Accuracy of package inserts of SARS-CoV-2 rapid antigen tests: a secondary analysis of manufacturer versus systematic review data.

BACKGROUND: Rapid antigen tests (RATs) were crucial during the COVID-19 pandemic. Information provided by the test manufacturer in product package inserts, also known as instructions for use (IFUs), is often the only data available to clinicians, public health professionals, and individuals on the diagnostic accuracy of these tests. We aimed to assess whether manufacturer IFU accuracy data aligned with evidence from independent research. METHODS: We searched company websites for package inserts for RATs that were included in the July 2022 update of the Cochrane meta-analysis of SARS-CoV-2 RATs, which served as a benchmark for research evidence. We fitted bivariate hierarchical models to obtain absolute differences in sensitivity and specificity between IFU and Cochrane Review estimates for each test, as well as overall combined differences. FINDINGS: We found 22 (100%) of 22 IFUs of the RATs included in the Cochrane Review. IFUs for 12 (55%) of 22 RATs reported statistically significantly higher sensitivity estimates than the Cochrane Review, and none reported lower estimates. The mean difference between IFU and Cochrane Review sensitivity estimates across tests was 12·0% (95% CI 7·5-16·6). IFUs in three (14%) of 22 diagnostic tests had significantly higher specificity estimates than the Cochrane Review and two (9%) of 22 had lower estimates. The mean difference between IFU and Cochrane Review specificity estimates across tests was 0·3% (95% CI 0·1-0·5). If 100 people with SARS-CoV-2 infection were tested with each of the tests in this study, on average 12 fewer people would be correctly diagnosed than is suggested by the package inserts. INTERPRETATION: Health professionals and the public should be aware that package inserts for SARS-CoV-2 RATs might provide an overly optimistic picture of the sensitivity of a test. Regulatory bodies should strengthen their requirements for the reporting of diagnostic accuracy data in package inserts and policy makers should demand independent validation data for decision making. FUNDING: None.

How can we tackle the overuse of antibiotics in low- and middle-income countries?

INTRODUCTION: Antibiotic overuse is a pressing global health concern, particularly in low- and middle-income countries (LMICs) where there is limited access to quality healthcare and insufficient regulation of antibiotic dispensation. This perspective piece highlights the challenges of antibiotic overuse in LMICs and provides insights into potential solutions to address this issue. AREAS COVERED: This perspective explores key factors contributing to antibiotic overuse in LMICs, encompassing weak healthcare infrastructure, limited access to quality services, and deficiencies in diagnostic capabilities. It discusses regulatory frameworks to curb non-prescription sales, the role of accessible point-of-care diagnostic tools, challenges in implementing effective stewardship programs, the expanded use of vaccines, and the importance of health systems, hygiene, and sanitation. EXPERT OPINION: In this article, we emphasize the need for a comprehensive approach involving collaboration among healthcare professionals, policymakers, researchers, and educators. We underscore the importance of improving healthcare infrastructure, enhancing access to quality services, and strengthening diagnostic capabilities. The article also highlights the significance of education and awareness in promoting responsible antibiotic use, the role of regulatory measures, the expanded utilization of vaccines, and the need for international collaboration to address the challenges of antibiotic overuse in LMICs.

Do private providers initiate anti-tuberculosis therapy on the basis of chest radiographs? A standardised patient study in urban India.

Background: The initiation of anti-tuberculosis treatment (ATT) based on results of WHO-approved microbiological diagnostics is an important marker of quality tuberculosis (TB) care. Evidence suggests that other diagnostic processes leading to treatment initiation may be preferred in high TB incidence settings. This study examines whether private providers start anti-TB therapy on the basis of chest radiography (CXR) and clinical examinations. Methods: This study uses the standardized patient (SP) methodology to generate accurate and unbiased estimates of private sector, primary care provider practice when a patient presents a standardized TB case scenario with an abnormal CXR. Using multivariate log-binomial and linear regressions with standard errors clustered at the provider level, we analyzed 795 SP visits conducted over three data collection waves from 2014 to 2020 in two Indian cities. Data were inverse-probability-weighted based on the study sampling strategy, resulting in city-wave-representative results. Findings: Amongst SPs who presented to a provider with an abnormal CXR, 25% (95% CI: 21-28%) visits resulted in ideal management, defined as the provider prescribing a microbiological test and not offering a concurrent prescription for a corticosteroid or antibiotic (including anti-TB medications). In contrast, 23% (95% CI: 19-26%) of 795 visits were prescribed anti-TB medications. Of 795 visits, 13% (95% CI: 10-16%) resulted in anti-TB treatment prescriptions/dispensation and an order for confirmatory microbiological testing. Interpretation: One in five SPs presenting with abnormal CXR were prescribed ATT by private providers. This study contributes novel insights to empiric treatment prevalence based on CXR abnormality. Further work is needed to understand how providers make trade-offs between existing diagnostic practices, new technologies, profits, clinical outcomes, and the market dynamics with laboratories. Funding: This study was funded by the Bill & Melinda Gates Foundation (grant OPP1091843), and the Knowledge for Change Program at The World Bank.

