Eligibility of patients with Staphylococcus aureus bacteraemia for early oral switch

To identify people with low-risk Staphylococcus aureus bacteraemia (SAB), the SABATO investigators screened 5063 people, finding 213 (4·2%) meeting their eligibility criteria1. This low proportion of eligible patients led the authors to question if low-risk SAB is clinically relevant. We aimed to determine the clinical relevance of the SABATO definition of low-risk SAB, and if the trial population was representative of potentially eligible real-world patients. Data was collected retrospectively for 464 consecutive adults with SAB at our institution (Supplementary Figure), approved by the South East Scotland Research Ethics Committee (23/SS/0025). We then applied the SABATO inclusion and exclusion criteria to identify potentially eligible real-world patients.Of the 464 patients in our cohort, 71 (15·3%) would have been potentially eligible for inclusion in the trial. Acquisition of SAB in these patients was mainly nosocomial (35/71, 49·3%). Key cohort characteristics reported by the trial were very similar when comparing trial participants with potentially eligible real-world patients, although the median Charlson Comorbidity Index was lower in the trial cohort (Table). An intravenous catheter was the most common source of SAB in both cohorts, but there was a higher proportion of SAB from an unknown source in the real-world group (p=0·0015). An unknown source is a risk factor for complications2,3 and further evaluation combined with intensive follow-up of early oral switch should be considered in this group.Implanted prosthetic material is a component of the IDSA definition of complicated SAB4 but with certain caveats was not an absolute exclusion criterion in the SABATO trial. Nine potentially eligible real-world patients had prosthetic material in situ (n=4 cardiac devices and n=5 orthopaedic implants). This data was not reported for trial participants but could further increase confidence in applicability of the findings. No laboratory or physiology data from the time of the index blood culture was reported but might have been helpful to quantify disease severity and guide patient selection (Supplementary Table). We suggest this supports standardised collection and reporting of cohort characteristics in SAB trials to improve comparability between studies, which is often complicated by variability in the cohort characteristics reported5.We conclude that the sub-group of low-risk SAB studied in the SABATO trial is clinically relevant and find the similarities between randomised and real-world eligible patients re-assuring. Implementation of SABATO findings should be done cautiously and studied prospectively, especially when applied to patients with SAB of unknown source who were infrequently included in the trial.<br/

Detomidine and butorphanol for standing sedation in a range of zoo-kept ungulate species

General anesthesia poses risks for larger zoo species, like cardiorespiratory depression, myopathy, and hyperthermia. In ruminants, ruminal bloat and regurgitation of rumen contents with potential aspiration pneumonia are added risks. Thus, the use of sedation to perform minor procedures is justified in zoo animals. A combination of detomidine and butorphanol has been routinely used in domestic animals. This drug combination, administered by remote intramuscular injection, can also be applied for standing sedation in a range of zoo animals, allowing a number of minor procedures. The combination was successfully administered in five species of nondomesticated equids (Przewalski horse [Equus ferus przewalskii; n = 1], onager [Equus hemionus onager; n = 4], kiang [Equus kiang; n = 3], Grevy's zebra [Equus grevyi; n = 4], and Somali wild ass [Equus africanus somaliensis; n = 7]), with a mean dose range of 0.10-0.17 mg/kg detomidine and 0.07-0.13 mg/kg butorphanol; the white (Ceratotherium simum simum; n = 12) and greater one-horned rhinoceros (Rhinoceros unicornis; n = 4), with a mean dose of 0.015 mg/kg of both detomidine and butorphanol; and Asiatic elephant bulls (Elephas maximus; n = 2), with a mean dose of 0.018 mg/kg of both detomidine and butorphanol. In addition, the combination was successfully used for standing sedation in six species of artiodactylids: giraffe (Giraffa camelopardalis reticulata; n = 3), western bongo (Tragelaphus eurycerus eurycerus; n = 2), wisent (Bison bonasus; n = 5), yak (Bos grunniens; n = 1), water buffalo (Bubalus bubalis; n = 4) and Bactrian camel (Camelus bactrianus; n = 5). The mean dose range for artiodactylid species except bongo was 0.04-0.06 mg/kg detomidine and 0.03-0.06 mg/kg butorphanol. The dose in bongo, 0.15-0.20 mg/kg detomidine and 0.13-0.15 mg/kg butorphanol, was considerably higher. Times to first effect, approach, and recovery after antidote were short. The use of detomidine and butorphanol has been demonstrated to be a reliable, safe alternative to general anesthesia for a number of large ungulate species

Helminth induced monocytosis conveys protection from respiratory syncytial virus infection in mice

Flow cytometry data were generated with support from the QMRI Flow Cytometry and cell sorting facility, University of Edinburgh. We acknowledge Alison Munro of HTPU Microarray Services at the Institute of Genetics and Cancer for their technical support. or the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission. We thank Amy Buck (University of Edinburgh, United Kingdom) for providing H. polygyrus L3 larvae and Samanta Mariani (University of Edinburgh, United Kingdom) for advice on bone marrow Methocult assays.Peer reviewe

