborne observations of primary and secondary pollutants and the ratios between species having different chemical lifetimes. Photochemical processing of aerosol and secondary formation or organic acids was evident during the transport of MPC plumes. Urban plumes mix efficiently with natural sources as mineral dust and with biomass burning emissions from vegetation and forest fires. This confirms the importance of wildland fire emissions in Europe and indicates an important but discontinuous contribution to the European emission budget that might be of relevance in the design of efficient mitigation strategies. The present work provides an overview of the most salient results in the European context, with these being addressed in more detail within additional dedicated EMeRGe studies. The deployment and results obtained in Asia will be the subject of separate publications