A pesquisa Letalidade da ação policial e teoria interacional: análise integrada do sistema paulista de segurança pública visa dimensionar os fatores associados a letalidade policial. Dada a complexidade da ação policial, que envolve aspectos criminais, sociais e institucionais, a pesquisa propõe a formulação de um modelo teórico penológico que unifique diferentes tradições das Ciências Sociais. O modelo teórico interacional, adotado na tese, integra em uma dimensão analítica as premissas presentes nas teorias racionalista, contextual, institucional e ecológica. Tal estratégica metodológica é necessária, porque os modelos paradigmáticos selecionam um único parâmetro analítico para correlacionar com a ação policial e essa simplificação do comportamento policial não encontra suporte na realidade. Nesse sentido, encontrar uma alternativa as preposições teóricas clássicas foi o principal objetivo desse trabalho. Como estratégia de comprovação empírica do modelo teórico interacional foram utilizadas técnicas de regressão multivariadas, que permitem o teste simultâneo de validade das hipóteses alternativas e a verificação das interações entre os modelos teóricos e as variáveis independentes. A base empírica foi coletada junto a Comissão de Letalidade Policial da Secretaria de Segurança Pública do Estado de São Paulo. A amostra é de 1.111 casos de letalidade de não-policias registradas no Estado, entre 2001 e 2003 / The objective of the research Lethality of police action and interaction theory: integrated analysis of São Paulo public security system is to understand factors connected with police lethality. As police action is a complex issue, with criminal, social and institutional aspects, the study aims to formulate a penal theoretical model able to unify different traditions of Social Sciences. The interaction theoretical model adopted in the thesis integrates in an analytical dimension the premises presented in the rational, contextual, institutional and ecological thesis. This methodological strategy is necessary because the traditional models select only one parameter to police action. This simplification of police behavior does not find basis in social reality. The main proposal of this work was to find as alternative to classical theory propositions. As empiric form to check strategy of interaction theory model, the author used multiple regression techniques that permit simultaneous test of alternative hypothesis validation and the verification of interaction between theoretical models and independent variables. The empiric basis was the São Paulo State Public Security Secretary of Police Lethality Committee with 1.111 lethality non-policeman cases in the State in 2001-2003

Philosophiae Doctor - PhD / African medicinal plants are commonly used throughout Africa to treat a variety of ailments including wounds and ulcers, cough and chest complaints, gingivitis, fever and gonorrhoea, indication all related to infection and inflammation. In screening several plant species from an inventory of common medicinal plants from both South and West Africa for diverse medicinal purposes, 6 plants were selected because of their interesting and useful ethnomedicinal values. / South Africa

Background: Despite multi-modality therapy, the majority of patients with metastatic or recurrent Ewing sarcoma (ES), the second most common pediatric bone malignancy, will die of their disease. ES tumors express aberrantly activated ETS transcription factors through translocations that fuse the EWS gene to ETS family genes FLI1 or ERG. The aberrant activation of ETS transcription factors promotes malignant transformation and proliferation. While, FLI1 or ERG cannot be readily targeted, there is an opportunity to deploy functional genomics screens, to develop novel therapeutic approaches by identifying targetable liabilities in EWS/FLI1 dependent tumors. Materials and Methods: We performed a near whole-genome pooled shRNA screen in a panel of five EWS/FLI1 dependent Ewing sarcoma cell lines and one EWS/ERG cell line to identify essential genes. Essential genes were defined as those genes whose loss resulted in reduced viability selectively in ES cells compared to non-Ewing cancer cell lines. Essential hits were subsequently validated with genomic knockdown and chemical inhibition in vitro, followed by validation of the on-target effect of chemical inhibition. Next, we determined the in vivo effects of small-molecule inhibition on survival and tumor growth in NOD scid gamma (NSG) mice with established subcutaneous ES xenografts. Results: Top hits in our screen that could be readily targeted by small-molecule inhibitors, and thus have potential for rapid clinical validation, were selected for further