Publications by authors named "Sarah Walker"

493 Publications

Quantitative SARS-CoV-2 anti-spike responses to Pfizer-BioNTech and Oxford-AstraZeneca vaccines by previous infection status.

Clin Microbiol Infect 2021 Jun 7. Epub 2021 Jun 7.

Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Objectives: We investigate determinants of SARS-CoV-2 anti-spike IgG responses in healthcare workers (HCWs) following one or two doses of Pfizer-BioNTech or Oxford-AstraZeneca vaccines.

Methods: HCWs participating in regular SARS-CoV-2 PCR and antibody testing were invited for serological testing prior to first and second vaccination, and 4 weeks post-vaccination if receiving a 12-week dosing interval. Quantitative post-vaccination anti-spike antibody responses were measured using the Abbott SARS-CoV-2 IgG II Quant assay (detection threshold: ≥50 AU/ml). We used multivariable logistic regression to identify predictors of seropositivity and generalised additive models to track antibody responses over time.

Results: 3570/3610(98.9%) HCWs were seropositive >14 days post-first vaccination and prior to second vaccination, 2706/2720(99.5%) after Pfizer-BioNTech and 864/890(97.1%) following Oxford-AstraZeneca vaccines. Previously infected and younger HCWs were more likely to test seropositive post-first vaccination, with no evidence of differences by sex or ethnicity. All 470 HCWs tested >14 days after second vaccine were seropositive. Quantitative antibody responses were higher after previous infection: median(IQR) >21 days post-first Pfizer-BioNTech 14,604(7644-22,291) AU/ml vs. 1028(564-1985) AU/ml without prior infection (p<0.001). Oxford-AstraZeneca vaccine recipients had lower readings post-first dose compared to Pfizer-BioNTech, with and without previous infection, 10,095(5354-17,096) and 435(203-962) AU/ml respectively (both p<0.001 vs. Pfizer-BioNTech). Antibody responses >21 days post-second Pfizer vaccination in those not previously infected, 10,058 (6408-15,582) AU/ml, were similar to those after prior infection and one vaccine dose.

Conclusions: SARS-CoV-2 vaccination leads to detectable anti-spike antibodies in nearly all adult HCWs. Whether differences in response impact vaccine efficacy needs further study.
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http://dx.doi.org/10.1016/j.cmi.2021.05.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180449PMC
June 2021

Utility of whole genome sequencing in assessing and enhancing partner notification of Neisseria gonorrhoeae infection.

Sex Transm Dis 2021 Mar 12. Epub 2021 Mar 12.

1Leeds Teaching Hospitals NHS Trust, UK 2Leeds Institute for Medical Research, Faculty of Medicine and Health, University of Leeds, UK 3Leeds Sexual Health, UK 4Nuffield Department of Medicine, University of Oxford, UK 5Public Health England, UK 6NIHR Oxford Biomedical Research Centre, University of Oxford, UK 7NIHR Health Protection Research Centre in Antimicrobial Resistance and Healthcare Associated Infections, University of Oxford, UK.

Background: Gonorrhea is a sexually transmitted infection of global concern. We investigated whole genome sequencing (WGS) as a tool to measure and enhance partner notification (PN) in gonorrhea management.

Methods: Between May-November 2018, all N. gonorrhoeae isolated from patients attending Leeds Sexual Health, UK, underwent WGS. Reports listing sequences within 20 single nucleotide polymorphisms (SNPs) of study isolates within a database containing select isolates from April 1 2016 to November 15 2018 were issued to clinicians. The proportion of cases with a potential transmission partner identified by PN was determined from patient and PN data. WGS reports were reviewed to identify additional cases within ≤6 SNPs and verified for PN concordance.

Results: 380 isolates from 377 cases were successfully sequenced; 292 had traceable/contactable partners and 69 (18%) had a potential transmission partner identified by PN. Concordant PN and WGS links were identified in 47 partner pairs. Of 308 cases with no transmission partner by PN, 185 (60%) had a case within ≤6 SNPs; examination of these cases' PN data identified seven partner pairs with previously unrecognized PN link, giving a total of 54 pairs; all had ≤4 SNP differences. WGS clusters confirmed gaps in partner finding, at individual and group levels. Despite the clinic providing sexual health services to the whole city, 35 cases with multiple partners had no genetically related case, suggesting multiple undiagnosed infections.

Conclusions: WGS could improve gonorrhea PN and control by identifying new links and clusters with significant gaps in partner finding.
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http://dx.doi.org/10.1097/OLQ.0000000000001419DOI Listing
March 2021

Impact of vaccination on new SARS-CoV-2 infections in the United Kingdom.

Nat Med 2021 Jun 9. Epub 2021 Jun 9.

National Institute for Health Research (NIHR) Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, University of Oxford, Oxford, UK.

The effectiveness of COVID-19 vaccination in preventing new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the general community is still unclear. Here, we used the Office for National Statistics COVID-19 Infection Survey-a large community-based survey of individuals living in randomly selected private households across the United Kingdom-to assess the effectiveness of the BNT162b2 (Pfizer-BioNTech) and ChAdOx1 nCoV-19 (Oxford-AstraZeneca; ChAdOx1) vaccines against any new SARS-CoV-2 PCR-positive tests, split according to self-reported symptoms, cycle threshold value (<30 versus ≥30; as a surrogate for viral load) and gene positivity pattern (compatible with B.1.1.7 or not). Using 1,945,071 real-time PCR results from nose and throat swabs taken from 383,812 participants between 1 December 2020 and 8 May 2021, we found that vaccination with the ChAdOx1 or BNT162b2 vaccines already reduced SARS-CoV-2 infections ≥21 d after the first dose (61% (95% confidence interval (CI) = 54-68%) versus 66% (95% CI = 60-71%), respectively), with greater reductions observed after a second dose (79% (95% CI = 65-88%) versus 80% (95% CI = 73-85%), respectively). The largest reductions were observed for symptomatic infections and/or infections with a higher viral burden. Overall, COVID-19 vaccination reduced the number of new SARS-CoV-2 infections, with the largest benefit received after two vaccinations and against symptomatic and high viral burden infections, and with no evidence of a difference between the BNT162b2 and ChAdOx1 vaccines.
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http://dx.doi.org/10.1038/s41591-021-01410-wDOI Listing
June 2021

Essential role of the histone lysine demethylase KDM4A in the biology of malignant pleural mesothelioma (MPM).

