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Final-year medical students, Ibrahim and Alicia, share details of their Special Studies Module (SSM) project; carried out alongside Dr. David Nunan at the Centre for Evidence-Based Medicine.
The impact of the COVID-19 pandemic on antimicrobial usage: an international patient-level cohort study
Background: This study aimed to evaluate the trends in antimicrobial prescription during the first 1.5 years of COVID-19 pandemic. Methods: This was an observational, retrospective cohort study using patient-level data from Bangladesh, Brazil, India, Italy, Malawi, Nigeria, South Korea, Switzerland and Turkey from patients with pneumonia and/or acute respiratory distress syndrome and/or sepsis, regardless of COVID-19 positivity, who were admitted to critical care units or COVID-19 specialized wards. The changes of antimicrobial prescription between pre-pandemic and pandemic were estimated using logistic or linear regression. Pandemic effects on month-wise antimicrobial usage were evaluated using interrupted time series analyses (ITSAs). Results: Antimicrobials for which prescriptions significantly increased during the pandemic were as follows: meropenem in Bangladesh (95% CI: 1.94–4.07) with increased prescribed daily dose (PDD) (95% CI: 1.17–1.58) and Turkey (95% CI: 1.09–1.58), moxifloxacin in Bangladesh (95% CI: 4.11–11.87) with increased days of therapy (DOT) (95% CI: 1.14–2.56), piperacillin/tazobactam in Italy (95% CI: 1.07–1.48) with increased DOT (95% CI: 1.01–1.25) and PDD (95% CI: 1.05–1.21) and azithromycin in Bangladesh (95% CI: 3.36–21.77) and Brazil (95% CI: 2.33–8.42). ITSA showed a significant drop in azithromycin usage in India (95% CI: −8.38 to −3.49 g/100 patients) and South Korea (95% CI: −2.83 to −1.89 g/100 patients) after WHO guidelines v1 release and increased meropenem usage (95% CI: 93.40–126.48 g/100 patients) and moxifloxacin (95% CI: 5.40–13.98 g/100 patients) in Bangladesh and sulfamethoxazole/trimethoprim in India (95% CI: 0.92–9.32 g/100 patients) following the Delta variant emergence. Conclusions: This study reinforces the importance of developing antimicrobial stewardship in the clinical settings during inter-pandemic periods.
Prevalence of orthostatic intolerance in long covid clinic patients and healthy volunteers: A multicenter study
Orthostatic intolerance (OI), including postural orthostatic tachycardia syndrome (PoTS) and orthostatic hypotension (OH), are often reported in long covid, but published studies are small with inconsistent results. We sought to estimate the prevalence of objective OI in patients attending long covid clinics and healthy volunteers and associations with OI symptoms and comorbidities. Participants with a diagnosis of long covid were recruited from eight UK long covid clinics, and healthy volunteers from general population. All undertook standardized National Aeronautics and Space Administration Lean Test (NLT). Participants' history of typical OI symptoms (e.g., dizziness, palpitations) before and during the NLT were recorded. Two hundred seventy-seven long covid patients and 50 frequency-matched healthy volunteers were tested. Healthy volunteers had no history of OI symptoms or symptoms during NLT or PoTS, 10% had asymptomatic OH. One hundred thirty (47%) long covid patients had previous history of OI symptoms and 144 (52%) developed symptoms during the NLT. Forty-one (15%) had an abnormal NLT, 20 (7%) met criteria for PoTS, and 21 (8%) had OH. Of patients with an abnormal NLT, 45% had no prior symptoms of OI. Relaxing the diagnostic thresholds for PoTS from two consecutive abnormal readings to one abnormal reading during the NLT, resulted in 11% of long covid participants (an additional 4%) meeting criteria for PoTS, but not in healthy volunteers. More than half of long covid patients experienced OI symptoms during NLT and more than one in 10 patients met the criteria for either PoTS or OH, half of whom did not report previous typical OI symptoms. We therefore recommend all patients attending long covid clinics are offered an NLT and appropriate management commenced.
What is quality in long covid care? Lessons from a national quality improvement collaborative and multi-site ethnography
Background: Long covid (post covid-19 condition) is a complex condition with diverse manifestations, uncertain prognosis and wide variation in current approaches to management. There have been calls for formal quality standards to reduce a so-called “postcode lottery” of care. The original aim of this study—to examine the nature of quality in long covid care and reduce unwarranted variation in services—evolved to focus on examining the reasons why standardizing care was so challenging in this condition. Methods: In 2021–2023, we ran a quality improvement collaborative across 10 UK sites. The dataset reported here was mostly but not entirely qualitative. It included data on the origins and current context of each clinic, interviews with staff and patients, and ethnographic observations at 13 clinics (50 consultations) and 45 multidisciplinary team (MDT) meetings (244 patient cases). Data collection and analysis were informed by relevant lenses from clinical care (e.g. evidence-based guidelines), improvement science (e.g. quality improvement cycles) and philosophy of knowledge. Results: Participating clinics made progress towards standardizing assessment and management in some topics; some variation remained but this could usually be explained. Clinics had different histories and path dependencies, occupied a different place in their healthcare ecosystem and served a varied caseload including a high proportion of patients with comorbidities. A key mechanism for achieving high-quality long covid care was when local MDTs deliberated on unusual, complex or challenging cases for which evidence-based guidelines provided no easy answers. In such cases, collective learning occurred through idiographic (case-based) reasoning, in which practitioners build lessons from the particular to the general. This contrasts with the nomothetic reasoning implicit in evidence-based guidelines, in which reasoning is assumed to go from the general (e.g. findings of clinical trials) to the particular (management of individual patients). Conclusion: Not all variation in long covid services is unwarranted. Largely because long covid’s manifestations are so varied and comorbidities common, generic “evidence-based” standards require much individual adaptation. In this complex condition, quality improvement resources may be productively spent supporting MDTs to optimise their case-based learning through interdisciplinary discussion. Quality assessment of a long covid service should include review of a sample of individual cases to assess how guidelines have been interpreted and personalized to meet patients’ unique needs. Study registration: NCT05057260, ISRCTN15022307.
