Challenges in epidemiological modelling: from socio-virulence dynamics to HIV interventions in MSM populations.

The spread of infectious diseases is one of the biggest challenges that public health faces nowadays. Their control is often not an easy task. Social behaviour plays an important role in disease prevention. However, the complex interplay between social behaviour and transmission dynamics is still not very well understood. This thesis tackles this topic by introducing a dynamic variable representing social behaviour that is coupled with epidemiological compartmental models. Under certain conditions, social behaviour can greatly impact the outcomes of an emerging virulent pathogen and thus it is necessary to explicitly model social behaviour for better understanding of transmission dynamics, and better and more accurate predictions. The Human Immunodeficiency Virus (HIV) is a disease that attacks the immune system of its host. Since its emergence in the 1970s, it remains an epidemic that disproportionately affects gay and bisexual men who have sex with men (GbMSM). While diagnosis and treatment procedures kept improving, it still poses a public health concern. The introduction of Pre-Exposure Prophylaxis (PrEP) as a preventive drug in Canada in 2015 was a crucial step to help with decreasing HIV prevalence. PrEP however doesn't prevent the transmission of bacterial sexually transmitted infections (STIs). Previous studies have found a positive correlation between the increase in PrEP use and the decrease of condom usage. We investigated conditions under which the prevalence of bacterial STIs remains low under a PrEP regimen and we found that population level annual testing is essential for risk mitigation. While PrEP has a great potential in reducing HIV prevalence, its impact might not be as strong as that created by frequent testing. In a final study, we examined different strategies, that are season specific and risk level specific, to derive an optimal strategy that aims to reduce HIV prevalence in Toronto by 2050. Given that higher risk sexual behaviour is more observed during the summer months, we concluded that testing the entire population twice during the summer is the most effective way to get a low HIV prevalence subject to plausible levels of testing and PrEP recruitment

Set-Valued Maps and Their Applications

The serious investigation of set-valued maps began only in the mid 1900s when mathematicians realized that their uses go far beyond a mere generalization of single-valued maps. We explore their fundamental properties and emphasize their continuity. We present extensions of fixed point theorems to the set-valued case and we conclude with an application to Game Theory

Building an innovation culture : a case of pharmaceutical industry in Jordan

The purpose of this research is to support organizations to sustain competitiveness by building an innovation culture and supportive climate which empower employees to provide new valuable creative ideas and achieve better performance. Studies into innovation are generally devoted to studying process innovation and/or new product introduction neglecting organizational culture as a major determinant of continuous innovation. The Innovation Culture Enhancing Model (The ICE Model) and guidelines developed in this research were based upon extensive literature survey and practical feedback. The ICE model was tested over a two-year period in a large pharmaceutical company in Jordan using an action research methodology in an in depth case study obtaining major improvements to the innovative capacity of the company involved. The intervention designed for the company was based upon the ICE model components and thorough culture and climate assessments and interviews with over 638 individuals representing all levels of the company's hierarchy. In the foundation stage, the intervention involved; a flexible structure and strategy devoted to innovation supported by full management commitment. In the culture change stage, the ICE Model Dimensions: (1) Leaders as change agents dimension, (2) Shared work values dimension and (3) Motivation dimension were used to create an innovation culture. Interventions were also introduced to Keys to creativity items: (1) organizational encouragement, (2) supervisory encouragement, (3) work group support, (4) freedom, (5) sufficient resources, (6) and challenging work. The significant change to the culture and climate inside the company assessed using established climate to creativity assessment instruments was associated with improved performance measured using Key Performance Indicators (KPIs), successful achievement in international audit and empowered motivated individuals. Based upon an extensive literature survey and the action research experience, the ICE Model was refined to include two main contexts: (1) an understanding of the national culture (social structure, religion, language, education, political and economic environments), and (2) organizational environment (technological development, economic environment, socio-cultural changes, political and legal environment). This research provided background information about the national culture in the Middle East and its implications on Organizational Development (OD) interventions and MNCs investments. The research also introduced a new approach for OD interventions; named the Change by Values approach in which spiritual values are utilized as motivators to enhance successful application of culture change interventions. The outcomes of this research are particularly valuable to companies involved in mergers/acquisitions or joint ventures, which are likely to face cultural integration difficulties that might place the new endeavour at risk due to cultural differences. The developed ICE model and guidelines are major contributions to the innovation culture literature presenting innovation as a core value and creating innovation as a continuous competitive edge in a changing businesses environment.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The influence of social behaviour on competition between virulent pathogen strains