Br J Cancer 2021 Jun 4. Epub 2021 Jun 4.

Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA.

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a dismal prognosis. There is increasing interest in targeting chromatin regulatory pathways in difficult-to-treat cancers. In preliminary studies, we found that KDM4A (lysine-specific histone demethylase 4) was overexpressed in MPM.

Methods: KDM4A protein expression was determined by immunohistochemistry or immunoblotting. Functional inhibition of KDM4A by targeted knockdown and small molecule drugs was correlated to cell growth using cell lines and a xenograft mouse model. Gene expression profiling was performed to identify KDM4A-dependent signature pathways.

Results: Levels of KDM4A were found to be significantly elevated in MPM patients compared to normal mesothelial tissue. Inhibiting the enzyme activity efficiently reduced cell growth in vitro and reduced tumour growth in vivo. KDM4A inhibitor-induced apoptosis was further enhanced by the BH3 mimetic navitoclax. KDM4A expression was associated with pathways involved in cell growth and DNA repair. Interestingly, inhibitors of the DNA damage and replication checkpoint regulators CHK1 (prexasertib) and WEE1 (adavosertib) within the DNA double-strand break repair pathway, cooperated in the inhibition of cell growth.

Conclusions: The results establish a novel and essential role for KDM4A in growth in preclinical models of MPM and identify potential therapeutic approaches to target KDM4A-dependent vulnerabilities.
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http://dx.doi.org/10.1038/s41416-021-01441-7DOI Listing
June 2021

Global antibiotic dosing strategies in hospitalised children: Characterising variation and implications for harmonisation of international guidelines.

PLoS One 2021 27;16(5):e0252223. Epub 2021 May 27.

Paediatric Infectious Diseases Research Group, Institute for Infection and Immunity, St George's University, London, United Kingdom.

Background: Paediatric global antibiotic guidelines are inconsistent, most likely due to the limited pharmacokinetic and efficacy data in this population. We investigated factors underlying variation in antibiotic dosing using data from five global point prevalence surveys.

Methods & Findings: Data from 3,367 doses of the 16 most frequent intravenous antibiotics administered to children 1 month-12 years across 23 countries were analysed. For each antibiotic, we identified standard doses given as either weight-based doses (in mg/kg/day) or fixed daily doses (in mg/day), and investigated the pattern of dosing using each strategy. Factors underlying observed variation in weight-based doses were investigated using linear mixed effects models. Weight-based dosing (in mg/kg/day) clustered around a small number of peaks, and all antibiotics had 1-3 standard weight-based doses used in 5%-48% of doses. Dosing strategy was more often weight-based than fixed daily dosing for all antibiotics apart from teicoplanin, which had approximately equal proportions of dosing attributable to each strategy. No strong consistent patterns emerged to explain the historical variation in actual weight-based doses used apart from higher dosing seen in central nervous system infections, and lower in skin and soft tissue infections compared to lower respiratory tract infections. Higher dosing was noted in the Americas compared to the European region.

Conclusions: Antibiotic dosing in children clusters around a small number of doses, although variation remains. There is a clear opportunity for the clinical, scientific and public health communities to consolidate behind a consistent set of global antibiotic dosing guidelines to harmonise current practice and prioritise future research.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252223PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159011PMC
May 2021

Flipping the Switch: An Unexpected Role for aEF1B in Modulating aEF1A Interactions with the Ribosome and tRNA.

J Mol Biol 2021 May 18:167052. Epub 2021 May 18.

Department of Biological Sciences, The State University of New York at Buffalo, United States. Electronic address:

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http://dx.doi.org/10.1016/j.jmb.2021.167052DOI Listing
May 2021

SARS-CoV-2 infectivity by viral load, S gene variants and demographic factors and the utility of lateral flow devices to prevent transmission.

Clin Infect Dis 2021 May 11. Epub 2021 May 11.

NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.

Background: How SARS-CoV-2 infectivity varies with viral load is incompletely understood. Whether rapid point-of-care antigen lateral flow devices (LFDs) detect most potential transmission sources despite imperfect clinical sensitivity is unknown.

Methods: We combined SARS-CoV-2 testing and contact tracing data from England between 01-September-2020 and 28-February-2021. We used multivariable logistic regression to investigate relationships between PCR-confirmed infection in contacts of community-diagnosed cases and index case viral load, S gene target failure (proxy for B.1.1.7 infection), demographics, SARS-CoV-2 incidence, social deprivation, and contact event type. We used LFD performance to simulate the proportion of cases with a PCR-positive contact expected to be detected using one of four LFDs.

Results: 231,498/2,474,066(9%) contacts of 1,064,004 index cases tested PCR-positive. PCR-positive results in contacts independently increased with higher case viral loads (lower Ct values) e.g., 11.7%(95%CI 11.5-12.0%) at Ct=15 and 4.5%(4.4-4.6%) at Ct=30. B.1.1.7 infection increased PCR-positive results by ~50%, (e.g. 1.55-fold, 95%CI 1.49-1.61, at Ct=20). PCR-positive results were most common in household contacts (at Ct=20.1, 8.7%[95%CI 8.6-8.9%]), followed by household visitors (7.1%[6.8-7.3%]), contacts at events/activities (5.2%[4.9-5.4%]), work/education (4.6%[4.4-4.8%]), and least common after outdoor contact (2.9%[2.3-3.8%]). Contacts of children were the least likely to test positive, particularly following contact outdoors or at work/education. The most and least sensitive LFDs would detect 89.5%(89.4-89.6%) and 83.0%(82.8-83.1%) of cases with PCR-positive contacts respectively.

Conclusions: SARS-CoV-2 infectivity varies by case viral load, contact event type, and age. Those with high viral loads are the most infectious. B.1.1.7 increased transmission by ~50%. The best performing LFDs detect most infectious cases.
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http://dx.doi.org/10.1093/cid/ciab421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136027PMC
May 2021

Sleep in Aneurysmal Subarachnoid Hemorrhage Patients During Critical and Acute Care.

