Search

To reduce antimicrobial resistance (AMR), pathogen-specific AMR burden data are crucial to guide target selection for research and development of vaccines and monoclonal antibodies (mAbs). We identified knowledge gaps through previously conducted systematic reviews, which informed a Delphi expert consultation on future AMR research priorities and harmonisation strategies to support data-driven decision-making. Consensus (≥80% agreement) on importance and feasibility of research topics was achieved in two rounds, involving 24 of 39 and 19 of 24 invited experts, respectively. Priority pathogens and resistance profiles for future research were identified: third generation cephalosporin-resistant Klebsiella pneumoniae and Escherichia coli, for bloodstream and urinary tract infections, respectively, and meticillin-resistant Staphylococcus aureus for surgical-site infections. Prioritised high-risk populations included surgical, haemato-oncological and transplant patients. Mortality and resource use were prioritised as health-economic outcomes. The importance of age-stratified data and inclusion of a non-infected comparator group were highlighted. This agenda provides guidance for future research to fill knowledge gaps and support data-driven selection of target pathogens and populations for new preventive and treatment strategies, specifically vaccines and mAbs, to effectively address the AMR burden in Europe. These research priorities are also relevant to improve the evidence base for future AMR burden estimates.

Lassa fever is a zoonotic disease identified by the World Health Organization (WHO) as having pandemic potential. This study estimates the health-economic burden of Lassa fever throughout West Africa and projects impacts of a series of vaccination campaigns. We also model the emergence of "Lassa-X" - a hypothetical pandemic Lassa virus variant - and project impacts of achieving 100 Days Mission vaccination targets. Our model predicted 2.7M (95% uncertainty interval: 2.1M-3.4M) Lassa virus infections annually, resulting over ten years in 2.0M (793.8K-3.9M) disability-adjusted life years (DALYs). The most effective vaccination strategy was a population-wide preventive campaign primarily targeting WHO-classified "endemic" districts. Under conservative vaccine efficacy assumptions, this campaign averted $20.1M ($8.2M-$39.0M) in lost DALY value and $128.2M ($67.2M-$231.9M) in societal costs (International dollars 2021). Reactive vaccination in response to local outbreaks averted just one-tenth the health-economic burden of preventive campaigns. In the event of Lassa-X emerging, spreading throughout West Africa and causing approximately 1.2M DALYs within two years, 100 Days Mission vaccination averted 22% of DALYs given a vaccine 70% effective against disease, and 74% of DALYs given a vaccine 70% effective against both infection and disease. These findings suggest how vaccination could alleviate Lassa fever's burden and assist in pandemic preparedness.

Bacteria are becoming increasingly resistant to antibiotics, reducing our ability to treat infections and threatening to undermine modern health care. Optimising antibiotic use is a key element in tackling the problem. Traditional economic evaluation methods do not capture many of the benefits from improved antibiotic use and the potential impact on resistance. Not capturing these benefits is a major obstacle to optimising antibiotic use, as it fails to incentivise the development and use of interventions to optimise the use of antibiotics and preserve their effectiveness (stewardship interventions). Estimates of the benefits of improving antibiotic use involve considerable uncertainty as they depend on the evolution of resistance and associated health outcomes and costs. Here we discuss how economic evaluation methods might be adapted, in the face of such uncertainties. We propose a threshold-based approach that estimates the minimum resistance-related costs that would need to be averted by an intervention to make it cost-effective. If it is probable that without the intervention costs will exceed the threshold then the intervention should be deemed cost-effective., (© 2024. The Author(s).)

