Impact of Reversion of Mycobacterium tuberculosis Immunoreactivity Tests on the Estimated Annual Risk of Infection

A key metric in tuberculosis epidemiology is the annual risk of infection (ARI), which is usually derived from tuberculin skin test (TST) and interferon-gamma release assay (IGRA) prevalence surveys in children. Deriving the ARI assumes that immunoreactivity is persistent over time; however, reversion of immunoreactivity has long been documented. Here we use a deterministic, compartmental model of Mycobacterium tuberculosis (Mtb) infection to explore the impact of reversion on ARI estimation using age-specific reversion probabilities for TST and IGRA. Using empirical data of TST reversion (22.2%/year for 0-19yo), the true ARI is 2-5 times higher than estimated from immunoreactivity studies in 8-12 year-olds. Applying empirical reversion probabilities for IGRA (9.9%/year for 12-18yo) showed a 1.5-2-fold underestimation. ARIs are increasingly underestimated in older populations, due to the cumulative impact of reversion on population reactivity over time. Declines in annual risk did not largely affect the results. Ignoring reversion leads to a stark underestimation of the true ARI in populations and our interpretation of Mtb transmission intensity. Future surveys should adjust for reversion probabilities and its cumulative effect with increasing age to provide a more accurate reflection of the burden and dynamics of Mtb infection

Variation in inbreeding rates across the range of Northern Spotted Owls (\u3ci\u3eStrix occidentalis caurina\u3c/i\u3e): Insights from over 30 years of monitoring data

Inbreeding has been difficult to quantify in wild populations because of incomplete parentage information. We applied and extended a recently developed framework for addressing this problem to infer inbreeding rates in Northern Spotted Owls (Strix occidentalis caurina) across the Pacific Northwest, USA. Using pedigrees from 14,187 Northern Spotted Owls, we inferred inbreeding rates for 14 types of matings among relatives that produce pedigree inbreeding coefficients of F=0.25 or F=0.125. Inbreeding was most common in the Washington Cascades, where an estimated 15% of individuals are inbred. Inbreeding was lowest in western Oregon (3.5%) and northern California (2.7%), and intermediate for the Olympic Peninsula of Washington (6.1%). Estimates from the Olympic Peninsula were likely underestimates because of small sample sizes and the presence of few pedigrees capable of resolving inbreeding events. Most inbreeding resulted from matings between full siblings or half siblings, although a high rate of inbreeding from mother–son pairs was identified in the Olympic Peninsula. Geographic variation in inbreeding rates may reflect population declines and bottlenecks that have been detected in prior investigations. We show that there is strong selection against inbred birds. Only 3 of 44 inbred birds were later identified as parents (6.8%), whereas 2,823 of 10,380 birds that represented a comparable cross section of the data were later seen as reproducing parents (27.2%). Habitat loss and competition with Barred Owls (S. varia) remain primary threats to Northern Spotted Owls. However, given the negative consequences of inbreeding, Spotted Owl populations in Washington with suitable habitat and manageable numbers of Barred Owls may benefit from translocations of individuals from Oregon and California to introduce new genetic variation and reduce future inbreeding events. La endogamia ha sido dif´ıcil de cuantificar en las poblaciones silvestres debido a la falta de informaci ´on sobre los parentescos. Aplicamos y extendimos un marco conceptual recientemente desarrollado para encarar el problema de inferir las tasas de endogamia en Strix occidentalis caurina a trav´es del noroeste del Pac´ıfico, EEUU. Usando los pedigr´ıes provenientes de 14187 individuos, inferimos las tasas de endogamia para 14 tipos de apareamiento entre parientes que producen coeficientes de endogamia de pedigr´ı de F=0.25 o F=0.125. La endogamia fue ma´s com´un en las Cascadas de Washington, donde se estima que 15% de los individuos son endoga´micos. La endogamia fue menor en el oeste de Oreg´on (3.5%) y el norte de California (2.7%), e intermedia en la Pen´ınsula Ol´ımpica de Washington (6.1%). Las estimaciones de la Pen´ınsula Ol´ımpica fueron probablemente subestimadas debido a los peque ˜nos tama ˜nos de muestreo y a la presencia de pocos pedigr´ıes capaces de resolver los eventos de endogamia. La mayor´ıa de la endogamia result ´o de los apareamientos entre hermanos completos o medios hermanos, aunque se identific ´o una alta tasa de endogamia en parejas madre/hijo en la Pen´ınsula Ol´ımpica. La variaci ´on geogra´ fica en las tasas de endogamia puede reflejar disminuciones poblacionales y cuellos de botella que han sido detectados en investigaciones previas. Mostramos que hay una fuerte selecci ´on contra las aves endoga´micas. Solo tres de 44 aves endoga´micas fueron ma´s tarde identificadas como progenitores (6.8%), mientras que 2823 de 10380 aves que representaron una secci ´on transversal comparable de datos fueron vistas ma´s tarde como progenitores reproductivos (27.2%). La p´erdida de ha´bitat y la competencia con Strix varia sigue siendo la principal amenaza para S. o. caurina. Sin embargo, dadas las consecuencias negativas de la endogamia, las poblaciones de S. occidentalis en Washington con ha´bitat adecuado y n´umeros manejables de Strix varia pueden beneficiarse de traslocaciones de individuos de Oreg´on y California para introducir nueva variaci ´on gen´etica y reducir futuros eventos de endogamia