investigation. These hits included IKBKE, CCND1 and CDK4. IKBKΕ, a non-canonical IKK with an oncogenic role in breast cancer, was one of the top kinase hits in the screen. IKBKΕ shares significant homology to TBK1, another non-canonical IKK that is essential in k-RAS dependent lung cancer. We validated IKBKE through small-molecule inhibition of IKBKE/TBK1 and shRNA based knockdown. Ewing sarcoma cell lines are sensitive to low micromolar concentrations of two IKBKE/TBK1 inhibitors (CYT387 and MRT67307). Additionally, in a panel of ES cell lines, knockdown of IKBKE resulted in decreased growth and impaired colony formation. These observations, paired with impairment of NF-κB nuclear localization following CYT387 treatment suggests that non-canonical IKK mediated signaling may be essential in Ewing sarcoma. We further validated these results through inhibition of IKBKE/TBK1 in in vivo xenograft models treated with 100 mg/kg/day of CYT387. Treatment over the course of twenty-nine days resulted in a significant increase in survival (p-value = 0.0231) and a significant decrease (p-value = 0.036) in tumor size after fifteen days of treatment. CDK4 and CCND1 are highly expressed in Ewing sarcoma as compared to other tumor types. shRNA mediated knockdown of CDK4 and CCND1 resulted in impaired viability and anchorage independent growth. Furthermore, treatment of Ewing sarcoma cell lines with a highly selective CDK4/6 inhibitor, LEE011, resulted in decreased viability (IC50 range of 0.26-18.06 μM), potent G1 arrest in six of eight EWS/FLI1 containing Ewing sarcoma lines tested and apoptosis in a panel of four highly sensitive lines. Administration of 75 mg/kg/day and 250 mg/kg/day of LEE011 in NSG mice with Ewing xenografts resulted in significant impairment of tumor growth, (p-value <0.001 for both treatment arms), as compared to vehicle control. Conclusions: These studies suggest a role for the targeting of IKBKE and CDK 4/6 in Ewing sarcoma, findings with immediate clinical relevance for patients with this malignancy, because small-molecule inhibitors of these proteins have already entered clinical trial for other disease indications.

Introduction : Selon la publication conjointe par l’Organisation Mondiale de la Santé (OMS) et la Banque Mondiale du rapport mondial sur la prévention des traumatismes chaque année les accidents de la route sont responsables de plus de 1,2 million de morts dans le monde. 90% de ces décès surviennent dans les pays à revenu faible ou intermédiaire. Les accidents de la route concernent toutes les tranches d’âge, mais touchent plus particulièrement les jeunes actifs. La lutte contre ce fléau se heurte à la qualité des données sur les accidents de la route recueillies et rapportées, par le défaut de performance ou d’efficacité des outils de collecte des données existants et la non-représentativité des populations d’étude. Face à l’augmentation grandissante des accidents de la circulation dans les pays en développement et particulièrement dans notre pays, le Mali, et l’absence notoire d’un système de collecte de données fiable et extrapolable à la population générale, nous avons mis en en place un projet de recherche. Objectif : Etait de caractériser les accidents corporels de la route enregistrés dans les structures de santé et dans tous les commissariats de police du District de Bamako afin de proposer un système d’information efficace et durable permettant de doter le Mali d’un système de surveillance opérationnel et pertinent, à même d’aider à la prise de décision et aux actions opérationnelles de prévention et de prise en charge des accidents de la route favorisant ainsi la création d’un observatoire national de la sécurité routière basé sur la remontée et le codage des procès-verbaux. Méthode : A partir d’un appariement des données accidentelles corporelles de la route des structures de santé et de la police. Nous avons procédé à une estimation du nombre d’accidents par la méthode de capture-recapture sur une période de quatre mois (de Janvier à Avril) et assuré une surveillance épidémiologique sur 12 mois (de janvier à Décembre 2012) ne portant que sur les données collectées à la police. Résultats : L’estimation globale des accidentés a été nettement supérieur au dénombrement des 2 sources soit 8518 (8047-8990) victimes, contre 1432 pour la police et 3586 pour la santé. Nous pouvons conclure que la capture-recapture est une méthode sensible d’estimation de l’exhaustivité du nombre d’accidents de la route applicable dans les pays à revenu faible. Par contre avec la mortalité, cette sous-estimation diminue soit 99 versus 57 pour la police et 54 pour la santé. L’étude de la surveillance des AVP de Janvier à décembre 2012 a enregistré 2512 accidents