Background: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) aims to reduce and maintain infection levels through mass drug administration (MDA), but there is evidence of ongoing transmission after MDA in areas where Culex mosquitoes are the main transmission vector, suggesting that a more stringent criterion is required for MDA decision making in these settings., Methods: We use a transmission model to investigate how a lower prevalence threshold (<1% antigenemia [Ag] prevalence compared with <2% Ag prevalence) for MDA decision making would affect the probability of local elimination, health outcomes, the number of MDA rounds, including restarts, and program costs associated with MDA and surveys across different scenarios. To determine the cost-effectiveness of switching to a lower threshold, we simulated 65% and 80% MDA coverage of the total population for different willingness to pay per disability-adjusted life-year averted for India ($446.07), Tanzania ($389.83), and Haiti ($219.84)., Results: Our results suggest that with a lower Ag threshold, there is a small proportion of simulations where extra rounds are required to reach the target, but this also reduces the need to restart MDA later in the program. For 80% coverage, the lower threshold is cost-effective across all baseline prevalences for India, Tanzania, and Haiti. For 65% MDA coverage, the lower threshold is not cost-effective due to additional MDA rounds, although it increases the probability of local elimination. Valuing the benefits of elimination to align with the GPELF goals, we find that a willingness to pay per capita government expenditure of approximately $1000-$4000 for 1% increase in the probability of local elimination would be required to make a lower threshold cost-effective., Conclusions: Lower Ag thresholds for stopping MDAs generally mean a higher probability of local elimination, reducing long-term costs and health impacts. However, they may also lead to an increased number of MDA rounds required to reach the lower threshold and, therefore, increased short-term costs. Collectively, our analyses highlight that lower target Ag thresholds have the potential to assist programs in achieving lymphatic filariasis goals., Competing Interests: Potential conflicts of interest. KMG reports being employed by the Neglected Tropical Disease Support Center, Task Force for Global Health. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Reported bacteraemia outcomes following inactive empirical antibiotics (based on in vitro testing) are conflicting, potentially reflecting heterogeneity in causative species, MIC breakpoints defining resistance/susceptibility, and times to rescue therapy., Methods: We investigated adult inpatients with Escherichia coli bacteraemia at Oxford University Hospitals, UK, from 4 February 2014 to 30 June 2021 who were receiving empirical amoxicillin/clavulanate with/without other antibiotics. We used Cox regression to analyse 30 day all-cause mortality by in vitro amoxicillin/clavulanate susceptibility (activity) using the EUCAST resistance breakpoint (>8/2 mg/L), categorical MIC, and a higher resistance breakpoint (>32/2 mg/L), adjusting for other antibiotic activity and confounders including comorbidities, vital signs and blood tests., Results: A total of 1720 E. coli bacteraemias (1626 patients) were treated with empirical amoxicillin/clavulanate. Thirty-day mortality was 193/1400 (14%) for any active baseline therapy and 52/320 (16%) for inactive baseline therapy (P = 0.17). With EUCAST breakpoints, there was no evidence that mortality differed for inactive versus active amoxicillin/clavulanate [adjusted HR (aHR) = 1.27 (95% CI 0.83-1.93); P = 0.28], nor of an association with active aminoglycoside (P = 0.93) or other active antibiotics (P = 0.18). Considering categorical amoxicillin/clavulanate MIC, MICs > 32/2 mg/L were associated with mortality [aHR = 1.85 versus MIC = 2/2 mg/L (95% CI 0.99-3.73); P = 0.054]. A higher resistance breakpoint (>32/2 mg/L) was independently associated with higher mortality [aHR = 1.82 (95% CI 1.07-3.10); P = 0.027], as were MICs > 32/2 mg/L with active empirical aminoglycosides [aHR = 2.34 (95% CI 1.40-3.89); P = 0.001], but not MICs > 32/2 mg/L with active non-aminoglycoside antibiotic(s) [aHR = 0.87 (95% CI 0.40-1.89); P = 0.72]., Conclusions: We found no evidence that EUCAST-defined amoxicillin/clavulanate resistance was associated with increased mortality, but a higher resistance breakpoint (MIC > 32/2 mg/L) was. Additional active baseline non-aminoglycoside antibiotics attenuated amoxicillin/clavulanate resistance-associated mortality, but aminoglycosides did not. Granular phenotyping and comparison with clinical outcomes may improve AMR breakpoints., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Antimicrobial resistance (AMR) may negatively impact surgery patients through reducing the efficacy of treatment of surgical site infections, also known as the "primary effects" of AMR. Previous estimates of the burden of AMR have largely ignored the potential "secondary effects," such as changes in surgical care pathways due to AMR, such as different infection prevention procedures or reduced access to surgical procedures altogether, with literature providing limited quantifications of this potential burden. Former conceptual models and approaches for quantifying such impacts are available, though they are often high-level and difficult to utilize in practice. We therefore expand on this earlier work to incorporate heterogeneity in antimicrobial usage, AMR, and causative organisms, providing a detailed decision-tree-Markov-hybrid conceptual model to estimate the burden of AMR on surgery patients. We collate available data sources in England and describe how routinely collected data could be used to parameterise such a model, providing a useful repository of data systems for future health economic evaluations. The wealth of national-level data available for England provides a case study in describing how current surveillance and administrative data capture systems could be used in the estimation of transition probability and cost parameters. However, it is recommended that such data are utilized in combination with expert opinion (for scope and scenario definitions) to robustly estimate both the primary and secondary effects of AMR over time. Though we focus on England, this discussion is useful in other settings with established and/or developing infectious diseases surveillance systems that feed into AMR National Action Plans., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Naylor, Evans, Pouwels, Troughton, Lamagni, Muller-Pebody, Knight, Atun and Robotham.)

