Reducing the Antigen Prevalence Target Threshold for Stopping and Restarting Mass Drug Administration for Lymphatic Filariasis Elimination: A Model-Based Cost-effectiveness Simulation in Tanzania, India and Haiti.

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.

Distinct patterns of vital sign and inflammatory marker responses in adults with suspected bloodstream infection.

OBJECTIVES: To identify patterns in inflammatory marker and vital sign responses in adult with suspected bloodstream infection (BSI) and define expected trends in normal recovery. METHODS: We included patients ≥16 y from Oxford University Hospitals with a blood culture taken between 1-January-2016 and 28-June-2021. We used linear and latent class mixed models to estimate trajectories in C-reactive protein (CRP), white blood count, heart rate, respiratory rate and temperature and identify CRP response subgroups. Centile charts for expected CRP responses were constructed via the lambda-mu-sigma method. RESULTS: In 88,348 suspected BSI episodes; 6908 (7.8%) were culture-positive with a probable pathogen, 4309 (4.9%) contained potential contaminants, and 77,131(87.3%) were culture-negative. CRP levels generally peaked 1-2 days after blood culture collection, with varying responses for different pathogens and infection sources (p < 0.0001). We identified five CRP trajectory subgroups: peak on day 1 (36,091; 46.3%) or 2 (4529; 5.8%), slow recovery (10,666; 13.7%), peak on day 6 (743; 1.0%), and low response (25,928; 33.3%). Centile reference charts tracking normal responses were constructed from those peaking on day 1/2. CONCLUSIONS: CRP and other infection response markers rise and recover differently depending on clinical syndrome and pathogen involved. However, centile reference charts, that account for these differences, can be used to track if patients are recovering line as expected and to help personalise infection.

SARS-CoV-2, influenza A/B and respiratory syncytial virus positivity and association with influenza-like illness and self-reported symptoms, over the 2022/23 winter season in the UK: a longitudinal surveillance cohort.

BACKGROUND: Syndromic surveillance often relies on patients presenting to healthcare. Community cohorts, although more challenging to recruit, could provide additional population-wide insights, particularly with SARS-CoV-2 co-circulating with other respiratory viruses. METHODS: We estimated the positivity and incidence of SARS-CoV-2, influenza A/B, and RSV, and trends in self-reported symptoms including influenza-like illness (ILI), over the 2022/23 winter season in a broadly representative UK community cohort (COVID-19 Infection Survey), using negative-binomial generalised additive models. We estimated associations between test positivity and each of the symptoms and influenza vaccination, using adjusted logistic and multinomial models. RESULTS: Swabs taken at 32,937/1,352,979 (2.4%) assessments tested positive for SARS-CoV-2, 181/14,939 (1.2%) for RSV and 130/14,939 (0.9%) for influenza A/B, varying by age over time. Positivity and incidence peaks were earliest for RSV, then influenza A/B, then SARS-CoV-2, and were highest for RSV in the youngest and for SARS-CoV-2 in the oldest age groups. Many test positives did not report key symptoms: middle-aged participants were generally more symptomatic than older or younger participants, but still, only ~ 25% reported ILI-WHO and ~ 60% ILI-ECDC. Most symptomatic participants did not test positive for any of the three viruses. Influenza A/B-positivity was lower in participants reporting influenza vaccination in the current and previous seasons (odds ratio = 0.55 (95% CI 0.32, 0.95)) versus neither season. CONCLUSIONS: Symptom profiles varied little by aetiology, making distinguishing SARS-CoV-2, influenza and RSV using symptoms challenging. Most symptoms were not explained by these viruses, indicating the importance of other pathogens in syndromic surveillance. Influenza vaccination was associated with lower rates of community influenza test positivity.

Costs-effectiveness and cost components of pharmaceutical and non-pharmaceutical interventions affecting antibiotic resistance outcomes in hospital patients: a systematic literature review.

