Semiparametric g-computation for survival outcomes with time-fixed exposures: An illustration.

PURPOSE: Generalized (g-) computation is a useful tool for causal inference in epidemiology. However, in settings when the outcome is a survival time subject to right censoring, the standard pooled logistic regression approach to g-computation requires arbitrary discretization of time, parametric modeling of the baseline hazard function, and the need to expand one's dataset. We illustrate a semiparametric Breslow estimator for g-computation with time-fixed treatments and survival outcomes that is not subject to these limitations. METHODS: We compare performance of the Breslow g-computation estimator to the pooled logistic g-computation estimator in simulations and illustrate both approaches to estimate the effect of a 3-drug vs 2-drug antiretroviral therapy regimen among people with HIV. RESULTS: In simulations, both approaches performed well at the end of follow-up. The pooled logistic approach was biased at times between the endpoints of the discrete time intervals used, while the Breslow approach was not. In the example, both approaches estimated a 1-year risk difference of about 6 % in favor of the 3-drug regimen, but the shape of the survival curves differed. CONCLUSIONS: The Breslow g-computation estimator of counterfactual risk functions does not rely on strong parametric assumptions about the time-to-event distribution or onerous dataset expansions.

Prevalence and molecular epidemiology of carbapenemase-producing Enterobacterales isolated from dog and cat faeces submitted to veterinary laboratories in the USA.

AIMS: To estimate the prevalence of carbapenemase-producing Enterobacterales (CPE) carriage among pets using faecal specimens submitted to veterinary diagnostic laboratories throughout the US. A secondary aim was to employ whole-genome sequencing (WGS) to characterize isolates of CPE from companion animals and compare them to publicly available CPE genomes. METHODS AND RESULTS: To estimate the prevalence of CPE in companion animals in the USA, a multicenter surveillance study including 8 different veterinary diagnostic laboratories from across the USA was conducted. Briefly, remnant faecal specimens from dogs and cats were screened using two selective agar plates (CHROMID Carba and MacConkey with 1 mg/L cefotaxime and 0.125 mg/L meropenem) and presumptive CPE isolates screened by the modified carbapenemase inactivation method for carbapenemase production. A total of 2393 specimens were screened and yielded 196 isolates for carbapenemase screening. A total of 5 isolates from 4 dogs and 1 cat at 3 different veterinary diagnostic laboratories were confirmed to produce a carbapenemase (0.21%). Whole-genome sequencing (WGS) revealed two E. coli (ST167) isolates that both produced an NDM-5 carbapenemase, two Enterobacter hormaechei (ST171) isolates that produced an NDM-5 carbapenemase and a KPC-4 carbapenemase respectively and one Klebsiella oxytoca (ST199) that produced an Oxa-48-type carbapenemase. Both E. coli isolates were found to be within at least 22 SNPs of previously characterized canine and human CPE isolates. CONCLUSIONS: This study demonstrates that the prevalence of CPE among companion animals is relatively low (0.21%) but that given the genetic relatedness of animal isolates to human isolates, additional surveillance is needed.

Clinical Differences in Dogs with Enterococcal Bacteriuria Compared with Other Bacteriuria: A Retrospective, Case-Control Study.

A retrospective case-control study was performed to determine the clinical differences between dogs with enterococcal bacteriuria (n = 96 cases) and control dogs with any other bacteriuria (n = 288). More dogs with nonenterococcal bacteriuria demonstrated lower urinary tract clinical signs such as hematuria, pollakiuria, and stranguria (40% versus 27%, P = .02). Recessed vulva (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.4-4.2, P < .001), hyperadrenocorticism (OR 0.149, 95% CI 0.004-0.066, P = .03), chronic kidney disease (OR 2.29, 95% CI 1.14-4.51, P = .01), and myelopathy (OR 5.77, 95% CI 3.07-10.82, P < .001) were more common in dogs with enterococcal bacteriuria. Enterococcus spp. cases were more likely to have polymicrobial growth than controls (OR 28.52; 95% CI 12.63-69.62, P ≤ .001). Pugs (OR 7.4, 95% CI 2.6-19.9, P < .001), bearded collies (OR 24.3, 95% CI 2.9-205.5, P = .003), and Saint Bernards (OR 17.3, CI 1.9-154.4, P = .01) had increased odds of enterococcal growth compared with mixed-breed dogs. In the control (but not the case) population, there was an association between resolution of clinical signs and administration of antimicrobials (P = .01). The signalment, clinical signs, comorbidities, and response to therapy in dogs with enterococcal bacteriuria are different from dogs with other bacteriuria.