Background: The SARS-CoV-2 Delta variant has been replaced by the highly transmissible Omicron BA.1 variant, and subsequently by Omicron BA.2. It is important to understand how these changes in dominant variants affect reported symptoms, while also accounting for symptoms arising from other co-circulating respiratory viruses., Methods: In a nationally representative UK community study, the COVID-19 Infection Survey, we investigated symptoms in PCR-positive infection episodes vs. PCR-negative study visits over calendar time, by age and vaccination status, comparing periods when the Delta, Omicron BA.1 and BA.2 variants were dominant., Results: Between October-2020 and April-2022, 120,995 SARS-CoV-2 PCR-positive episodes occurred in 115,886 participants, with 70,683 (58%) reporting symptoms. The comparator comprised 4,766,366 PCR-negative study visits (483,894 participants); 203,422 (4%) reporting symptoms. Symptom reporting in PCR-positives varied over time, with a marked reduction in loss of taste/smell as Omicron BA.1 dominated, maintained with BA.2 (44%/45% 17 October 2021, 16%/13% 2 January 2022, 15%/12% 27 March 2022). Cough, fever, shortness of breath, myalgia, fatigue/weakness and headache also decreased after Omicron BA.1 dominated, but sore throat increased, the latter to a greater degree than concurrent increases in PCR-negatives. Fatigue/weakness increased again after BA.2 dominated, although to a similar degree to concurrent increases in PCR-negatives. Symptoms were consistently more common in adults aged 18-65 years than in children or older adults., Conclusions: Increases in sore throat (also common in the general community), and a marked reduction in loss of taste/smell, make Omicron harder to detect with symptom-based testing algorithms, with implications for institutional and national testing policies., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: To assess the risk of covid-19 death after infection with omicron BA.1 compared with delta (B.1.617.2)., Design: Retrospective cohort study., Setting: England, United Kingdom, from 1 December 2021 to 30 December 2021., Participants: 1 035 149 people aged 18-100 years who tested positive for SARS-CoV-2 under the national surveillance programme and had an infection identified as omicron BA.1 or delta compatible., Main Outcome Measures: The main outcome measure was covid-19 death as identified from death certification records. The exposure of interest was the SARS-CoV-2 variant identified from NHS Test and Trace PCR positive tests taken in the community (pillar 2) and analysed by Lighthouse laboratories. Cause specific Cox proportional hazard regression models (censoring non-covid-19 deaths) were adjusted for sex, age, vaccination status, previous infection, calendar time, ethnicity, index of multiple deprivation rank, household deprivation, university degree, keyworker status, country of birth, main language, region, disability, and comorbidities. Interactions between variant and sex, age, vaccination status, and comorbidities were also investigated., Results: The risk of covid-19 death was 66% lower (95% confidence interval 54% to 75%) for omicron BA.1 compared with delta after adjusting for a wide range of potential confounders. The reduction in the risk of covid-19 death for omicron compared with delta was more pronounced in people aged 18-59 years (number of deaths: delta=46, omicron=11; hazard ratio 0.14, 95% confidence interval 0.07 to 0.27) than in those aged ≥70 years (number of deaths: delta=113, omicron=135; hazard ratio 0.44, 95% confidence interval 0.32 to 0.61, P<0.0001). No evidence of a difference in risk was found between variant and number of comorbidities., Conclusions: The results support earlier studies showing a reduction in severity of infection with omicron BA.1 compared with delta in terms of hospital admission. This study extends the research to also show a reduction in the risk of covid-19 death for the omicron variant compared with the delta variant., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; KK is chair of the ethnicity subgroup of the UK Scientific Advisory Group for Emergencies (SAGE) and is a member of SAGE. JH-C is chair of the NERVTAG risk stratification subgroup and is a member of SAGE., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Given high SARS-CoV-2 incidence, coupled with slow and inequitable vaccine roll-out in many settings, there is a need for evidence to underpin optimum vaccine deployment, aiming to maximise global population immunity. We evaluate whether a single vaccination in individuals who have already been infected with SARS-CoV-2 generates similar initial and subsequent antibody responses to two vaccinations in those without prior infection. We compared anti-spike IgG antibody responses after a single vaccination with ChAdOx1, BNT162b2, or mRNA-1273 SARS-CoV-2 vaccines in the COVID-19 Infection Survey in the UK general population. In 100,849 adults median (50 (IQR: 37-63) years) receiving at least one vaccination, 13,404 (13.3%) had serological/PCR evidence of prior infection. Prior infection significantly boosted antibody responses, producing higher peak levels and/or longer half-lives after one dose of all three vaccines than those without prior infection receiving one or two vaccinations. In those with prior infection, the median time above the positivity threshold was >1 year after the first vaccination. Single-dose vaccination targeted to those previously infected may provide at least as good protection to two-dose vaccination among those without previous infection., (© 2022. The Author(s).)

Antibody responses are an important part of immunity after Coronavirus Disease 2019 (COVID-19) vaccination. However, antibody trajectories and the associated duration of protection after a second vaccine dose remain unclear. In this study, we investigated anti-spike IgG antibody responses and correlates of protection after second doses of ChAdOx1 or BNT162b2 vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the United Kingdom general population. In 222,493 individuals, we found significant boosting of anti-spike IgG by the second doses of both vaccines in all ages and using different dosing intervals, including the 3-week interval for BNT162b2. After second vaccination, BNT162b2 generated higher peak levels than ChAdOX1. Older individuals and males had lower peak levels with BNT162b2 but not ChAdOx1, whereas declines were similar across ages and sexes with ChAdOX1 or BNT162b2. Prior infection significantly increased antibody peak level and half-life with both vaccines. Anti-spike IgG levels were associated with protection from infection after vaccination and, to an even greater degree, after prior infection. At least 67% protection against infection was estimated to last for 2-3 months after two ChAdOx1 doses, for 5-8 months after two BNT162b2 doses in those without prior infection and for 1-2 years for those unvaccinated after natural infection. A third booster dose might be needed, prioritized to ChAdOx1 recipients and those more clinically vulnerable., (© 2022. The Author(s).)

