No evidence for persistent natural plague reservoirs in historical and modern Europe.

Caused by Yersinia pestis, plague ravaged the world through three known pandemics: the First or the Justinianic (6th-8th century); the Second (beginning with the Black Death during c.1338-1353 and lasting until the 19th century); and the Third (which became global in 1894). It is debatable whether Y. pestis persisted in European wildlife reservoirs or was repeatedly introduced from outside Europe (as covered by European Union and the British Isles). Here, we analyze environmental data (soil characteristics and climate) from active Chinese plague reservoirs to assess whether such environmental conditions in Europe had ever supported "natural plague reservoirs". We have used new statistical methods which are validated through predicting the presence of modern plague reservoirs in the western United States. We find no support for persistent natural plague reservoirs in either historical or modern Europe. Two factors make Europe unfavorable for long-term plague reservoirs: 1) Soil texture and biochemistry and 2) low rodent diversity. By comparing rodent communities in Europe with those in China and the United States, we conclude that a lack of suitable host species might be the main reason for the absence of plague reservoirs in Europe today. These findings support the hypothesis that long-term plague reservoirs did not exist in Europe and therefore question the importance of wildlife rodent species as the primary plague hosts in Europe.

Assessing the origins of the European Plagues following the Black Death: A synthesis of genomic, historical, and ecological information.

The second plague pandemic started in Europe with the Black Death in 1346 and lasted until the 19th century. Based on ancient DNA studies, there is a scientific disagreement over whether the bacterium, Yersinia pestis, came into Europe once (Hypothesis 1) or repeatedly over the following four centuries (Hypothesis 2). Here, we synthesize the most updated phylogeny together with historical, archeological, evolutionary, and ecological information. On the basis of this holistic view, we conclude that Hypothesis 2 is the most plausible. We also suggest that Y. pestis lineages might have developed attenuated virulence during transmission, which can explain the convergent evolutionary signals, including pla decay, that appeared at the end of the pandemics.

A genomic and historical synthesis of plague in 18th century Eurasia.

Plague continued to afflict Europe for more than five centuries after the Black Death. Yet, by the 17th century, the dynamics of plague had changed, leading to its slow decline in Western Europe over the subsequent 200 y, a period for which only one genome was previously available. Using a multidisciplinary approach, combining genomic and historical data, we assembled Y. pestis genomes from nine individuals covering four Eurasian sites and placed them into an historical context within the established phylogeny. CHE1 (Chechnya, Russia, 18th century) is now the latest Second Plague Pandemic genome and the first non-European sample in the post-Black Death lineage. Its placement in the phylogeny and our synthesis point toward the existence of an extra-European reservoir feeding plague into Western Europe in multiple waves. By considering socioeconomic, ecological, and climatic factors we highlight the importance of a noneurocentric approach for the discussion on Second Plague Pandemic dynamics in Europe.

Historical and genomic data reveal the influencing factors on global transmission velocity of plague during the Third Pandemic.

Quantitative knowledge about which natural and anthropogenic factors influence the global spread of plague remains sparse. We estimated the worldwide spreading velocity of plague during the Third Pandemic, using more than 200 years of extensive human plague case records and genomic data, and analyzed the association of spatiotemporal environmental factors with spreading velocity. Here, we show that two lineages, 2.MED and 1.ORI3, spread significantly faster than others, possibly reflecting differences among strains in transmission mechanisms and virulence. Plague spread fastest in regions with low population density and high proportion of pasture- or forestland, findings that should be taken into account for effective plague monitoring and control. Temperature exhibited a nonlinear, U-shaped association with spread speed, with a minimum around 20 °C, while precipitation showed a positive association. Our results suggest that global warming may accelerate plague spread in warm, tropical regions and that the projected increased precipitation in the Northern Hemisphere may increase plague spread in relevant regions.

The biological index of frailty: A new index for the assessment of frailty in human skeletal remains.