M-estimation for common epidemiological measures: introduction and applied examples.

M-estimation is a statistical procedure that is particularly advantageous for some comon epidemiological analyses, including approaches to estimate an adjusted marginal risk contrast (i.e. inverse probability weighting and g-computation) and data fusion. In such settings, maximum likelihood variance estimates are not consistent. Thus, epidemiologists often resort to bootstrap to estimate the variance. In contrast, M-estimation allows for consistent variance estimates in these settings without requiring the computational complexity of the bootstrap. In this paper, we introduce M-estimation and provide four illustrative examples of implementation along with software code in multiple languages. M-estimation is a flexible and computationally efficient estimation procedure that is a powerful addition to the epidemiologist's toolbox.

Current state and future directions for veterinary antimicrobial resistance research.

Antimicrobial resistance (AMR) is a critical One Health concern with implications for human, animal, plant, and environmental health. Antimicrobial susceptibility testing (AST), antimicrobial resistance testing (ART), and surveillance practices must be harmonized across One Health sectors to ensure consistent detection and reporting practices. Veterinary diagnostic laboratory stewardship, clinical outcomes studies, and training for current and future generations of veterinarians and laboratorians are necessary to minimize the spread of AMR and move veterinary medicine forward into an age of better antimicrobial use practices. The purpose of this article is to describe current knowledge gaps present in the literature surrounding ART, AST, and clinical or surveillance applications of these methods and to suggest areas where AMR research can fill these knowledge gaps. The related Currents in One Health by Maddock et al, JAVMA, March 2024, addresses current limitations to the use of genotypic ART methods in clinical veterinary practice.

Higher-order evidence.

Higher-order evidence is evidence about evidence. Epidemiologic examples of higher-order evidence include the settings where the study data constitute first-order evidence and estimates of misclassification comprise the second-order evidence (e.g., sensitivity, specificity) of a binary exposure or outcome collected in the main study. While sampling variability in higher-order evidence is typically acknowledged, higher-order evidence is often assumed to be free of measurement error (e.g., gold standard measures). Here we provide two examples, each with multiple scenarios where second-order evidence is imperfectly measured, and this measurement error can either amplify or attenuate standard corrections to first-order evidence. We propose a way to account for such imperfections that requires third-order evidence. Further illustrations and exploration of how higher-order evidence impacts results of epidemiologic studies is warranted.

A One Health perspective on the use of genotypic methods for antimicrobial resistance prediction.

Antimicrobial resistance is a global One Health concern with critical implications for the health of humans, animals, and the environment. Phenotypic methods of bacterial culture and antimicrobial susceptibility testing remain the gold standards for the detection of antimicrobial resistance and appropriate patient care; however, genotypic-based methods, such as PCR, whole genome sequencing, and metagenomic sequencing, for detection of genes conferring antimicrobial resistance are increasingly available without inclusion of appropriate standards for quality or interpretation. Misleading test results may lead to inappropriate antimicrobial treatment and, in turn, poor patient outcomes and the potential for increased incidence of antimicrobial resistance. This article explores the current landscape of clinical and methodological aspects of antimicrobial susceptibility testing and genotypic antimicrobial resistance test methods. Additionally, it describes the limitations associated with employing genotypic-based test methods in the management of veterinary patients from a One Health perspective. The companion Currents in One Health by Maddock et al, AJVR, March 2024, addresses current and future needs for veterinary antimicrobial resistance research.

Assessment of a virtual disaster preparedness and response simulation compared to previous in-person iterations: successful translation of the Penndemic framework.