Mobilisation in the EveNing to prevent and TreAt deLirium (MENTAL): a mixed-methods, randomised controlled feasibility trial
Background: Delirium is common in critically ill patients and associated with longer hospital stays, increased morbidity and higher healthcare costs. Non-pharmacological interventions have been advocated for delirium management, however there is little evidence evaluating feasibility and acceptability of physical interventions administered in the evening. The aim of this study was to conduct a feasibility trial of evening mobilisation to prevent and treat delirium in patients admitted to intensive care. Methods: In this mixed-methods, randomised controlled feasibility trial we recruited participants from intensive care units at two university hospitals in the United Kingdom. Eligible participants who were able to respond to verbal stimulus (Richmond agitation and sedation scale ≥3) and expected to stay in intensive care for at least 24 h were randomly assigned (1:1) to receive usual care or usual care plus evening mobilisation. The evening mobilisation was delivered between 19:00 and 21:00, for up to seven consecutive evenings or ICU discharge, whichever was sooner. All outcome assessments were completed by a team member blinded to randomisation and group allocation. Primary objective was to assess feasibility and acceptability of evening mobilisation. Primary feasibility outcomes were recruitment, consent and retention rates, and intervention fidelity. Intervention acceptability was evaluated through semi-structured interviews of participants and staff. Secondary outcomes included prevalence in incidence and duration of delirium, measured using the Confusion Assessment Method for ICU. This trial is registered at ClinicalTrials.gov, NCT05401461. Findings: Between July 16th, 2022, and October 31st, 2022, 58 eligible patients (29 usual care; 29 usual care plus evening mobilisation) were enrolled. We demonstrated the feasibility and acceptability of both the trial design and evening mobilisation intervention. Consent and retention rates over three months were 88% (58/66) and 90% (52/58) respectively, with qualitative analysis demonstrating good acceptability reported by both participants and staff. Secondary outcomes for the evening intervention group compared with the control group were: delirium incidence 5/26 (19%; 95% CI: 6–39%) vs 8/28 (29%; 95% CI: 13–49%) and mean delirium duration 2 days (SD 0.7) vs 4.25 days (SD 2.0). Interpretation: Results of this trial will inform the development of a definitive full-scale randomised controlled trial investigating the effects of evening mobilisation to treat delirium and improve health-related outcomes. Funding: None.
Mobilisation in the EveNing to TreAt deLirium (MENTAL): Protocol for a mixed-methods feasibility randomised controlled trial
Introduction Delirium is common in critically ill patients and is associated with longer hospital stays, increased mortality and higher healthcare costs. A number of risk factors have been identified for the development of delirium in intensive care, two of which are sleep disturbance and immobilisation. Non-pharmacological interventions for the management of intensive care unit (ICU) delirium have been advocated, including sleep protocols and early mobilisation. However, there is a little published evidence evaluating the feasibility and acceptability of evening mobilisation. Methods and analysis Mobilisation in the EveNing to TreAt deLirium (MENTAL) is a two-centre, mixed-methods feasibility randomised controlled trial (RCT). Sixty patients will be recruited from ICUs at two acute NHS trusts and randomised on a 1:1 basis to receive additional evening mobilisation, delivered between 19:00 and 21:00, or standard care. The underpinning hypothesis is that the physical exertion associated with evening mobilisation will promote better sleep, subsequently having the potential to reduce delirium incidence. The primary objective is to assess the feasibility and acceptability of a future, multicentre RCT. The primary outcome measures, which will determine feasibility, are recruitment and retention rates, and intervention fidelity. Acceptability of the intervention will be evaluated through semi-structured interviews of participants and staff. Secondary outcome measures include collecting baseline, clinical and outcome data to inform the power calculations of a future definitive trial. Ethics and dissemination Ethical approval has been obtained through the Wales Research and Ethics Committee 6 (22/WA/0106). Participants are required to provide written informed consent. We aim to disseminate the findings through international conferences, international peer-reviewed journals and social media. Trial registration number NCT05401461.