Self-clearance of Mycobacterium tuberculosis infection: implications for lifetime risk and population at-risk of tuberculosis disease.

Background: it is widely assumed that individuals with Mycobacterium tuberculosis (Mtb) infection remain at lifelong risk of tuberculosis (TB) disease. However, there is substantial evidence that self-clearance of Mtb infection can occur. We infer a curve of self-clearance by time since infection and explore its implications for TB epidemiology. Methods and findings: data for self-clearance were inferred using post-mortem and tuberculin-skin-test reversion studies. A cohort model allowing for self-clearance was fitted in a Bayesian framework before estimating the lifetime risk of TB disease and the population infected with Mtb in India, China and Japan in 2019. We estimated that 24.4% (17.8-32.6%, 95% uncertainty interval (UI)) of individuals self-clear within 10 years of infection, and 73.1% (64.6-81.7%) over a lifetime. The lifetime risk of TB disease was 17.0% (10.9-22.5%), compared to 12.6% (10.1-15.0%) assuming lifelong infection. The population at risk of TB disease in India, China and Japan was 35-80% (95% UI) smaller in the self-clearance scenario. Conclusions: the population with a viable Mtb infection may be markedly smaller than generally assumed, with such individuals at greater risk of TB disease. The ability to identify these individuals could dramatically improve the targeting of preventive programmes and inform TB vaccine development, bringing TB elimination within reach of feasibility

The past and future roles of competition and habitat in the range-wide occupancy dynamics of Northern Spotted Owls

Slow ecological processes challenge conservation. Short-term variability can obscure the importance of slower processes that may ultimately determine the state of a system. Furthermore, management actions with slow responses can be hard to justify. One response to slow processes is to explicitly concentrate analysis on state dynamics. Here, we focus on identifying drivers of Northern Spotted Owl (Strix occidentalis caurina) territorial occupancy dynamics across 11 study areas spanning their geographic range and forecasting response to potential management actions. Competition with Barred Owls (Strix varia) has increased Spotted Owl territory extinction probabilities across all study areas and driven recent declines in Spotted Owl populations. Without management intervention, the Northern Spotted Owl subspecies will be extirpated from parts of its current range within decades. In the short term, Barred Owl removal can be effective. Over longer time spans, however, maintaining or improving habitat conditions can help promote the persistence of northern spotted owl populations. In most study areas, habitat effects on expected Northern Spotted Owl territorial occupancy are actually greater than the effects of competition from Barred Owls. This study suggests how intensive management actions (removal of a competitor) with rapid results can complement a slower management action (i.e., promoting forest succession)

Embodied spatial practices and everyday organization: the work of tour guides and their audiences

This article introduces an interactional perspective to the analysis of organizational space. The study is based on the analysis of over 100 hours of video recordings of guided tours undertaken within two sites (an historic house and a world-famous museum), coupled with interviews and field observations. The analysis is informed by ethnomethodology and conversation analysis in order to focus on the everyday organization of these tours, and the lived experience of inhabiting museum spaces. We use an interactional lens to unpack the ‘embodied spatial practices’ critical to the work of tour guides and their audiences, which reveals how the sense and significance of the workspace emerges moment to moment, and in relation to the ongoing work at hand. As a result, for those with an interest in organizational space, the article introduces a novel perspective, and methods, to highlight the dynamic and interactional production of workspaces. Additionally, for those with an interest in practice, the article demonstrates the fundamental import of taking spatial arrangements seriously when analysing the organization of work