Collaborative learning has documented benefits. Restrictions because of the COVID-19 pandemic prevented in-person collaborative experiences, therefore creating a pathway for online ones. An inter-university team previously created and published a novel framework that fosters collaborative learning for emergency/disaster preparedness and uses scenarios that attract student participation from a spectrum of disciplines. Here, we detail the implementation and evaluation of this framework in a virtual setting. Analysis of pre- and post-surveys from the virtual event revealed similar results to the previous in-person iterations. Results for both in-person and virtual events demonstrated that students had higher confidence and interest in emergency/disaster preparedness and interprofessional teamwork after participation. Implementation of this framework in a virtual setting can facilitate a positive student learning experience and inter-university collaboration.

HIV Prevention Among Men Who Have Sex With Men: Tenofovir Alafenamide Combination Preexposure Prophylaxis Versus Placebo.

BACKGROUND: While noninferiority of tenofovir alafenamide and emtricitabine (TAF/FTC) as preexposure prophylaxis (PrEP) for the prevention of human immunodeficiency virus (HIV) has been shown, interest remains in its efficacy relative to placebo. We estimate the efficacy of TAF/FTC PrEP versus placebo for the prevention of HIV infection. METHODS: We used data from the DISCOVER and iPrEx trials to compare TAF/FTC to placebo. DISCOVER was a noninferiority trial conducted from 2016 to 2017. iPrEx was a placebo-controlled trial conducted from 2007 to 2009. Inverse probability weights were used to standardize the iPrEx participants to the distribution of demographics and risk factors in the DISCOVER trial. To check the comparison, we evaluated whether risk of HIV infection in the shared tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) arms was similar. RESULTS: Notable differences in demographics and risk factors occurred between trials. After standardization, the difference in risk of HIV infection between the TDF/FTC arms was near zero. The risk of HIV with TAF/FTC was 5.8 percentage points lower (95% confidence interval [CI], -2.0% to -9.6%) or 12.5-fold lower (95% CI, .02 to .31) than placebo standardized to the DISCOVER population. CONCLUSIONS: There was a reduction in HIV infection with TAF/FTC versus placebo across 96 weeks of follow-up. CLINICAL TRIALS REGISTRATION: NCT02842086 and NCT00458393.

Leveraging External Validation Data: The Challenges of Transporting Measurement Error Parameters.

Approaches to address measurement error frequently rely on validation data to estimate measurement error parameters (e.g., sensitivity and specificity). Acquisition of validation data can be costly, thus secondary use of existing data for validation is attractive. To use these external validation data, however, we may need to address systematic differences between these data and the main study sample. Here, we derive estimators of the risk and the risk difference that leverage external validation data to account for outcome misclassification. If misclassification is differential with respect to covariates that themselves are differentially distributed in the validation and study samples, the misclassification parameters are not immediately transportable. We introduce two ways to account for such covariates: (1) standardize by these covariates or (2) iteratively model the outcome. If conditioning on a covariate for transporting the misclassification parameters induces bias of the causal effect (e.g., M-bias), the former but not the latter approach is biased. We provide proof of identification, describe estimation using parametric models, and assess performance in simulations. We also illustrate implementation to estimate the risk of preterm birth and the effect of maternal HIV infection on preterm birth. Measurement error should not be ignored and it can be addressed using external validation data via transportability methods.

Use of a chromogenic medium with and without selective enrichment to screen for carbapenemase-producing Enterobacterales (CPE) from canine and feline fecal specimens during an outbreak of NDM-5-producing Escherichia coli.

Carbapenemase-producing Enterobacterales (CPE) are one of the most urgent threats to human healthcare globally. Descriptions of CPE outbreaks in veterinary hospitals suggest the need for screening strategies for CPE from companion animals. Our aim was to optimize a chromogenic agar method with and without selective enrichment to isolate CPE from companion animal feces in an ongoing outbreak of New Delhi metallo-ß-lactamse-5 Escherichia coli. A limit of detection (LOD) assay for spiked canine and feline feces was performed for both methods using a carbapenamase-producing E. coli (24213-18); the LOD (1.5 × 103 cfu/g of feces) was equivalent to that reported for human fecal specimens. We screened 1,247 companion animal fecal specimens for carriage of CPE by 1) direct plating to chromogenic agar and 2) plating to chromogenic agar following selective enrichment. Twenty-one specimens were positive for CPE by both direct culture and enrichment culture. No specimens were positive with selective enrichment and negative by direct culture. A selective enrichment step did not result in any increased recovery of CPE from companion animals, which suggests that enrichment broth may not be necessary for outbreak surveillance testing. It is important to continue to validate methods for the detection of CPE in companion animals as outbreaks become more common in veterinary facilities.