Use of standardised patients to assess tuberculosis case management by private pharmacies in Patna, India: A repeat cross-sectional study.

As the first point of care for many healthcare seekers, private pharmacies play an important role in tuberculosis (TB) care. However, previous studies in India have showed that private pharmacies commonly dispense symptomatic treatments and broad-spectrum antibiotics over-the-counter (OTC), rather than referring patients for TB testing. Such inappropriate management by pharmacies can delaye TB diagnosis. We assessed medical advice and OTC drug dispensing practices of pharmacists for standardized patients presenting with classic symptoms of pulmonary TB (case 1) and for those with sputum smear positive pulmonary TB (case 2), and examined how practices have changed over time in an urban Indian site. We examined how and whether private pharmacies improved practices for TB in 2019 compared to a baseline study conducted in 2015 in the city of Patna, using the same survey sampling techniques and study staff. The proportion of patient-pharmacist interactions that resulted in correct or ideal management, as well as the proportion of interactions resulting in antibiotic, quinolone, and corticosteroid are presented, with standard errors clustered at the provider level. To assess the difference in case management and the use of drugs across the two cases by round, a difference in difference (DiD) model was employed. A total of 936 SP interactions were completed over both rounds of survey. Our results indicate that across both rounds of data collection, 331 of 936 (35%; 95% CI: 32-38%) of interactions were correctly managed. At baseline, 215 of 500 (43%; 95% CI: 39-47%) of interactions were correctly managed whereas 116 of 436 (27%; 95% CI: 23-31%) were correctly managed in the second round of data collection. Ideal management, where in addition to a referral, patients were not prescribed any potentially harmful medications, was seen in 275 of 936 (29%; 95% CI: 27-32%) of interactions overall, with 194 of 500 (39%; 95% CI: 35-43%) of interactions at baseline and 81 of 436 (19%; 95% CI: 15-22%) in round 2. No private pharmacy dispensed anti-TB medications without a prescription. On average, the difference in correct case management between case 1 vs. case 2 dropped by 20 percent points from baseline to the second round of data collection. Similarly, ideal case management decreased by 26 percentage points between rounds. This is in contrast with the dispensation of medicines, which had the opposite effect between rounds; the difference in dispensation of quinolones between case 1 and case 2 increased by 14 percentage points, as did corticosteroids by 9 percentage points, antibiotics by 25 percentage points and medicines generally by 30 percentage points. Our standardised patient study provides valuable insights into how private pharmacies in an Indian city changed their management of patients with TB symptoms or with confirmed TB over a 5-year period. We saw that overall, private pharmacy performance has weakened over time. However, no OTC dispensation of anti-TB medications occurred in either survey round. As the first point of contact for many care seekers, continued and sustained efforts to engage with Indian private pharmacies should be prioritized.

Sex-disaggregated effectiveness data reporting in COVID-19 vaccine research: a systematic review.

BACKGROUND: Sex and gender are believed to influence vaccine response. Yet, the relationship between sex and gender and COVID-19 vaccine efficacy is poorly understood and remains under-investigated. METHODS: We conducted a systematic review to determine whether and to what extent post-approval COVID-19 vaccine effectiveness (VE) studies report sex-disaggregated VE data. We searched four publication and pre-publication databases and additional grey literature sources for relevant published/preprint studies released between 1 January 2020 and 1 October 2021 (i.e., pre-Omicron era). We included observational studies providing VE estimates for one or more licensed/approved COVID-19 vaccines and including both males and females. Two reviewers independently assessed study eligibility, extracted data, and assessed risk-of-bias through a modified version of Cochrane's ROBINS-I tool. A qualitative data synthesis was performed. RESULTS: Here we show that, among 240 eligible publications, 68 (28.3%) do not report the sex distribution among participants. Only 21/240 (8.8%) studies provide sex-disaggregated VE estimates, and high between-study heterogeneity regarding design, target population, outcomes, and vaccine type/timing prevent the assessment of sex in determining COVID-19 VE across studies. CONCLUSIONS: Our findings indicate that few COVID-19 vaccine research publications account for sex. Improved adherence to recommended reporting guidelines will ensure that the evidence generated can be used to better understand the relationship between sex and gender and VE.