Dimens Crit Care Nurs 2021 Mar-Apr 01;40(2):118-124

Background: Nurses caring for intensive care patients diagnosed with an aneurysmal subarachnoid hemorrhage (aSAH) conduct frequent neurological assessments and vital signs over an extended period during which patients are at risk of vasospasm. The frequency of assessments can negatively impact sleep, resulting in altered thought processes and mood, including delirium. There are 2 types of sleep during the night: non-rapid eye movement (non-REM) sleep and REM sleep (also called stage R). Non-REM sleep is subdivided into 3 stages: stage N1, stage N2, and stage N3. These 4 stages of sleep are referred to as sleep architecture.

Objective: The aim of this study was to explore patterns of sleep in patients with aSAH over time during hospitalization.

Methods: Sleep data of stages and cycles were collected with use of a Fitbit activity tracker in this pilot, exploratory research study. Demographic data included age and gender. Six English-speaking patients, diagnosed with an aneurysmal SAH, confirmed by diagnostic angiogram, were followed in neuro-intensive care unit (ICU), neuro-step-down, neuroscience unit, and inpatient rehabilitation.

Results: There were a total of 226 sleep events. A sleep event encompassed a recorded start and end time on a single date. Each event included several sleep cycles. Each sleep cycle consisted of wakefulness, light sleep, deep sleep, and REM sleep. In 79 sleep events, light and deep sleep did add up to more than 4 hours; only 38 sleep events indicated more than 90 minutes of REM/night; 61 events showed the cycle of light-deep-light-REM cycles; 80 events showed 3 to 5 REM periods/night; and only 46 events demonstrated that the early-morning REM cycle was the longest. The average number of REM cycles increased from ICU (n = 4.6) to rehabilitation (n = 6.5). The percentage of days with sleep cycles also increased from ICU to rehabilitation (42 to 64).

Discussion: "Normal" sleep patterns are disrupted in aSAH patients throughout their hospitalization. Data in this study revealed that the patients do sleep; however, it is rarely organized. Patients were not always able to progress through the expected sleep cycle of light to deep to light to REM. Hospitalized aSAH patients do engage in REM sleep, but its pattern is abnormal. Staff should strategize on minimizing interruptions, clustering care, and minimizing sounds. Nurses should advocate for the frequency of assessments and vital signs based on hospital/unit policy and individual patient needs.
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http://dx.doi.org/10.1097/DCC.0000000000000467DOI Listing
May 2021

Transfusion management of severe anaemia in African children: a consensus algorithm.

Br J Haematol 2021 May 6. Epub 2021 May 6.

Medical Research Council Clinical Trials Unit (MRC CTU), University College London, London, UK.

The phase III Transfusion and Treatment of severe anaemia in African Children Trial (TRACT) found that conservative management of uncomplicated severe anaemia [haemoglobin (Hb) 40-60 g/l] was safe, and that transfusion volume (20 vs. 30 ml/kg whole blood equivalent) for children with severe anaemia (Hb <60 g/l) had strong but opposing effects on mortality, depending on fever status (>37·5°C). In 2020 a stakeholder meeting of paediatric and blood transfusion groups from Africa reviewed the results and additional analyses. Among all 3196 children receiving an initial transfusion there was no evidence that nutritional status, presence of shock, malaria parasite burden or sickle cell disease status influenced outcomes or modified the interaction with fever status on volume required. Fever status at the time of ordering blood was a reliable determinant of volume required for optimal outcome. Elevated heart and respiratory rates normalised irrespective of transfusion volume and without diuretics. By consensus, a transfusion management algorithm was developed, incorporating three additional measurements of Hb post-admission, alongside clinical monitoring. The proposed algorithm should help clinicians safely implement findings from TRACT. Further research should assess its implementation in routine clinical practice.
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http://dx.doi.org/10.1111/bjh.17429DOI Listing
May 2021

Do existing real-world data sources generate suitable evidence for the HTA of medical devices in Europe? Mapping and critical appraisal.

Int J Technol Assess Health Care 2021 Apr 26;37(1):e62. Epub 2021 Apr 26.

Centre for Health Economics, University of York, York, UK.

Aim: Technological and computational advancements offer new tools for the collection and analysis of real-world data (RWD). Considering the substantial effort and resources devoted to collecting RWD, a greater return would be achieved if real-world evidence (RWE) was effectively used to support Health Technology Assessment (HTA) and decision making on medical technologies. A useful question is: To what extent are RWD suitable for generating RWE?

Methods: We mapped existing RWD sources in Europe for three case studies: hip and knee arthroplasty, transcatheter aortic valve implantation (TAVI) and mitral valve repair (TMVR), and robotic surgery procedures. We provided a comprehensive assessment of their content and appropriateness for conducting the HTA of medical devices. The identification of RWD sources was performed combining a systematic search on PubMed with gray literature scoping, covering fifteen European countries.

Results: We identified seventy-one RWD sources on arthroplasties; ninety-five on TAVI and TMVR; and seventy-seven on robotic procedures. The number, content, and integrity of the sources varied dramatically across countries. Most sources included at least one health outcome (97.5%), with mortality and rehospitalization/reoperation the most common; 80% of sources included resource outcomes, with length of stay the most common, and comparators were available in almost 70% of sources.

Conclusions: RWD sources bear the potential for the HTA of medical devices. The main challenges are data accessibility, a lack of standardization of health and economic outcomes, and inadequate comparators. These findings are crucial to enabling the incorporation of RWD into decision making and represent a readily available tool for getting acquainted with existing information sources.
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http://dx.doi.org/10.1017/S0266462321000301DOI Listing
April 2021

Personalised randomised controlled trial designs-a new paradigm to define optimal treatments for carbapenem-resistant infections.

Lancet Infect Dis 2021 06 21;21(6):e175-e181. Epub 2021 Apr 21.

