BackgroundPlague is a zoonotic disease that, despite affecting humans for more than 5000 years, has historically been the subject of limited drug development activity. Drugs that are currently recommended in treatment guidelines have been approved based on animal studies alone–no pivotal clinical trials in humans have yet been completed. As a result of the sparse clinical research attention received, there are a number of methodological challenges that need to be addressed in order to facilitate the collection of clinical trial data that can meaningfully inform clinicians and policy-makers. One such challenge is the identification of clinically-relevant endpoints, which are informed by understanding the clinical characterisation of the disease–how it presents and evolves over time, and important patient outcomes, and how these can be modified by treatment.Methodology/Principal findingsThis systematic review aims to summarise the clinical profile of 1343 patients with bubonic plague described in 87 publications, identified by searching bibliographic databases for studies that meet pre-defined eligibility criteria. The majority of studies were individual case reports. A diverse group of signs and symptoms were reported at baseline and post-baseline timepoints–the most common of which was presence of a bubo, for which limited descriptive and longitudinal information was available. Death occurred in 15% of patients; although this varied from an average 10% in high-income countries to an average 17% in low- and middle-income countries. The median time to death was 1 day, ranging from 0 to 16 days.Conclusions/SignificanceThis systematic review elucidates the restrictions that limited disease characterisation places on clinical trials for infectious diseases such as plague, which not only impacts the definition of trial endpoints but has the knock-on effect of challenging the interpretation of a trial’s results. For this reason and despite interventional trials for plague having taken place, questions around optimal treatment for plague persist.

Yersinia pestis has spilled over from wild rodent reservoirs to commensal rodents and humans causing three historically recorded pandemics. Depletion in the copy number of the plasmid-encoded virulence gene pla occurred in later-dated strains of the first and second pandemics, yet the biological relevance of the pla deletion has been difficult to test. We identified modern Y. pestis strains that independently acquired the same pla depletion as ancient strains, and herein show that excision of pla from the multi-copy pPCP1 plasmid is accompanied by the integration of a separate full pPCP1 harboring pla into the single-copy pCD1 plasmid, reducing pla dosage. Moreover, we demonstrate that this depletion decreases mortality of mice in models of bubonic plague, but not in the pneumonic and septicemic forms of the disease. We hypothesize that pla depletion may have been selectively advantageous in bubonic plague due to rodent fragmentation following pandemic-induced mortality., , , # Attenuation of virulence in Yersinia pestis across three plague pandemics

https://doi.org/10.5061/dryad.xksn02vs1

Description of the data and file structure

Supplementary figures have been uploaded as individual .PDF files and their figure captions are listed below. Data files have been uploaded within a single excel file, descriptions/titles for each table are listed below. The filtered multiple sequence alignment of 317 Y. pestis samples used to create Figure 1 and Fig. S5 and its description are also listed below. For detailed methodology please refer to the materials and methods section of the manuscript.Â

Figures were made using R-studio, Geneious, and BioRender, and Mummerplot. Edits were made in Adobe Illustrator.Â

Files and variables

File: raw_chromosome.snps.filter5.aln

Description: Filtered multiple sequence alignment of 317 Y. pestis samples. Alignment file for a maximum likelihood phylogenetic analysi...,

The Black Death was a pandemic that spread through Africa, Asia, and Europe. It was caused by a zoonotic disease known as the bubonic plague. This disease is transmitted by the bacterium Yersinia pestis. In England, the Black Death was an unprecedented catastrophic event dated between the years AD 1348-1350. There are multiple debates in relation to the exact mortality of the plague. However, it was estimated to have been between 30% and 60% of the population. Although traditionally it was considered that the plague had started a period of crisis, further studies indicate that the outbreak was part of a longer period of hardship that started in the 12th century. More recent studies have tackled analysing the period leading to the Black Death. However, these studies have focused exclusively on individuals living in London.This investigation aimed to evaluate childhood health in the period leading to the Black Death and its possible influence on the outbreak within and outside London to assess whether population human health was failing before the pandemic. The study sample comprised primary and secondary data from individuals from five sites outside of London (n=1341) and five sites from the London region (n=724).Individuals were examined for multiple indicators of physiological stress (cribra orbitalia, DEH), dietary indicators (vitamin C and D deficiency, folic acid), infections related to immunosuppression (tuberculosis), and estimates of disrupted growth and development (puberty stage estimation, VNC dimensions, and long bone osteometrics).Results showed evidence of stress during the late pre-Black Death period. However, when compared to the early pre- and post-Black Death periods, few statistically significant differences were found. The London region showed a significant decline in health during the Black Death period which represented not only the catastrophic outbreak but also a decline in health in the period immediately before the pandemic. This decline was followed by an improvement in health, especially for men, which reflected an increase in access to resources and higher wages after the plague. Changes in the health of females were less clear. Comparisons between regions showed different patterns, especially between males and females.These differences show the variability existing in the extra-London region concerning how the plague developed and affected rural populations. This study highlights the importance of studying health status not only after but also before a pandemic, as well as analysing regions outside London to create a more comprehensive image of health in medieval England.

Taxonomy presents itself as the critical basis of any modern scientific decision-making approach in the living world, and therefore accurate classifications have to be sought. Due to ongoing species naming debates, here we would like to facilitate a discussion on the methods and validity used for taxonomic claims and their influence on conservation, ecology, and management for squirrels in the western world as a wider example. Following the established epigenetic approach, we examine the rodent genus Tamiasciurus. We include in our assessment all relevant species-interfering characteristics and present one new perspective, ecological niches. The ecological niche is essential for explaining the species’ behavior patterns and their discrepancies among the congeners, adding insights into phylogenesis. We add the usage of mapping software such as geographic information systems (ArcGIS, Open QGIS) for this genus, as well as best-available open access data and the statistical aid from R. Misclassifications in the taxonomy are known to lead to conservation failures on a continental and societal scale, in part caused by a lack of knowledge by the public and the miscommunication between scientists and the public. As one possible solution, here we suggest a reclassification for Mearns’s squirrel (Tamiasciurus mearnsi) and a description update for the entire Tamiasciurus genus to improve conservation success. Additional solutions are presented to simplify classification with reduced errors and confusion in the animal kingdom. A larger future effort of this style is sought to greatly decrease marginalization, to improve the current lack of research priority and “laissez-faire” attitudes on environmental issues for a better relationship between humans and the biotic world. In conclusion we present important topics and yet unaddressed problems, such as how the rodent’s marginalization influences the pandemic disease transmission to humans (e.g. Covid-19, rabies, and bubonic plague), appropriately assigned budgets for their conservation, and the data transparency in a continuously accelerating climate-changing world.