OBJECTIVE: Frailty is the physiological stress that individuals suffer during their life. In past populations, frailty is conventionally assessed through the occurrence of different biomarkers of biological stress. Some efforts have been made to propose indexes that combine all biomarkers. However, these indices have some critical limitations: they cannot be used on incomplete skeletons, do not consider the severity and/or healing of lesions, and assign equal importance to different biomarkers. To address these limitations, we propose a new index to assess frailty in skeletal individuals. MATERIAL AND METHODS: By statistically analyzing a large amount of osteological data available from the Museum of London, and using a Logit model, we were able to define a different weight for each reported biomarker of frailty, based on their importance in increasing the risk of premature death for the individuals. RESULTS: The biological index of frailty (BIF) is the weighted mean of all biomarkers scored on the individuals, according to a different degree of importance assigned to each one. It also considers the severity and healing of the biomarkers when this is relevant to diagnose frailty. We applied BIF on a sample of Monastics and Non-Monastics from medieval England and compared it with the skeletal index of frailty (SFI). DISCUSSION: BIF is the first frailty index that gives a different weight to each skeletal biomarker of stress, considers both severity and healing of the lesions, and can be applied on partial skeletal remains. The comparison with SFI showed that BIF is applicable to a larger number of skeletal individuals, revealing new differences between the Monastic and the Non-Monastic groups.

Genomic blueprint of a relapsing fever pathogen in 15th century Scandinavia.

Louse-borne relapsing fever (LBRF) is known to have killed millions of people over the course of European history and remains a major cause of mortality in parts of the world. Its pathogen, Borrelia recurrentis, shares a common vector with global killers such as typhus and plague and is known for its involvement in devastating historical epidemics such as the Irish potato famine. Here, we describe a European and historical genome of Brecurrentis, recovered from a 15th century skeleton from Oslo. Our distinct European lineage has a discrete genomic makeup, displaying an ancestral oppA-1 gene and gene loss in antigenic variation sites. Our results illustrate the potential of ancient DNA research to elucidate dynamics of reductive evolution in a specialized human pathogen and to uncover aspects of human health usually invisible to the archaeological record.

Human ectoparasites and the spread of plague in Europe during the Second Pandemic.

Plague, caused by the bacterium Yersinia pestis, can spread through human populations by multiple transmission pathways. Today, most human plague cases are bubonic, caused by spillover of infected fleas from rodent epizootics, or pneumonic, caused by inhalation of infectious droplets. However, little is known about the historical spread of plague in Europe during the Second Pandemic (14-19th centuries), including the Black Death, which led to high mortality and recurrent epidemics for hundreds of years. Several studies have suggested that human ectoparasite vectors, such as human fleas (Pulex irritans) or body lice (Pediculus humanus humanus), caused the rapidly spreading epidemics. Here, we describe a compartmental model for plague transmission by a human ectoparasite vector. Using Bayesian inference, we found that this model fits mortality curves from nine outbreaks in Europe better than models for pneumonic or rodent transmission. Our results support that human ectoparasites were primary vectors for plague during the Second Pandemic, including the Black Death (1346-1353), ultimately challenging the assumption that plague in Europe was predominantly spread by rats.

Integrative approach using Yersinia pestis genomes to revisit the historical landscape of plague during the Medieval Period.

Over the last few years, genomic studies on Yersinia pestis, the causative agent of all known plague epidemics, have considerably increased in numbers, spanning a period of about 5,000 y. Nonetheless, questions concerning historical reservoirs and routes of transmission remain open. Here, we present and describe five genomes from the second half of the 14th century and reconstruct the evolutionary history of Y. pestis by reanalyzing previously published genomes and by building a comprehensive phylogeny focused on strains attributed to the Second Plague Pandemic (14th to 18th century). Corroborated by historical and ecological evidence, the presented phylogeny, which includes our Y. pestis genomes, could support the hypothesis of an entry of plague into Western European ports through distinct waves of introduction during the Medieval Period, possibly by means of fur trade routes, as well as the recirculation of plague within the human population via trade routes and human movement.

Autopsy or anatomical dissection: evidence of a craniotomy in a 17th-eighteenth century burial site (Ravenna, Italy).