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression

Azetidines Kill Multidrug-Resistant <i>Mycobacterium tuberculosis</i> without Detectable Resistance by Blocking Mycolate Assembly

Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10.6 million new cases and 1.4 million deaths in 2021. This global emergency is exacerbated by the emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB; therefore, new drugs and new drug targets are urgently required. From a whole cell phenotypic screen, a series of azetidines derivatives termed BGAz, which elicit potent bactericidal activity with MIC99 values &lt;10 μM against drug-sensitive Mycobacterium tuberculosis and MDR-TB, were identified. These compounds demonstrate no detectable drug resistance. The mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from the existing mycobacterial cell wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as antitubercular chemotherapies. </p

A knowledge translation collaborative to improve the use of therapeutic hypothermia in post-cardiac arrest patients: protocol for a stepped wedge randomized trial

<p>Abstract</p> <p>Background</p> <p>Advances in resuscitation science have dramatically improved survival rates following cardiac arrest. However, about 60% of adults that regain spontaneous circulation die before leaving the hospital. Recently it has been shown that inducing hypothermia in cardiac arrest survivors immediately following their arrival in hospital can dramatically improve both overall survival and neurological outcomes. Despite the strong evidence for its efficacy and the apparent simplicity of this intervention, recent surveys show that therapeutic hypothermia is delivered inconsistently, incompletely, and often with delay.</p> <p>Methods and design</p> <p>This study will evaluate a multi-faceted knowledge translation strategy designed to increase the utilization rate of induced hypothermia in survivors of cardiac arrest across a network of 37 hospitals in Southwestern Ontario, Canada. The study is designed as a stepped wedge randomized trial lasting two years. Individual hospitals will be randomly assigned to four different wedges that will receive the active knowledge translation strategy according to a sequential rollout over a number of time periods. By the end of the study, all hospitals will have received the intervention. The primary aim is to measure the effectiveness of a multifaceted knowledge translation plan involving education, reminders, and audit-feedback for improving the use of induced hypothermia in survivors of cardiac arrest presenting to the emergency department. The primary outcome is the proportion of eligible OHCA patients that are cooled to a body temperature of 32 to 34°C within six hours of arrival in the hospital. Secondary outcomes will include process of care measures and clinical outcomes.</p> <p>Discussion</p> <p>Inducing hypothermia in cardiac arrest survivors immediately following their arrival to hospital has been shown to dramatically improve both overall survival and neurological outcomes. However, this lifesaving treatment is frequently not applied in practice. If this trial is positive, our results will have broad implications by showing that a knowledge translation strategy shared across a collaborative network of hospitals can increase the number of patients that receive this lifesaving intervention in a timely manner.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Trial Identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00683683">NCT00683683</a></p

Range-wide sources of variation in reproductive rates of northern spotted owls

We conducted a range-wide investigation of the dynamics of site-level reproductive rate of northern spotted owls using survey data from 11 study areas across the subspecies geographic range collected during 1993–2018. Our analytical approach accounted for imperfect detection of owl pairs and misclassification of successful reproduction (i.e., at least one young fledged) and contributed further insights into northern spotted owl population ecology and dynamics. Both nondetection and state misclassification were important, especially because factors affecting these sources of error also affected focal ecological parameters. Annual probabilities of site occupancy were greatest at sites with successful reproduction in the previous year and lowest for sites not occupied by a pair in the previous year. Site-specific occupancy transition probabilities declined over time and were negatively affected by barred owl presence. Overall, the site-specific probability of successful reproduction showed substantial year-to-year fluctuations and was similar for occupied sites that did or did not experience successful reproduction the previous year. Site-specific probabilities for successful reproduction were very small for sites that were unoccupied the previous year. Barred owl presence negatively affected the probability of successful reproduction by northern spotted owls in Washington and California, as predicted, but the effect in Oregon was mixed. The proportions of sites occupied by northern spotted owl pairs showed steep, near-monotonic declines over the study period, with all study areas showing the lowest observed levels of occupancy to date. If trends continue it is likely that northern spotted owls will become extirpated throughout large portions of their range in the coming decades