Transportability Without Positivity: A Synthesis of Statistical and Simulation Modeling.

Studies designed to estimate the effect of an action in a randomized or observational setting often do not represent a random sample of the desired target population. Instead, estimates from that study can be transported to the target population. However, transportability methods generally rely on a positivity assumption, such that all relevant covariate patterns in the target population are also observed in the study sample. Strict eligibility criteria, particularly in the context of randomized trials, may lead to violations of this assumption. Two common approaches to address positivity violations are restricting the target population and restricting the relevant covariate set. As neither of these restrictions is ideal, we instead propose a synthesis of statistical and simulation models to address positivity violations. We propose corresponding g-computation and inverse probability weighting estimators. The restriction and synthesis approaches to addressing positivity violations are contrasted with a simulation experiment and an illustrative example in the context of sexually transmitted infection testing uptake. In both cases, the proposed synthesis approach accurately addressed the original research question when paired with a thoughtfully selected simulation model. Neither of the restriction approaches was able to accurately address the motivating question. As public health decisions must often be made with imperfect target population information, model synthesis is a viable approach given a combination of empirical data and external information based on the best available knowledge.

"Like fighting a fire with a water pistol": A qualitative study of the work experiences of critical care nurses during the COVID-19 pandemic.

AIM: To understand the experience of critical care nurses during the COVID-19 pandemic, through the application of the Job-Demand-Resource model of occupational stress. DESIGN: Qualitative interview study. METHODS: Twenty-eight critical care nurses (CCN) working in ICU in the UK NHS during the COVID-19 pandemic took part in semi-structured interviews between May 2021 and May 2022. Interviews were guided by the constructs of the Job-Demand Resource model. Data were analysed using framework analysis. RESULTS: The most difficult job demands were the pace and amount, complexity, physical and emotional effort of their work. Prolonged high demands led to CCN experiencing emotional and physical exhaustion, burnout, post-traumatic stress symptoms and impaired sleep. Support from colleagues and supervisors was a core job resource. Sustained demands and impaired physical and psychological well-being had negative organizational consequences with CCN expressing increased intention to leave their role. CONCLUSIONS: The combination of high demands and reduced resources had negative impacts on the psychological well-being of nurses which is translating into increased consideration of leaving their profession. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The full impacts of the pandemic on the mental health of CCN are unlikely to resolve without appropriate interventions. IMPACT: Managers of healthcare systems should use these findings to inform: (i) the structure and organization of critical care workplaces so that they support staff to be well, and (ii) supportive interventions for staff who are carrying significant psychological distress as a result of working during and after the pandemic. These changes are required to improve staff recruitment and retention. REPORTING METHOD: We used the COREQ guidelines for reporting qualitative studies. PATIENT AND PUBLIC CONTRIBUTION: Six CCN provided input to survey content and interview schedule. Two authors and members of the study team (T.S. and S.C.) worked in critical care during the pandemic.

Fusing trial data for treatment comparisons: Single vs multi-span bridging.

While randomized controlled trials (RCTs) are critical for establishing the efficacy of new therapies, there are limitations regarding what comparisons can be made directly from trial data. RCTs are limited to a small number of comparator arms and often compare a new therapeutic to a standard of care which has already proven efficacious. It is sometimes of interest to estimate the efficacy of the new therapy relative to a treatment that was not evaluated in the same trial, such as a placebo or an alternative therapy that was evaluated in a different trial. Such dual-study comparisons are challenging because of potential differences between trial populations that can affect the outcome. In this article, two bridging estimators are considered that allow for comparisons of treatments evaluated in different trials, accounting for measured differences in trial populations. A "multi-span" estimator leverages a shared arm between two trials, while a "single-span" estimator does not require a shared arm. A diagnostic statistic that compares the outcome in the standardized shared arms is provided. The two estimators are compared in simulations, where both estimators demonstrate minimal empirical bias and nominal confidence interval coverage when the identification assumptions are met. The estimators are applied to data from the AIDS Clinical Trials Group 320 and 388 to compare the efficacy of two-drug vs four-drug antiretroviral therapy on CD4 cell counts among persons with advanced HIV. The single-span approach requires weaker identification assumptions and was more efficient in simulations and the application.