Cognitive dysfunction after covid-19
As of March 2023, when the Office for National Statistics stopped collecting data on this condition, 1.879 million individuals had self-assessed as having long covid - symptoms lasting more than 12 weeks following acute covid-19 infection. Of these, the proportion of individuals with symptoms lasting two years or more is around 42%, suggesting a decline in new cases of long covid but a persistence of those with ongoing symptoms.1 Some systematic reviews and meta-analyses have reported that up to a third of such individuals have persistent symptoms of cognitive impairment,23 but estimates vary widely and are complicated by methodological heterogeneity - eg, study size, assessment approach, follow-up duration, and different sampling frames (from self-reported surveys4 to large retrospective matched cohort studies of health records5), as discussed in a recent meta-analysis.6
Hypertension and Atrial Fibrillation: A Frontier Review From the AF-SCREEN International Collaboration.
Hypertension is the leading modifiable risk factor for atrial fibrillation (AF) and is estimated to be present in >70% of AF patients. This Frontiers Review was prepared by 29 expert members of the AF-SCREEN International Collaboration to summarize existing evidence and knowledge gaps on links between hypertension, AF, and their cardiovascular sequelae; simultaneous screening for hypertension and AF; and the prevention of AF through antihypertensive therapy. Hypertension and AF are inextricably connected. Both are easily diagnosed, often silent, and frequently treated inadequately. Together, they additively increase the risk of ischemic stroke, heart failure, and many types of dementia, resulting in greater all-cause mortality, considerable disease burden, and increased health care expenditures. Automated upper arm cuff blood pressure devices with implemented technology can be used to simultaneously detect both hypertension and AF. However, positive screening for AF with an oscillometric blood pressure monitor still requires ECG confirmation. The current evidence suggests that high-risk individuals aged ≥65 years or with treatment-resistant hypertension could benefit from AF screening. Since antihypertensive therapy effectively lowers AF risk, particularly in individuals with left ventricular dysfunction, hypertension should be the key target for AF prediction and prevention rather than merely a comorbidity of AF. Nevertheless, several important gaps in knowledge need to be filled over the next years, including the ideal method and selection of patients for simultaneous screening of hypertension and AF and the optimal antihypertensive drug class and blood pressure targets for AF prevention.
The burden of bacterial antimicrobial resistance in the WHO European region in 2019: a cross-country systematic analysis
Background: Antimicrobial resistance (AMR) represents one of the most crucial threats to public health and modern health care. Previous studies have identified challenges with estimating the magnitude of the problem and its downstream effect on human health and mortality. To our knowledge, this study presents the most comprehensive set of regional and country-level estimates of AMR burden in the WHO European region to date. Methods: We estimated deaths and disability-adjusted life-years attributable to and associated with AMR for 23 bacterial pathogens and 88 pathogen–drug combinations for the WHO European region and its countries in 2019. Our methodological approach consisted of five broad components: the number of deaths in which infection had a role, the proportion of infectious deaths attributable to a given infectious syndrome, the proportion of infectious syndrome deaths attributable to a given pathogen, the percentage of a given pathogen resistant to an antimicrobial drug of interest, and the excess risk of mortality (or duration of an infection) associated with this resistance. These components were then used to estimate the disease burden by using two counterfactual scenarios: deaths attributable to AMR (considering an alternative scenario where infections with resistant pathogens are replaced with susceptible ones) and deaths associated with AMR (considering an alternative scenario where drug-resistant infections would not occur at all). Data were solicited from a wide array of international stakeholders; these included research hospitals, surveillance networks, and infection databases maintained by private laboratories and medical technology companies. We generated 95% uncertainty intervals (UIs) for final estimates as the 25th and 975th ordered values across 1000 posterior draws, and models were cross-validated for out-of-sample predictive validity. Findings: We estimated 541 000 deaths (95% UI 370 000–763 000) associated with bacterial AMR and 133 000 deaths (90 100–188 000) attributable to bacterial AMR in the whole WHO European region in 2019. The largest fatal burden of AMR in the region came from bloodstream infections, with 195 000 deaths (104 000–333 000) associated with resistance, followed by intra-abdominal infections (127 000 deaths [81 900–185 000]) and respiratory infections (120 000 deaths [94 500–154 000]). Seven leading pathogens were responsible for about 457 000 deaths associated with resistance in 53 countries of this region; these pathogens were, in descending order of mortality, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecium, Streptococcus pneumoniae, and Acinetobacter baumannii. Methicillin-resistant S aureus was shown to be the leading pathogen–drug combination in 27 countries for deaths attributable to AMR, while aminopenicillin-resistant E coli predominated in 47 countries for deaths associated with AMR. Interpretation: The high levels of resistance for several important bacterial pathogens and pathogen–drug combinations, together with the high mortality rates associated with these pathogens, show that AMR is a serious threat to public health in the WHO European region. Our regional and cross-country analyses open the door for strategies that can be tailored to leading pathogen–drug combinations and the available resources in a specific location. These results underscore that the most effective way to tackle AMR in this region will require targeted efforts and investments in conjunction with continuous outcome-based research endeavours. Funding: Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care using UK aid funding managed by the Fleming Fund.