avec 3905 victimes dont 407 blessés graves et 142 tués, impliquant 4434 véhicules. L’analyse des facteurs prédictifs de la gravité a révélé une vulnérabilité des moins de 15 ans OR=1,10(1,05-1,15) et des 60 ans et plus OR=1,15(1,06-1,25). Parmi les causes des accidents, l’imprudence du piéton a été le facteur le plus associé à la gravité des AVP OR=1,22 (1,06-1,40). Le défaut de lumière a été significativement associé à la gravité des accidents de la route à Bamako OR=1,05 (1,02-1,09). L’analyse des facteurs prédictifs de la létalité a élucidé un risque de mourir plus élevé chez les 60 ans et plus OR=1,06 (1,01-1,12). Les ménagères auraient un risque plus faible de décès que les autres couches socio professionnelles OR=0,97 (0,96-0,99). Parmi les causes des accidents de la route, l’imprudence du piéton a été le facteur le plus associé au risque de décès 1,11 (1,02-1,23) Les conditions climatiques surtout la saison des pluies et la saison froide ont été les périodes assez mortelles des accidentés de la route OR=1,08 (1,03-1,13). Conclusion : nous pouvons dire que cette étude a permis d'élucider les facteurs humains significativement associés à la gravité et la létalité des accidents de la route, mais aussi mis en évidence la nette sous-estimation du nombre des victimes de la route par la méthode de capture-recapture ayant comparé deux sources de données (police et hôpital). / Introduction: According to the joint publication by the World Health Organization (WHO) and the World Bankof the world report on the prevention of the traumas every year the road accidents are responsible for more than1.2 million deaths. 90 % of these deaths arise in low-income countries or intermediary. The fight against thisplague is impeded by the quality of the data which were collected and reported concerning road accidents, by thelack of performance and efficiency of the existing tools of data collection and the non-representativeness of thepopulations of study. In the face of the growing increase of the traffic accidents in developing countries andparticularly in our country, Mali, and the serious lack of a reliable and extrapolable data collection system in thegeneral population, we put in position a research project.Objective: It is to characterize the personal accidents of the road recorded in the structures of health and in allthe police stations of the District of Bamako in order to propose an effective and sustainable information systemallowing to endow Mali of an operational and relevant monitoring system which is able to help in the decisionmakingand in the operational actions of prevention and coverage of the road accidents thus, favoring thecreation of a national monitoring observatory of the road safety based on the rise and the coding of reports.Methods: we proceeded to an estimation of the number of accidents by the method of capture - recapture over aperiod of four months (from January to April, 2012) from a matching of the physical accidental data of the roadof the structures of health and the police. We also led an epidemiological surveillance over 12 months (fromJanuary to April 2012) concerning only the data collected in the police services.Results: The global estimation of the accident victims was absolutely upper to the enumeration of 2 sources thatis 8518 (8047-8990) victims, against 1432 for the police and 3586 for the health services. We can conclude thatthe capture - recapture is a sensitive method of estimation of the exhaustiveness of the applicable number of roadaccidents in low-income countries. On the other hand with the mortality, this underestimate decreases 99 versus57 for the police and 54 for the health services. The study of the surveillance of the RTA from January toDecember, 2012 recorded 2512 accidents with 3905 victims, among whom 407 badly wounded persons and 142persons killed, involving 4434 vehicles.The analysis of the predictive factors of the gravity revealed a vulnerability of individuals who were under 15OR=1.10 (1.05-1.15) and those who were 60 years old or above OR=1.15 (1.06-1.25).Among the causes of the accidents, the carelessness of the pedestrian was the factor the most associated with thegravity of the RTA OR=1.22 (1.06-1.40). The defect of light was associated significantly with the gravity of theroad accidents in Bamako OR=1.05 (1.02-1.09).The analysis of the predictive factors of the lethality showed arisk of dying higher with those were 60 years old and above OR=1.06 (1.01-1.12). The housewives had a lowerrisk of death more important than the other socio-professional classes OR=0.97 (0.96-0.99). Among the causesof the road accidents, the carelessness of the pedestrian was the factor the most associated with the risk of death1.11 (1.02-1.23). Weather conditions especially the rainy season and the cold season were the most lethal periodsof the road accident victims OR=1.08 (1.03-1.13).Conclusion: we can say that this study allowed to clarify human factors significantly associated to the gravityand the lethality of the road accidents, but it has also highlighted the important under estimation of the number ofthe victims of the road by the capture-recapture method which has compared two springs of data (police andhospital)

