The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors

Acknowledgments The authors wish to acknowledge the NIH-sponsored Mutant Mouse Regional Resource Center (MMRRC) National System as the source of genetically-altered mice (C57BL/6-Clec4etm1.1Cfg/Mmucd 031936-UCD) for use in this study. The mice were produced and deposited to the MMRRC by the Consortium for Functional Glycomics supported by the National Institute of General Medical Sciences (GM62116). We would like to thank Catherine Neiseryan and Ann Kift-Morgan for cell sorting. We would like to thank Wales Gene Park for providing computer resources that assisted this research. Funding: SJO was funded by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 099953/Z/12/Z) and by a Wellcome Trust ISSF Cross-Disciplinary Award. LCD is supported by a Henry Wellcome Trust Postdoctoral Fellowship (103973/Z/14/Z). CL is supported by a Kidney Research UK/MedImmune Joint Fellowship Award (PDF_006_20151127). GDB is funded by a Wellcome Trust Investigator Award (102705) and the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1). IRH is supported by a Wellcome Trust Senior Research Fellowship (207503/Z/17/Z). PRT is supported by a Wellcome Trust Investigator Award (107964/Z/15/Z) and the UK Dementia Research Institute. Funding URLs: https://wellcome.ac.uk/ https://royalsociety.org/ https://www.kidneyresearchuk.org/ https://mrc.ukri.org/ https://ukdri.ac.uk/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability: All relevant data apart from RNAseq files are within the manuscript and its Supporting Information files. RNAseq data files are available from ArrayExpress (https://www.ebi.ac.uk/arrayexpress/), (accession number E-MTAB-8030).Peer reviewedPublisher PD

Prioritization in visual search: Visual marking is not dependent on a mnemonic search

Visual marking (VM) refers to our ability to completely exclude old items from search when new stimuli are presented in our visual field. We examined whether this ability reflects an attentional scan of the old items, possibly allowing observers to apply inhibition of return or maintain a memory representation of already seen locations. In four experiments, we compared performance in two search conditions. In the double-search (DS) condition, we required participants to pay attention to a first set of items by having them search for a target within the set. Subsequently, they had to search a second set while the old items remained in the field. In the VM condition, the participants expected the target only to be in the second (new) set. Selection of new items in the DS condition was relatively poor and was always worse than would be expected if only the new stimuli had been searched. In contrast, selection of the new items in the VM condition was good and was equal to what would be expected if there had been an exclusive search of the new stimuli. These results were not altered when differences in Set 1 difficulty, task switching, and response generation were controlled for. We conclude that the mechanism of VM is distinct from mnemonic and/or serial inhibition-of-return processes as involved in search, although we also discuss possible links to more global and flexible inhibition-of-return processes not necessarily related to search

Causation, complexity, and the concert: the pragmatics of causal explanation in international relations

A causal explanation provides information about the causal history of whatever is being explained. However, most causal histories extend back almost infinitely and can be described in almost infinite detail. Causal explanations therefore involve choices about which elements of causal histories to pick out. These choices are pragmatic: they reflect our explanatory interests. When adjudicating between competing causal explanations, we must therefore consider not only questions of epistemic adequacy (whether we have good grounds for identifying certain factors as causes) but also questions of pragmatic adequacy (whether the aspects of the causal history picked out are salient to our explanatory interests). Recognizing that causal explanations differ pragmatically as well as epistemically is crucial for identifying what is at stake in competing explanations of the relative peacefulness of the nineteenth-century Concert system. It is also crucial for understanding how explanations of past events can inform policy prescription

Risk of Recurrent Arterial Ischemic Stroke in Childhood: A Prospective International Study.