Fatal journeys: causes of death in international travellers in South America
BACKGROUND: Understanding mortality among travellers is essential for mitigating risks and enhancing travel safety. However, limited evidence exists on severe illnesses and injuries leading to death among travellers, particularly in low- and middle-income countries and remote regions. METHODS: We conducted a retrospective census study using country-level observational data from death certificates of travellers of seven South American countries (Argentina, Brazil, Chile, Colombia, Ecuador, Peru and Uruguay) from 2017 to 2021. Causes of death were evaluated using ICD-10 codes, categorized into non-communicable diseases (NCDs), communicable diseases and injuries. We quantified causes of death by demographic characteristics (e.g. age, sex) and geographical variables. Chi-square tests were used to assess differences between categories. We calculated crude mortality rates and incidence rate ratios (IRRs) per country's subregions. RESULTS: A total of 17 245 deaths were reported. NCDs (55%) were the most common cause of death, followed by communicable diseases (23.4%) and injuries (18.1%). NCD-associated deaths increased after age 55 years and were highest among ≥85 years. Communicable diseases were more common at younger age (<20 years). Injury-associated deaths were more common in men (79.9%) and 25-29-year-olds (17.1%). Most deaths (68.2%) could have been avoided by prevention or treatment. Mortality risk was higher among travellers in bordering regions between countries. In Roraima (Brazil) and Norte de Santander (Colombia), locations bordering Venezuela, the death IRR was 863 and 60, respectively. These countries' reference mortality rates in those regions were much lower. More than 80% of the deaths in these border regions of Brazil and Colombia involved Venezuelan citizens. CONCLUSION: The study identified risk factors and high-risk locations for deaths among travellers in seven countries of South America. Our findings underscore the need for specific health interventions tailored to traveller demographics and destination to optimize prevention of avoidable deaths in South America.
Contamination effects in cluster randomised trials of TB interventions
BACKGROUNDCluster randomised trials (CRTs) of TB interventions have achieved mixed results, with many lacking significant reductions in outcomes. Contamination in CRTs, resulting from short and long-term movement between clusters and the general population, may dilute the impact of measured intervention.METHODSWe systematically reviewed the literature to identify CRTs that aimed to capture the population-level effects of the intervention on TB. Details of trial designs, interventions, outcomes, populations, cluster configurations, and geographic data were extracted to produce text summaries, descriptive statistics, and spatial analyses.RESULTSWe screened 1,039 abstracts and included 20 reports from seven CRTs. The median number of clusters was 32 (IQR 23-61), with populations ranging from 400-50,000 individuals per cluster. Four trials reported spatial data, from which the mean distance between clusters was 12.3 km (range 3.71-35.9). Several trials acknowledged design limitations, such as small cluster sizes and population mobility, which could have led to underestimations of intervention impact. Trials used various geographic, social, and pre-existing TB measures to select and allocate study clusters. Data on the potential for contamination are inconsistent.CONCLUSIONGaps remain in the reporting of methods and results, suggesting necessary improvements to standardised reporting tools. These insights can inform recommendations for improved CRT design and reporting practices..
Cost-effectiveness of integrated maternal HIV, syphilis, and hepatitis B screening opt-out strategies in Nepal: a modelling study
Background: The World Health Organisation (WHO) developed a comprehensive framework encouraging an integrated approach to achieve triple elimination of vertical transmission of HIV, syphilis, and hepatitis B in Asia. Current screening practices in Nepal show significantly lower coverage for syphilis and hepatitis B compared to HIV suggesting potential for integration. In this study, we aimed to model the cost-effectiveness of triple screening during antenatal care in Nepal. Methods: We modelled maternal HIV, hepatitis B, and syphilis cascade of care and their corresponding disease states using disease-specific Markov models over a 20-year horizon with a cycle length of one year. We compared dual integrated screening for HIV and syphilis and triple integrated screening for HIV, syphilis, and hepatitis B with HIV screening only. Costs were estimated from a provider's perspective. Results were presented as incremental cost-effectiveness ratios (ICERs). Univariable and probabilistic sensitivity analyses were conducted. Findings: Our modelling analysis showed that dual-integrated screening for HIV and syphilis was highly cost-effective when compared to current strategy of screening for HIV only (ICERs of US$18). Triple-integrated antenatal screening for HIV, syphilis, and hepatitis B was highly cost-effective compared with dual-integrated strategy with an ICER of US$114. Moreover, 100% and 98% of the probabilistic sensitivity analysis estimates for dual- and triple-integrated screening were proven cost-effective, compared to HIV-only screening. Interpretation: Our results support WHO recommendations for implementing integrated triple antenatal screening in Nepal and Asia more broadly, aiming to reduce maternal and neonatal morbidity through early detection and intervention. Funding: No funding was reported.
Impact of inappropriate empirical antibiotic therapy on in-hospital mortality: a retrospective multicentre cohort study of patients with bloodstream infections in Chile, 2018-2022.