Clinical sub-phenotypes of Staphylococcus aureus bacteraemia

Background: Staphylococcus aureus bacteraemia (SAB) is a clinically heterogeneous disease. The ability to identify sub-groups of patients with shared traits (sub-phenotypes) is an unmet need that could allow patient stratification for clinical management and research. We aimed to test the hypothesis that clinically-relevant sub-phenotypes can be reproducibly identified amongst patients with SAB. Methods: We studied three cohorts of hospitalised adults with monomicrobial SAB: a UK retrospective observational study (Edinburgh cohort, n=458), the UK ARREST randomised trial (n=758), and the Spanish SAFO randomised trial (n=214). Latent class analysis was used to identify sub-phenotypes using routinely-collected clinical data, without considering outcomes. Mortality and microbiologic outcomes were then compared between sub-phenotypes. Results: Included patients had predominantly methicillin-susceptible SAB (1366/1430,95.5%). We identified five distinct, reproducible clinical sub-phenotypes: (A) SAB associated with older age and comorbidity, (B) nosocomial intravenous catheter-associated SAB in younger people without comorbidity, (C) community-acquired metastatic SAB, (D) SAB associated with chronic kidney disease, and (E) SAB associated with injection drug use. Survival and microbiologic outcomes differed between the sub-phenotypes. 84-day mortality was highest in sub-phenotype A, and lowest in B and E. Microbiologic outcomes were worse in sub-phenotype C. In a secondary analysis of the ARREST trial, adjunctive rifampicin was associated with increased 84-day mortality in sub-phenotype B and improved microbiologic outcomes in sub-phenotype C. Conclusions: We have identified reproducible and clinically-relevant sub-phenotypes within SAB, and provide proof-of-principle of differential treatment effects. Through clinical trial enrichment and patient stratification, these sub-phenotypes could contribute to a personalised medicine approach to SAB

Vascular mechanisms of post-COVID-19 conditions: rho-kinase is a novel target for therapy

BackgroundIn post-COVID-19 conditions (Long COVID), systemic vascular dysfunction is implicated but the mechanisms are uncertain, and treatment is imprecise.MethodsPatients convalescing after hospitalisation for COVID-19 and risk-factor matched controls underwent multisystem phenotyping using blood biomarkers, cardiorenal and pulmonary imaging, and gluteal subcutaneous biopsy (NCT04403607). Small resistance arteries were isolated and examined using wire myography, histopathology, immunohistochemistry, and spatial transcriptomics. Endothelium-independent (sodium nitroprusside) and -dependent (acetylcholine) vasorelaxation and vasoconstriction to the thromboxane A2 receptor agonist, U46619, and endothelin-1 (ET-1) in the presence or absence of a RhoA/Rho-kinase inhibitor (fasudil), were investigated.ResultsThirty-seven patients, including 27 (mean age 57 years, 48% women, 41% cardiovascular disease) three months post-COVID-19 and 10 controls (mean age 57 years, 20% women, 30% cardiovascular disease), were included. Compared with control responses, U46619-induced constriction was increased (p = 0.002) and endothelium-independent vasorelaxation was reduced in arteries from COVID-19 patients (p < 0.001). This difference was abolished by fasudil. Histopathology revealed greater collagen abundance in COVID-19 arteries (Masson's Trichrome (MT) 69.7% [95%CI: 67.8, 71.7]; picrosirius red 68.6% [95% CI: 64.4, 72.8]) versus controls (MT 64.9% [95%CI:59.4, 70.3] [p = 0.028]; picrosirius red 60.1% [95% CI: 55.4, 64.8], [p = 0.029]). Greater phosphorylated myosin light chain antibody-positive staining in vascular smooth muscle cells was observed in COVID-19 arteries (40.1%; 95% CI: 30.9, 49.3) vs. controls (10.0%; 95% CI: 4.4, 15.6) (p < 0.001). In proof-of-concept studies, gene pathways associated with extracellular matrix alteration, proteoglycan synthesis, and viral mRNA replication appeared to be upregulated.ConclusionPatients with post-COVID-19 conditions have enhanced vascular fibrosis and myosin light change phosphorylation. Rho-kinase activation represents a novel therapeutic target for clinical trials

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

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

MUSiC : a model-unspecific search for new physics in proton-proton collisions at root s=13TeV

Results of the Model Unspecific Search in CMS (MUSiC), using proton-proton collision data recorded at the LHC at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1), are presented. The MUSiC analysis searches for anomalies that could be signatures of physics beyond the standard model. The analysis is based on the comparison of observed data with the standard model prediction, as determined from simulation, in several hundred final states and multiple kinematic distributions. Events containing at least one electron or muon are classified based on their final state topology, and an automated search algorithm surveys the observed data for deviations from the prediction. The sensitivity of the search is validated using multiple methods. No significant deviations from the predictions have been observed. For a wide range of final state topologies, agreement is found between the data and the standard model simulation. This analysis complements dedicated search analyses by significantly expanding the range of final states covered using a model independent approach with the largest data set to date to probe phase space regions beyond the reach of previous general searches.Peer reviewe

Search for new particles in events with energetic jets and large missing transverse momentum in proton-proton collisions at root s=13 TeV

A search is presented for new particles produced at the LHC in proton-proton collisions at root s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data sample corresponding to an integrated luminosity of 101 fb(-1), collected in 2017-2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with an earlier search based on a data sample of 36 fb(-1), collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control samples in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.Peer reviewe

Measurement of prompt open-charm production cross sections in proton-proton collisions at root s=13 TeV

The production cross sections for prompt open-charm mesons in proton-proton collisions at a center-of-mass energy of 13TeV are reported. The measurement is performed using a data sample collected by the CMS experiment corresponding to an integrated luminosity of 29 nb(-1). The differential production cross sections of the D*(+/-), D-+/-, and D-0 ((D) over bar (0)) mesons are presented in ranges of transverse momentum and pseudorapidity 4 < p(T) < 100 GeV and vertical bar eta vertical bar < 2.1, respectively. The results are compared to several theoretical calculations and to previous measurements.Peer reviewe