Available carbon source influences the resistance of Neisseria meningitidis against complement

Neisseria meningitidis is an important cause of septicaemia and meningitis. To cause disease, the bacterium must acquire essential nutrients for replication in the systemic circulation, while avoiding exclusion by host innate immunity. Here we show that the utilization of carbon sources by N. meningitidis determines its ability to withstand complement-mediated lysis, through the intimate relationship between metabolism and virulence in the bacterium. The gene encoding the lactate permease, lctP, was identified and disrupted. The lctP mutant had a reduced growth rate in cerebrospinal fluid compared with the wild type, and was attenuated during bloodstream infection through loss of resistance against complement-mediated killing. The link between lactate and complement was demonstrated by the restoration of virulence of the lctP mutant in complement (C3−/−)-deficient animals. The underlying mechanism for attenuation is mediated through the sialic acid biosynthesis pathway, which is directly connected to central carbon metabolism. The findings highlight the intimate relationship between bacterial physiology and resistance to innate immune killing in the meningococcus

Distinct Binding and Immunogenic Properties of the Gonococcal Homologue of Meningococcal Factor H Binding Protein

Neisseria meningitidis is a leading cause of sepsis and meningitis. The bacterium recruits factor H (fH), a negative regulator of the complement system, to its surface via fH binding protein (fHbp), providing a mechanism to avoid complement-mediated killing. fHbp is an important antigen that elicits protective immunity against the meningococcus and has been divided into three different variant groups, V1, V2 and V3, or families A and B. However, immunisation with fHbp V1 does not result in cross-protection against V2 and V3 and vice versa. Furthermore, high affinity binding of fH could impair immune responses against fHbp. Here, we investigate a homologue of fHbp in Neisseria gonorrhoeae, designated as Gonococcal homologue of fHbp (Ghfp) which we show is a promising vaccine candidate for N. meningitidis. We demonstrate that Gfhp is not expressed on the surface of the gonococcus and, despite its high level of identity with fHbp, does not bind fH. Substitution of only two amino acids in Ghfp is sufficient to confer fH binding, while the corresponding residues in V3 fHbp are essential for high affinity fH binding. Furthermore, immune responses against Ghfp recognise V1, V2 and V3 fHbps expressed by a range of clinical isolates, and have serum bactericidal activity against N. meningitidis expressing fHbps from all variant groups

A generic mechanism in Neisseria meningitidis for enhanced resistance against bactericidal antibodies

The presence of serum bactericidal antibodies is a proven correlate of protection against systemic infection with the important human pathogen Neisseria meningitidis. We have identified three serogroup C N. meningitidis (MenC) isolates recovered from patients with invasive meningococcal disease that resist killing by bactericidal antibodies induced by the MenC conjugate vaccine. None of the patients had received the vaccine, which has been successfully introduced in countries in North America and Europe. The increased resistance was not caused by changes either in lipopolysaccharide sialylation or acetylation of the α2-9–linked polysialic acid capsule. Instead, the resistance of the isolates resulted from the presence of an insertion sequence, IS1301, in the intergenic region (IGR) between the sia and ctr operons, which are necessary for capsule biosynthesis and export, respectively. The insertion sequence led to an increase in the transcript levels of surrounding genes and the amount of capsule expressed by the strains. The increased amount of capsule was associated with down-regulation of the alternative pathway of complement activation, providing a generic mechanism by which the bacterium protects itself against bactericidal antibodies. The strains with IS1301 in the IGR avoided complement-mediated lysis in the presence of bactericidal antibodies directed at the outer membrane protein, PorA, or raised against whole cells

Towards a standardized protocol to assess natural capital and ecosystem services in solar parks