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK; and Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam. Electronic address:

Antimicrobial resistance is impacting treatment decisions for, and patient outcomes from, bacterial infections worldwide, with particular threats from infections with carbapenem-resistant Enterobacteriaceae, Acinetobacter baumanii, or Pseudomonas aeruginosa. Numerous areas of clinical uncertainty surround the treatment of these highly resistant infections, yet substantial obstacles exist to the design and conduct of treatment trials for carbapenem-resistant bacterial infections. These include the lack of a widely acceptable optimised standard of care and control regimens, varying antimicrobial susceptibilities and clinical contraindications making specific intervention regimens infeasible, and diagnostic and recruitment challenges. The current single comparator trials are not designed to answer the urgent public health question, identified as a high priority by WHO, of what are the best regimens out of the available options that will significantly reduce morbidity, costs, and mortality. This scenario has an analogy in network meta-analysis, which compares multiple treatments in an evidence synthesis to rank the best of a set of available treatments. To address these obstacles, we propose extending the network meta-analysis approach to individual randomisation of patients. We refer to this approach as a Personalised RAndomised Controlled Trial (PRACTical) design that compares multiple treatments in an evidence synthesis, to identify, overall, which is the best treatment out of a set of available treatments to recommend, or how these different treatments rank against each other. In this Personal View, we summarise the design principles of personalised randomised controlled trial designs. Specifically, of a network of different potential regimens for life-threatening carbapenem-resistant infections, each patient would be randomly assigned only to regimens considered clinically reasonable for that patient at that time, incorporating antimicrobial susceptibility, toxicity profile, pharmacometric properties, availability, and physician assessment. Analysis can use both direct and indirect comparisons across the network, analogous to network meta-analysis. This new trial design will maximise the relevance of the findings to each individual patient, and enable the top-ranked regimens from any personalised randomisation list to be identified, in terms of both efficacy and safety.
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http://dx.doi.org/10.1016/S1473-3099(20)30791-XDOI Listing
June 2021

Failure of Vitek2 to reliably detect vanB-mediated vancomycin resistance in Enterococcus faecium.

J Antimicrob Chemother 2021 Apr 14. Epub 2021 Apr 14.

Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, Cologne, Germany.

Objectives: The increasing prevalence of VRE necessitates their reliable detection, especially for low-level resistance mediated by vanB in Enterococcus faecium. In this prospective study we analysed if vanB-mediated vancomycin resistance can be reliably detected by Vitek2.

Methods: One thousand, three hundred and forty-four enterococcal isolates from routine clinical specimens were tested by Vitek2 (bioMérieux, Nürtingen, Germany). Additionally, a bacterial suspension (with a turbidity equivalent to that of a 0.5 McFarland standard) was inoculated on chromID VRE screening agar (bioMérieux) and incubated for 48 h. If vancomycin tested susceptible by Vitek2 but growth was detected on the screening agar, PCR for vanA/vanB was performed (GeneXpert vanA/B test, Cepheid, Frankfurt, Germany). For isolates that tested susceptible to vancomycin by Vitek2 but were vanA/B positive, MICs were determined before and after cultivation in broth with increasing concentrations of vancomycin.

Results: One hundred and fifty-six out of 491 E. faecium were VRE and were predominantly vanB positive (81.0%). Of these, Vitek2 did not identify 14 as VRE (sensitivity 91.0%). By broth microdilution 9/14 isolates demonstrated high MICs (≥32 mg/L) and 5/14 showed low vancomycin MICs, which did not increase despite vancomycin exposure. Three of the 14 isolates demonstrated growth on chromID VRE; after vancomycin exposure seven additional isolates were able to grow on chromID VRE.

Conclusions: Vitek2 fails to detect vanB-mediated vancomycin resistance consistently, especially, but not limited to, low-level resistance. As this may lead to treatment failure and further dissemination of vanB VRE, additional methods (e.g. culture on VRE screening agar or PCR) are necessary to reliably identify vanB-positive enterococci in clinical routine.
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http://dx.doi.org/10.1093/jac/dkab101DOI Listing
April 2021

Niche and local geography shape the pangenome of wastewater- and livestock-associated Enterobacteriaceae.

Sci Adv 2021 Apr 9;7(15). Epub 2021 Apr 9.

Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.

and other Enterobacteriaceae are diverse species with "open" pangenomes, where genes move intra- and interspecies via horizontal gene transfer. However, most analyses focus on clinical isolates. The pangenome dynamics of natural populations remain understudied, despite their suggested role as reservoirs for antimicrobial resistance (AMR) genes. Here, we analyze near-complete genomes for 827 Enterobacteriaceae (553 and 274 non- spp.) with 2292 circularized plasmids in total, collected from 19 locations (livestock farms and wastewater treatment works in the United Kingdom) within a 30-km radius at three time points over a year. We find different dynamics for chromosomal and plasmid-borne genes. Plasmids have a higher burden of AMR genes and insertion sequences, and AMR-gene-carrying plasmids show evidence of being under stronger selective pressure. Environmental niche and local geography both play a role in shaping plasmid dynamics. Our results highlight the importance of local strategies for controlling the spread of AMR.
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http://dx.doi.org/10.1126/sciadv.abe3868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034854PMC
April 2021

Bis(Iminophosphorano)-Substituted Pyridinium Ions and their Corresponding Bispyridinylidene Organic Electron Donors.

Chemistry 2021 Jun 14;27(33):8528-8536. Epub 2021 May 14.

Department of Chemistry, University of New Brunswick, Fredericton, New Brunswick, E3B 5A3, Canada.

Optimized synthetic procedures for pyridinium ions featuring iminophosphorano (-N=PR ; R=Ph, Cy) π-donor substituents in the 2- and 4- positions are described. Crystallographic and theoretical studies reveal that the strongly donating substituents severely polarize the π-electrons of the pyridyl ring at the expense of aromaticity. Moreover, the pyridinium ions are readily deprotonated to generate powerful bispyridinylidene (BPY) organic electron donors. Electrochemical studies show exceptionally low redox potentials for the two-electron BPY/BPY couples, ranging from -1.71 V vs the saturated calomel electrode for 3PhPh (with four Ph P=N- groups) to -1.85 V for 3CyCy (with four Cy P=N- groups). These new compounds represent the most reducing neutral organic electron donors (OEDs) currently known. Some preliminary reductions involving 3CyCy showed enhanced capability owing to its low redox potential, such as the thermally activated reduction of an aryl chloride, but purification challenges were often encountered.
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http://dx.doi.org/10.1002/chem.202100318DOI Listing
June 2021

Antibody testing for COVID-19: A report from the National COVID Scientific Advisory Panel.

Wellcome Open Res 2020 11;5:139. Epub 2020 Jun 11.

Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 9DU, UK.