Surgical procedures undergone in life, autopsies and anatomical preparations can all leave clearly identifiable traces on human skeletal remains. Several studies on skeletons from archeological contexts have identified traces of these practices. However, the distinction between medical/forensic autopsy and anatomical dissections for scientific research can be challenging. We report the case of a middle-aged female skeleton from the cemetery of the church of San Biagio (Ravenna, Italy), dating back to the 17th-19th centuries, that shows signs of a complete craniotomy. In an attempt to clarify the reason for this practice, we analyzed all pathological and non-pathological markers on the skeleton. We carried out anthropological analyses and osteometric measurements to determine the biological profile and the cranial capacity of the individual. Paleopathological investigation and analyses of traumatic injury patterns were carried out using both a morphological and a microscopic approach. While we observed that the craniotomy was performed with a rip saw, we identified perimortem blunt force trauma to the frontal bone and an osteolytic lesion on the inner surface of the frontal bone. No other pathology was recognizable on the skeleton. Our differential diagnosis confidently proved that the craniotomy was due to an autoptsy procedure and was not the result of an anatomical dissection. We believe that, among other possible reasons, failed surgery could likely be the motive behind the ordering of the autopsy.

Body image perception and body composition: assessment of perception inconsistency by a new index.

BACKGROUND: A correct perception of the body image, as defined by comparison with actual anthropometric analyses, is crucial to ensure the best possible nutritional status of each individual. Bioimpedance analysis (BIA) represents a leading technique to assess body composition parameters and, in particular, the fat mass. This study examined the self-perception of body image at various levels of adiposity proposing a new index. METHODS: We investigated 487 young Italian adults (mean age of males: 21.9 ± 2.4 years; mean age of females: 21.0 ± 2.2 years). Each subject could choose, on the Contour Drawing Rating Scale, the silhouette that he/she considered most resembling his/her perceived body image as well as his/her ideal body image. On each subject, we performed anthropometric measurements and determined the values of Fat mass and  %Fat with BIA. A new index, FAIFAT (Feel fat status minus Actual fat status Inconsistency), was developed to evaluate possible fat status perception inconsistencies by BIA. RESULTS: Based on ideal and feel body image comparison, women showed higher dissatisfaction than men and preferred slimmer silhouettes. FAIFAT values indicated that the fat status perception was correct in the majority of the examined individuals and only three subjects showed a serious misperception. CONCLUSIONS: Our findings suggest that FAIFAT is an appropriate index for assessing the perceived fat status from the body image when compared with data obtained by BIA. In a population, the use of this index will allow the correct identification of groups at risk for eating disorders.

COVID-19 and Individual Genetic Susceptibility/Receptivity: Role of ACE1/ACE2 Genes, Immunity, Inflammation and Coagulation. Might the Double X-chromosome in Females Be Protective against SARS-CoV-2 Compared to the Single X-Chromosome in Males?

In December 2019, a novel severe acute respiratory syndrome (SARS) from a new coronavirus (SARS-CoV-2) was recognized in the city of Wuhan, China. Rapidly, it became an epidemic in China and has now spread throughout the world reaching pandemic proportions. High mortality rates characterize SARS-CoV-2 disease (COVID-19), which mainly affects the elderly, causing unrestrained cytokines-storm and subsequent pulmonary shutdown, also suspected micro thromboembolism events. At the present time, no specific and dedicated treatments, nor approved vaccines, are available, though very promising data come from the use of anti-inflammatory, anti-malaria, and anti-coagulant drugs. In addition, it seems that males are more susceptible to SARS-CoV-2 than females, with males 65% more likely to die from the infection than females. Data from the World Health Organization (WHO) and Chinese scientists show that of all cases about 1.7% of women who contract the virus will die compared with 2.8% of men, and data from Hong Kong hospitals state that 32% of male and 15% of female COVID-19 patients required intensive care or died. On the other hand, the long-term fallout of coronavirus may be worse for women than for men due to social and psychosocial reasons. Regardless of sex- or gender-biased data obtained from WHO and those gathered from sometimes controversial scientific journals, some central points should be considered. Firstly, SARS-CoV-2 has a strong interaction with the human ACE2 receptor, which plays an essential role in cell entry together with transmembrane serine protease 2 (TMPRSS2); it is interesting to note that the ACE2 gene lays on the X-chromosome, thus allowing females to be potentially heterozygous and differently assorted compared to men who are definitely hemizygous. Secondly, the higher ACE2 expression rate in females, though controversial, might ascribe them the worst prognosis, in contrast with worldwide epidemiological data. Finally, several genes involved in inflammation are located on the X-chromosome, which also contains high number of immune-related genes responsible for innate and adaptive immune responses to infection. Other genes, out from the RAS-pathway, might directly or indirectly impact on the ACE1/ACE2 balance by influencing its main actors (e.g., ABO locus, SRY, SOX3, ADAM17). Unexpectedly, the higher levels of ACE2 or ACE1/ACE2 rebalancing might improve the outcome of COVID-19 in both sexes by reducing inflammation, thrombosis, and death. Moreover, X-heterozygous females might also activate a mosaic advantage and show more pronounced sex-related differences resulting in a sex dimorphism, further favoring them in counteracting the progression of the SARS-CoV-2 infection.