INTRODUCTION: Limited information on costs and the cost-effectiveness of hospital interventions to reduce antibiotic resistance (ABR) hinder efficient resource allocation. METHODS: We conducted a systematic literature review for studies evaluating the costs and cost-effectiveness of pharmaceutical and non-pharmaceutical interventions aimed at reducing, monitoring and controlling ABR in patients. Articles published until 12 December 2023 were explored using EconLit, EMBASE and PubMed. We focused on critical or high-priority bacteria, as defined by the WHO, and intervention costs and incremental cost-effectiveness ratio (ICER). Following Preferred Reporting Items for Systematic review and Meta-Analysis guidelines, we extracted unit costs, ICERs and essential study information including country, intervention, bacteria-drug combination, discount rates, type of model and outcomes. Costs were reported in 2022 US dollars ($), adopting the healthcare system perspective. Country willingness-to-pay (WTP) thresholds from Woods et al 2016 guided cost-effectiveness assessments. We assessed the studies reporting checklist using Drummond's method. RESULTS: Among 20 958 articles, 59 (32 pharmaceutical and 27 non-pharmaceutical interventions) met the inclusion criteria. Non-pharmaceutical interventions, such as hygiene measures, had unit costs as low as $1 per patient, contrasting with generally higher pharmaceutical intervention costs. Several studies found that linezolid-based treatments for methicillin-resistant Staphylococcus aureus were cost-effective compared with vancomycin (ICER up to $21 488 per treatment success, all 16 studies' ICERs

Employment outcomes of people with Long Covid symptoms: community-based cohort study.

BACKGROUND: Evidence on the long-term employment consequences of SARS-CoV-2 infection is lacking. We used data from a large, community-based sample in the UK to estimate associations between Long Covid and employment outcomes. METHODS: This was an observational, longitudinal study using a pre-post design. We included survey participants from 3 February 2021 to 30 September 2022 when they were aged 16-64 years and not in education. Using conditional logit modelling, we explored the time-varying relationship between Long Covid status ≥12 weeks after a first test-confirmed SARS-CoV-2 infection (reference: pre-infection) and labour market inactivity (neither working nor looking for work) or workplace absence lasting ≥4 weeks. RESULTS: Of 206 299 participants (mean age 45 years, 54% female, 92% white), 15% were ever labour market inactive and 10% were ever long-term absent during follow-up. Compared with pre-infection, inactivity was higher in participants reporting Long Covid 30 to <40 weeks [adjusted odds ratio (aOR): 1.45; 95% CI: 1.17-1.81] or 40 to <52 weeks (aOR: 1.34; 95% CI: 1.05-1.72) post-infection. Combining with official statistics on Long Covid prevalence, and assuming a correct statistical model, our estimates translate to 27 000 (95% CI: 6000-47 000) working-age adults in the UK being inactive because of Long Covid in July 2022. CONCLUSIONS: Long Covid is likely to have contributed to reduced participation in the UK labour market, though it is unlikely to be the sole driver. Further research is required to quantify the contribution of other factors, such as indirect health effects of the pandemic.

Risk of SARS-CoV-2 reinfection during multiple Omicron variant waves in the UK general population.

SARS-CoV-2 reinfections increased substantially after Omicron variants emerged. Large-scale community-based comparisons across multiple Omicron waves of reinfection characteristics, risk factors, and protection afforded by previous infection and vaccination, are limited. Here we studied ~45,000 reinfections from the UK's national COVID-19 Infection Survey and quantified the risk of reinfection in multiple waves, including those driven by BA.1, BA.2, BA.4/5, and BQ.1/CH.1.1/XBB.1.5 variants. Reinfections were associated with lower viral load and lower percentages of self-reporting symptoms compared with first infections. Across multiple Omicron waves, estimated protection against reinfection was significantly higher in those previously infected with more recent than earlier variants, even at the same time from previous infection. Estimated protection against Omicron reinfections decreased over time from the most recent infection if this was the previous or penultimate variant (generally within the preceding year). Those 14-180 days after receiving their most recent vaccination had a lower risk of reinfection than those >180 days from their most recent vaccination. Reinfection risk was independently higher in those aged 30-45 years, and with either low or high viral load in their most recent previous infection. Overall, the risk of Omicron reinfection is high, but with lower severity than first infections; both viral evolution and waning immunity are independently associated with reinfection.

A systematic review on the excess health risk of antibiotic-resistant bloodstream infections for six key pathogens in Europe.

