Modelling Evolution of Virulence in Populations with a Distributed Parasite Load

Modelling evolution of virulence in host-parasite systems is an actively developing area of research with ever-growing literature. However, most of the existing studies overlook the fact that individuals within an infected population may have a variable infection load, i.e. infected populations are naturally structured with respect to the parasite burden. Empirical data suggests that the mortality and infectiousness of individuals can strongly depend on their infection load; moreover, the shape of distribution of infection load may vary on ecological and evolutionary time scales. Here we show that distributed infection load may have important consequences for the eventual evolution of virulence as compared to a similar model without structuring. Mathematically, we consider an SI model, where the dynamics of the infected subpopulation is described by a von Förster-type model, in which the infection load plays the role of age. We implement the adaptive dynamics framework to predict evolutionary outcomes in this model. We demonstrate that for simple trade-off functions between virulence, disease transmission and parasite growth rates, multiple evolutionary attractors are possible. Interestingly, unlike in the case of unstructured models, achieving an evolutionary stable strategy becomes possible even for a variation of a single ecological parameter (the parasite growth rate) and keeping the other parameters constant. We conclude that evolution in disease-structured populations is strongly mediated by alterations in the overall shape of the parasite load distribution

Investigating Cutaneous Squamous Cell Carcinoma in vitro and in vivo: Novel 3D Tools and Animal Models

Cutaneous Squamous Cell Carcinoma (cSCC) represents the second most common type of skin cancer, which incidence is continuously increasing worldwide. Given its high frequency, cSCC represents a major public health problem. Therefore, to provide the best patients' care, it is necessary having a detailed understanding of the molecular processes underlying cSCC development, progression, and invasion. Extensive efforts have been made in developing new models allowing to study the molecular pathogenesis of solid tumors, including cSCC tumors. Traditionally, in vitro studies were performed with cells grown in a two-dimensional context, which, however, does not represent the complexity of tumor in vivo. In the recent years, new in vitro models have been developed aiming to mimic the three-dimensionality (3D) of the tumor, allowing the evaluation of tumor cell-cell and tumor-microenvironment interaction in an in vivo-like setting. These models include spheroids, organotypic cultures, skin reconstructs and organoids. Although 3D models demonstrate high potential to enhance the overall knowledge in cancer research, they lack systemic components which may be solved only by using animal models. Zebrafish is emerging as an alternative xenotransplant model in cancer research, offering a high-throughput approach for drug screening and real-time in vivo imaging to study cell invasion. Moreover, several categories of mouse models were developed for pre-clinical purpose, including xeno- and syngeneic transplantation models, autochthonous models of chemically or UV-induced skin squamous carcinogenesis, and genetically engineered mouse models (GEMMs) of cSCC. These models have been instrumental in examining the molecular mechanisms of cSCC and drug response in an in vivo setting. The present review proposes an overview of in vitro, particularly 3D, and in vivo models and their application in cutaneous SCC research

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Mathematical Modelling of Evolution in Complex Biological Systems

Modelling biological evolution is a growing area of research with different approaches used with ever-growing applications, proved to be beneficial in various real-world applications such as engineering, economics, biology, machine learning, optimal control. However, many aspects of modelling evolution remain understudied, especially concerning the situation where the life history trait/behaviour is described by a set of functions whose shape is unknown and/or the underlying system is highly complex, for example, infinite-dimensional. This thesis is comprised of two main parts, each of which investigates a different mathematical approach to reveal behaviours and life-history traits that emerged as a result of long-term evolution.Here, we attempt to formalise Darwin’s fundamental ideas of survival of the fittest to develop a new framework to obtain evolutionarily optimal life-history traits/behavioural patterns based on the reconstruction of evolutionary fitness using underlying equations for population dynamics, applicable to Hilbert spaces with infinitely high dimensional spaces for life-history traits. This inspired the novel method, based on the principles of evolution, of stochastic global optimisation in high or even infinite-dimensional Hilbert spaces, named Survival of the Fittest Algorithm (SoFA). We test the novel algorithm on a phenomenon of particular interest, the mass synchronised diel vertical migration (DVM) of zooplankton, whose fitness is highly dependent on the trajectories of these movements. Using this ecologically relevant case study, we demonstrate that for maximising fitness in high-dimensional spaces, our proposed novel evolutionary algorithm, SoFA, provides better performances compared to other stochastic global optimisation algorithms.We then apply current game-theoretical approaches to evolutionary optimisation to various complex models. Among many insightful results are the following. Considering an SI model with the infected subpopulation described by a von Förster-type model, in which the infection load plays the role of age. We demonstrate that in this infinite-dimensional system, for simple trade-off functions between virulence, disease transmission and parasite growth rates, multiple evolutionary attractors are possible. A result not observed in the case of unstructured models, indicating the benefits of additional complexity within modelling pathogens. Furthermore, theoretically exploring the co-evolution of life-history traits in a generic host-parasite-hyperparasite system, we find that in the presence of hyperparasites, the evolutionarily optimal pathogen virulence generally shifts towards more virulent strains. However, the use of hyperparasites in biocontrol is still justifiable since overall host mortality decreases. An intriguing possible outcome of the evolution of the hyperparasite can be its evolutionary suicide. The presented results help warrant biocontrol agents and programs in pathogen management and provide a better understanding of pathogenic infections.</div