Estimating SARS-CoV-2 seroprevalence.

Governments and public health authorities use seroprevalence studies to guide responses to the COVID-19 pandemic. Seroprevalence surveys estimate the proportion of individuals who have detectable SARS-CoV-2 antibodies. However, serologic assays are prone to misclassification error, and non-probability sampling may induce selection bias. In this paper, non-parametric and parametric seroprevalence estimators are considered that address both challenges by leveraging validation data and assuming equal probabilities of sample inclusion within covariate-defined strata. Both estimators are shown to be consistent and asymptotically normal, and consistent variance estimators are derived. Simulation studies are presented comparing the estimators over a range of scenarios. The methods are used to estimate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence in New York City, Belgium, and North Carolina.

The pregnant traveller: An overview of common preventable infections.

Pregnant travellers are often unaware of the various infections that can be acquired during travel and that pregnant people may be at increased risk of severe disease compared to their non-pregnant counterparts. Pregnant people often seek pre-travel counselling from their obstetrician or primary care physicians, who may not be well versed in travel medicine. This paper aims to provide information for maternity care providers regarding important travel-related food, water and mosquito-borne illnesses, including their prevention and treatment methods, equipping maternity care providers to confidently counsel prospective travellers during pregnancy.

Vaccination recommendations for pregnant people travelling overseas.

With international travel on the rise following pandemic restrictions, the number of pregnant travellers is likely to proportionally increase. Recent published data suggest most pregnant travellers seek pre-travel advice from their maternity and primary care providers. With these data, it is important to provide maternity and primary care providers with guidelines and resources to help aid safe, informed, and timely delivery of vaccinations prior to travel. Vaccination for travel during pregnancy is fundamental in mitigating maternal and fetal communicable disease morbidity and mortality. This clinical perspective provides an overview of the indications, safety, and recommendations for pre-travel vaccines in pregnancy.

The pregnant traveller: An overview of general travel advice.

Travel during pregnancy is common, but is associated with a number of risks and potential problems. There are many pregnancy-specific and destination-specific issues to be considered along with issues related to method of transport. Travel experiences should be made as safe as possible through evidence-based counselling via pregnancy healthcare providers prior to travel. This travelling in pregnancy article has been created to facilitate pregnancy healthcare providers in having these pre-travel discussions to optimise maternal and fetal wellbeing.

The potential role of veterinary technicians in promoting antimicrobial stewardship.

BACKGROUND: A core principle of antimicrobial stewardship (AMS) in veterinary settings is the need for engagement of all stakeholders; however, no studies have addressed the role of veterinary technicians in AMS specifically. The objective of this study was to qualitatively assess knowledge, opinions, and practices related to AMS among technicians. Semi-structured interviews were conducted with 33 veterinary technicians with varied backgrounds, experience and roles. Interviews centered on participants work experience and interactions with their employer, perceptions of antimicrobial resistance and overuse in veterinary medicine, observed application of AMS principles, opinions on potential opportunities for technicians to contribute to AMS and concomitant potential barriers to these opportunities. Transcripts of interviews were coded thematically by two authors, then organized into a hierarchical framework, and the characterization of codes was compared across different categories of respondents. RESULTS: Most veterinary technicians were knowledgeable about antimicrobial drugs but could not provide a complete definition of antimicrobial resistance or AMS. Most veterinary technicians could identify examples of antimicrobial misuse. Participants identified areas of client education and discussion with veterinarians as potential areas to contribute to AMS. Barriers identified included hierarchical structures of veterinary practices and time-constraints. Most participants expressed a personal interest in participating in AMS. CONCLUSIONS: There is a possible appetite among some veterinary technicians to participate in AMS and they already play applicable roles in practices. Barriers such as educational needs, hierarchical structures of veterinary practices and time constraints will need to be addressed if technicians are included in AMS efforts.