BACKGROUND: Antimicrobial resistance is a global threat, which requires novel intervention strategies, for which priority pathogens and settings need to be determined. OBJECTIVES: We evaluated pathogen-specific excess health burden of drug-resistant bloodstream infections (BSIs) in Europe. METHODS: A systematic review and meta-analysis. DATA SOURCES: MEDLINE, Embase, and grey literature for the period January 1990 to May 2022. STUDY ELIGIBILITY CRITERIA: Studies that reported burden data for six key drug-resistant pathogens: carbapenem-resistant (CR) Pseudomonas aeruginosa and Acinetobacter baumannii, third-generation cephalosporin or CR Escherichia coli and Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Excess health outcomes compared with drug-susceptible BSIs or uninfected patients. For MRSA and third-generation cephalosporin E. coli and K. pneumoniae BSIs, five or more European studies were identified. For all others, the search was extended to high-income countries. PARTICIPANTS: Paediatric and adult patients diagnosed with drug-resistant BSI. INTERVENTIONS: Not applicable. ASSESSMENT OF RISK OF BIAS: An adapted version of the Joanna-Briggs Institute assessment tool. METHODS OF DATA SYNTHESIS: Random-effect models were used to pool pathogen-specific burden estimates. RESULTS: We screened 7154 titles, 1078 full-texts and found 56 studies on BSIs. Most studies compared outcomes of drug-resistant to drug-susceptible BSIs (46/56, 82.1%), and reported mortality (55/56 studies, 98.6%). The pooled crude estimate for excess all-cause mortality of drug-resistant versus drug-susceptible BSIs ranged from OR 1.31 (95% CI 1.03-1.68) for CR P. aeruginosa to OR 3.44 (95% CI 1.62-7.32) for CR K. pneumoniae. Pooled crude estimates comparing mortality to uninfected patients were available for vancomycin-resistant Enterococcus and MRSA BSIs (OR of 11.19 [95% CI 6.92-18.09] and OR 6.18 [95% CI 2.10-18.17], respectively). CONCLUSIONS: Drug-resistant BSIs are associated with increased mortality, with the magnitude of the effect influenced by pathogen type and comparator. Future research should address crucial knowledge gaps in pathogen- and infection-specific burdens to guide development of novel interventions.

Excess resource use and cost of drug-resistant infections for six key pathogens in Europe: a systematic review and Bayesian meta-analysis.

BACKGROUND: Quantifying the resource use and cost of antimicrobial resistance establishes the magnitude of the problem and drives action. OBJECTIVES: Assessment of resource use and cost associated with infections with six key drug-resistant pathogens in Europe. METHODS: A systematic review and Bayesian meta-analysis. DATA SOURCES: MEDLINE (Ovid), Embase (Ovid), Econlit databases, and grey literature for the period 1 January 1990, to 21 June 2022. STUDY ELIGIBILITY CRITERIA: Resource use and cost outcomes (including excess length of stay, overall costs, and other excess in or outpatient costs) were compared between patients with defined antibiotic-resistant infections caused by carbapenem-resistant (CR) Pseudomonas aeruginosa and Acinetobacter baumannii, CR or third-generation cephalosporin Escherichia coli (3GCREC) and Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium, and patients with drug-susceptible or no infection. PARTICIPANTS: All patients diagnosed with drug-resistant bloodstream infections (BSIs). INTERVENTIONS: NA. ASSESSMENT OF RISK OF BIAS: An adapted version of the Joanna Briggs Institute assessment tool, incorporating case-control, cohort, and economic assessment frameworks. METHODS OF DATA SYNTHESIS: Hierarchical Bayesian meta-analyses were used to assess pathogen-specific resource use estimates. RESULTS: Of 5969 screened publications, 37 were included in the review. Data were sparse and heterogeneous. Most studies estimated the attributable burden by, comparing resistant and susceptible pathogens (32/37). Four studies analysed the excess cost of hospitalization attributable to 3GCREC BSIs, ranging from -€ 2465.50 to € 6402.81. Eight studies presented adjusted excess length of hospital stay estimates for methicillin-resistant S. aureus and 3GCREC BSIs (4 each) allowing for Bayesian hierarchical analysis, estimating means of 1.26 (95% credible interval [CrI], -0.72 to 4.17) and 1.78 (95% CrI, -0.02 to 3.38) days, respectively. CONCLUSIONS: Evidence on most cost and resource use outcomes and across most pathogen-resistance combinations was severely lacking. Given the importance of this evidence for rational policymaking, further research is urgently needed.