1. Natural capital and ecosystem services have emerged as fundamental concepts of ecosystem management strategies in the past two decades, particularly within major international land assessment frameworks, including the UN's Millennium Ecosystem Assessment and the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services' Global Assessment Report. 2. Despite the recent development of several analytical methods and models to quantify changes in natural capital and ecosystem services resulting from land use change, incorporating them into the land planning process can be challenging from a practical point of view without guidance on standard methods. 3. In an attempt to decarbonize energy supply systems to meet internationally agreed targets on climate change, solar energy production, in the form of ground-mounted solar parks, is emerging as one of the dominant forms of temporary land use for renewable energies globally. 4. We propose 19 directly measurable indicators associated with 16 ecosystem services within three major stocks of natural capital (biodiversity, soil and water) that are most likely to be impacted by the development of solar parks. Indicators are supported by well-established methods that have been widely used in pure and applied land use research within terrestrial ecosystems. Moreover, they can be implemented flexibly according to interest or land management objectives. 5. Whilst not intended as a precise recipe for how to assess the effects of solar park development on hosting ecosystems, the protocol will guide the solar energy industry and all actors involved, be they researchers, practitioners, ecological consultancies or statutory bodies, to implement a standardized approach to evaluate temporal and spatial changes in natural capital and ecosystem services resulting from solar park development and operation, with the ultimate aim of generating comparable and reproducible data on ecosystem impact assessment across the solar energy sector

Environmental factors associated with general practitioner consultations for allergic rhinitis in London, England: a retrospective time series analysis

Objectives: To identify key predictors of general practitioner (GP) consultations for allergic rhinitis (AR) using meteorological and environmental data. Design: A retrospective, time series analysis of GP consultations for AR. Setting: A large GP surveillance network of GP practices in the London area. Participants: The study population was all persons who presented to general practices in London that report to the Public Health England GP in-hours syndromic surveillance system during the study period (3 April 2012 to 11 August 2014). Primary measure: Consultations for AR (numbers of consultations). Results: During the study period there were 186 401 GP consultations for AR. High grass and nettle pollen counts (combined) were associated with the highest increases in consultations (for the category 216-270 grains/m3, relative risk (RR) 3.33, 95% CI 2.69 to 4.12) followed by high tree (oak, birch and plane combined) pollen counts (for the category 260–325 grains/m3, RR 1.69, 95% CI 1.32 to 2.15) and average daily temperatures between 15°C and 20°C (RR 1.47, 95% CI 1.20 to 1.81). Higher levels of nitrogen dioxide (NO2) appeared to be associated with increased consultations (for the category 70–85 µg/m3, RR 1.33, 95% CI 1.03 to 1.71), but a significant effect was not found with ozone. Higher daily rainfall was associated with fewer consultations (15–20 mm/day; RR 0.812, 95% CI 0.674 to 0.980). Conclusions: Changes in grass, nettle or tree pollen counts, temperatures between 15°C and 20°C, and (to a lesser extent) NO2 concentrations were found to be associated with increased consultations for AR. Rainfall has a negative effect. In the context of climate change and continued exposures to environmental air pollution, intelligent use of these data will aid targeting public health messages and plan healthcare demand

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Paramedic Acute Stroke Treatment Assessment (PASTA): study protocol for a randomised controlled trial

BACKGROUND: Despite evidence from clinical trials that intravenous (IV) thrombolysis is a cost-effective treatment for selected acute ischaemic stroke patients, there remain large variations in the rate of IV thrombolysis delivery between stroke services. This study is evaluating whether an enhanced care pathway delivered by paramedics (the Paramedic Acute Stroke Treatment Assessment (PASTA)) could increase the number of patients who receive IV thrombolysis treatment. METHODS: Study design: Cluster randomised trial with economic analysis and parallel process evaluation. SETTING: National Health Service ambulance services, emergency departments and hyper-acute stroke units within three geographical regions of England and Wales. Randomisation: Ambulance stations within each region are the units of randomisation. According to station allocation, paramedics based at a station deliver the PASTA pathway (intervention) or continue with standard stroke care (control). Study intervention: The PASTA pathway includes structured pre-hospital information collection, prompted pre-notification, structured handover of information in hospital and assistance with simple tasks during the initial hospital assessment. Study-trained intervention group paramedics deliver this pathway to adults within 4 h of suspected stroke onset. Study control: Standard stroke care according to national and local guidelines for the pre-hospital and hospital assessment of suspected stroke. PARTICIPANTS: Participants enrolled in the study are adults with confirmed stroke who were assessed by a study paramedic within 4 h of symptom onset. PRIMARY OUTCOME: Proportion of participants receiving IV thrombolysis. SAMPLE SIZE: 1297 participants provide 90% power to detect a 10% difference in the proportion of patients receiving IV thrombolysis. DISCUSSION: The results from this trial will determine whether an enhanced care pathway delivered by paramedics can increase thrombolysis delivery rates. TRIAL REGISTRATION: ISRCTN registry, ISRCTN12418919 . Registered on 5 November 2015