The Third Plague Pandemic in Europe.

Plague has a long history on the European continent, with evidence of the disease dating back to the Stone Age. Plague epidemics in Europe during the First and Second Pandemics, including the Black Death, are infamous for their widespread mortality and lasting social and economic impact. Yet, Europe still experienced plague outbreaks during the Third Pandemic, which began in China and spread globally at the end of the nineteenth century. The digitization of international records of notifiable diseases, including plague, has enabled us to retrace the introductions of the disease to Europe from the earliest reported cases in 1899, to its disappearance in the 1940s. Using supplemental literature, we summarize the potential sources of plague in Europe and the transmission of the disease, including the role of rats. Finally, we discuss the international efforts aimed at prevention and intervention measures, namely improved hygiene and sanitation, that ultimately led to the disappearance of plague in Europe.

"Bridging the Gap" Everything that Could Have Been Avoided If We Had Applied Gender Medicine, Pharmacogenetics and Personalized Medicine in the Gender-Omics and Sex-Omics Era.

. Gender medicine is the first step of personalized medicine and patient-centred care, an essential development to achieve the standard goal of a holistic approach to patients and diseases. By addressing the interrelation and integration of biological markers (i.e., sex) with indicators of psychological/cultural behaviour (i.e., gender), gender medicine represents the crucial assumption for achieving the personalized health-care required in the third millennium. However, 'sex' and 'gender' are often misused as synonyms, leading to frequent misunderstandings in those who are not deeply involved in the field. Overall, we have to face the evidence that biological, genetic, epigenetic, psycho-social, cultural, and environmental factors mutually interact in defining sex/gender differences, and at the same time in establishing potential unwanted sex/gender disparities. Prioritizing the role of sex/gender in physiological and pathological processes is crucial in terms of efficient prevention, clinical signs' identification, prognosis definition, and therapy optimization. In this regard, the omics-approach has become a powerful tool to identify sex/gender-specific disease markers, with potential benefits also in terms of socio-psychological wellbeing for each individual, and cost-effectiveness for National Healthcare systems. "Being a male or being a female" is indeed important from a health point of view and it is no longer possible to avoid "sex and gender lens" when approaching patients. Accordingly, personalized healthcare must be based on evidence from targeted research studies aimed at understanding how sex and gender influence health across the entire life span. The rapid development of genetic tools in the molecular medicine approaches and their impact in healthcare is an example of highly specialized applications that have moved from specialists to primary care providers (e.g., pharmacogenetic and pharmacogenomic applications in routine medical practice). Gender medicine needs to follow the same path and become an established medical approach. To face the genetic, molecular and pharmacological bases of the existing sex/gender gap by means of omics approaches will pave the way to the discovery and identification of novel drug-targets/therapeutic protocols, personalized laboratory tests and diagnostic procedures (sex/gender-omics). In this scenario, the aim of the present review is not to simply resume the state-of-the-art in the field, rather an opportunity to gain insights into gender medicine, spanning from molecular up to social and psychological stances. The description and critical discussion of some key selected multidisciplinary topics considered as paradigmatic of sex/gender differences and sex/gender inequalities will allow to draft and design strategies useful to fill the existing gap and move forward.