Bleeding risk in patients prescribed dual antiplatelet therapy and triple therapy after coronary interventions: the ADAPTT retrospective population-based cohort studies.

Background: Bleeding among populations undergoing percutaneous coronary intervention or coronary artery bypass grafting and among conservatively managed patients with acute coronary syndrome exposed to different dual antiplatelet therapy and triple therapy (i.e. dual antiplatelet therapy plus an anticoagulant) has not been previously quantified. Objectives: The objectives were to estimate hazard ratios for bleeding for different antiplatelet and triple therapy regimens, estimate resources and the associated costs of treating bleeding events, and to extend existing economic models of the cost-effectiveness of dual antiplatelet therapy. Design: The study was designed as three retrospective population-based cohort studies emulating target randomised controlled trials. Setting: The study was set in primary and secondary care in England from 2010 to 2017. Participants: Participants were patients aged ≥ 18 years undergoing coronary artery bypass grafting or emergency percutaneous coronary intervention (for acute coronary syndrome), or conservatively managed patients with acute coronary syndrome. Data sources: Data were sourced from linked Clinical Practice Research Datalink and Hospital Episode Statistics. Interventions: Coronary artery bypass grafting and conservatively managed acute coronary syndrome: aspirin (reference) compared with aspirin and clopidogrel. Percutaneous coronary intervention: aspirin and clopidogrel (reference) compared with aspirin and prasugrel (ST elevation myocardial infarction only) or aspirin and ticagrelor. Main outcome measures: Primary outcome: any bleeding events up to 12 months after the index event. Secondary outcomes: major or minor bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular events. Results: The incidence of any bleeding was 5% among coronary artery bypass graft patients, 10% among conservatively managed acute coronary syndrome patients and 9% among emergency percutaneous coronary intervention patients, compared with 18% among patients prescribed triple therapy. Among coronary artery bypass grafting and conservatively managed acute coronary syndrome patients, dual antiplatelet therapy, compared with aspirin, increased the hazards of any bleeding (coronary artery bypass grafting: hazard ratio 1.43, 95% confidence interval 1.21 to 1.69; conservatively-managed acute coronary syndrome: hazard ratio 1.72, 95% confidence interval 1.15 to 2.57) and major adverse cardiovascular events (coronary artery bypass grafting: hazard ratio 2.06, 95% confidence interval 1.23 to 3.46; conservatively-managed acute coronary syndrome: hazard ratio 1.57, 95% confidence interval 1.38 to 1.78). Among emergency percutaneous coronary intervention patients, dual antiplatelet therapy with ticagrelor, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.47, 95% confidence interval 1.19 to 1.82), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.06, 95% confidence interval 0.89 to 1.27). Among ST elevation myocardial infarction percutaneous coronary intervention patients, dual antiplatelet therapy with prasugrel, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.48, 95% confidence interval 1.02 to 2.12), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.10, 95% confidence interval 0.80 to 1.51). Health-care costs in the first year did not differ between dual antiplatelet therapy with clopidogrel and aspirin monotherapy among either coronary artery bypass grafting patients (mean difference £94, 95% confidence interval -£155 to £763) or conservatively managed acute coronary syndrome patients (mean difference £610, 95% confidence interval -£626 to £1516), but among emergency percutaneous coronary intervention patients were higher for those receiving dual antiplatelet therapy with ticagrelor than for those receiving dual antiplatelet therapy with clopidogrel, although for only patients on concurrent proton pump inhibitors (mean difference £1145, 95% confidence interval £269 to £2195). Conclusions: This study suggests that more potent dual antiplatelet therapy may increase the risk of bleeding without reducing the incidence of major adverse cardiovascular events. These results should be carefully considered by clinicians and decision-makers alongside randomised controlled trial evidence when making recommendations about dual antiplatelet therapy. Limitations: The estimates for bleeding and major adverse cardiovascular events may be biased from unmeasured confounding and the exclusion of an eligible subgroup of patients who could not be assigned an intervention. Because of these limitations, a formal cost-effectiveness analysis could not be conducted. Future work: Future work should explore the feasibility of using other UK data sets of routinely collected data, less susceptible to bias, to estimate the benefit and harm of antiplatelet interventions. Trial registration: This trial is registered as ISRCTN76607611. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 8. See the NIHR Journals Library website for further project information.