INTRODUCTION: Empirical antibiotic therapy is essential for treating bloodstream infections (BSI), yet there is limited evidence from resource-limited settings. We quantified the association of inappropriate empirical antibiotic therapy (IEAT) with in-hospital mortality and the associated burden on BSI patients in Chile. METHODS: We used a retrospective multicentre cohort study of BSI cases in three Chilean tertiary hospitals (2018-2022) to assess the impact of IEAT on 30-day and overall in-hospital mortality and quantify excess disease and economic burdens associated with IEAT. We determined the appropriateness of pathogen-antimicrobial pairings based on in vitro susceptibilities and pathogen-corresponding antibiotic treatment, allowing a 48-hour window after the initial blood culture. We addressed confounding using propensity scores and inverse probability weights (IPW). We used IPW-weighted logistic competing-risk survival models, including time-varying independent variables after blood tests as controls. RESULTS: Among 1323 BSI episodes, 432 (33%) received IEAT, with an average time to adequate therapy of 4.6 days. Compared with adequate treatment, IEAT was associated with 30-day and overall mortality risks that were 1.31 and 1.24 times higher, respectively. These risks were further inflated between twofold and fourfold when antibiotic-resistant bacteria (ARB) was included. Competing-risk models showed associations between IEAT and IEAT-ARB combinations with in-hospital mortality. Accounting for time-varying variables yielded similar results. The economic burden of IEAT resulted in an additional cost of ~US$9900 from premature mortality and 0.46 disability-adjusted life-years per patient with BSI. CONCLUSION: Approximately one in three patients received IEAT, often associated with ARB. IEAT was linked to increased mortality risk and higher economic costs. Timely appropriate treatment, early pathogen detection and resistance profiling are likely to improve health and financial outcomes at the population level.
Identification and Characterization of Salmonella Phages and Absence of Salmonella Strains from Three Different Study Areas of Cattle Livestock
Background: Salmonella represents a significant risk to both public and animal health. Although Salmonella strains have not been isolated from cattle livestock, Salmonella phages have been successfully identified. Materials and Methods: Our study was conducted through (i) investigating the presence of Salmonella strains and Salmonella phages in three study areas, (ii) phenotypic screening by lytic profile (LP); (iii) selecting nine phages for sequencing; and (iv) genomic comparison to evaluate their relative diversity. Results: A total of 307 samples were analyzed, resulting in a total of 162 virus-like particles (VLPs) analyzed. The LP was performed to identify Salmonella strains susceptible to phage infection, including the most frequent serovars: Dublin, Enteritidis, and Javiana. From the VLPs, nine phages were selected for genomic comparison. These phages represent three morphotypes: siphoviruses, myoviruses, and podoviruses, originating from different geographic and productive sites. Conclusions: This study enhances the understanding of the presence and diversity of Salmonella phages in cattle livestock, even in the absence of Salmonella strains.
Global burden of bacterial antimicrobial resistance 1990–2021: a systematic analysis with forecasts to 2050
Background: Antimicrobial resistance (AMR) poses an important global health challenge in the 21st century. A previous study has quantified the global and regional burden of AMR for 2019, followed with additional publications that provided more detailed estimates for several WHO regions by country. To date, there have been no studies that produce comprehensive estimates of AMR burden across locations that encompass historical trends and future forecasts. Methods: We estimated all-age and age-specific deaths and disability-adjusted life-years (DALYs) attributable to and associated with bacterial AMR for 22 pathogens, 84 pathogen–drug combinations, and 11 infectious syndromes in 204 countries and territories from 1990 to 2021. We collected and used multiple cause of death data, hospital discharge data, microbiology data, literature studies, single drug resistance profiles, pharmaceutical sales, antibiotic use surveys, mortality surveillance, linkage data, outpatient and inpatient insurance claims data, and previously published data, covering 520 million individual records or isolates and 19 513 study-location-years. We used statistical modelling to produce estimates of AMR burden for all locations, including those with no data. Our approach leverages the estimation of five broad component quantities: the number of deaths involving sepsis; the proportion of infectious deaths attributable to a given infectious syndrome; the proportion of infectious syndrome deaths attributable to a given pathogen; the percentage of a given pathogen resistant to an antibiotic of interest; and the excess risk of death or duration of an infection associated with this resistance. Using these components, we estimated disease burden attributable to and associated with AMR, which we define based on two counterfactuals; respectively, an alternative scenario in which all drug-resistant infections are replaced by drug-susceptible infections, and an alternative scenario in which all drug-resistant infections were replaced by no infection. Additionally, we produced global and regional forecasts of AMR burden until 2050 for three scenarios: a reference scenario that is a probabilistic forecast of the most likely future; a Gram-negative drug scenario that assumes future drug development that targets Gram-negative pathogens; and a better care scenario that assumes future improvements in health-care quality and access to appropriate antimicrobials. We present final estimates aggregated to the global, super-regional, and regional level. Findings: In 2021, we estimated 4·71 million (95% UI 4·23–5·19) deaths were associated with bacterial AMR, including 1·14 million (1·00–1·28) deaths attributable to bacterial AMR. Trends in AMR mortality over the past 31 years varied substantially by age and location. From 1990 to 2021, deaths from AMR decreased by more than 50% among children younger than 5 years yet increased by over 80% for adults 70 years and older. AMR mortality decreased for