Background: Natural and vaccine-induced immunity will play a key role in controlling the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. SARS-CoV-2 variants have the potential to evade natural and vaccine-induced immunity., Methods: In a longitudinal cohort study of healthcare workers (HCWs) in Oxfordshire, United Kingdom, we investigated the protection from symptomatic and asymptomatic polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection conferred by vaccination (Pfizer-BioNTech BNT162b2, Oxford-AstraZeneca ChAdOx1 nCOV-19) and prior infection (determined using anti-spike antibody status), using Poisson regression adjusted for age, sex, temporal changes in incidence and role. We estimated protection conferred after 1 versus 2 vaccinations and from infections with the B.1.1.7 variant identified using whole genome sequencing., Results: In total, 13 109 HCWs participated; 8285 received the Pfizer-BioNTech vaccine (1407 two doses), and 2738 the Oxford-AstraZeneca vaccine (49 two doses). Compared to unvaccinated seronegative HCWs, natural immunity and 2 vaccination doses provided similar protection against symptomatic infection: no HCW vaccinated twice had symptomatic infection, and incidence was 98% lower in seropositive HCWs (adjusted incidence rate ratio 0.02 [95% confidence interval {CI} < .01-.18]). Two vaccine doses or seropositivity reduced the incidence of any PCR-positive result with or without symptoms by 90% (0.10 [95% CI .02-.38]) and 85% (0.15 [95% CI .08-.26]), respectively. Single-dose vaccination reduced the incidence of symptomatic infection by 67% (0.33 [95% CI .21-.52]) and any PCR-positive result by 64% (0.36 [95% CI .26-.50]). There was no evidence of differences in immunity induced by natural infection and vaccination for infections with S-gene target failure and B.1.1.7., Conclusions: Natural infection resulting in detectable anti-spike antibodies and 2 vaccine doses both provide robust protection against SARS-CoV-2 infection, including against the B.1.1.7 variant., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: The COVID-19 pandemic is rapidly evolving, with emerging variants and fluctuating control policies. Real-time population screening and identification of groups in whom positivity is highest could help monitor spread and inform public health messaging and strategy., Methods: To develop a real-time screening process, we included results from nose and throat swabs and questionnaires taken 19 July 2020-17 July 2021 in the UK's national COVID-19 Infection Survey. Fortnightly, associations between SARS-CoV-2 positivity and 60 demographic and behavioural characteristics were estimated using logistic regression models adjusted for potential confounders, considering multiple testing, collinearity, and reverse causality., Findings: Of 4,091,537 RT-PCR results from 482,677 individuals, 29,903 (0·73%) were positive. As positivity rose September-November 2020, rates were independently higher in younger ages, and those living in Northern England, major urban conurbations, more deprived areas, and larger households. Rates were also higher in those returning from abroad, and working in healthcare or outside of home. When positivity peaked December 2020-January 2021 (Alpha), high positivity shifted to southern geographical regions. With national vaccine roll-out from December 2020, positivity reduced in vaccinated individuals. Associations attenuated as rates decreased between February-May 2021. Rising positivity rates in June-July 2021 (Delta) were independently higher in younger, male, and unvaccinated groups. Few factors were consistently associated with positivity. 25/45 (56%) confirmed associations would have been detected later using 28-day rather than 14-day periods., Interpretation: Population-level demographic and behavioural surveillance can be a valuable tool in identifying the varying characteristics driving current SARS-CoV-2 positivity, allowing monitoring to inform public health policy., Funding: Department of Health and Social Care (UK), Welsh Government, Department of Health (on behalf of the Northern Ireland Government), Scottish Government, National Institute for Health Research., Competing Interests: DWE declares lecture fees from Gilead outside the submitted work. DC is a committee member for the International Development Section of the Royal Statistical Society, and a trustee for the Carers’ Hub Lambeth charity. No other author has a conflict of interest to declare., (© 2021 The Author(s).)

Global and national surveillance of SARS-CoV-2 epidemiology is mostly based on targeted schemes focused on testing individuals with symptoms. These tested groups are often unrepresentative of the wider population and exhibit test positivity rates that are biased upwards compared with the true population prevalence. Such data are routinely used to infer infection prevalence and the effective reproduction number, R t , which affects public health policy. Here, we describe a causal framework that provides debiased fine-scale spatiotemporal estimates by combining targeted test counts with data from a randomized surveillance study in the United Kingdom called REACT. Our probabilistic model includes a bias parameter that captures the increased probability of an infected individual being tested, relative to a non-infected individual, and transforms observed test counts to debiased estimates of the true underlying local prevalence and R t . We validated our approach on held-out REACT data over a 7-month period. Furthermore, our local estimates of R t are indicative of 1-week- and 2-week-ahead changes in SARS-CoV-2-positive case numbers. We also observed increases in estimated local prevalence and R t that reflect the spread of the Alpha and Delta variants. Our results illustrate how randomized surveys can augment targeted testing to improve statistical accuracy in monitoring the spread of emerging and ongoing infectious disease., (© 2021. The Author(s).)