People who have a heart attack are treated with a stent to open up the blocked artery that caused the heart attack, with surgery to bypass the blocked artery or with medication only. Whatever the treatment, they are prescribed one or more antiplatelet drugs, either aspirin only or aspirin and an additional antiplatelet (clopidogrel, prasugrel or ticagrelor), for 12 months after the heart attack. Antiplatelets are given to prevent another heart attack, but increase the risk of bleeding. We used a large general practice database and a database describing patients' attendances and admissions to hospital to determine how many people bleed with different antiplatelet combinations. We found that, overall, up to 1 in 10 people taking antiplatelets (rising to 2 in 10 if also taking an anticoagulant such as warfarin or dabigatran) reported a bleed. Among patients treated with surgery or medication only, we compared aspirin only (which is a less potent therapy) with aspirin and clopidogrel (a more potent therapy). Among patients treated with stents, we compared aspirin and clopidogrel (less potent therapy) with aspirin and prasugrel or ticagrelor (more potent therapy). In all three populations, the more potent therapy increased the risk of bleeding by about one and a half times, but this was not offset by a reduced risk of having a subsequent heart attack. This may be explained by low adherence to the medication: between one-third and almost half of all patients did not adhere to their regimen, and non-adherence was generally higher among patients taking a more potent therapy. It may also be explained by bias inherent in the study, for example if the groups prescribed different antiplatelet regimens had different risks of having another heart attack. Nevertheless, the results show that doctors should be cautious about prescribing more potent antiplatelet therapy because it may increase serious bleeds without necessarily reducing the number of heart attacks.

Impact of the COVID-19 pandemic on antimicrobial stewardship support for general practices in England: a qualitative interview study.

BACKGROUND: In England, clinical commissioning group (CCG; now replaced by Integrated Care Systems [ICSs]) and primary care network (PCN) professionals support primary care prescribers to optimise antimicrobial stewardship (AMS). AIM: To explore views and experiences of CCG and PCN staff in supporting AMS, and the impact of COVID-19 on this support. DESIGN & SETTING: Qualitative interview study in primary care in England. METHOD: Semi-structured interviews with staff from CCG and PCNs responsible for AMS were conducted at two timepoints via telephone. These were audio-recorded, transcribed, and analysed thematically. RESULTS: Twenty-seven interviews were conducted with 14 participants (nine CCG, five PCN) in December 2020-January 2021 and February-May 2021. The study found that AMS support was (1) deprioritised in order to keep general practice operational and deliver COVID-19 vaccines; (2) disrupted as social distancing made it harder to build relationships, conduct routine AMS activities, and challenge prescribing decisions; and (3) adapted, with opportunities identified for greater use of technology and changing patient and public perceptions of viruses and self-care. It was also found that resources to support AMS were valued if they were both novel, to counter AMS 'fatigue', and sufficiently familiar to fit with existing and/or future AMS. CONCLUSION: AMS needs to be reprioritised in general practice in the post-pandemic era and within the new ICSs in England. This should include interventions and strategies that combine novel elements with already familiar strategies to refresh prescribers' motivation and opportunities for AMS. Behaviour change interventions should be aimed at improving the culture and processes for how PCN pharmacists voice concerns about AMS to prescribers in general practice and take advantage of the changed patient and public perceptions of viruses and self-care.

Incidence of Respiratory Syncytial Virus Infection in Older Adults: Limitations of Current Data.