The final publication is available at Elsevier via https://doi.org/10.1016/j.jtbi.2018.06.028. © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/Infectious disease interventions like contact precautions and vaccination have proven effective in disease control and elimination. The priority given to interventions can depend strongly on how virulent the pathogen is, and interventions may also depend partly for their success on social processes that respond adaptively to disease dynamics. However, mathematical models of competition between pathogen strains with differing natural history profiles typically assume that human behaviour is fixed. Here, our objective is to model the influence of social behaviour on the competition between pathogen strains with differing virulence. We couple a compartmental Susceptible-Infectious-Recovered model for a resident pathogen strain and a mutant strain with higher virulence, with a differential equation of a population where individuals learn to adopt protective behaviour from others according to the prevalence of infection of the two strains and the perceived severity of the respective strains in the population. We perform invasion analysis, time series analysis and phase plane analysis to show that perceived severities of pathogen strains and the efficacy of infection control against them can greatly impact the invasion of more virulent strain. We demonstrate that adaptive social behaviour enables invasion of the mutant strain under plausible epidemiological scenarios, even when the mutant strain has a lower basic reproductive number than the resident strain. Surprisingly, in some situations, increasing the perceived severity of the resident strain can facilitate invasion of the more virulent mutant strain. Our results demonstrate that for certain applications, it may be necessary to include adaptive social behaviour in models of the emergence of virulent pathogens, so that the models can better assist public health efforts to control infectious diseases.Natural Sciences and Engineering Research Council || Discovery Gran

Usefulness of Circulating Tumor DNA in Identifying Somatic Mutations and Tracking Tumor Evolution in Patients With Non-small Cell Lung Cancer

Background The usefulness of circulating tumor DNA (ctDNA) in detecting mutations and monitoring treatment response has not been well studied beyond a few actionable biomarkers in non-small cell lung cancer (NSCLC). Research Question How does the usefulness of ctDNA analysis compare with that of solid tumor biopsy analysis in patients with NSCLC? Methods We retrospectively evaluated 370 adult patients with NSCLC treated at the City of Hope between November 2015 and August 2019 to assess the usefulness of ctDNA in mutation identification, survival, concordance with matched tissue samples in 32 genes, and tumor evolution. Results A total of 1,688 somatic mutations were detected in 473 ctDNA samples from 370 patients with NSCLC. Of the 473 samples, 177 showed at least one actionable mutation with currently available Food and Drug Administration-approved NSCLC therapies. MET and CDK6 amplifications co-occurred with BRAF amplifications (false discovery rate [FDR], \u3c 0.01), and gene-level mutations were mutually exclusive in KRAS and EGFR (FDR, 0.0009). Low cumulative percent ctDNA levels were associated with longer progression-free survival (hazard ratio [HR], 0.56; 95% CI, 0.37-0.85; P = .006). Overall survival was shorter in patients harboring BRAF mutations (HR, 2.35; 95% CI, 1.24-4.6; P = .009), PIK3CA mutations (HR, 2.77; 95% CI, 1.56-4.9; P \u3c .001) and KRAS mutations (HR, 2.32; 95% CI, 1.30-4.1; P = .004). Gene-level concordance was 93.8%, whereas the positive concordance rate was 41.6%. More mutations in targetable genes were found in ctDNA than in tissue biopsy samples. Treatment response and tumor evolution over time were detected in repeated ctDNA samples. Interpretation Although ctDNA analysis exhibited similar usefulness to tissue biopsy analysis, more mutations in targetable genes were missed in tissue biopsy analyses. Therefore, the evaluation of ctDNA in conjunction with tissue biopsy samples may help to detect additional targetable mutations to improve clinical outcomes in advanced NSCLC