The COVID-19 pandemic caused >1 million infections during January-March 2020. There is an urgent need for reliable antibody detection approaches to support diagnosis, vaccine development, safe release of individuals from quarantine, and population lock-down exit strategies. We set out to evaluate the performance of ELISA and lateral flow immunoassay (LFIA) devices. We tested plasma for COVID (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2) IgM and IgG antibodies by ELISA and using nine different LFIA devices. We used a panel of plasma samples from individuals who have had confirmed COVID infection based on a PCR result (n=40), and pre-pandemic negative control samples banked in the UK prior to December-2019 (n=142). ELISA detected IgM or IgG in 34/40 individuals with a confirmed history of COVID infection (sensitivity 85%, 95%CI 70-94%), vs. 0/50 pre-pandemic controls (specificity 100% [95%CI 93-100%]). IgG levels were detected in 31/31 COVID-positive individuals tested ≥10 days after symptom onset (sensitivity 100%, 95%CI 89-100%). IgG titres rose during the 3 weeks post symptom onset and began to fall by 8 weeks, but remained above the detection threshold. Point estimates for the sensitivity of LFIA devices ranged from 55-70% versus RT-PCR and 65-85% versus ELISA, with specificity 95-100% and 93-100% respectively. Within the limits of the study size, the performance of most LFIA devices was similar. Currently available commercial LFIA devices do not perform sufficiently well for individual patient applications. However, ELISA can be calibrated to be specific for detecting and quantifying SARS-CoV-2 IgM and IgG and is highly sensitive for IgG from 10 days following first symptoms.
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http://dx.doi.org/10.12688/wellcomeopenres.15927.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941096PMC
June 2020

Spontaneous fundal uterine rupture in a non-labouring 31-week twin pregnancy and unknown previous hysteroscopic adhesiolysis: A case report.

Case Rep Womens Health 2021 Apr 27;30:e00302. Epub 2021 Feb 27.

Gloucestershire NHS Foundation Trust, Gloucester Royal Hospital, Great Western Road, Gloucester, GL1 3NN.

A 46-year-old woman presented at 31 weeks of gestation with a twin pregnancy (dichorionic, diamniotic) and with mild abdominal pain, not in labour, leading to complete spontaneous fundal uterine rupture. She underwent prompt surgical intervention and resuscitation with packed red cells, cell-salvage blood and fresh frozen plasma (FFP). Twin 1 survived and twin 2 died. Risk factors for uterine rupture were multiple pregnancy and hysteroscopic adhesiolysis, which was unknown during antenatal care. The mother and twin 1 made excellent progress post-operatively. This case highlights the importance of swift intervention to minimise maternal and perinatal morbidity and mortality.
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http://dx.doi.org/10.1016/j.crwh.2021.e00302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941072PMC
April 2021

Preferences for Medical Consultations from Online Providers: Evidence from a Discrete Choice Experiment in the United Kingdom.

Appl Health Econ Health Policy 2021 Mar 8. Epub 2021 Mar 8.

Health Economics Research Centre, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Headington, Oxford, OX3 9NS, UK.

Background: In the UK, consultations for prescription medicines are available via private providers such as online pharmacies. However, these providers may have lower thresholds for prescribing certain drugs. This is a particular concern for antibiotics, given the increasing burden of antimicrobial resistance. Public preferences for consultations with online providers are unknown, hence the impact of increased availability of online consultations on antibiotic use and population health is unclear.

Objective: To conduct a discrete choice experiment survey to understand UK public preferences for seeking online consultations, and the factors that influence these preferences, in the context of having symptoms for which antibiotics may be appropriate.

Methods: In a survey conducted between July and August 2018, general population respondents completed 16 questions in which they chose a primary care consultation via either their local medical centre or an online provider. Consultations were described in terms of five attributes, including cost and similarity to traditional 'face-to-face' appointments. Choices were modelled using regression analysis.

Results: Respondents (n = 734) placed a high value on having a consultation via their local medical centre rather than an online provider, and a low value on consultations by phone or video. However, respondents characterised as 'busy young professionals' showed a lower strength of preference for traditional consultations, with a higher concern for convenience.

Conclusion: Before COVID-19, the UK public had limited appetite for consultations with online providers, or for consultations that were not face-to-face. Nevertheless, prescriptions from online providers should be monitored going forward, particularly for antibiotics, and in key patient groups.
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http://dx.doi.org/10.1007/s40258-021-00642-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937442PMC
March 2021

Integrating Focused Cardiac Ultrasound Into Pediatric Septic Shock Assessment.

Pediatr Crit Care Med 2021 03;22(3):262-274

Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA.

Objectives: To assess focused cardiac ultrasound impact on clinician hemodynamic characterization of patients with suspected septic shock as well as expert-generated focused cardiac ultrasound algorithm performance.

Design: Retrospective, observational study.

Setting: Single-center, noncardiac PICU.

Patients: Less than 18 years old receiving focused cardiac ultrasound study within 72 hours of sepsis pathway initiation from January 2014 to December 2016.

Interventions: Hemodynamics of patients with suspected septic shock were characterized as fluid responsive, myocardial dysfunction, obstructive physiology, and/or reduced systemic vascular resistance by a bedside clinician before and immediately following focused cardiac ultrasound performance. The clinician's post-focused cardiac ultrasound hemodynamic assessments were compared with an expert-derived focused cardiac ultrasound algorithmic hemodynamic interpretation. Subsequent clinical management was assessed for alignment with focused cardiac ultrasound characterization and association with patient outcomes.

Measurements And Main Results: Seventy-one patients with suspected septic shock (median, 4.7 yr; interquartile range, 1.6-8.1) received clinician performed focused cardiac ultrasound study within 72 hours of sepsis pathway initiation (median, 2.1 hr; interquartile range, -1.5 to 11.8 hr). Two patients did not have pre-focused cardiac ultrasound and 23 patients did not have post-focused cardiac ultrasound hemodynamic characterization by clinicians resulting in exclusion from related analyses. Post-focused cardiac ultrasound clinician hemodynamic characterization differed from pre-focused cardiac ultrasound characterization in 67% of patients (31/46). There was substantial concordance between clinician's post-focused cardiac ultrasound and algorithm hemodynamic characterization (33/48; κ = 0.66; CI, 0.51-0.80). Fluid responsive (κ = 0.62; CI, 0.40-0.84), obstructive physiology (к = 0.87; CI, 0.64-1.00), and myocardial dysfunction (1.00; CI, 1.00-1.00) demonstrated substantial to perfect concordance. Management within 4 hours of focused cardiac ultrasound aligned with algorithm characterization in 53 of 71 patients (75%). Patients with aligned management were less likely to have a complicated course (14/52, 27%) compared with misaligned management (8/19, 42%; p = 0.25).

Conclusions: Incorporation of focused cardiac ultrasound in the evaluation of patients with suspected septic shock frequently changed a clinician's characterization of hemodynamics. An expert-developed algorithm had substantial concordance with a clinician's post-focused cardiac ultrasound hemodynamic characterization. Management aligned with algorithm characterization may improve outcomes in children with suspected septic shock.
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http://dx.doi.org/10.1097/PCC.0000000000002658DOI Listing
March 2021

Genomic network analysis of environmental and livestock F-type plasmid populations.

ISME J 2021 Mar 1. Epub 2021 Mar 1.

Nuffield Department of Medicine, University of Oxford, Oxford, UK.

F-type plasmids are diverse and of great clinical significance, often carrying genes conferring antimicrobial resistance (AMR) such as extended-spectrum β-lactamases, particularly in Enterobacterales. Organising this plasmid diversity is challenging, and current knowledge is largely based on plasmids from clinical settings. Here, we present a network community analysis of a large survey of F-type plasmids from environmental (influent, effluent and upstream/downstream waterways surrounding wastewater treatment works) and livestock settings. We use a tractable and scalable methodology to examine the relationship between plasmid metadata and network communities. This reveals how niche (sampling compartment and host genera) partition and shape plasmid diversity. We also perform pangenome-style analyses on network communities. We show that such communities define unique combinations of core genes, with limited overlap. Building plasmid phylogenies based on alignments of these core genes, we demonstrate that plasmid accessory function is closely linked to core gene content. Taken together, our results suggest that stable F-type plasmid backbone structures can persist in environmental settings while allowing dramatic variation in accessory gene content that may be linked to niche adaptation. The association of F-type plasmids with AMR may reflect their suitability for rapid niche adaptation.
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http://dx.doi.org/10.1038/s41396-021-00926-wDOI Listing
March 2021

Uncovering an allosteric mode of action for a selective inhibitor of human Bloom syndrome protein.

Elife 2021 Mar 1;10. Epub 2021 Mar 1.

Cancer Research UK DNA Repair Enzymes Group, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, United Kingdom.

BLM (Bloom syndrome protein) is a RECQ-family helicase involved in the dissolution of complex DNA structures and repair intermediates. Synthetic lethality analysis implicates BLM as a promising target in a range of cancers with defects in the DNA damage response; however, selective small molecule inhibitors of defined mechanism are currently lacking. Here, we identify and characterise a specific inhibitor of BLM's ATPase-coupled DNA helicase activity, by allosteric trapping of a DNA-bound translocation intermediate. Crystallographic structures of BLM-DNA-ADP-inhibitor complexes identify a hitherto unknown interdomain interface, whose opening and closing are integral to translocation of ssDNA, and which provides a highly selective pocket for drug discovery. Comparison with structures of other RECQ helicases provides a model for branch migration of Holliday junctions by BLM.
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http://dx.doi.org/10.7554/eLife.65339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924943PMC
March 2021

Endometriosis: A Malignant Fingerprint.

J Cancer Res Ther Oncol 2020 Apr 29;8(2). Epub 2020 Dec 29.

Creighton University School of Medicine, Omaha, NE, United States.

Background: Endometriosis is complex, but identifying the novel biomarkers, inflammatory molecules, and genetic links holds the key to the enhanced detection, prediction and treatment of both endometriosis and endometriosis related malignant neoplasia. Here we review the literature relating to the specific molecular mechanism(s) mediating tumorigenesis arising within endometriosis.

Methods: Guidance (e.g. Cochrane) and published studies were identified. The Published studies were identified through PubMed using the systematic review methods filter, and the authors' topic knowledge. These data were reviewed to identify key and relevant articles to create a comprehensive review article to explore the molecular fingerprint associated with in endometriosis-driven tumorigenesis.

Results: An important focus is the link between C3aR1, PGR, ER1, SOX-17 and other relevant gene expression profiles and endometriosis-driven tumorigenesis. Further studies should also focus on the combined use of CA-125 with HE-4, and the role for OVA1/MIA as clinically relevant diagnostic biomarkers in the prediction of endometriosis-driven tumorigenesis.

Conclusions: Elucidating endometriosis' molecular fingerprint is to understand the molecular mechanisms that drive the endometriosis-associated malignant phenotype. A better understanding of the predictive roles of these genes and the value of the biomarker proteins will allow for the derivation of unique molecular treatment algorithms to better serve our patients.
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http://dx.doi.org/10.17303/jcrto.2020.8.206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909468PMC
April 2020

Does the maturation of early sleep patterns predict language ability at school entry? A Born in Bradford study.

J Child Lang 2021 Feb 3:1-23. Epub 2021 Feb 3.

Department of Psychology, University of York, York, YO10 5DD, UK.

Children's vocabulary ability at school entry is highly variable and predictive of later language and literacy outcomes. Sleep is potentially useful in understanding and explaining that variability, with sleep patterns being predictive of global trajectories of language acquisition. Here, we looked to replicate and extend these findings. Data from 354 children (without English as an additional language) in the Born in Bradford study were analysed, describing the mean intercepts and linear trends in parent-reported day-time and night-time sleep duration over five time points between 6 and 36 months-of-age. The mean difference between night-time and day-time sleep was predictive of receptive vocabulary at age five, with more night-time sleep relative to day-time sleep predicting better language. An exploratory analysis suggested that socioeconomic status was predictive of vocabulary outcomes, with sleep patterns partially mediating this relationship. We suggest that the consolidation of sleep patterns acts as a driver of early language development.
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http://dx.doi.org/10.1017/S0305000920000677DOI Listing
February 2021

Cognition-oriented treatments for older adults: A systematic review of the influence of depression and self-efficacy individual differences factors.

Neuropsychol Rehabil 2021 Jan 28:1-37. Epub 2021 Jan 28.

Academic Unit for Psychiatry of Old Age, The University of Melbourne, Melbourne, Australia.

The increasing prevalence of cognitive decline, mild cognitive impairment (MCI), and dementia with the aging population has led to scrutiny of the efficacy of cognition-oriented treatments (COTs) aiming to maintain functioning, and delay or prevent further cognitive decline. However, little is known regarding the role of individual differences patient-variables (such as depression, self-efficacy, and motivation) in moderating the efficacy of COTs. This systematic review aimed to identify and analyze COT trials which investigated the relationship between differences in these patient-variables and intervention outcomes for older adults across healthy, MCI, and dementia populations. Of the 4854 studies extracted from the systematic search, 14 were included for analysis. While results were mixed across interventions and populations, on balance, greater depression severity predicted poorer cognitive functioning, and improvement in depressive symptom severity may account for at least part of the cognitive benefits seen at post-intervention. These findings were strongest for studies of MCI populations, with there being limited evidence of a relationship for healthy older adults or those with dementia. Overall, this review demonstrates the need for further investigation into the role of individual differences and clinical variables - particularly depression symptom severity - in attenuating COT outcomes through larger sample, high-quality randomized controlled trials.
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http://dx.doi.org/10.1080/09602011.2020.1869567DOI Listing
January 2021

Implementing interventions to reduce antibiotic use: a qualitative study in high-prescribing practices.

BMC Fam Pract 2021 01 23;22(1):25. Epub 2021 Jan 23.

Nuffield Department of Primary Care Health Sciences, University of Oxford, Radcliffe Observatory Quarter, Woodstock Road, Oxford, OX2 6GG, UK.

Background: Trials have shown that delayed antibiotic prescriptions (DPs) and point-of-care C-Reactive Protein testing (POC-CRPT) are effective in reducing antibiotic use in general practice, but these were not typically implemented in high-prescribing practices. We aimed to explore views of professionals from high-prescribing practices about uptake and implementation of DPs and POC-CRPT to reduce antibiotic use.

Methods: This was a qualitative focus group study in English general practices. The highest antibiotic prescribing practices in the West Midlands were invited to participate. Clinical and non-clinical professionals attended focus groups co-facilitated by two researchers. Focus groups were audio-recorded, transcribed verbatim and analysed thematically.

Results: Nine practices (50 professionals) participated. Four main themes were identified. Compatibility of strategies with clinical roles and experience - participants viewed the strategies as having limited value as 'clinical tools', perceiving them as useful only in 'rare' instances of clinical uncertainty and/or for those less experienced. Strategies as 'social tools' - participants perceived the strategies as helpful for negotiating treatment decisions and educating patients, particularly those expecting antibiotics. Ambiguities - participants perceived ambiguities around when they should be used, and about their impact on antibiotic use. Influence of context - various other situational and practical issues were raised with implementing the strategies.

Conclusions: High-prescribing practices do not view DPs and POC-CRPT as sufficiently useful 'clinical tools' in a way which corresponds to the current policy approach advocating their use to reduce clinical uncertainty and improve antimicrobial stewardship. Instead, policy attention should focus on how these strategies may instead be used as 'social tools' to reduce unnecessary antibiotic use. Attention should also focus on the many ambiguities (concerns and questions) about, and contextual barriers to, using these strategies that need addressing to support wider and more consistent implementation.
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http://dx.doi.org/10.1186/s12875-021-01371-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825381PMC
January 2021

Probabilistic transmission models incorporating sequencing data for healthcare-associated Clostridioides difficile outperform heuristic rules and identify strain-specific differences in transmission.

PLoS Comput Biol 2021 01 14;17(1):e1008417. Epub 2021 Jan 14.

Big Data Institute, Nuffield Department of Population Health, University of Oxford, United Kingdom.

Fitting stochastic transmission models to electronic patient data can offer detailed insights into the transmission of healthcare-associated infections and improve infection control. Pathogen whole-genome sequencing may improve the precision of model inferences, but computational constraints have limited modelling applications predominantly to small datasets and specific outbreaks, whereas large-scale sequencing studies have mostly relied on simple rules for identifying/excluding plausible transmission. We present a novel approach for integrating detailed epidemiological data on patient contact networks in hospitals with large-scale pathogen sequencing data. We apply our approach to study Clostridioides difficile transmission using a dataset of 1223 infections in Oxfordshire, UK, 2007-2011. 262 (21% [95% credibility interval 20-22%]) infections were estimated to have been acquired from another known case. There was heterogeneity by sequence type (ST) in the proportion of cases acquired from another case with the highest rates in ST1 (ribotype-027), ST42 (ribotype-106) and ST3 (ribotype-001). These same STs also had higher rates of transmission mediated via environmental contamination/spores persisting after patient discharge/recovery; for ST1 these persisted longer than for most other STs except ST3 and ST42. We also identified variation in transmission between hospitals, medical specialties and over time; by 2011 nearly all transmission from known cases had ceased in our hospitals. Our findings support previous work suggesting only a minority of C. difficile infections are acquired from known cases but highlight a greater role for environmental contamination than previously thought. Our approach is applicable to other healthcare-associated infections. Our findings have important implications for effective control of C. difficile.
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http://dx.doi.org/10.1371/journal.pcbi.1008417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840057PMC
January 2021

Ten years of population-level genomic Escherichia coli and Klebsiella pneumoniae serotype surveillance informs vaccine development for invasive infections.

Clin Infect Dis 2021 Jan 7. Epub 2021 Jan 7.

Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Background: The incidence of bloodstream infections (BSIs) caused by Escherichia coli and Klebsiella pneumoniae is increasing, with substantial associated morbidity, mortality and antimicrobial resistance. Unbiased serotyping studies to guide vaccine target selection are limited.

Methods: We conducted unselected, population-level genomic surveillance of bloodstream E. coli and Klebsiella pneumoniae isolates from 2008-2018 in Oxfordshire, UK. We supplemented this with an analysis of publicly available global sequencing data (n=3678).

Results: We sequenced 3478 E. coli isolates (3278 passed quality control) and 556 K. pneumoniae isolates (535 (K-antigen) and 549 (O-antigen) passed quality control). The four most common E. coli O-antigens (O1/O2/O6/O25) were identified in 1499/3278 isolates; the incidence of these O-types increased over time (IRRy=1.14, 95% CI:1.11-1.16). These O-types accounted for 616/1434 multidrug resistant (MDR) and 173/256 extended-spectrum beta-lactamase(ESBL)-resistant isolates in Oxfordshire, but only 19/90 carbapenem-resistant isolates across all studies. For Klebsiella pneumoniae, the most common O-antigens (O2v2/O1v1/O3b/O1v2) accounted for 410/549 isolates; the incidence of BSIs caused by these also increased annually (IRRy=1.09; 95% CI:1.05-1.12). These O-types accounted for 122/148 MDR and 106/123 ESBL isolates in Oxfordshire and 557/734 carbapenem-resistant isolates across all studies. Conversely we observed substantial capsular antigen diversity. Analysis of 3678 isolates from global studies demonstrated the generalisability of these findings. For E. coli, based on serotyping, the ExPEC4V and ExPEC10V vaccines under investigation would cover 46% and 72% of Oxfordshire isolates respectively, and 47% and 71% of MDR isolates.

Conclusions: O-antigen targeted vaccines may be useful in reducing the morbidity, mortality and antimicrobial resistance associated with E. coli and K. pneumoniae BSIs.
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http://dx.doi.org/10.1093/cid/ciab006DOI Listing
January 2021

The duration, dynamics and determinants of SARS-CoV-2 antibody responses in individual healthcare workers.

Clin Infect Dis 2021 Jan 6. Epub 2021 Jan 6.

Big Data Institute, University of Oxford, Oxford, UK.

Background: SARS-CoV-2 IgG antibody measurements can be used to estimate the proportion of a population exposed or infected and may be informative about the risk of future infection. Previous estimates of the duration of antibody responses vary.

Methods: We present 6 months of data from a longitudinal seroprevalence study of 3276 UK healthcare workers (HCWs). Serial measurements of SARS-CoV-2 anti-nucleocapsid and anti-spike IgG were obtained. Interval censored survival analysis was used to investigate the duration of detectable responses. Additionally, Bayesian mixed linear models were used to investigate anti-nucleocapsid waning.

Results: Anti-spike IgG levels remained stably detected after a positive result, e.g., in 94% (95% credibility interval, CrI, 91-96%) of HCWs at 180 days. Anti-nucleocapsid IgG levels rose to a peak at 24 (95% credibility interval, CrI 19-31) days post first PCR-positive test, before beginning to fall. Considering 452 anti-nucleocapsid seropositive HCWs over a median of 121 days from their maximum positive IgG titre, the mean estimated antibody half-life was 85 (95%CrI, 81-90) days. Higher maximum observed anti-nucleocapsid titres were associated with longer estimated antibody half-lives. Increasing age, Asian ethnicity and prior self-reported symptoms were independently associated with higher maximum anti-nucleocapsid levels and increasing age and a positive PCR test undertaken for symptoms with longer anti-nucleocapsid half-lives.

Conclusion: SARS-CoV-2 anti-nucleocapsid antibodies wane within months, and faster in younger adults and those without symptoms. However, anti-spike IgG remains stably detected. Ongoing longitudinal studies are required to track the long-term duration of antibody levels and their association with immunity to SARS-CoV-2 reinfection.
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http://dx.doi.org/10.1093/cid/ciab004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929225PMC
January 2021

Isoniazid preventive therapy plus antiretroviral therapy for the prevention of tuberculosis: a systematic review and meta-analysis of individual participant data.

Lancet HIV 2021 01;8(1):e8-e15

Department of Global Health, University of Washington, Seattle, WA, USA; Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA.

Background: Isoniazid preventive therapy prevents active tuberculosis in people with HIV, but previous studies have found no evidence of benefit in people with HIV who had a negative tuberculin skin test, and a non-significant effect on mortality. We aimed to estimate the effect of isoniazid preventive therapy given with antiretroviral therapy (ART) for the prevention of tuberculosis and death among people with HIV across population subgroups.

Methods: We searched PubMed, Embase, the Cochrane database, and conference abstracts from database inception to Jan 15, 2019, to identify potentially eligible randomised trials. Eligible studies were trials that enrolled HIV-positive adults (age ≥15 years) taking ART who were randomly assigned to either daily isoniazid preventive therapy plus ART or ART alone and followed up longitudinally for outcomes of incident tuberculosis and mortality. We approached all authors of included trials and requested individual participant data: coprimary outcomes were relative risk of incident tuberculosis and all-cause mortality. We did a single-stage meta-analysis of individual participant data using stratified Cox-proportional hazards models. We did prespecified subgroup analyses by sex, CD4 cell count, and evidence of immune sensitisation to tuberculosis (indicated by tuberculin skin test or interferon-γ release assays [IGRAs]). We also assessed the relative risk of liver injury in an additional prespecified analysis. This study is registered with PROSPERO, CRD42019121400.

Findings: Of 838 records, we included three trials with data for 2611 participants and 8584·8 person-years of follow-up for the outcome of incident tuberculosis, and a subset of 2362 participants with 8631·6 person-years of follow-up for the coprimary outcome of all-cause mortality. Risk for tuberculosis was lower in participants given isoniazid preventive therapy and ART than participants given ART alone (hazard ratio [HR] 0·68, 95% CI 0·49-0·95, p=0·02). Risk of all-cause mortality was lower in participants given isoniazid preventive therapy and ART than participants given ART alone, but this difference was non-significant (HR 0·69, 95% CI 0·43-1·10, p=0·12). Participants with baseline CD4 counts of less than 500 cells per μL had increased risk of tuberculosis, but there was no significant difference in the benefit of isoniazid preventive therapy with ART by sex, baseline CD4 count, or results of tuberculin skin test or IGRAs. 65 (2·5%) of 2611 participants had raised alanine aminotransferase, but data were insufficient to calculate an HR.

Interpretation: Isoniazid preventive therapy with ART prevents tuberculosis across demographic and HIV-specific and tuberculosis-specific subgroups, which supports efforts to further increase use of isoniazid preventive therapy with ART broadly among people living with HIV.

Funding: National Institutes of Health and National Institute of Allergy and Infectious Diseases.
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http://dx.doi.org/10.1016/S2352-3018(20)30299-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875572PMC
January 2021