INTRODUCTION: Respiratory syncytial virus (RSV) is an important cause of severe respiratory illness in older adults and adults with respiratory or cardiovascular comorbidities. Published estimates of its incidence and prevalence in adult groups vary widely. This article reviews the potential limitations affecting RSV epidemiology studies and suggests points to consider when evaluating or designing them. METHODS: Studies reporting the incidence or prevalence of RSV infection in adults in high-income Western countries from 2000 onwards were identified via a rapid literature review. Author-reported limitations were recorded, together with presence of other potential limitations. Data were synthesized narratively, with a focus on factors affecting incidence estimates for symptomatic infection in older adults. RESULTS: A total of 71 studies met the inclusion criteria, most in populations with medically attended acute respiratory illness (ARI). Only a minority used case definitions and sampling periods tailored specifically to RSV; many used influenza-based or other criteria that are likely to result in RSV cases being missed. The great majority relied solely on polymerase chain reaction (PCR) testing of upper respiratory tract samples, which is likely to miss RSV cases compared with dual site sampling and/or addition of serology. Other common limitations were studying a single season, which has potential for bias due to seasonal variability; failure to stratify results by age, which underestimates the burden of severe disease in older adults; limited generalizability beyond a limited study setting; and absence of measures of uncertainty in the reporting of results. CONCLUSIONS: A significant proportion of studies are likely to underestimate the incidence of RSV infection in older adults, although the effect size is unclear and there is also potential for overestimation. Well-designed studies, together with increased testing for RSV in patients with ARI in clinical practice, are required to accurately capture both the burden of RSV and the potential public health impact of vaccines.

Estimating global and regional between-country inequality in routine childhood vaccine coverage in 195 countries and territories from 2019 to 2021: a longitudinal study.

Background: Global routine childhood vaccine coverage has plateaued in recent years, and the COVID-19 pandemic further disrupted immunisation services. We estimated global and regional inequality of routine childhood vaccine coverage from 2019 to 2021, particularly assessing the impacts of the COVID-19 pandemic. Methods: We used longitudinal data for 11 routine childhood vaccines from the WHO-UNICEF Estimates of National Immunization Coverage (WUENIC), including 195 countries and territories in 2019-2021. The slope index of inequality (SII) and relative index of inequality (RII) of each vaccine were calculated through linear regression to express the difference in coverage between the top and bottom 20% of countries at the global and regional levels. We also explored inequalities of routine childhood vaccine coverage by WHO regions and unvaccinated children by income groups. Findings: Globally between January 1, 2019 and December 31, 2021, most childhood vaccines showed a declining trend in coverage, and therefore an increasing number of unvaccinated children, especially in low-income and lower-middle-income countries. Between-country inequalities existed for all 11 routine childhood vaccine coverage indicators. The SII for the third dose of diphtheria-tetanus-pertussis-containing vaccine (DTP3) coverage was 20.1 percentage points (95% confidence interval: 13.7, 26.5) in 2019, and rose to 23.6 (17.5, 30.0) in 2020 and 26.9 (20.0, 33.8) in 2021. Similar patterns were found for RII results and in other routine vaccines. In 2021, the second dose of measles-containing vaccine (MCV2) coverage had the highest global absolute inequality (31.2, [21.5-40.8]), and completed rotavirus vaccine (RotaC) coverage had the lowest (7.8, [-3.9, 19.5]). Among six WHO regions, the European Region consistently had the lowest inequalities, and the Western Pacific Region had the largest inequalities for many indicators, although both increased from 2019 to 2021. Interpretation: Global and regional inequalities of routine childhood vaccine coverage persisted and substantially increased from 2019 to 2021. These findings reveal economic-related inequalities by vaccines, regions, and countries, and underscore the importance of reducing such inequalities. These inequalities were widened during the COVID-19 pandemic, resulting in even lower coverage and more unvaccinated children in low-income countries. Funding: Bill & Melinda Gates Foundation.

Protection against SARS-CoV-2 Omicron BA.4/5 variant following booster vaccination or breakthrough infection in the UK.

Following primary SARS-CoV-2 vaccination, whether boosters or breakthrough infections provide greater protection against SARS-CoV-2 infection is incompletely understood. Here we investigated SARS-CoV-2 antibody correlates of protection against new Omicron BA.4/5 (re-)infections and anti-spike IgG antibody trajectories after a third/booster vaccination or breakthrough infection following second vaccination in 154,149 adults ≥18 y from the United Kingdom general population. Higher antibody levels were associated with increased protection against Omicron BA.4/5 infection and breakthrough infections were associated with higher levels of protection at any given antibody level than boosters. Breakthrough infections generated similar antibody levels to boosters, and the subsequent antibody declines were slightly slower than after boosters. Together our findings show breakthrough infection provides longer-lasting protection against further infections than booster vaccinations. Our findings, considered alongside the risks of severe infection and long-term consequences of infection, have important implications for vaccine policy.

COVID-19 vaccination, risk-compensatory behaviours, and contacts in the UK.