The level of protection that vaccines provide against COVID-19 might depend on a person's sex or gender. However, sex and gender are not always reported in studies on the effectiveness of COVID-19 vaccines. Here, we systematically reviewed the literature on COVID-19 vaccine effectiveness and looked at whether the studies we found separated out their data on vaccine effectiveness by participants' sex. Out of the 240 publications we identified, 68 (28.3%) did not report the sex of the participants in their study, and only 21 studies (8.8%) reported vaccine effectiveness data separated by sex. These results show that a substantial proportion of COVID-19 vaccine research publications do not account for sex. Efforts should be made by researchers to study and report the relationship between sex and vaccine effectiveness, to help to optimise vaccination strategies so that all people are adequately protected.

Integrating tuberculosis and COVID-19 molecular testing in Lima, Peru: a cross-sectional, diagnostic accuracy study.

BACKGROUND: Integrated molecular testing could be an opportunity to detect and provide care for both tuberculosis and COVID-19. Many high tuberculosis burden countries, such as Peru, have existing GeneXpert systems for tuberculosis testing with GeneXpert Xpert MTB/RIF Ultra (Xpert Ultra), and a GeneXpert SARS-CoV-2 assay, GeneXpert Xpert Xpress SARS-CoV-2 (Xpert Xpress), is also available. We aimed to assess the feasibility of integrating tuberculosis and COVID-19 testing using one sputum specimen with Xpert Ultra and Xpert Xpress in Lima, Peru. METHODS: In this cross-sectional, diagnostic accuracy study, we recruited adults presenting with clinical symptoms or suggestive history of tuberculosis or COVID-19, or both. Participants were recruited from a total of 35 primary health facilities in Lima, Peru. Participants provided one nasopharyngeal swab and one sputum sample. For COVID-19, we tested nasopharyngeal swabs and sputum using Xpert Xpress; for tuberculosis, we tested sputum using culture and Xpert Ultra. We compared diagnostic accuracy of sputum testing using Xpert Xpress with nasopharyngeal swab testing using Xpert Xpress. Individuals with positive Xpert Xpress nasopharyngeal swab results were considered COVID-19 positive, and a positive culture indicated tuberculosis. To assess testing integration, the proportion of cases identified in sputum by Xpert Xpress was compared with Xpert Xpress on nasopharyngeal swabs, and sputum by Xpert Ultra was compared with culture. FINDINGS: Between Jan 11, 2021, and April 26, 2022, we recruited 600 participants (312 [52%] women and 288 [48%] men). In-study prevalence of tuberculosis was 13% (80 participants, 95% CI 11-16) and of SARS-CoV-2 was 35% (212 participants, 32-39). Among tuberculosis cases, 13 (2·2%, 1·2-3·7) participants were concurrently positive for SARS-CoV-2. Regarding the diagnostic yield of integrated testing, Xpert Ultra detected 96% (89-99) of culture-confirmed tuberculosis cases (n=77), and Xpert Xpress-sputum detected 67% (60-73) of COVID-19 cases (n=134). All five study staff reported that integrated molecular testing was easy and acceptable. INTERPRETATION: The diagnostic yield of Xpert Xpress on sputum was moderate, but integrated testing for tuberculosis and COVID-19 with GeneXpert was feasible. However, systematic testing for both diseases might not be the ideal approach for everyone presenting with presumptive tuberculosis or COVID-19, as concurrent positive cases were rare during the study period. Further research might help to identify when integrated testing is most worthwhile and its optimal implementation. FUNDING: Canadian Institutes of Health Research and International Development Research Centre. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Lassa fever vaccine candidates: A scoping review of vaccine clinical trials.

OBJECTIVE: Lassa fever (LF) is caused by a viral pathogen with pandemic potential. LF vaccines have the potential to prevent significant disease in individuals at risk of infection, but no such vaccine has been licensed or authorised for use thus far. We conducted a scoping review to identify and compare registered phase 1, 2 or 3 clinical trials of LF vaccine candidates, and appraise the current trajectory of LF vaccine development. METHOD: We systematically searched 24 trial registries, PubMed, relevant conference abstracts and additional grey literature sources up to 27 October 2022. After extracting key details about each vaccine candidate and each eligible trial, we qualitatively synthesised the evidence. RESULTS: We found that four LF vaccine candidates (INO-4500, MV-LASV, rVSV∆G-LASV-GPC, and EBS-LASV) have entered the clinical stage of assessment. Five phase 1 trials (all focused on healthy adults) and one phase 2 trial (involving a broader age group from 18 months to 70 years) evaluating one of these vaccines have been registered to date. Here, we describe the characteristics of each vaccine candidate and trial and compare them to WHO's target product profile for Lassa vaccines. CONCLUSION: Though LF vaccine development is still in early stages, current progress towards a safe and effective vaccine is encouraging.

A scoping review on the risk of tuberculosis in specific population groups: can we expand the World Health Organization recommendations?