children younger than 5 years in all super-regions, whereas AMR mortality in people 5 years and older increased in all super-regions. For both deaths associated with and deaths attributable to AMR, meticillin-resistant Staphylococcus aureus increased the most globally (from 261 000 associated deaths [95% UI 150 000–372 000] and 57 200 attributable deaths [34 100–80 300] in 1990, to 550 000 associated deaths [500 000–600 000] and 130 000 attributable deaths [113 000–146 000] in 2021). Among Gram-negative bacteria, resistance to carbapenems increased more than any other antibiotic class, rising from 619 000 associated deaths (405 000–834 000) in 1990, to 1·03 million associated deaths (909 000–1·16 million) in 2021, and from 127 000 attributable deaths (82 100–171 000) in 1990, to 216 000 (168 000–264 000) attributable deaths in 2021. There was a notable decrease in non-COVID-related infectious disease in 2020 and 2021. Our forecasts show that an estimated 1·91 million (1·56–2·26) deaths attributable to AMR and 8·22 million (6·85–9·65) deaths associated with AMR could occur globally in 2050. Super-regions with the highest all-age AMR mortality rate in 2050 are forecasted to be south Asia and Latin America and the Caribbean. Increases in deaths attributable to AMR will be largest among those 70 years and older (65·9% [61·2–69·8] of all-age deaths attributable to AMR in 2050). In stark contrast to the strong increase in number of deaths due to AMR of 69·6% (51·5–89·2) from 2022 to 2050, the number of DALYs showed a much smaller increase of 9·4% (–6·9 to 29·0) to 46·5 million (37·7 to 57·3) in 2050. Under the better care scenario, across all age groups, 92·0 million deaths (82·8–102·0) could be cumulatively averted between 2025 and 2050, through better care of severe infections and improved access to antibiotics, and under the Gram-negative drug scenario, 11·1 million AMR deaths (9·08–13·2) could be averted through the development of a Gram-negative drug pipeline to prevent AMR deaths. Interpretation: This study presents the first comprehensive assessment of the global burden of AMR from 1990 to 2021, with results forecasted until 2050. Evaluating changing trends in AMR mortality across time and location is necessary to understand how this important global health threat is developing and prepares us to make informed decisions regarding interventions. Our findings show the importance of infection prevention, as shown by the reduction of AMR deaths in those younger than 5 years. Simultaneously, our results underscore the concerning trend of AMR burden among those older than 70 years, alongside a rapidly ageing global community. The opposing trends in the burden of AMR deaths between younger and older individuals explains the moderate future increase in global number of DALYs versus number of deaths. Given the high variability of AMR burden by location and age, it is important that interventions combine infection prevention, vaccination, minimisation of inappropriate antibiotic use in farming and humans, and research into new antibiotics to mitigate the number of AMR deaths that are forecasted for 2050. Funding: UK Department of Health and Social Care's Fleming Fund using UK aid, and the Wellcome Trust.
Global, regional, and national age-specific progress towards the 2020 milestones of the WHO End TB Strategy: a systematic analysis for the Global Burden of Disease Study 2021
Background: Global evaluations of the progress towards the WHO End TB Strategy 2020 interim milestones on mortality (35% reduction) and incidence (20% reduction) have not been age specific. We aimed to assess global, regional, and national-level burdens of and trends in tuberculosis and its risk factors across five separate age groups, from 1990 to 2021, and to report on age-specific progress between 2015 and 2020. Methods: We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 (GBD 2021) analytical framework to compute age-specific tuberculosis mortality and incidence estimates for 204 countries and territories (1990–2021 inclusive). We quantified tuberculosis mortality among individuals without HIV co-infection using 22 603 site-years of vital registration data, 1718 site-years of verbal autopsy data, 825 site-years of sample-based vital registration data, 680 site-years of mortality surveillance data, and 9 site-years of minimally invasive tissue sample (MITS) diagnoses data as inputs into the Cause of Death Ensemble modelling platform. Age-specific HIV and tuberculosis deaths were established with a population attributable fraction approach. We analysed all available population-based data sources, including prevalence surveys, annual case notifications, tuberculin surveys, and tuberculosis mortality, in DisMod-MR 2.1 to produce internally consistent age-specific estimates of tuberculosis incidence, prevalence, and mortality. We also estimated age-specific tuberculosis mortality without HIV co-infection that is attributable to the independent and combined effects of three risk factors (smoking, alcohol use, and diabetes). As a secondary analysis, we examined the potential impact of the COVID-19 pandemic on tuberculosis mortality without HIV co-infection by comparing expected tuberculosis deaths, modelled with trends in tuberculosis deaths from 2015 to 2019 in vital registration data, with observed tuberculosis deaths in 2020 and 2021 for countries with available cause-specific mortality data. Findings: We estimated 9·40 million (95% uncertainty interval [UI] 8·36 to 10·5) tuberculosis incident cases and 1·35 million (1·23 to 1·52) deaths due to tuberculosis in 2021. At the global level, the all-age tuberculosis incidence rate declined by 6·26% (5·27 to 7·25) between 2015 and 2020 (the WHO End TB strategy evaluation period). 15 of 204 countries achieved a 20% decrease in all-age tuberculosis incidence between 2015 and 2020, eight of which were in western sub-Saharan Africa. When stratified by age, global tuberculosis incidence rates decreased by 16·5% (14·8 to 18·4) in children younger than 5 years, 16·2% (14·2 to 17·9) in those aged 5–14 years, 6·29% (5·05 to 7·70) in those aged 15–49 years, 5·72% (4·02 to 7·39) in those aged 50–69 years, and 8·48% (6·74 to 10·4) in those aged 70 years and older, from 2015 to 2020. Global tuberculosis deaths decreased by 11·9% (5·77 to 17·0) from 2015 to 2020. 