The effectiveness of the BNT162b2 and ChAdOx1 vaccines against new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections requires continuous re-evaluation, given the increasingly dominant B.1.617.2 (Delta) variant. In this study, we investigated the effectiveness of these vaccines in a large, community-based survey of randomly selected households across the United Kingdom. We found that the effectiveness of BNT162b2 and ChAdOx1 against infections (new polymerase chain reaction (PCR)-positive cases) with symptoms or high viral burden is reduced with the B.1.617.2 variant (absolute difference of 10-13% for BNT162b2 and 16% for ChAdOx1) compared to the B.1.1.7 (Alpha) variant. The effectiveness of two doses remains at least as great as protection afforded by prior natural infection. The dynamics of immunity after second doses differed significantly between BNT162b2 and ChAdOx1, with greater initial effectiveness against new PCR-positive cases but faster declines in protection against high viral burden and symptomatic infection with BNT162b2. There was no evidence that effectiveness varied by dosing interval, but protection was higher in vaccinated individuals after a prior infection and in younger adults. With B.1.617.2, infections occurring after two vaccinations had similar peak viral burden as those in unvaccinated individuals. SARS-CoV-2 vaccination still reduces new infections, but effectiveness and attenuation of peak viral burden are reduced with B.1.617.2., (© 2021. The Author(s).)

Understanding the trajectory, duration, and determinants of antibody responses after SARS-CoV-2 infection can inform subsequent protection and risk of reinfection, however large-scale representative studies are limited. Here we estimated antibody response after SARS-CoV-2 infection in the general population using representative data from 7,256 United Kingdom COVID-19 infection survey participants who had positive swab SARS-CoV-2 PCR tests from 26-April-2020 to 14-June-2021. A latent class model classified 24% of participants as 'non-responders' not developing anti-spike antibodies, who were older, had higher SARS-CoV-2 cycle threshold values during infection (i.e. lower viral burden), and less frequently reported any symptoms. Among those who seroconverted, using Bayesian linear mixed models, the estimated anti-spike IgG peak level was 7.3-fold higher than the level previously associated with 50% protection against reinfection, with higher peak levels in older participants and those of non-white ethnicity. The estimated anti-spike IgG half-life was 184 days, being longer in females and those of white ethnicity. We estimated antibody levels associated with protection against reinfection likely last 1.5-2 years on average, with levels associated with protection from severe infection present for several years. These estimates could inform planning for vaccination booster strategies., (© 2021. The Author(s).)

Objectives: To estimate the hospital costs among persons with obesity undergoing bariatric surgery compared with those without bariatric surgery., Methods: We analysed the UK Biobank Cohort study linked to Hospital Episode Statistics, for all adults with obesity undergoing bariatric surgery at National Health Service hospitals in England, Scotland, or Wales from 2006 to 2017. Surgery patients were matched with controls who did not have bariatric surgery using propensity scores approach with a ratio of up to 1-to-5 by year. Inverse probability of censoring weighting was used to correct for potential informative censoring. Annual and cumulative hospital costs were assessed for the surgery and control groups., Results: We identified 348 surgical patients (198 gastric bypass, 73 sleeve gastrectomy, 77 gastric banding) during the study period. In total, 324 surgical patients and 1506 matched control participants were included after propensity score matching. Mean 5-year cumulative hospital costs were €11,659 for 348 surgical patients. Compared with controls, surgical patients (n = 324) had significantly higher inpatient expenditures in the surgery year (€7289 vs. €2635, P < 0.001), but lower costs in the subsequent 4 years. The 5-year cumulative costs were €11,176 for surgical patients and €8759 for controls (P = 0.001)., Conclusions: Bariatric surgery significantly increased the inpatient costs in the surgery year, but was associated with decreased costs in the subsequent 4 years. However, any cost savings made up to 4 years were not enough to compensate for the initial surgical expenditure., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: We investigated determinants of severe acute respiratory syndrome coronavirus 2 (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 generalized additive models to track antibody responses over time., Results: 3570/3610 HCWs (98.9%) were seropositive >14 days post first vaccination and prior to second vaccination: 2706/2720 (99.5%) were seropositive after the Pfizer-BioNTech and 864/890 (97.1%) following the 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 the second vaccination 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 versus 1028 (564-1985) AU/mL without prior infection (p < 0.001). Oxford-AstraZeneca vaccine recipients had lower readings post first dose than Pfizer-BioNTech recipients, with and without previous infection, 10 095 (5354-17 096) and 435 (203-962) AU/mL respectively (both p < 0.001 versus 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 followed by 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., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Avoidance of unnecessary antimicrobial administration is a key tenet of antimicrobial stewardship; knowing the optimal duration of therapy obviates over-treatment. However, little research has been performed to establish course lengths for common canine infections. In clinical practice, antimicrobial therapy is frequently prescribed in dogs presenting lower urinary tract signs (haematuria, pollakiuria and dysuria/stranguria). The proposed length of treatment in International Consensus guidelines has decreased with each iteration, but these recommendations remain arbitrary and largely extrapolated from experience in people., Methods: The objective of this prospective, multi-centre study is to find the shortest course duration that is non-inferior to the standard duration of 7 days of amoxicillin/clavulanate in terms of clinical outcomes for female dogs with lower urinary tract signs consistent with a urinary tract infection. An electronic data capture platform will be used by participating veterinarians working in clinical practice in the United Kingdom. Eligible dogs must be female, aged between 6 months and 10 years and have lower urinary tract signs of up to seven days' duration. Enrolment will be offered in cases where the case clinician intends to prescribe antimicrobial therapy. Automatic pseudo-randomisation to treatment group will be based on the day of presentation (Monday-Friday); all antimicrobial courses will be completed on the Sunday after presentation generating different treatment durations. Follow-up data will be collected 1, 8 and 22-26 days after completion of the antimicrobial course to ensure effective safety netting, and to monitor short-term outcome and recurrence rates. Informed owner consent will be obtained in all cases. The study is approved by the Ethical Review Board of the University of Nottingham and has an Animal Test Certificate from the Veterinary Medicine's Directorate., Discussion: This study has been designed to mirror current standards of clinical management; conclusions should therefore, be widely applicable and guide practising veterinarians in their antimicrobial decision-making process. A duration-response curve will be created allowing determination of the optimal treatment duration for the management of female dogs with lower urinary tract signs. It is hoped that these results will contribute valuable information to improve future antimicrobial stewardship as part of a wider one-health perspective., (© 2021. The Author(s).)