Since 2015, the World Health Organization (WHO) has recommended prioritising testing and treatment of tuberculosis (TB) infection (TBI) in 11 high-risk groups. With new options emerging for TB preventive treatment, we conducted a scoping review, in consultation with the WHO's Global Tuberculosis Programme, to explore the evidence for other population groups at potentially high risk of progression to active TB. We searched six databases for preprints and articles published between 2000 and August 2022. 18 out of 33 668 screened records were included (six meta-analyses and 12 original research studies). Most were observational studies reporting the incidence of active TB in a risk group versus control. Glomerular diseases had the strongest association with active TB (standardised incidence ratio 23.36, 95% CI 16.76-31.68) based on an unpublished study. Other conditions associated with increased risk of active TB included hepatitis C, malignancies, diabetes mellitus, rheumatoid arthritis and vitamin D deficiency. Corticosteroid use was also associated with increased risk in several studies, although heterogeneous definitions of exposure and indications for use challenge interpretation. Despite methodological limitations of the identified studies, expanding the recommendations for TBI screening and treatment to new risk groups such as those reported here should be considered. Further group-specific systematic reviews may provide additional data for decision-making.

Antibody tests for identification of current and past infection with SARS-CoV-2.

BACKGROUND: The diagnostic challenges associated with the COVID-19 pandemic resulted in rapid development of diagnostic test methods for detecting SARS-CoV-2 infection. Serology tests to detect the presence of antibodies to SARS-CoV-2 enable detection of past infection and may detect cases of SARS-CoV-2 infection that were missed by earlier diagnostic tests. Understanding the diagnostic accuracy of serology tests for SARS-CoV-2 infection may enable development of effective diagnostic and management pathways, inform public health management decisions and understanding of SARS-CoV-2 epidemiology. OBJECTIVES: To assess the accuracy of antibody tests, firstly, to determine if a person presenting in the community, or in primary or secondary care has current SARS-CoV-2 infection according to time after onset of infection and, secondly, to determine if a person has previously been infected with SARS-CoV-2. Sources of heterogeneity investigated included: timing of test, test method, SARS-CoV-2 antigen used, test brand, and reference standard for non-SARS-CoV-2 cases. SEARCH METHODS: The COVID-19 Open Access Project living evidence database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) was searched on 30 September 2020. We included additional publications from the Evidence for Policy and Practice Information and Co-ordinating Centre (EPPI-Centre) 'COVID-19: Living map of the evidence' and the Norwegian Institute of Public Health 'NIPH systematic and living map on COVID-19 evidence'. We did not apply language restrictions. SELECTION CRITERIA: We included test accuracy studies of any design that evaluated commercially produced serology tests, targeting IgG, IgM, IgA alone, or in combination. Studies must have provided data for sensitivity, that could be allocated to a predefined time period after onset of symptoms, or after a positive RT-PCR test. Small studies with fewer than 25 SARS-CoV-2 infection cases were excluded. We included any reference standard to define the presence or absence of SARS-CoV-2 (including reverse transcription polymerase chain reaction tests (RT-PCR), clinical diagnostic criteria, and pre-pandemic samples). DATA COLLECTION AND ANALYSIS: We use standard screening procedures with three reviewers. Quality assessment (using the QUADAS-2 tool) and numeric study results were extracted independently by two people. Other study characteristics were extracted by one reviewer and checked by a second. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test and, for meta-analysis, we fitted univariate random-effects logistic regression models for sensitivity by eligible time period and for specificity by reference standard group. Heterogeneity was investigated by including indicator variables in the random-effects logistic regression models. We tabulated results by test manufacturer and summarised results for tests that were evaluated in 200 or more samples and that met a modification of UK Medicines and Healthcare products Regulatory Agency (MHRA) target performance criteria. MAIN RESULTS: We included 178 separate studies (described in 177 study reports, with 45 as pre-prints) providing 527 test evaluations. The studies included 64,688 samples including 25,724 from people with confirmed SARS-CoV-2; most compared the accuracy of two or more assays (102/178, 57%). Participants with confirmed SARS-CoV-2 infection were most commonly hospital inpatients (78/178, 44%), and