Climate-driven introduction of the Black Death and successive plague reintroductions into Europe.

The Black Death, originating in Asia, arrived in the Mediterranean harbors of Europe in 1347 CE, via the land and sea trade routes of the ancient Silk Road system. This epidemic marked the start of the second plague pandemic, which lasted in Europe until the early 19th century. This pandemic is generally understood as the consequence of a singular introduction of Yersinia pestis, after which the disease established itself in European rodents over four centuries. To locate these putative plague reservoirs, we studied the climate fluctuations that preceded regional plague epidemics, based on a dataset of 7,711 georeferenced historical plague outbreaks and 15 annually resolved tree-ring records from Europe and Asia. We provide evidence for repeated climate-driven reintroductions of the bacterium into European harbors from reservoirs in Asia, with a delay of 15 ± 1 y. Our analysis finds no support for the existence of permanent plague reservoirs in medieval Europe.

Stature estimation from tibia percutaneous length: New equations derived from a Mediterranean population.

Stature is a fundamental anthropometric character to trace the biological profile of a person. In some cases, when dismembered or mutilated bodies are discovered in a forensic context, it is essential to estimate stature from single districts of the body. Nevertheless, to date and worldwide, there are only few population-specific studies on stature estimation from leg length and none of them concerns modern populations in southern Europe. We attempted to fill this gap, focusing on the estimation of stature from the length of the tibia in a Mediterranean population (Italians). We carried out the current study on a sample of 374 Italian university students of both sexes (age range: 19.9-34.4). Both, actual stature and percutaneous length of tibia were measured and new equations were developed for stature estimation. We tested separate regression equations for each sex, as well as an equation for remains, whose sex is unknown. To assess their reliability, the equations were tested on a holdout sample of 30 individuals from the same population. Moreover, results of new specific linear regression equations were compared to others from the literature. We demonstrated that the newly proposed formulae (for males and combined sexes) and the ones by Olivier (for females) provided the most reliable estimations of stature for southern Europeans.

Plague: A Disease Which Changed the Path of Human Civilization.

Plague caused by Yersinia pestis is a zoonotic infection, i.e., it is maintained in wildlife by animal reservoirs and on occasion spills over into human populations, causing outbreaks of different entities. Large epidemics of plague, which have had significant demographic, social, and economic consequences, have been recorded in Western European historical documents since the sixth century. Plague has remained in Europe for over 1400 years, intermittently disappearing, yet it is not clear if there were reservoirs for Y. pestis in Western Europe or if the pathogen was rather reimported on different occasions from Asian reservoirs by human agency. The latter hypothesis thus far seems to be the most plausible one, as it is sustained by both ecological and climatological evidence, helping to interpret the phylogeny of this bacterium.

Yersinia pestis DNA from skeletal remains from the 6(th) century AD reveals insights into Justinianic Plague.

Yersinia pestis, the etiologic agent of the disease plague, has been implicated in three historical pandemics. These include the third pandemic of the 19(th) and 20(th) centuries, during which plague was spread around the world, and the second pandemic of the 14(th)-17(th) centuries, which included the infamous epidemic known as the Black Death. Previous studies have confirmed that Y. pestis caused these two more recent pandemics. However, a highly spirited debate still continues as to whether Y. pestis caused the so-called Justinianic Plague of the 6(th)-8(th) centuries AD. By analyzing ancient DNA in two independent ancient DNA laboratories, we confirmed unambiguously the presence of Y. pestis DNA in human skeletal remains from an Early Medieval cemetery. In addition, we narrowed the phylogenetic position of the responsible strain down to major branch 0 on the Y. pestis phylogeny, specifically between nodes N03 and N05. Our findings confirm that Y. pestis was responsible for the Justinianic Plague, which should end the controversy regarding the etiology of this pandemic. The first genotype of a Y. pestis strain that caused the Late Antique plague provides important information about the history of the plague bacillus and suggests that the first pandemic also originated in Asia, similar to the other two plague pandemics.