The physiological effects of vaccination against SARS-CoV-2 (COVID-19) are well documented, yet the behavioural effects not well known. Risk compensation suggests that gains in personal safety, as a result of vaccination, are offset by increases in risky behaviour, such as socialising, commuting and working outside the home. This is potentially important because transmission of SARS-CoV-2 is driven by contacts, which could be amplified by vaccine-related risk compensation. Here, we show that behaviours were overall unrelated to personal vaccination, but-adjusting for variation in mitigation policies-were responsive to the level of vaccination in the wider population: individuals in the UK were risk compensating when rates of vaccination were rising. This effect was observed across four nations of the UK, each of which varied policies autonomously.

Implementing antibiotic stewardship in high-prescribing English general practices: a mixed-methods study.

BACKGROUND: Trials have identified antimicrobial stewardship (AMS) strategies that effectively reduce antibiotic use in primary care. However, many are not commonly used in England. The authors co-developed an implementation intervention to improve use of three AMS strategies: enhanced communication strategies, delayed prescriptions, and point-of-care C-reactive protein tests (POC-CRPTs). AIM: To investigate the use of the intervention in high-prescribing practices and its effect on antibiotic prescribing. DESIGN AND SETTING: Nine high-prescribing practices had access to the intervention for 12 months from November 2019. This was primarily delivered remotely via a website with practices required to identify an 'antibiotic champion'. METHOD: Routinely collected prescribing data were compared between the intervention and the control practices. Intervention use was assessed through monitoring. Surveys and interviews were conducted with professionals to capture experiences of using the intervention. RESULTS: There was no evidence that the intervention affected prescribing. Engagement with intervention materials differed substantially between practices and depended on individual champions' preconceptions of strategies and the opportunity to conduct implementation tasks. Champions in five practices initiated changes to encourage use of at least one AMS strategy, mostly POC-CRPTs; one practice chose all three. POC-CRPTs was used more when allocated to one person. CONCLUSION: Clinicians need detailed information on exactly how to adopt AMS strategies. Remote, one-sided provision of AMS strategies is unlikely to change prescribing; initial clinician engagement and understanding needs to be monitored to avoid misunderstanding and suboptimal use.

Estimation of the impact of hospital-onset SARS-CoV-2 infections on length of stay in English hospitals using causal inference.

BACKGROUND: From March 2020 through August 2021, 97,762 hospital-onset SARS-CoV-2 infections were detected in English hospitals. Resulting excess length of stay (LoS) created a potentially substantial health and economic burden for patients and the NHS, but we are currently unaware of any published studies estimating this excess. METHODS: We implemented appropriate causal inference methods to determine the extent to which observed additional hospital stay is attributable to the infection rather than the characteristics of the patients. Hospital admissions records were linked to SARS-CoV-2 test data to establish the study population (7.5 million) of all non-COVID-19 admissions to English hospitals from 1st March 2020 to 31st August 2021 with a stay of at least two days. The excess LoS due to hospital-onset SARS-CoV-2 infection was estimated as the difference between the mean LoS observed and in the counterfactual where infections do not occur. We used inverse probability weighted Kaplan-Meier curves to estimate the mean survival time if all hospital-onset SARS-CoV-2 infections were to be prevented, the weights being based on the daily probability of acquiring an infection. The analysis was carried out for four time periods, reflecting phases of the pandemic differing with respect to overall case numbers, testing policies, vaccine rollout and prevalence of variants. RESULTS: The observed mean LoS of hospital-onset cases was higher than for non-COVID-19 hospital patients by 16, 20, 13 and 19 days over the four phases, respectively. However, when the causal inference approach was used to appropriately adjust for time to infection and confounding, the estimated mean excess LoS caused by hospital-onset SARS-CoV-2 was: 2.0 [95% confidence interval 1.8-2.2] days (Mar-Jun 2020), 1.4 [1.2-1.6] days (Sep-Dec 2020); 0.9 [0.7-1.1] days (Jan-Apr 2021); 1.5 [1.1-1.9] days (May-Aug 2021). CONCLUSIONS: Hospital-onset SARS-CoV-2 is associated with a small but notable excess LoS, equivalent to 130,000 bed days. The comparatively high LoS observed for hospital-onset COVID-19 patients is mostly explained by the timing of their infections relative to admission. Failing to account for confounding and time to infection leads to overestimates of additional length of stay and therefore overestimates costs of infections, leading to inaccurate evaluations of control strategies.