pre-pandemic samples were used by 45% (81/178) to estimate specificity. Over two-thirds of studies recruited participants based on known SARS-CoV-2 infection status (123/178, 69%). All studies were conducted prior to the introduction of SARS-CoV-2 vaccines and present data for naturally acquired antibody responses. Seventy-nine percent (141/178) of studies reported sensitivity by week after symptom onset and 66% (117/178) for convalescent phase infection. Studies evaluated enzyme-linked immunosorbent assays (ELISA) (165/527; 31%), chemiluminescent assays (CLIA) (167/527; 32%) or lateral flow assays (LFA) (188/527; 36%). Risk of bias was high because of participant selection (172, 97%); application and interpretation of the index test (35, 20%); weaknesses in the reference standard (38, 21%); and issues related to participant flow and timing (148, 82%). We judged that there were high concerns about the applicability of the evidence related to participants in 170 (96%) studies, and about the applicability of the reference standard in 162 (91%) studies. Average sensitivities for current SARS-CoV-2 infection increased by week after onset for all target antibodies. Average sensitivity for the combination of either IgG or IgM was 41.1% in week one (95% CI 38.1 to 44.2; 103 evaluations; 3881 samples, 1593 cases), 74.9% in week two (95% CI 72.4 to 77.3; 96 evaluations, 3948 samples, 2904 cases) and 88.0% by week three after onset of symptoms (95% CI 86.3 to 89.5; 103 evaluations, 2929 samples, 2571 cases). Average sensitivity during the convalescent phase of infection (up to a maximum of 100 days since onset of symptoms, where reported) was 89.8% for IgG (95% CI 88.5 to 90.9; 253 evaluations, 16,846 samples, 14,183 cases), 92.9% for IgG or IgM combined (95% CI 91.0 to 94.4; 108 evaluations, 3571 samples, 3206 cases) and 94.3% for total antibodies (95% CI 92.8 to 95.5; 58 evaluations, 7063 samples, 6652 cases). Average sensitivities for IgM alone followed a similar pattern but were of a lower test accuracy in every time slot. Average specificities were consistently high and precise, particularly for pre-pandemic samples which provide the least biased estimates of specificity (ranging from 98.6% for IgM to 99.8% for total antibodies). Subgroup analyses suggested small differences in sensitivity and specificity by test technology however heterogeneity in study results, timing of sample collection, and smaller sample numbers in some groups made comparisons difficult. For IgG, CLIAs were the most sensitive (convalescent-phase infection) and specific (pre-pandemic samples) compared to both ELISAs and LFAs (P < 0.001 for differences across test methods). The antigen(s) used (whether from the Spike-protein or nucleocapsid) appeared to have some effect on average sensitivity in the first weeks after onset but there was no clear evidence of an effect during convalescent-phase infection. Investigations of test performance by brand showed considerable variation in sensitivity between tests, and in results between studies evaluating the same test. For tests that were evaluated in 200 or more samples, the lower bound of the 95% CI for sensitivity was 90% or more for only a small number of tests (IgG, n = 5; IgG or IgM, n = 1; total antibodies, n = 4). More test brands met the MHRA minimum criteria for specificity of 98% or above (IgG, n = 16; IgG or IgM, n = 5; total antibodies, n = 7). Seven assays met the specified criteria for both sensitivity and specificity. In a low-prevalence (2%) setting, where antibody testing is used to diagnose COVID-19 in people with symptoms but who have had a negative PCR test, we would anticipate that 1 (1 to 2) case would be missed and 8 (5 to 15) would be falsely positive in 1000 people undergoing IgG or IgM testing in week three after onset of SARS-CoV-2 infection. In a seroprevalence survey, where prevalence of prior infection is 50%, we would anticipate that 51 (46 to 58) cases would be missed and 6 (5 to 7) would be falsely positive in 1000 people having IgG tests during the convalescent phase (21 to 100 days post-symptom onset or post-positive PCR) of SARS-CoV-2 infection. AUTHORS' CONCLUSIONS: Some antibody tests could be a useful diagnostic tool for those in whom molecular- or antigen-based tests have failed to detect the SARS-CoV-2 virus, including in those with ongoing symptoms of acute infection (from week three onwards) or those presenting with post-acute sequelae of COVID-19. However, antibody tests have an increasing likelihood of detecting an immune response to infection as time since onset of infection progresses and have demonstrated adequate performance for detection of prior infection for sero-epidemiological purposes. The applicability of results for detection of vaccination-induced antibodies is uncertain.

Pneumococcal vaccination uptake and missed opportunities for vaccination among Canadian adults: A cross-sectional analysis of the Canadian Longitudinal Study on Aging (CLSA).