Predicting Survival of NSCLC Patients Treated with Immune Checkpoint Inhibitors: Impact and Timing of Immune-related Adverse Events and Prior Tyrosine Kinase Inhibitor Therapy

Introduction: Immune checkpoint inhibitors (ICIs) produce a broad spectrum of immune-related adverse events (irAEs) affecting various organ systems. While ICIs are established as a therapeutic option in non-small cell lung cancer (NSCLC) treatment, most patients receiving ICI relapse. Additionally, the role of ICIs on survival in patients receiving prior targeted tyrosine kinase inhibitor (TKI) therapy has not been well-defined. Objective: To investigate the impact of irAEs, the relative time of occurrence, and prior TKI therapy to predict clinical outcomes in NSCLC patients treated with ICIs. Methods: A single center retrospective cohort study identified 354 adult patients with NSCLC receiving ICI therapy between 2014 and 2018. Survival analysis utilized overall survival (OS) and real-world progression free survival (rwPFS) outcomes. Model performance matrices for predicting 1-year OS and 6-month rwPFS using linear regression baseline, optimal, and machine learning modeling approaches. Results: Patients experiencing an irAE were found to have a significantly longer OS and rwPFS compared to patients who did not (median OS 25.1 vs. 11.1 months; hazard ratio [HR] 0.51, confidence interval [CI] 0.39- 0.68, P-value \u3c0.001, median rwPFS 5.7 months vs. 2.3; HR 0.52, CI 0.41- 0.66, P-value \u3c0.001, respectively). Patients who received TKI therapy before initiation of ICI experienced significantly shorter OS than patients without prior TKI therapy (median OS 7.6 months vs. 18.5 months; P-value \u3c 0.01). After adjusting for other variables, irAEs and prior TKI therapy significantly impacted OS and rwPFS. Lastly, the performances of models implementing logistic regression and machine learning approaches were comparable in predicting 1-year OS and 6-month rwPFS. Conclusion: The occurrence of irAEs, the timing of the events, and prior TKI therapy were significant predictors of survival in NSCLC patients on ICI therapy. Therefore, our study supports future prospective studies to investigate the impact of irAEs, and sequence of therapy on the survival of NSCLC patients taking ICIs

Juvenile Swine Surgical Alveolar Cleft Model to Test Novel Autologous Stem Cell Therapies

Reconstruction of craniofacial congenital bone defects has historically relied on autologous bone grafts. Engineered bone using mesenchymal stem cells from the umbilical cord on electrospun nanomicrofiber scaffolds offers an alternative to current treatments. This preclinical study presents the development of a juvenile swine model with a surgically created maxillary cleft defect for future testing of tissue-engineered implants for bone generation. Five-week-old pigs (n=6) underwent surgically created maxillary (alveolar) defects to determine critical-sized defect and the quality of treatment outcomes with rib, iliac crest cancellous bone, and tissue-engineered scaffolds. Pigs were sacrificed at 1 month. Computed tomography scans were obtained at days 0 and 30, at the time of euthanasia. Histological evaluation was performed on newly formed bone within the surgical defect. A 1 cm surgically created defect healed with no treatment, the 2 cm defect did not heal. A subsequently created 1.7 cm defect, physiologically similar to a congenitally occurring alveolar cleft in humans, from the central incisor to the canine, similarly did not heal. Rib graft treatment did not incorporate into adjacent normal bone; cancellous bone and the tissue-engineered graft healed the critical-sized defect. This work establishes a juvenile swine alveolar cleft model with critical-sized defect approaching 1.7 cm. Both cancellous bone and tissue engineered graft generated bridging bone formation in the surgically created alveolar cleft defect

Precision Medicine and Actionable Alterations in Lung Cancer: A Single Institution Experience