A review of next generation sequencing technologies used in the evaluation of the skin microbiome: what a time to be alive

The role of the microbiome in healthy and disease states of the human body is progressively being found to extend beyond the gastrointestinal tract and into other organ systems such as the skin. Researching the microbiome thus has become paramount to understanding additional physiological and pathophysiological mechanisms that may be at play between microbes and their hosts. Cell cultures have traditionally been used to study the microbiome, but in our current day and age, advanced metagenomic techniques - such as 16S rRNA amplicon sequencing and whole metagenomic shotgun sequencing - are better able to classify the microorganisms making up the microbiome. Utilizing metagenomics alone, however, does not allow for the study of the more complex effects of the microbiome, such as changes in gene expression and metabolic byproducts. Thus, incorporation of other modalities such as metatranscriptomics, metaproteomics, and metabolomics are needed to further elucidate the extensive intricacies of the skin microbiome

Clinical utility of daylight photodynamic therapy in the treatment of actinic keratosis – a review of the literature

Actinic keratosis (AK) is an early in situ squamous cell carcinoma that results from UV light exposure and has the potential to evolve into invasive tumor. Therefore, it is crucial that AKs are monitored and treated appropriately. Photodynamic therapy (PDT) is a treatment option that is minimally invasive and leaves patients with cosmetically superior results. However, disadvantages of PDT include pain and lengthy clinic visits. Accordingly, there has been much interest in the use of daylight photodynamic therapy (daylight-PDT) as a more convenient and less painful alternative to conventional photodynamic therapy (c-PDT). Current evidence shows that daylight-PDT is noninferior to c-PDT in the short and long term. Patients reported decreased pain with daylight-PDT and were more satisfied with the procedure (P&lt;0.001). Current evidence suggests that 2 hrs of daylight exposure was sufficient for treatment, and its efficacy does not appear to be limited by weather conditions. Given the decreased intensity of treatment, daylight-PDT is better for mild disease, as it is less effective in moderate-to-thick AKs. Though further studies are still needed to refine the technique, daylight-PDT is a potential alternative to c-PDT for thin-to-moderate AKs and should be offered to patients with lower pain tolerance or busy schedules

Prospective Placebo-Controlled Assessment of Spore-Based Probiotic Supplementation on Sebum Production, Skin Barrier Function, and Acne

Probiotic supplementation has been shown to modulate the gut-skin axis. The goal of this study was to investigate whether oral spore-based probiotic ingestion modulates the gut microbiome, plasma short-chain fatty acids (SCFAs), and skin biophysical properties. This was a single-blinded, 8-week study (NCT03605108) in which 25 participants, 7 with noncystic acne, were assigned to take placebo capsules for the first 4 weeks, followed by 4 weeks of probiotic supplementation. Blood and stool collection, facial photography, sebum production, transepidermal water loss (TEWL), skin hydration measurements, and acne assessments were performed at baseline, 4, and 8 weeks. Probiotic supplementation resulted in a decreasing trend for the facial sebum excretion rate and increased TEWL overall. Subanalysis of the participants with acne showed improvement in total, noninflammatory, and inflammatory lesion counts, along with improvements in markers of gut permeability. The gut microbiome of the nonacne population had an increase in the relative abundance of Akkermansia, while the subpopulation of those with acne had an increase in the relative abundance of Lachnospiraceae and Ruminococcus gnavus. Probiotic supplementation augmented the circulating acetate/propionate ratio. There is preliminary evidence for the use of spore-based probiotic supplementation to shift the gut microbiome and augment short-chain fatty acids in those with and without acne. Further spore-based supplementation studies in those with noncystic acne are warranted

The Skin and Gut Microbiome and Its Role in Common Dermatologic Conditions

Microorganisms inhabit various areas of the body, including the gut and skin, and are important in maintaining homeostasis. Changes to the normal microflora due to genetic or environmental factors can contribute to the development of various disease states. In this review, we will discuss the relationship between the gut and skin microbiome and various dermatological diseases including acne, psoriasis, rosacea, and atopic dermatitis. In addition, we will discuss the impact of treatment on the microbiome and the role of probiotics

The Skin and Gut Microbiome and Its Role in Common Dermatologic Conditions

Microorganisms inhabit various areas of the body, including the gut and skin, and are important in maintaining homeostasis. Changes to the normal microflora due to genetic or environmental factors can contribute to the development of various disease states. In this review, we will discuss the relationship between the gut and skin microbiome and various dermatological diseases including acne, psoriasis, rosacea, and atopic dermatitis. In addition, we will discuss the impact of treatment on the microbiome and the role of probiotics