INTRODUCTION: In Canada, pneumococcal vaccination is recommended to all adults aged ≥65 and those <65 who have one or more chronic medical conditions (CMCs). Understanding vaccine uptake and its determinants among eligible groups has important implications for reducing the burden of pneumococcal disease. METHODS: Using data from a large national cohort of Canadian residents aged ≥47 years between 2015-2018, we calculated self-reported pneumococcal vaccine uptake among eligible groups, estimated associations between key factors and non-vaccination, assessed missed opportunities for vaccination (MOV) and examined risk factors for MOV. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for relevant associations were estimated through logistic regression. RESULTS: 45.8% (95% CI: 45.2-46.5) of 22,246 participants aged ≥65 and 81.3% (95% CI: 80.5-82.0) of 10,815 individuals aged 47-64 with ≥1 CMC reported never having received a pneumococcal vaccine. Receipt of influenza vaccination in the previous year was associated with the lowest odds of pneumococcal non-vaccination (aOR = 0.14 [95% CI: 0.13-0.15] for older adults and aOR = 0.23 [95% CI: 0.20-0.26] for those aged 47-64 with ≥1 CMC). Pneumococcal vaccine uptake was also more likely in case of contact with a family doctor in the previous year (versus no contact), increased with age and varied widely across provinces. Among individuals recently vaccinated against influenza, 32.6% (95% CI: 31.9-33.4) of those aged ≥65 and 71.1% (95% CI: 69.9-72.3) of those aged 47-64 with ≥1 CMC missed an opportunity to get a pneumococcal vaccine. Among individuals who had contact with a family doctor, 44.8% (95% CI: 44.1-45.5) of those aged ≥65 and 80.4% (95% CI: 79.6-81.2) of those aged 47-64 with ≥1 CMC experienced a MOV. CONCLUSIONS: Pneumococcal vaccine uptake remains suboptimal among at-risk Canadian adults who are eligible for vaccination. Further research is needed to clarify the reasons behind missed opportunities for vaccination and adequately address the main barriers to pneumococcal vaccination.

Influenza vaccine coverage and factors associated with non-vaccination among adults at high risk for severe outcomes: An analysis of the Canadian Longitudinal Study on Aging.

BACKGROUND: Influenza vaccination is recommended in Canada for older adults and those with underlying health conditions due to their increased risk of severe outcomes. Further research is needed to identify who within these groups is not receiving influenza vaccine to identify opportunities to increase coverage. OBJECTIVES: We aimed to 1) estimate influenza non-vaccination prevalence and 2) assess factors associated with non-vaccination among Canadian adults aged ≥65 and adults aged 46-64 with ≥1 chronic medical condition (CMC) due to their high risk of severe influenza outcomes. METHODS: We conducted a secondary analysis of cross-sectional data collected from 2015-2018 among participants of the Canadian Longitudinal Study on Aging. For both groups of interest, we estimated non-vaccination prevalence and used logistic regression models to identify factors associated with non-vaccination. We report adjusted odds ratios and 95% confidence intervals for the investigated variables. RESULTS: Overall, 29.5% (95% CI: 28.9%, 30.1%) of the 23,226 participants aged ≥65 years and 50.4% (95% CI: 49.4%, 51.3%) of the 11,250 participants aged 46-64 years with ≥1 CMC reported not receiving an influenza vaccination in the past 12 months. For both groups, lack of recent contact with a family doctor and current smoking were independently associated with non-vaccination. DISCUSSION: Influenza vaccination helps prevent severe influenza outcomes. Yet, half of adults aged 46-64 years with ≥1 CMC and more than one-quarter of all adults aged ≥65 years did not receive a recommended influenza vaccine in the year prior to the survey. Innovation in vaccination campaigns for routinely recommended vaccines, especially among those without annual family doctor visits, may improve coverage. CONCLUSION: Influenza vaccination coverage among Canadian adults aged 46-64 years with ≥1 CMC and adults aged ≥65 years remains suboptimal. Vaccination campaigns targeting those at high risk of severe outcomes without routine physician engagement should be evaluated to improve uptake.

Comparative Effectiveness of Regimens for Drug-Susceptible Tuberculous Meningitis in Children and Adolescents: A Systematic Review and Aggregate-Level Data Meta-Analysis.

Background: Before August 2021, the only regimen recommended by the World Health Organization (WHO) to treat pediatric drug-susceptible tuberculous meningitis was a 12-month regimen consisting of isoniazid, rifampicin, ethambutol, and pyrazinamide (2HRZE/10HR). The comparative effectiveness of shorter regimens is unknown. Methods: To inform a WHO guideline update, we undertook a systematic review and meta-analysis to evaluate outcomes from regimens of 6- to less than 12-months' duration that included, at a minimum, isoniazid, rifampicin, and pyrazinamide. We included studies that applied rigorous diagnostic criteria and reported outcomes for ≥10 children or adolescents. Using generalized linear mixed models, we estimated the random effects pooled proportions of patients with key outcomes. Results: Of 7 included studies, none compared regimens head-to-head. Three studies (724 patients) used a 6-month intensive regimen, which includes isoniazid and rifampicin at higher doses, pyrazinamide, and ethionamide instead of ethambutol (6HRZEto). Outcomes for this versus the 12-month regimen (282 patients, 3 studies) were, respectively, as follows: death, 5.5% (95% confidence interval [CI], 2.1%-13.4%) vs 23.9% (95% CI, 17.5%-31.7%); treatment success (survival with or without sequelae), 94.6% (95% CI, 73.9%-99.1%) vs 75.4% (95% CI, 68.7%-81.1%); and neurological sequelae among survivors, 66.0% (95% CI, 55.3%-75.3%) vs 36.3% (95% CI, 30.1%-43.0%). Relapse did not occur among 148 patients followed-up for 2 years after completing the 6-month intensive regimen. Conclusions: Our findings are limited by the small number of studies and substantial potential for confounding. Nonetheless, the 6HRZEto regimen was associated with high treatment success and is now recommended by WHO as an alternative to the 12-month regimen.

A comparison of national vaccination policies to prevent serogroup B meningococcal disease.

OBJECTIVES: To understand the global landscape of prevention and control efforts targeting serogroup B meningococcal (MenB) disease and to identify the key challenges and gaps yet to be addressed. METHODS: We conducted a comprehensive review of policies and practices for the use of protein-based MenB vaccines (Bexsero® [GlaxoSmithKline] and Trumenba® [Pfizer]) in all countries (n = 58) where either or both vaccine is authorized for use. We searched the literature (PubMed) and websites of health ministries and other relevant agencies to identify policy documents and plans and collect information about implementation timelines, target groups, vaccines being used, recommended schedules, and coverage data. Experts in the field were contacted for additional details andclarifications, as needed. RESULTS: We found evidence of a national MenB vaccination policy in 24 out of 58 countries where one or both protein-based MenB vaccines are authorized. Of these, 15 countries have included MenB vaccination in their immunization plans for at least one age-based risk group (mostly infants), 21 have issued recommendations for various risk groups based on underlying medical conditions (e.g. asplenia), and 13 have done so for select groups at increased risk of exposure (e.g. laboratory staff). Recommended vaccination schedules and number of doses, where available, varied widely. Vaccination coverage data for age-based risk groups were not obtained for most countries. CONCLUSIONS: Our findings highlighted the significant heterogeneity in recommendations for MenB vaccination across countries. Greater transparency in reporting MenB vaccination recommendations and more robust data on implementation and the impact of vaccination would better facilitate optimizing MenB prevention strategies.

India's ban on antimicrobial fixed-dose combinations: winning the battle, losing the war?

BACKGROUND AND OBJECTIVES: India, the country with the largest market availability of antimicrobial fixed-dose combinations (FDCs), banned certain antimicrobial FDCs in September 2018. Our objective was to examine the impact of Government ban on the sales of antimicrobial FDCs. METHODS: The sales patterns of 14 of the 26 banned antimicrobial FDCs were analyzed using monthly private sector drug sales data from IQVIA (a comprehensive and nationally representative drug sales database) between January 2018 and December 2019. We carried out descriptive analyses to evaluate the trend in sales over time for banned and non-banned antimicrobial FDCs using cumulative sales volumes. RESULTS: Overall, the cumulative sales volume of banned antimicrobial FDCs declined by 75% between January and September 2018 and the same months of 2019, although some banned FDCs continued to be available in significant volumes. The effectiveness of the ban was offset by several pathways. First, the sales of combinations containing moieties belonging to the same drug-classes as the antimicrobials in the banned FDCs increased after the ban. Second, while certain formulations of particular combinations were banned, the sales of other non-banned formulation of these combinations increased. Third, in some cases, products containing new non-antimicrobial components added to the banned combinations remained available. INTERPRETATION AND CONCLUSIONS: While sales of the banned antimicrobial FDCs decreased in 2019, we identified several mechanisms that counterbalanced the ban, including implementation failure, rising sales of congeners, and products with additional non-antimicrobial components.

Exposure to World Health Organization's AWaRe antibiotics and isolation of multidrug resistant bacteria: a systematic review and meta-analysis.