17 countries attained a 35% reduction in deaths due to tuberculosis between 2015 and 2020, most of which were in eastern Europe (six countries) and central Europe (four countries). There was variable progress by age: a 35·3% (26·7 to 41·7) decrease in tuberculosis deaths in children younger than 5 years, a 29·5% (25·5 to 34·1) decrease in those aged 5–14 years, a 15·2% (10·0 to 20·2) decrease in those aged 15–49 years, a 7·97% (0·472 to 14·1) decrease in those aged 50–69 years, and a 3·29% (–5·56 to 9·07) decrease in those aged 70 years and older. Removing the combined effects of the three attributable risk factors would have reduced the number of all-age tuberculosis deaths from 1·39 million (1·28 to 1·54) to 1·00 million (0·703 to 1·23) in 2020, representing a 36·5% (21·5 to 54·8) reduction in tuberculosis deaths compared to those observed in 2015. 41 countries were included in our analysis of the impact of the COVID-19 pandemic on tuberculosis deaths without HIV co-infection in 2020, and 20 countries were included in the analysis for 2021. In 2020, 50 900 (95% CI 49 700 to 52 400) deaths were expected across all ages, compared to an observed 45 500 deaths, corresponding to 5340 (4070 to 6920) fewer deaths; in 2021, 39 600 (38 300 to 41 100) deaths were expected across all ages compared to an observed 39 000 deaths, corresponding to 657 (–713 to 2180) fewer deaths. Interpretation: Despite accelerated progress in reducing the global burden of tuberculosis in the past decade, the world did not attain the first interim milestones of the WHO End TB Strategy in 2020. The pace of decline has been unequal with respect to age, with older adults (ie, those aged >50 years) having the slowest progress. As countries refine their national tuberculosis programmes and recalibrate for achieving the 2035 targets, they could consider learning from the strategies of countries that achieved the 2020 milestones, as well as consider targeted interventions to improve outcomes in older age groups. Funding: Bill & Melinda Gates Foundation.
Opportunities and challenges in antimicrobial resistance policy including animal production systems and humans across stakeholders in Argentina: A context and qualitative analysis
Introduction Gaps in antimicrobial resistance (AMR) surveillance and control, including implementation of national action plans (NAPs), are evident internationally. Countries' capacity to translate political commitment into action is crucial to cope with AMR at the human-animal-environment interface. Methods We employed a two-stage process to understand opportunities and challenges related to AMR surveillance and control at the human-animal interface in Argentina. First, we compiled the central AMR policies locally and mapped vital stakeholders around the NAP and the national commission against bacterial resistance. Second, we conducted qualitative interviews using a semistructured questionnaire covering stakeholders' understanding and progress towards AMR and NAP. We employed a mixed deductive-inductive approach and used the constant comparative analysis method. We created categories and themes to cluster subthemes and determined crucial relationships among thematic groups. Results Crucial AMR policy developments have been made since 1969, including gradually banning colistin in food-producing animals. In 2023, a new government decree prioritised AMR following the 2015 NAP launch. Our qualitative analyses identified seven major themes for tackling AMR: (I) Cultural factors and sociopolitical country context hampering AMR progress, (II) Fragmented governance, (III) Antibiotic access and use, (IV) AMR knowledge and awareness throughout stakeholders, (V) AMR surveillance, (VI) NAP efforts and (VII) External drivers. We identified a fragmented structure of the food production chain, poor cross-coordination between stakeholders, limited surveillance and regulation among food-producing animals and geographical disparities over access, diagnosis and treatment. The country is moving to integrate animal and food production into its surveillance system, with most hospitals experienced in monitoring AMR through antimicrobial stewardship programmes. Conclusion AMR accountability should involve underpinning collaboration at different NAP implementation levels and providing adequate resources to safeguard long-term sustainability. Incorporating a multisectoral context-specific approach relying on different One Health domains is crucial to strengthening local AMR surveillance.
Extended-Spectrum β-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae: Risk Factors and Economic Burden Among Patients with Bloodstream Infections
Introduction: Although Extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae (ESBL-EK) significantly contribute to bloodstream infections, their economic repercussions remain largely unquantified. Data Source and Methods: We performed a retrospective analysis of inpatients diagnosed with Escherichia coli or Klebsiella pneumoniae bacteremia in a tertiary hospital from January 2020 to December 2022 in Guangzhou, China. We employed the chi-square test to examine ESBL risk factors and utilized propensity score matching (PSM) to negate baseline confounding factors, assessing economic burden through disability-adjusted life years (DALYs), hospital costs and productivity losses. We employed mediation analysis to eliminate confounding factors and better identify ESBL sources of burden related. Results: We found 166 ESBL-EC/KP BSI patients (52.2% of the total examined 318 patients). Post-PSM analysis revealed that ESBL-producing EC/KP will reduce the effectiveness of empirical medication by 19.8%, extend the total length of hospitalization by an average of 3 days, and increase the patient’s financial burden by US$2047. No significant disparity was found in overall mortality and mean DALYs between the groups. Mediation analysis showed that the link between ESBL and hospital costs is predominantly, if not entirely, influenced by the appropriateness of empirical antibiotic treatment and length of hospital stay. Conclusion: Patients with BSI due to ESBL-producing ESBL-EK incur higher costs compared to those with non-ESBL-EK BSI. This cost disparity is rooted in varying rates of effective empirical antimicrobial therapy and differences in hospital stay durations. A nuanced approach, incorporating a thorough understanding of regional epidemiological trends and judicious antibiotic use, is crucial for mitigating the financial impact on patients.