We report that in a cohort of 45,965 adults, who were receiving either the ChAdOx1 or the BNT162b2 SARS-CoV-2 vaccines, in those who had no prior infection with SARS-CoV-2, seroconversion rates and quantitative antibody levels after a single dose were lower in older individuals, especially in those aged >60 years. Two vaccine doses achieved high responses across all ages. Antibody levels increased more slowly and to lower levels with a single dose of ChAdOx1 compared with a single dose of BNT162b2, but waned following a single dose of BNT162b2 in older individuals. In descriptive latent class models, we identified four responder subgroups, including a 'low responder' group that more commonly consisted of people aged >75 years, males and individuals with long-term health conditions. Given our findings, we propose that available vaccines should be prioritized for those not previously infected and that second doses should be prioritized for individuals aged >60 years. Further data are needed to better understand the extent to which quantitative antibody responses are associated with vaccine-mediated protection., (© 2021. The Author(s).)

Background: Delayed (or "backup") antibiotic prescription, where the patient is given a prescription but advised to delay initiating antibiotics, has been shown to be effective in reducing antibiotic use in primary care. However, this strategy is not widely used in the United Kingdom. This study aimed to identify factors influencing preferences among the UK public for delayed prescription, and understand their relative importance, to help increase appropriate use of this prescribing option., Methods and Findings: We conducted an online choice experiment in 2 UK general population samples: adults and parents of children under 18 years. Respondents were presented with 12 scenarios in which they, or their child, might need antibiotics for a respiratory tract infection (RTI) and asked to choose either an immediate or a delayed prescription. Scenarios were described by 7 attributes. Data were collected between November 2018 and February 2019. Respondent preferences were modelled using mixed-effects logistic regression. The survey was completed by 802 adults and 801 parents (75% of those who opened the survey). The samples reflected the UK population in age, sex, ethnicity, and country of residence. The most important determinant of respondent choice was symptom severity, especially for cough-related symptoms. In the adult sample, the probability of choosing delayed prescription was 0.53 (95% confidence interval (CI) 0.50 to 0.56, p < 0.001) for a chesty cough and runny nose compared to 0.30 (0.28 to 0.33, p < 0.001) for a chesty cough with fever, 0.47 (0.44 to 0.50, p < 0.001) for sore throat with swollen glands, and 0.37 (0.34 to 0.39, p < 0.001) for sore throat, swollen glands, and fever. Respondents were less likely to choose delayed prescription with increasing duration of illness (odds ratio (OR) 0.94 (0.92 to 0.96, p < 0.001)). Probabilities of choosing delayed prescription were similar for parents considering treatment for a child (44% of choices versus 42% for adults, p = 0.04). However, parents differed from the adult sample in showing a more marked reduction in choice of the delayed prescription with increasing duration of illness (OR 0.83 (0.80 to 0.87) versus 0.94 (0.92 to 0.96) for adults, p for heterogeneity p < 0.001) and a smaller effect of disruption of usual activities (OR 0.96 (0.95 to 0.97) versus 0.93 (0.92 to 0.94) for adults, p for heterogeneity p < 0.001). Females were more likely to choose a delayed prescription than males for minor symptoms, particularly minor cough (probability 0.62 (0.58 to 0.66, p < 0.001) for females and 0.45 (0.41 to 0.48, p < 0.001) for males). Older people, those with a good understanding of antibiotics, and those who had not used antibiotics recently showed similar patterns of preferences. Study limitations include its hypothetical nature, which may not reflect real-life behaviour; the absence of a "no prescription" option; and the possibility that study respondents may not represent the views of population groups who are typically underrepresented in online surveys., Conclusions: This study found that delayed prescription appears to be an acceptable approach to reducing antibiotic consumption. Certain groups appear to be more amenable to delayed prescription, suggesting particular opportunities for increased use of this strategy. Prescribing choices for sore throat may need additional explanation to ensure patient acceptance, and parents in particular may benefit from reassurance about the usual duration of these illnesses., Competing Interests: The authors have declared that no competing interests exist.