Background and purposePublished cohorts of children with arterial ischemic stroke (AIS) in the 1990s to early 2000s reported 5-year cumulative recurrence rates approaching 20%. Since then, utilization of antithrombotic agents for secondary stroke prevention in children has increased. We sought to determine rates and predictors of recurrent stroke in the current era.MethodsThe Vascular Effects of Infection in Pediatric Stroke (VIPS) study enrolled 355 children with AIS at 37 international centers from 2009 to 2014 and followed them prospectively for recurrent stroke. Index and recurrent strokes underwent central review and confirmation, as well as central classification of causes of stroke, including arteriopathies. Other predictors were measured via parental interview or chart review.ResultsOf the 355 children, 354 survived their acute index stroke, and 308 (87%) were treated with an antithrombotic medication. During a median follow-up of 2.0 years (interquartile range, 1.0-3.0), 40 children had a recurrent AIS, and none had a hemorrhagic stroke. The cumulative stroke recurrence rate was 6.8% (95% confidence interval, 4.6%-10%) at 1 month and 12% (8.5%-15%) at 1 year. The sole predictor of recurrence was the presence of an arteriopathy, which increased the risk of recurrence 5-fold when compared with an idiopathic AIS (hazard ratio, 5.0; 95% confidence interval, 1.8-14). The 1-year recurrence rate was 32% (95% confidence interval, 18%-51%) for moyamoya, 25% (12%-48%) for transient cerebral arteriopathy, and 19% (8.5%-40%) for arterial dissection.ConclusionsChildren with AIS, particularly those with arteriopathy, remain at high risk for recurrent AIS despite increased utilization of antithrombotic agents. Therapies directed at the arteriopathies themselves are needed

International Nonregimes: A Research Agenda1

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146934/1/j.1468-2486.2007.00672.x.pd

Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: a systematic review and meta-analysis of individual patient data

BACKGROUND: Gametocytes are responsible for transmission of malaria from human to mosquito. Artemisinin combination therapy (ACT) reduces post-treatment gametocyte carriage, dependent upon host, parasite and pharmacodynamic factors. The gametocytocidal properties of antimalarial drugs are important for malaria elimination efforts. An individual patient clinical data meta-analysis was undertaken to identify the determinants of gametocyte carriage and the comparative effects of four ACTs: artemether-lumefantrine (AL), artesunate/amodiaquine (AS-AQ), artesunate/mefloquine (AS-MQ), and dihydroartemisinin-piperaquine (DP). METHODS: Factors associated with gametocytaemia prior to, and following, ACT treatment were identified in multivariable logistic or Cox regression analysis with random effects. All relevant studies were identified through a systematic review of PubMed. Risk of bias was evaluated based on study design, methodology, and missing data. RESULTS: The systematic review identified 169 published and 9 unpublished studies, 126 of which were shared with the WorldWide Antimalarial Resistance Network (WWARN) and 121 trials including 48,840 patients were included in the analysis. Prevalence of gametocytaemia by microscopy at enrolment was 12.1 % (5887/48,589), and increased with decreasing age, decreasing asexual parasite density and decreasing haemoglobin concentration, and was higher in patients without fever at presentation. After ACT treatment, gametocytaemia appeared in 1.9 % (95 % CI, 1.7–2.1) of patients. The appearance of gametocytaemia was lowest after AS-MQ and AL and significantly higher after DP (adjusted hazard ratio (AHR), 2.03; 95 % CI, 1.24–3.12; P = 0.005 compared to AL) and AS-AQ fixed dose combination (FDC) (AHR, 4.01; 95 % CI, 2.40–6.72; P < 0.001 compared to AL). Among individuals who had gametocytaemia before treatment, gametocytaemia clearance was significantly faster with AS-MQ (AHR, 1.26; 95 % CI, 1.00–1.60; P = 0.054) and slower with DP (AHR, 0.74; 95 % CI, 0.63–0.88; P = 0.001) compared to AL. Both recrudescent (adjusted odds ratio (AOR), 9.05; 95 % CI, 3.74–21.90; P < 0.001) and new (AOR, 3.03; 95 % CI, 1.66–5.54; P < 0.001) infections with asexual-stage parasites were strongly associated with development of gametocytaemia after day 7. CONCLUSIONS: AS-MQ and AL are more effective than DP and AS-AQ FDC in preventing gametocytaemia shortly after treatment, suggesting that the non-artemisinin partner drug or the timing of artemisinin dosing are important determinants of post-treatment gametocyte dynamics

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice