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SynopsisFluoroquinolone resistance poses a threat to the successful treatment of tuberculosis. Whole genome sequencing (WGS), and the subsequent detection of catalogued resistance-associated mutations, offers an attractive solution to fluoroquinolone susceptibility testing. However, the bioinformatic pipelines used often mask the recognition of minor alleles which are implicated in fluoroquinolone resistance. Using the Comprehensive Resistance Prediction for Tuberculosis: an International Consortium’s (CRyPTIC) dataset of globally diverse WGSMycobacterium tuberculosisisolates, with matched minimum inhibitory concentrations for two fluoroquinolone drugs, we show that detecting minor alleles increased the sensitivity of WGS for moxifloxacin resistance prediction from 85.4% to 94.0%, without significantly reducing specificity. We also found no correlation between the proportion of anM. tuberculosispopulation containing a resistance-conferring allele and the magnitude of resistance. Together our results highlight the importance of detecting minor resistance conferring alleles when using WGS, or indeed any sequencing-based approach, to diagnose fluoroquinolone resistance.

Background The relationship between the presence of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the risk of subsequent reinfection remains unclear. Methods We investigated the incidence of SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) in seropositive and seronegative health care workers attending testing of asymptomatic and symptomatic staff at Oxford University Hospitals in the United Kingdom. Baseline antibody status was determined by anti-spike (primary analysis) and anti-nucleocapsid IgG assays, and staff members were followed for up to 31 weeks. We estimated the relative incidence of PCR-positive test results and new symptomatic infection according to antibody status, adjusting for age, participant-reported gender, and changes in incidence over time. Results A total of 12,541 health care workers participated and had anti-spike IgG measured; 11,364 were followed up after negative antibody results and 1265 after positive results, including 88 in whom seroconversion occurred during follow-up. A total of 223 anti-spike–seronegative health care workers had a positive PCR test (1.09 per 10,000 days at risk), 100 during screening while they were asymptomatic and 123 while symptomatic, whereas 2 anti-spike–seropositive health care workers had a positive PCR test (0.13 per 10,000 days at risk), and both workers were asymptomatic when tested (adjusted incidence rate ratio, 0.11; 95% confidence interval, 0.03 to 0.44; P=0.002). There were no symptomatic infections in workers with anti-spike antibodies. Rate ratios were similar when the anti-nucleocapsid IgG assay was used alone or in combination with the anti-spike IgG assay to determine baseline status. Conclusions The presence of anti-spike or anti-nucleocapsid IgG antibodies was associated with a substantially reduced risk of SARS-CoV-2 reinfection in the ensuing 6 months. (Funded by the U.K. Government Department of Health and Social Care and others.)

Background: Millions of women worldwide use exogenous hormones as oral contraceptives or hormone replacement therapy. Still, time-dependent and long-term consequences of exogenous hormones on stroke risk remains unclear. Methods: We examined the association between self-reported oral contraceptive and hormone replacement therapy use and stroke risk in 257 194 women from the UK Biobank, born between 1939 and 1970. Outcomes included any type of stroke, ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Exposures were analyzed as time-varying variables in Cox regression models. Results: During first year of oral contraceptive use, an increased event rate of any stroke was observed (hazard ratio [HR], 2.49 [95% CI, 1.44–4.30]), while the hazards were found to be comparable during remaining years of use (HR, 1.00 [95% CI, 0.86–1.14]), compared with nonusers. Similarly, first year of hormone replacement therapy use was associated with higher hazard rates of any stroke (HR, 2.12 [95% CI, 1.66–2.70]), as well as cause-specific stroke, including ischemic stroke (HR, 1.93 [95% CI, 1.05–3.57]) and subarachnoid hemorrhage (HR, 2.17 [95% CI, 1.25–3.78]), which remained increased for any stroke during remaining years of use (HR, 1.18 [95% CI, 1.05–1.31]), and after discontinuation (HR, 1.16 [95% CI, 1.02–1.32]). Conclusions: Oral contraceptive use and hormone replacement therapy were associated with an increased risk of stroke, especially during the first year of use, possibly due to immediate changes in hemostatic balance. This study provides new insights on the effects of hormone exposure on stroke risk and provide evidence of not only an overall risk but also a pronounced effects seen in the beginning of treatment.

The combination of registry and administrative claims data have facilitated research and quality improvement efforts. Using Vascular Quality Initiative (VQI) registry data and Medicare claims we have generated centre-specific survival, reintervention and surveillance reports which benchmark participating centres’ performance to the VQI as a whole and to published guidelines. In 2021, we distributed these reports to 303 participating centres. These reports offer an opportunity for centres to evaluate their performance and identify focus areas for quality improvement work.

Background Millions of women use exogenous hormones as hormone replacement therapy (HRT) or oral contraceptives (OC). Still, time-dependent and long-term consequences of exogenous hormones on cerebrovascular health remains unclear. Methods We examined the effects of HRT and OC usage on stroke risk in 256,661 women from UK Biobank, born between 1939 and 1970. Outcomes included any type of stroke, ischemic stroke (IS), intracerebral hemorrhage (IH), and subarachnoid hemorrhage (SH). Exposures were analyzed as time-dependent variables in Cox regression models. Results are expressed as hazard ratios (HR) with 95% confidence intervals. Results During first year of exposure, HRT usage was associated with higher hazard rates of any stroke (HR = 2.12[1.66-2.70]), IS (HR = 1.93[1.04-3.56]) and SH (HR = 2.14[1.23-3.72]) compared to non-usage, which remained significant only for any stroke during remaining years of exposure. Similarly, we observed an increased hazard of any stroke during first year of OC exposure (HR = 2.29[1.34-3.92]), while the hazards were found to be comparable during remaining years of use (HR = 1.03[0.92-1.17]). Conversely, women who previously had been exposed to OC, had a lower hazard rate of any stroke later in life, (HR = 0.88[0.82-0.94]). Conclusions Our findings suggest that HRT and OC use cause immediate changes in hemostatic balance, therefore increasing the short-term stroke risk. However, long-term effects of OC use during reproductive years might improve cerebrovascular health and prevent stroke events later in life. Key messages HRT usage increase the risk of stroke, both short-term and with longer use, while the increased stroke risk might be limited to the first year of OC use.

Drug susceptibility testing of M. tuberculosis is rooted in a binary susceptible/resistant paradigm.Whilst there are considerable advantages in measuring the minimum inhibitory concentrations (MICs) of a panel of drugs for an isolate it is n ecessary to measure the epidemiological cutoff values (ECOFF/ECVs) to permit comparison with qualitative data. Here we present ECOFF/ECVs for 13 anti-TB compounds, including bedaquiline and delamanid, derived from 20,637 clinical isolates collected by 14 laboratories based in 11 countries on five continents. Each isolate was incubated for 14 days on a dry 96-well broth microdilution plate and then read. Resistance to most of the drugs due to prior exposure is expected and the MIC distributions for many of the compounds are complex and therefore a phenotypically wild-type population could not be defined. Since a majority of samples also underwent genetic sequencing, we defined a genotypically wild-type population and measured the MIC of the 99th percentile by direct measurement and via fitting a Gaussian using interval regression.The proposed ECOFF/ECV values were then validated by comparing to the MIC distributions of high-confidence genetic variants that confer resistance and to qualitative drug susceptibility tests obtained via Mycobacterial Growth Indicator Tube and the Microscopic-Observation Drug-Susceptibility assay.These ECOFF/ECV values will inform and encourage the more widespread adoption of broth microdilution – this is a cheap culture-based method that tests the susceptibility of 12-14 antibiotics on a single 96-well plate and so could help personalise the treatment of tuberculosis.

Resistance to amoxicillin-clavulanate, a widely used beta-lactam/beta-lactamase inhibitor combination antibiotic, is rising globally, and yet susceptibility testing remains challenging. To test whether whole-genome sequencing (WGS) could provide a more reliable assessment of susceptibility than traditional methods, we predicted resistance from WGS for 976 Escherichia coli bloodstream infection isolates from Oxfordshire, United Kingdom, comparing against phenotypes from the BD Phoenix (calibrated against EUCAST guidelines)., Resistance to amoxicillin-clavulanate, a widely used beta-lactam/beta-lactamase inhibitor combination antibiotic, is rising globally, and yet susceptibility testing remains challenging. To test whether whole-genome sequencing (WGS) could provide a more reliable assessment of susceptibility than traditional methods, we predicted resistance from WGS for 976 Escherichia coli bloodstream infection isolates from Oxfordshire, United Kingdom, comparing against phenotypes from the BD Phoenix (calibrated against EUCAST guidelines). A total of 339/976 (35%) isolates were amoxicillin-clavulanate resistant. Predictions based solely on beta-lactamase presence/absence performed poorly (sensitivity, 23% [78/339]) but improved when genetic features associated with penicillinase hyperproduction (e.g., promoter mutations and copy number estimates) were considered (sensitivity, 82% [277/339]; P < 0.0001). Most discrepancies occurred in isolates with MICs within ±1 doubling dilution of the breakpoint. We investigated two potential causes: the phenotypic reference and the binary resistant/susceptible classification. We performed reference standard, replicated phenotyping in a random stratified subsample of 261/976 (27%) isolates using agar dilution, following both EUCAST and CLSI guidelines, which use different clavulanate concentrations. As well as disagreeing with each other, neither agar dilution phenotype aligned perfectly with genetic features. A random-effects model investigating associations between genetic features and MICs showed that some genetic features had small, variable and additive effects, resulting in variable resistance classification. Using model fixed-effects to predict MICs for the non-agar dilution isolates, predicted MICs were in essential agreement (±1 doubling dilution) with observed (BD Phoenix) MICs for 691/715 (97%) isolates. This suggests amoxicillin-clavulanate resistance in E. coli is quantitative, rather than qualitative, explaining the poorly reproducible binary (resistant/susceptible) phenotypes and suboptimal concordance between different phenotypic methods and with WGS-based predictions.

Proxy variables are often used in linear regression models with the aim of removing potential confounding bias. In this paper we formalise proxy variables within the potential outcomes framework, g ...

This paper presents a study protocol for the evaluation of a vocational rehabilitation, namely a collaboration between the Swedish Social Insurance Agency and the Public Employment Service, where individuals needing support to regain work ability were called to a joint assessment meeting. This protocol describes a matching study design using a lasso algorithm, where we do not have access to outcome data on work ability for the treated. The matching design is based on a collection of health and socio-economic covariates measured at baseline. We also have access to a prognosis made by caseworkers on the expected length of the individual sick leave. This prognosis variable is, we argue, a proxy variable for potential unmeasured confounders. We present results showing balance achieved on observed covariates.