OBJECTIVES: Oncology has become more reliant on new testing methods and a greater use of electronic medical records, which provide a plethora of information available to physicians and researchers. However, to take advantage of vital clinical and research data for precision medicine, we must initially make an effort to create an infrastructure for the collection, storage, and utilization of this information with uniquely designed disease-specific registries that could support the collection of a large number of patients. MATERIALS AND METHODS: In this study, we perform an in-depth analysis of a series of lung adenocarcinoma patients (n = 415) with genomic and clinical data in a recently created thoracic patient registry. RESULTS: Of the 415 patients with lung adenocarcinoma, 59% (n = 245) were female; the median age was 64 (range, 22-92) years with a median OS of 33.29 months (95% CI, 29.77-39.48). The most common actionable alterations were identified in EGFR (n = 177/415 [42.7%]), ALK (n = 28/377 [7.4%]), and BRAF V600E (n = 7/288 [2.4%]). There was also a discernible difference in survival for 222 patients, who had an actionable alteration, with a median OS of 39.8 months as compared to 193 wild-type patients with a median OS of 26.0 months (P CONCLUSION: The use of patient registries, focused genomic panels and the appropriate use of clinical guidelines in community and academic settings may influence cohort selection for clinical trials and improve survival outcomes

Evaluation of Somatic Mutations in Solid Metastatic Pan-Cancer Patients

Metastasis continues to be the primary cause of all cancer-related deaths despite the recent advancements in cancer treatments. To evaluate the role of mutations in overall survival (OS) and treatment outcomes, we analyzed 957 metastatic patients with seven major cancer types who had available molecular testing results with a FoundationOne CDx® panel. The most prevalent genes with somatic mutations were TP53, KRAS, APC, and LRP1B. In this analysis, these genes had mutation frequencies higher than in publicly available datasets. We identified that the somatic mutations were seven mutually exclusive gene pairs and an additional fifty-two co-occurring gene pairs. Mutations in the mutually exclusive gene pair APC and CDKN2A showed an opposite effect on the overall survival. However, patients with CDKN2A mutations showed significantly shorter OS (HR: 1.72, 95% CI: 1.34–2.21, p \u3c 0.001) after adjusting for cancer type, age at diagnosis, and sex. Five-year post metastatic diagnosis survival analysis showed a significant improvement in OS (median survival 28 and 43 months in pre-2015 and post-2015 metastatic diagnosis, respectively, p = 0.00021) based on the year of metastatic diagnosis. Although the use of targeted therapies after metastatic diagnosis prolonged OS, the benefit was not statistically significant. However, longer five-year progression-free survival (PFS) was significantly associated with targeted therapy use (median 10.9 months (CI: 9.7–11.9 months) compared to 9.1 months (CI: 8.1–10.1 months) for non-targeted therapy, respectively, p = 0.0029). Our results provide a clinically relevant overview of the complex molecular landscape and survival mechanisms in metastatic solid cancers

A Novel Pilot Study Using Spatial Frequency Domain Imaging to Assess Oxygenation of Perforator Flaps During Reconstructive Breast Surgery

INTRODUCTION: Although various methods exist for monitoring flaps during reconstructive surgery, surgeons primarily rely on assessment of clinical judgment. Early detection of vascular complications improves rate of flap salvage. Spatial frequency domain imaging (SFDI) is a promising new technology that provides oxygenation images over a large field of view. The goal of this clinical pilot study is to use SFDI in perforator flap breast reconstruction. METHODS: Three women undergoing unilateral breast reconstruction after mastectomy were enrolled for our study. The SFDI system was deployed in the operating room, and images acquired over the course of the operation. Time points included images of each hemiabdominal skin flap before elevation, the selected flap after perforator dissection, and after microsurgical transfer. RESULTS: Spatial frequency domain imaging was able to measure tissue oxy-hemoglobin concentration (ctO(2)Hb), tissue deoxyhemoglobin concentration, and tissue oxygen saturation (stO(2)). Images were created for each metric to monitor flap status and the results quantified throughout the various time points of the procedure. For 2 of 3 patients, the chosen flap had a higher ctO(2)Hb and stO(2). For 1 patient, the chosen flap had lower ctO(2)Hb and stO(2). There were no perfusion deficits observed based on SFDI and clinical follow-up. CONCLUSIONS: The results of our initial human pilot study suggest that SFDI has the potential to provide intraoperative oxygenation images in real-time during surgery. With the use of this technology, surgeons can obtain tissue oxygenation and hemoglobin concentration maps to assist in intraoperative planning; this can potentially prevent complications and improve clinical outcome