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., (© 2021. The Author(s).)

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., (© 2021. The Author(s).)

Background: Decisions about the continued need for control measures to contain the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rely on accurate and up-to-date information about the number of people testing positive for SARS-CoV-2 and risk factors for testing positive. Existing surveillance systems are generally not based on population samples and are not longitudinal in design., Methods: Samples were collected from individuals aged 2 years and older living in private households in England that were randomly selected from address lists and previous Office for National Statistics surveys in repeated cross-sectional household surveys with additional serial sampling and longitudinal follow-up. Participants completed a questionnaire and did nose and throat self-swabs. The percentage of individuals testing positive for SARS-CoV-2 RNA was estimated over time by use of dynamic multilevel regression and poststratification, to account for potential residual non-representativeness. Potential changes in risk factors for testing positive over time were also assessed. The study is registered with the ISRCTN Registry, ISRCTN21086382., Findings: Between April 26 and Nov 1, 2020, results were available from 1 191 170 samples from 280 327 individuals; 5231 samples were positive overall, from 3923 individuals. The percentage of people testing positive for SARS-CoV-2 changed substantially over time, with an initial decrease between April 26 and June 28, 2020, from 0·40% (95% credible interval 0·29-0·54) to 0·06% (0·04-0·07), followed by low levels during July and August, 2020, before substantial increases at the end of August, 2020, with percentages testing positive above 1% from the end of October, 2020. Having a patient-facing role and working outside your home were important risk factors for testing positive for SARS-CoV-2 at the end of the first wave (April 26 to June 28, 2020), but not in the second wave (from the end of August to Nov 1, 2020). Age (young adults, particularly those aged 17-24 years) was an important initial driver of increased positivity rates in the second wave. For example, the estimated percentage of individuals testing positive was more than six times higher in those aged 17-24 years than in those aged 70 years or older at the end of September, 2020. A substantial proportion of infections were in individuals not reporting symptoms around their positive test (45-68%, dependent on calendar time., Interpretation: Important risk factors for testing positive for SARS-CoV-2 varied substantially between the part of the first wave that was captured by the study (April to June, 2020) and the first part of the second wave of increased positivity rates (end of August to Nov 1, 2020), and a substantial proportion of infections were in individuals not reporting symptoms, indicating that continued monitoring for SARS-CoV-2 in the community will be important for managing the COVID-19 pandemic moving forwards., Funding: Department of Health and Social Care., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Deciding whether to discontinue antibiotics at early review is a cornerstone of hospital antimicrobial stewardship practice worldwide. In England, this approach is described in government guidance ('Start Smart then Focus'). However, < 10% of hospital antibiotic prescriptions are discontinued at review, despite evidence that 20-30% could be discontinued safely. We aimed to quantify the relative importance of factors influencing prescriber decision-making at review., Methods: We conducted an online choice experiment, a survey method to elicit preferences. Acute/general hospital prescribers in England were asked if they would continue or discontinue antibiotic treatment in 15 hypothetical scenarios. Scenarios were described according to six attributes, including patients' presenting symptoms and whether discontinuation would conflict with local prescribing guidelines. Respondents' choices were analysed using conditional logistic regression., Results: One hundred respondents completed the survey. Respondents were more likely to continue antibiotics when discontinuation would 'strongly conflict' with local guidelines (average marginal effect (AME) on the probability of continuing + 0.194 (p < 0.001)), when presenting symptoms more clearly indicated antibiotics (AME of urinary tract infection symptoms + 0.173 (p < 0.001) versus unclear symptoms) and when patients had severe frailty/comorbidities (AME = + 0.101 (p < 0.001)). Respondents were less likely to continue antibiotics when under no external pressure to continue (AME = - 0.101 (p < 0.001)). Decisions were also influenced by the risks to patient health of continuing/discontinuing antibiotic treatment., Conclusions: Guidelines that conflict with antibiotic discontinuation (e.g. pre-specify fixed durations) may discourage safe discontinuation at review. In contrast, guidelines conditional on patient factors/treatment response could help hospital prescribers discontinue antibiotics if diagnostic information suggesting they are no longer needed is available.

Background: For many infectious conditions, the optimal antibiotic course length remains unclear. The estimation of course length must consider the important trade-off between maximising short- and long-term efficacy and minimising antibiotic resistance and toxicity., Main Body: Evidence on optimal treatment durations should come from randomised controlled trials. However, most antibiotic randomised controlled trials compare two arbitrarily chosen durations. We argue that alternative trial designs, which allow allocation of patients to multiple different treatment durations, are needed to better identify optimal antibiotic durations. There are important considerations when deciding which design is most useful in identifying optimal treatment durations, including the ability to model the duration-response relationship (or duration-response 'curve'), the risk of allocation concealment bias, statistical efficiency, the possibility to rapidly drop arms that are clearly inferior, and the possibility of modelling the trade-off between multiple competing outcomes., Conclusion: Multi-arm designs modelling duration-response curves with the possibility to drop inferior arms during the trial could provide more information about the optimal duration of antibiotic therapies than traditional head-to-head comparisons of limited numbers of durations, while minimising the probability of assigning trial participants to an ineffective treatment regimen.

