Urinary tract infection (UTI) is a common ailment but can develop into sepsis. The outcomes related to UTI may potentially be affected by both patient and clinician management of UTI.
To explore the ...circumstances around a single UTI episode to determine whether there are patient and clinician-related variables that may contribute to differences in management.
Survey and clinical audit in 12 general practices in England.
Patients (
= 504) completed a bespoke survey and their corresponding index UTI consultation was audited. The TARGET (Treat Antibiotics Responsibly, Guidance, Education and Tools) UTI audit toolkit was utilised.
A significantly higher proportion of females compared with males used self-management measures. Increase in fluid intake was 78% for females aged <65 years and 71% for females aged >65 years compared with 53% for males (
<0.001, Χ
test). Analgesic use was 50% for females aged <65 years and 41% for females aged >65 years compared with 36% for males (
= 0.036, Χ
test). Males also indicated they lacked UTI knowledge when compared with females (
= 0.002, Kruskal-Wallis test). Males also claimed to have waited significantly longer for a consultation appointment (
= 0.027, Χ
test). Antibiotics were prescribed in 98% of all cases, with adherence to clinical diagnostic guidelines lowest in females aged <65 years. Only 40% (89/221 of cases in this guideline sub-cohort females aged >65 years) would have been a UTI, according to TARGET criteria, following a medical record audit.
UTI symptom management by clinicians is suboptimal; the presence or absence of symptoms is often insufficiently recorded in medical records. Additionally, suboptimal adherence to guidelines concerning urinalysis and microbiological investigation is common. Known increased clinical risks for males may be compounded by their more limited knowledge of (self)-managing UTI and their comparatively late presentation.
Rotavirus is the leading cause of acute gastroenteritis requiring hospitalization in young children. Data on the burden of rotavirus gastroenteritis are needed to guide recommendations for rotavirus ...vaccine use. This study was undertaken to estimate the burden of rotavirus gastroenteritis in European children <5 years of age.
This prospective, study was conducted in 12 hospitals in France, Germany, Italy, Spain, and the United Kingdom. A sample of all children aged <5 years presenting to emergency departments or hospitalized because of community-acquired acute gastroenteritis was enrolled for parental interview and stool collection. Acute gastroenteritis was defined as diarrhea (>/=3 loose stools per 24 hours) for <14 days. Rotavirus was detected by enzyme-linked immunosorbent assay and typed by reverse-transcriptase polymerase chain reaction.
Between February 2005 and August 2006, 3734 children with community-acquired acute gastroenteritis were recruited and retained for analysis (55.9% via the emergency department, 41.8% hospitalized). Of the 2928 community-acquired acute gastroenteritis cases for which stool samples were available, 43.4% were rotavirus-positive by enzyme-linked immunosorbent assay (32.8% emergency department, 56.2% hospitalized). Of these rotavirus gastroenteritis cases 80.9% occurred in children aged <2 years and 15.9% among infants aged <6 months. Acute gastroenteritis was more severe in rotavirus-positive subjects (Vesikari score >/= 11 in 53.3% compared with 31.0% of rotavirus-negative subjects). All 1271 rotavirus-positive strains were genotyped (G1P8: 40.3%; G9P8: 31.2%; G4P8: 13.5%; G3P8: 7.1%).
Rotavirus gastroenteritis places high demands on European health care systems, accounting for 56.2% of hospitalizations and 32.8% of emergency department visits because of community-acquired acute gastroenteritis in children aged <5 years. Most community-acquired rotavirus gastroenteritis occurs in children aged <2 years, and a high proportion occurs in infants aged <6 months. Cases were also observed among very young infants <2 months of age. Rotavirus vaccination is expected to have a major impact in reducing morbidity and the pressure on hospital services in Europe.