Inferring risks of coronavirus transmission from community household data.

The response of many governments to the COVID-19 pandemic has involved measures to control within- and between-household transmission, providing motivation to improve understanding of the absolute and relative risks in these contexts. Here, we perform exploratory, residual-based, and transmission-dynamic household analysis of the Office for National Statistics COVID-19 Infection Survey data from 26 April 2020 to 15 July 2021 in England. This provides evidence for: (i) temporally varying rates of introduction of infection into households broadly following the trajectory of the overall epidemic and vaccination programme; (ii) susceptible-Infectious transmission probabilities of within-household transmission in the 15-35% range; (iii) the emergence of the Alpha and Delta variants, with the former being around 50% more infectious than wildtype and 35% less infectious than Delta within households; (iv) significantly (in the range of 25-300%) more risk of bringing infection into the household for workers in patient-facing roles pre-vaccine; (v) increased risk for secondary school-age children of bringing the infection into the household when schools are open; (vi) increased risk for primary school-age children of bringing the infection into the household when schools were open since the emergence of new variants.

Risk of Long COVID in People Infected With Severe Acute Respiratory Syndrome Coronavirus 2 After 2 Doses of a Coronavirus Disease 2019 Vaccine: Community-Based, Matched Cohort Study.

We investigated long COVID incidence by vaccination status in a random sample of UK adults from April 2020 to November 2021. Persistent symptoms were reported by 9.5% of 3090 breakthrough severe acute respiratory syndrome coronavirus 2 infections and 14.6% of unvaccinated controls (adjusted odds ratio, 0.59 [95% confidence interval, .50-.69]), emphasizing the need for public health initiatives to increase population-level vaccine uptake.

Real-world bleeding in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) and prescribed different combinations of dual antiplatelet therapy (DAPT) in England: a population-based cohort study emulating a 'target trial'.

OBJECTIVE: To estimate the incidence and HRs for bleeding for different dual antiplatelet therapies (DAPT) in a real-world population with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) in England. DESIGN: A retrospective, population-based cohort study emulating a target randomised controlled trial (tRCT). DATA SOURCES: Linked Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES). SETTING: Primary and secondary care. PARTICIPANTS: Patients ≥18 years old with ACS undergoing emergency PCI. INTERVENTIONS: Aspirin and clopidogrel (AC, reference) versus aspirin and prasugrel (AP) or aspirin and ticagrelor (AT); AP evaluated only in patients with ST-elevation myocardial infarction (STEMI). MAIN OUTCOME MEASURES: Primary: any bleeding up to 12 months after the index event (HES- or CPRD- recorded). Secondary: HES-recorded bleeding, CPRD-recorded bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular and cerebrovascular events (MACCE). RESULTS: In ACS, the rates of any bleeding for AC and AT were 89 per 1000 person years and 134 per 1000 person years, respectively. In STEMI, rates for AC, AP and AT were 93 per 1000 person years, 138 per 1000 person years and 143 per 100 person years, respectively. In ACS, compared with AC, AT increased the hazard of any bleeding (HR: 1.47, 95% CI 1.19 to 1.82) but did not reduce MACCE (HR: 1.06, 95% CI 0.89 to 1.27). In STEMI, compared with AC, AP and AT increased the hazard of any bleeding (HR: 1.77, 95% CI 1.21 to 2.59 and HR: 1.50, 95% CI 1.10 to 2.05, respectively) but did not reduce MACCE (HR: 1.10, 95% CI 0.80 to 1.51 and HR: 1.21, 95% CI 0.94 to 1.51, respectively). Non-adherence to the prescribed DAPT regimen was 28% in AC (29% in STEMI only), 31% in AP (STEMI only) and 33% in AT (32% in STEMI only). CONCLUSIONS: In a real-world population with ACS, DAPT with ticagrelor or prasugrel are associated with increased bleeding compared with DAPT with clopidogrel. TRIAL REGISTRATION NUMBER: ISRCTN76607611.

Risk of covid-19 related deaths for SARS-CoV-2 omicron (B.1.1.529) compared with delta (B.1.617.2): retrospective cohort study.

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.