Background: Seeing one's practice as a high antibiotic prescriber compared to general practices with similar patient populations can be one of the best motivators for change. Current comparisons are based on age-sex weighting of the practice population for expected prescribing rates (STAR-PU). Here, we investigate whether there is a need to additionally account for further potentially legitimate medical reasons for higher antibiotic prescribing., Methods: Publicly available data from 7376 general practices in England between April 2014 and March 2015 were used. We built two different negative binomial regression models to compare observed versus expected antibiotic dispensing levels per practice: one including comorbidities as covariates and another with the addition of smoking prevalence and deprivation. We compared the ranking of practices in terms of items prescribed per STAR-PU according to i) conventional STAR-PU methodology, ii) observed vs expected prescribing levels using the comorbidity model, and iii) observed vs expected prescribing levels using the full model., Findings: The median number of antibiotic items prescribed per practice per STAR-PU was 1.09 (25th-75th percentile, 0.92-1.25). 1133 practices (76.8% of 1476) were consistently identified as being in the top 20% of high antibiotic prescribers. However, some practices that would be classified as high prescribers using the current STAR-PU methodology would not be classified as high prescribers if comorbidity was accounted for (n = 269, 18.2%) and if additionally smoking prevalence and deprivation were accounted for (n = 312, 21.1%)., Interpretation: Current age-sex weighted comparisons of antibiotic prescribing rates in England are fair for many, but not all practices. This new metric that accounts for legitimate medical reasons for higher antibiotic prescribing may have more credibility among general practitioners and, thus, more likely to be acted upon., Outstanding Questions: Findings of this study indicate that the antibiotic prescribing metric by which practices are measured (and need to implement interventions determined) may be inadequate, and therefore raises the question of how they should be measured. Substantial variation between practices remains after accounting for comorbidities, deprivation and smoking. There is a need for a better understanding of why such variation remains and, more importantly, what can be done to reduce it. While antibiotics are more frequently indicated in patients with comorbidities, it is unclear to what extent antibiotic prescribing can be lowered among that patient population and how this could be achieved.

Cervical cancer is a serious public-health problem in Asian countries. Since human papillomavirus (HPV) infection is the main risk factor for cervical cancer, HPV vaccination is considered a promising strategy to prevent cervical cancer. However, comprehensive immunogenicity and safety information for Asian populations is lacking. We searched four electronic databases including PubMed, EMBASE, Cochrane Library, and clinicaltrials.gov. We reviewed selected manuscripts and extracted the pooled relative risk (RR) from immunogenicity and safety information on HPV vaccination among women in Asian countries. We identified two quadrivalent-vaccine studies and eight bivalent-vaccine studies conducted in Asian countries. Analysis across these studies suggested that the HPV vaccines significantly enhanced HPV16- and HPV18-specific antibody among both uninfected (RR 85.69; 95% confidence interval (CI) 31.51-233.04 and 62.77; 95% CI 37.4-105.51) and infected individuals (RR 8.60; 95% CI 6.95-10.64 and RR 8.13; 95% CI 5.96-11.11). Furthermore, HPV vaccination among Asian populations has a favorable safety profile, with only slightly higher risks of local (RR: 1.89; 95% CI 1.65-2.17) and systemic (RR: 1.33; 95% CI 1.18-1.50) adverse events in vaccinated individuals compared with controls. For Asian populations, HPV vaccines enhance the level of HPV16- and HPV18-specific antibodies for both uninfected and infected individuals. Also, the risk of adverse events related to vaccination are acceptable. More data are needed to establish vaccine efficacy with regard to prevention of HPV infection and further outcomes including cervical intraepithelial neoplasia (CIN) and cervical cancer., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Poor quality of reporting of confounding has been observed in observational studies prior the STrenghtening the Reporting of Observational studies in Epidemiology (STROBE) statement, a reporting guideline for observational studies. We assessed whether the reporting of confounding improved after the STROBE statement., Study Design and Setting: We searched MEDLINE for all articles about observational cohort and case-control studies on interventions with a hypothesized beneficial effect in five general medical and five epidemiologic journals published between January 2010 and December 2012. We abstracted data for the baseline period before the publication of the STROBE statement (January 2004-April 2007) from a prior study. Six relevant items related to confounding were scored for each article. A comparison of the median number of items reported in both periods was made., Results: In total, 174 articles published before and 220 articles published after the STROBE statement were included. The median number reported items was similar before and after the publication of the STROBE statement [median, 4; interquartile range [IQR], 3-5 vs. median, 4; IQR, 3.75-5]. However, the distribution of the number of reported items shifted somewhat to the right (P = 0.01)., Conclusion: Although the quality of reporting of confounding improved in certain aspects, the overall quality remains suboptimal., (Copyright © 2016 Elsevier Inc. All rights reserved.)