BACKGROUND: Antibiotic use drives antibiotic resistance. OBJECTIVES: To systematically review the literature and estimate associations between prior exposure to antibiotics across World Health Organization's (WHO) AWaRe categories (Access, Watch, Reserve) and isolation of critical and high-priority multidrug resistant organisms (MDROs) on the WHO priority pathogen list. DATA SOURCES: Embase, Ovid Medline, Scopus, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov (from inception to 20/08/2020). STUDY ELIGIBILITY CRITERIA: Case-control, cohort, or experimental studies that assessed the risk of infection/colonization with MDROs. PARTICIPANTS: Inpatients or outpatients of any age and sex. INTERVENTIONS: Prior exposure to antibiotics that could be categorized into the AWaRe framework. DATA ANALYSIS: Tailored design-specific checklists applied to each included study. For each antibiotic/class, crude odds ratios (ORs) were pooled through random-effects meta-analyses, both overall and by MDRO. Heterogeneity was examined. RESULTS: We identified 349 eligible studies. All were observational, prone to bias due to design and lack of adjustment for confounding, and not primarily designed to compare associations across AWaRe categories. We found statistically significant associations between prior exposure to almost all antibiotics/classes across AWaRe categories and colonization/infection with any MDRO. We observed higher ORs for Watch and Reserve antibiotics than with Access antibiotics. First generation cephalosporins (Access) had the least association with any MDRO colonization/infection (58 studies; OR = 1.2 [95% CI: 1.0-1.4]), whereas strongest associations were estimated for linezolid (Reserve) (22 studies; OR = 2.6 [95% CI: 2.1-3.1]), followed by carbapenems (Watch) (237 studies; OR = 2.3 [95% CI: 2.1-2.5]). There was high heterogeneity for all antibiotic/MDRO associations. CONCLUSIONS: Optimising use of Access antibiotics is likely to reduce the selection of MDROs and global antibiotic resistance. Despite data limitations, our study offers a strong rationale for further adoption of AWaRe as an important tool to improve antibiotic use globally.

Do private providers give patients what they demand, even if it is inappropriate? A randomised study using unannounced standardised patients in Kenya.

INTRODUCTION: Low and varied quality of care has been demonstrated for childhood illnesses in low-income and middle-income countries. Some quality improvement strategies focus on increasing patient engagement; however, evidence suggests that patients demanding medicines can favour the selection of resistant microbial strains in the individual and the community if drugs are inappropriately used. This study examines the effects on quality of care when patients demand different types of inappropriate medicines. METHODS: We conducted an experiment where unannounced standardised patients (SPs), locally recruited individuals trained to simulate a standardised case, present at private clinics. Between 8 March and 28 May 2019, 10 SPs portraying caretakers of a watery diarrhoea childhood case scenario (in absentia) conducted N=200 visits at 200 private, primary care clinics in Kenya. Half of the clinics were randomly assigned to receive an SP demanding amoxicillin (an antibiotic); the other half, an SP demanding albendazole (an antiparasitic drug often used for deworming), with other presenting characteristics the same. We used logistic and linear regression models to assess the effects of demanding these inappropriate medicines on correct and unnecessary case management outcomes. RESULTS: Compared with 3% among those who did not demand albendazole, the dispensing rate increased significantly to 34% for those who did (adjusted OR 0.06, 95% CI 0.02 to 0.22, p<0.0001). Providers did not give different levels of amoxicillin between those demanding it and those not demanding it (adjusted OR 1.73, 95% CI 0.51 to 5.82). Neither significantly changed any correct management outcomes, such as treatment or referral elsewhere. CONCLUSION: Private providers appear to account for both business-driven benefits and individual health impacts when making prescribing decisions. Additional research is needed on provider knowledge and perceptions of profit and individual and community health trade-offs when making prescription decisions after patients demand different types of inappropriate medicines. TRIAL REGISTRATION NUMBERS: American Economic Association Registry (#AEARCTR-0000217) and Pan African Clinical Trial Registry (#PACTR201502000770329).

Factors Associated With Willingness to Receive a COVID-19 Vaccine Among 23,819 Adults Aged 50 Years or Older: An Analysis of the Canadian Longitudinal Study on Aging.

Identifying persons who are least willing to receive a coronavirus disease 2019 (COVID-19) vaccine is critical for increasing uptake via targeted outreach. We conducted a survey of 23,819 Canadian Longitudinal Study on Aging participants from September 29 to December 29, 2020, to assess factors associated with COVID-19 vaccination willingness and reasons for willingness or lack thereof. Among adults aged 50-96 years, 84.1% (95% confidence interval (CI): 83.7, 84.6) were very or somewhat willing to receive a COVID-19 vaccine; 15.9% (95% CI: 15.4, 16.3) were uncertain or very or somewhat unwilling. Based on logistic regression, those who were younger, female, had lower education and income, were non-White, and lived in a rural area were less willing to receive a COVID-19 vaccine. After controlling for these factors, recent receipt of influenza vaccine (adjusted odds ratio = 14.3, 95% CI: 12.5, 16.2) or planning to receive influenza vaccine (adjusted odds ratio = 10.5, 95% CI: 9.5, 11.6), as compared with no receipt or planning, was most strongly associated with COVID-19 vaccination willingness. Willingness was also associated with believing one had never been infected with severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) and experiencing negative pandemic consequences. Safety concerns were most common among those unwilling. Our comprehensive assessment of COVID-19 vaccination willingness among older adults in Canada, a prioritized group for vaccination due to their risk of severe COVID-19 outcomes, provides a road map for conducting outreach to increase uptake, which is urgently needed.