ObjectivesTo assess practice in the care of adults with suspected community-acquired bacterial meningitis in the UK and Ireland.DesignRetrospective cohort study.Setting64 UK and Irish ...hospitals.Participants1471 adults with community-acquired meningitis of any aetiology in 2017.ResultsNone of the audit standards, from the 2016 UK Joint Specialists Societies guideline on diagnosis and management of meningitis, were met in all cases. With respect to 20 of 30 assessed standards, clinical management provided for patients was in line with recommendations in less than 50% of cases. 45% of patients had blood cultures taken within an hour of admission, 0.5% had a lumbar puncture within 1 hour, 26% within 8 hours. 28% had bacterial molecular diagnostic tests on cerebrospinal fluid. Median time to first dose of antibiotics was 3.2 hours (IQR 1.3–9.2). 80% received empirical parenteral cephalosporins. 55% ≥60 years and 31% of immunocompromised patients received anti-Listeria antibiotics. 21% received steroids. Of the 1471 patients, 20% had confirmed bacterial meningitis. Among those with bacterial meningitis, pneumococcal aetiology, admission to intensive care and initial Glasgow Coma Scale Score less than 14 were associated with in-hospital mortality (adjusted OR (aOR) 2.08, 95% CI 0.96 to 4.48; aOR 4.28, 95% CI 1.81 to 10.1; aOR 2.90, 95% CI 1.26 to 6.71, respectively). Dexamethasone therapy was weakly associated with a reduction in mortality in both those with proven bacterial meningitis (aOR 0.57, 95% CI 0.28 to 1.17) and with pneumococcal meningitis (aOR 0.47, 95% CI 0.20 to 1.10).ConclusionThis study demonstrates that clinical care for patients with meningitis in the UK is not in line with current evidence-based national guidelines. Diagnostics and therapeutics should be targeted for quality improvement strategies. Work should be done to improve the impact of guidelines, understand why they are not followed and, once published, ensure they translate into changed practice.
bacteraemia is a common and frequently fatal infection. Adjunctive rifampicin may enhance early
killing, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, ...metastatic infection and death.
To determine whether or not adjunctive rifampicin reduces bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. Secondary objectives included evaluating the impact of rifampicin on all-cause mortality, clinically defined failure/recurrence or death, toxicity, resistance emergence, and duration of bacteraemia; and assessing the cost-effectiveness of rifampicin.
Parallel-group, randomised (1 : 1), blinded, placebo-controlled multicentre trial.
UK NHS trust hospitals.
Adult inpatients (≥ 18 years) with meticillin-resistant or susceptible
grown from one or more blood cultures, who had received < 96 hours of antibiotic therapy for the current infection, and without contraindications to rifampicin.
Adjunctive rifampicin (600-900 mg/day, oral or intravenous) or placebo for 14 days in addition to standard antibiotic therapy. Investigators and patients were blinded to trial treatment. Follow-up was for 12 weeks (assessments at 3, 7, 10 and 14 days, weekly until discharge and final assessment at 12 weeks post randomisation).
The primary outcome was all-cause bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation.
Between December 2012 and October 2016, 758 eligible participants from 29 UK hospitals were randomised: 370 to rifampicin and 388 to placebo. The median age was 65 years interquartile range (IQR) 50-76 years. A total of 485 (64.0%) infections were community acquired and 132 (17.4%) were nosocomial; 47 (6.2%) were caused by meticillin-resistant
. A total of 301 (39.7%) participants had an initial deep infection focus. Standard antibiotics were given for a median of 29 days (IQR 18-45 days) and 619 (81.7%) participants received flucloxacillin. By 12 weeks, 62 out of 370 (16.8%) patients taking rifampicin versus 71 out of 388 (18.3%) participants taking the placebo experienced bacteriological (microbiologically confirmed) failure/recurrence or died absolute risk difference -1.4%, 95% confidence interval (CI) -7.0% to 4.3%; hazard ratio 0.96, 95% CI 0.68 to 1.35;
= 0.81. There were 4 (1.1%) and 5 (1.3%) bacteriological failures (
= 0.82) in the rifampicin and placebo groups, respectively. There were 3 (0.8%) versus 16 (4.1%) bacteriological recurrences (
= 0.01), and 55 (14.9%) versus 50 (12.9%) deaths without bacteriological failure/recurrence (
= 0.30) in the rifampicin and placebo groups, respectively. Over 12 weeks, there was no evidence of differences in clinically defined failure/recurrence/death (
= 0.84), all-cause mortality (
= 0.60), serious (
= 0.17) or grade 3/4 (
= 0.36) adverse events (AEs). However, 63 (17.0%) participants in the rifampicin group versus 39 (10.1%) participants in the placebo group experienced antibiotic or trial drug-modifying AEs (
= 0.004), and 24 (6.5%) participants in the rifampicin group versus 6 (1.5%) participants in the placebo group experienced drug-interactions (
= 0.0005). Evaluation of the costs and health-related quality-of-life impacts revealed that an episode of
bacteraemia costs an average of £12,197 over 12 weeks. Rifampicin was estimated to save 10% of episode costs (
= 0.14). After adjustment, the effect of rifampicin on total quality-adjusted life-years (QALYs) was positive (0.004 QALYs), but not statistically significant (standard error 0.004 QALYs).
Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with
bacteraemia.
Given the substantial mortality, other antibiotic combinations or improved source management should be investigated.
Current Controlled Trials ISRCTN37666216, EudraCT 2012-000344-10 and Clinical Trials Authorisation 00316/0243/001.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 22, No. 59. See the NIHR Journals Library website for further project information.
A continuous time econometric modelling framework for
multivariate financial market event (or ‘transactions’) data is developed in which the model is specified via the vector conditional intensity. ...Generalised Hawkes models are introduced that incorporate inhibitory events and dependence between trading days. Novel omnibus specification tests based on a multivariate random time change theorem are proposed. A bivariate point process model of the timing of trades and mid-quote changes is then presented for a New York Stock Exchange stock and related to the market microstructure literature. The two-way interaction of trades and quote changes in continuous time is found to be important empirically.
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On 24th November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization ...titers of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, or the sera failed to neutralize. Titers against Omicron are boosted by third vaccine doses and are high in both vaccinated individuals and those infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of the large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses and uses mutations that confer tight binding to ACE2 to unleash evolution driven by immune escape. This leads to a large number of mutations in the ACE2 binding site and rebalances receptor affinity to that of earlier pandemic viruses.
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•Large reduction in Omicron neutralization titers, ameliorated by the 3rd booster vaccine•Failure of many potent mAbs to neutralize Omicron•Complex pattern of mutations balances ACE2 binding and antibody escape•Omicron RBD is structurally similar but the most antigenically distant variant
A comprehensive analysis of sera from vaccinees, convalescent patients previously infected by multiple variants, and potent monoclonal antibodies from early in the COVID-19 pandemic reveals a substantial overall reduction in the ability to neutralize the SARS-CoV-2 Omicron variant, which seems to ameliorate with a third vaccine dose. Structural analyses of the Omicron RBD suggest that selective pressure balances key changes that increase affinity for ACE2 with other changes in the receptor-binding motif that disfavor ACE2 binding but facilitate immune escape.
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The SARS-CoV-2 lineage B.1.1.7, designated variant of concern (VOC) 202012/01 by Public Health England
, was first identified in the UK in late summer to early autumn 2020
. Whole-genome SARS-CoV-2 ...sequence data collected from community-based diagnostic testing for COVID-19 show an extremely rapid expansion of the B.1.1.7 lineage during autumn 2020, suggesting that it has a selective advantage. Here we show that changes in VOC frequency inferred from genetic data correspond closely to changes inferred by S gene target failures (SGTF) in community-based diagnostic PCR testing. Analysis of trends in SGTF and non-SGTF case numbers in local areas across England shows that B.1.1.7 has higher transmissibility than non-VOC lineages, even if it has a different latent period or generation time. The SGTF data indicate a transient shift in the age composition of reported cases, with cases of B.1.1.7 including a larger share of under 20-year-olds than non-VOC cases. We estimated time-varying reproduction numbers for B.1.1.7 and co-circulating lineages using SGTF and genomic data. The best-supported models did not indicate a substantial difference in VOC transmissibility among different age groups, but all analyses agreed that B.1.1.7 has a substantial transmission advantage over other lineages, with a 50% to 100% higher reproduction number.
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The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the ...delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes.
This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status.
Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years IQR 17–43) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio HR 2·26 95% CI 1·32–3·89). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 1·08–1·95). Most patients were unvaccinated (32 078 74·0% across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 95% CI 0·47–8·05 and for hospital admission or emergency care attendance 1·58 0·69–3·61) were similar to the HRs for unvaccinated patients (2·32 1·29–4·16 and 1·43 1·04–1·97; p=0·82 for both) but the precision for the vaccinated subgroup was low.
This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant.
Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research.
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The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein
and is a major antibody target. Here ...we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.
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Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the ...hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant.
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•Increasing frequency of SARS-CoV-2 D614G is consistent with a selective advantage•Phylodynamic analyses do not show significantly different growth of D614G clusters•There is no association of D614G replacement with greater severity of infection•The D614G replacement is associated with higher viral loads and younger patient age
Analysis of the spread and frequency of SARS-CoV-2 D614G in the United Kingdom suggests a selective advantage for this strain that is associated with higher viral loads in younger patients but not higher COVID-19 clinical severity or mortality.
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