A decision support tool for risk–benefit analysis of Japanese encephalitis vaccine in travellers
Background: During pre-travel consultations, clinicians and travellers face the challenge of weighing the risks verus benefits of Japanese encephalitis (JE) vaccination due to the high cost of the vaccine, low incidence in travellers (∼1 in 1 million), but potentially severe consequences (∼30% case-fatality rate). Personalised JE risk assessment based on the travellers’ demographics and travel itinerary is challenging using standard risk matrices. We developed an interactive digital tool to estimate risks of JE infection and severe health outcomes under different scenarios to facilitate shared decision-making between clinicians and travellers. Methods: A Bayesian network (conditional probability) model risk–benefit analysis of JE vaccine in travellers was developed. The model considers travellers’ characteristics (age, sex, co-morbidities), itinerary (destination, departure date, duration, setting of planned activities) and vaccination status to estimate the risks of JE infection, the development of symptomatic disease (meningitis, encephalitis), clinical outcomes (hospital admission, chronic neurological complications, death) and adverse events following immunization. Results: In low-risk travellers (e.g. to urban areas for <1 month), the risk of developing JE and dying is low (<1 per million) irrespective of the destination; thus, the potential impact of JE vaccination in reducing the risk of clinical outcomes is limited. In high-risk travellers (e.g. to rural areas in high JE incidence destinations for >2 months), the risk of developing symptomatic disease and mortality is estimated at 9.5 and 1.4 per million, respectively. JE vaccination in this group would significantly reduce the risk of symptomatic disease and mortality (by ∼80%) to 1.9 and 0.3 per million, respectively.
A country-wide health policy in Chile for deaf adults using cochlear implants: Analysis of health determinants and social impacts
Background Post-lingual deafness represents a critical challenge for adults’ well-being with substantial public health burdens. One treatment of choice has been cochlear implants (CI) for people with severe to profound hearing loss (HL). Since 2018, Chile has implemented a high-cost policy to cover CI treatment, the “Ley Ricarte Soto" (LRS) health policy. However, wide variability exists in the use of this device. To date, no related study has been published on policy evaluation in Chile or other Latin American countries. Objectives This study aimed to evaluate the impact of the LRS policy on the treatment success and labour market inclusion among deaf or hard of hearing (DHH) adults using CI. We examined and characterised outcomes based on self-reports about treatment success and occupation status between 2018 and 2020. Design We performed a prospective study using hospital clinical records and an online questionnaire with 76 DHH adults aged >15 who had received CIs since the introduction of the LRS policy in 2018. Using univariate and multivariate regression models, we investigated the relationship between demographic, audiological, and social determinants of health and outcomes, including treatment success for social inclusion (International Outcome inventory for Hearing Aids and CIs assessment: IOI-HA) and occupation status for labour market inclusion. Results Our study showed elevated levels of treatment success in most of the seven sub-scores of the IOI-HA assessment. Similarly, around 70% of participants maintained or improved their occupations after receiving their CI. We found a significant positive association between treatment success and market inclusion. Participants diagnosed at younger ages had better results than older participants in both outcomes. Regarding social determinants of health, findings suggested participants with high social health insurance and a shorter commute time to the clinic had better results in treatment success. For labour market inclusion, participants with high education levels and better pre- CI occupation had better post-CI occupation status. Conclusions In evaluating the LRS policy for providing CIs for DHH adults in Chile, we found positive effects relating to treatment success and occupation status. Our study supports the importance of age at diagnosis and social determinants of health, which should be assessed by integrating public services and bringing them geographically closer to each beneficiary. Although evidence-based guidelines for candidate selection given by the LRS policy might contribute to good results, these guidelines could limit the policy access to people who do not meet the requirements of the guidelines due to social inequalities.
Antibiotic Consumption During the Coronavirus Disease 2019 Pandemic and Emergence of Carbapenemase-Producing Klebsiella pneumoniae Lineages Among Inpatients in a Chilean Hospital: A Time-Series Study and Phylogenomic Analysis
Background: The impact of coronavirus disease 2019 (COVID-19) on antimicrobial use (AU) and resistance has not been well evaluated in South America. These data are critical to inform national policies and clinical care. Methods: At a tertiary hospital in Santiago, Chile, between 2018 and 2022, subdivided into pre- (3/2018-2/2020) and post-COVID-19 onset (3/2020-2/2022), we evaluated intravenous AU and frequency of carbapenem-resistant Enterobacterales (CRE). We grouped monthly AU (defined daily doses [DDD]/1000 patient-days) into broad-spectrum β-lactams, carbapenems, and colistin and used interrupted time-series analysis to compare AU during pre- and post-pandemic onset. We studied the frequency of carbapenemase-producing (CP) CRE and performed whole-genome sequencing analyses of all carbapenem-resistant (CR) Klebsiella pneumoniae (CRKpn) isolates collected during the study period. Results: Compared with pre-pandemic, AU (DDD/1000 patient-days) significantly increased after the pandemic onset, from 78.1 to 142.5 (P