Suizid gehört in den meisten Ländern weltweit zu den zehn führenden Todesursachen und wird laut Studien der WHO im Jahr 2020 2,4% des weltweiten „Burden of Disease“ ausmachen (1998:1,8%). Auch Suizidversuche, deren Zahl auf das 10-20fache der Suizide geschätzt wird, stellen eine starke Belastung und einen hohen Kostenfaktor für die Gesundheitssysteme dar. Bezüglich der vollendeten Suizide sind Männer ungefähr 2 bis 3mal so häufig betroffen wie Frauen, bei Suizidversuchen verhält es sich umgekehrt. Mit dem Ziel, dieses Phänomen zu verstehen und effektivere Suizidpräventionsmethoden zu finden, wurden diverse Gründe für die Geschlechtsunterschiede diskutiert und beforscht. Die geschlechtsspezifische Methodenwahl, verschiedene Rollenmodelle, Suchterkrankungen und soziale Unterstützung werden unter anderem als Gründe benannt. Das Ziel dieser Dissertation ist zu untersuchen, ob die Geschlechtsunterschiede in Suizidraten alleine durch die Wahl letalerer Suizidmethoden durch Männer erklärt werden können. Es wird in vielen Studien angenommen, dass Männer zu harten Suizidmethoden wie Erschießen oder Erhängen und Frauen zu weichen Suizidmethoden wie Vergiften neigen. Anhand eines Datensatzes zu Suiziden und Suizidversuchen soll die methodenspezifische „Case Fatality“ (Suizide/Suizide+Suizidversuche) ermittelt werden. Die Hypothese lautet, dass unterschiedliche „Case Fatality rates“ darauf hinweisen, dass über die Methodenwahl hinaus weitere zentrale Gründe die höheren männlichen Suizidraten erklären bzw. dass gleiche „Case Fatality rates“ annehmen lassen, dass die Methodenwahl der Hauptgrund für die Geschlechtsunterschiede ist. In dem Artikel, welcher den Kern der Dissertation ausmacht, wird gezeigt, dass die Methodenwahl bei Männern nicht der ausschlaggebende Faktor für höhere Suizidraten ist. Vielmehr scheinen Männer einzelne Suizidmethoden mit einer höheren Letalität durchzuführen. Auch nach der Kontrolle von Alterseinflüssen zeigt sich dieses Ergebnis signifikant, speziell bei den Methoden Erhängen und Vergiften, Beispiele für eine harte und eine weiche Methode. Dies weist darauf hin, dass dahinterstehende Gründe, z.B. die Intention zu sterben, eine größere Rolle spielen und in zukünftigen Studien weiter beforscht werden sollten. / Background: In most countries worldwide suicide rates are higher for males whereas attempted suicide rates are higher for females. The aim is to investigate if the choice of more lethal methods by males explains gender differences in suicide rates. Methods: Data on completed and attempted suicides were collected (n=3235, Nuremberg and Wuerzburg, years 2000–2004). The research question was analyzed by comparing the methodspecific case fatality (= completed suicides /completed+attempted suicides) for males and females. Results: Among the events captured, men chose high-risk methods like hanging significantly more often than women ( =−0.27; pb0.001). However, except for drowning, case fatalities were higher for males than for females within each method. This was most apparent in “hanging” (men 83.5%, women 55.3%; =−0.28; pb0.001) and “poisoning by drugs” (men 7.2%, women 3.4%; =−0.09; pb0.001). Limitations: The sample size (n=3235) was not enough for comparing method and gender specific case fatalities with a fine-meshed stratification regarding age. Conclusions: Higher suicide rates in males not only result from the choice of more lethal methods. Other factors have to be considered.

Pancreatic cancer (PC) is a highly aggressive disease with unmet therapeutic needs. Recent advances in the use of oncolytic viruses (OVs) as cancer therapeutic agents bring new hope to fight the notorious disease that is PC. Although OVs have shown promising results in certain cancers, some tumors remain resistant to OV therapy due to their inherent residual antiviral mechanisms. We hypothesized that the use of OV-encoded artificial microRNAs (amiRNAs) could help target the cellular antiviral components associated with the observed OV resistance and could also sensitize neighboring tumor cells to OV therapy and small molecule inhibitors through the secretion of amiRNA-containing extracellular vesicles (EVs) from infected cells. To find such amiRNAs, a viral surrogate library encoding ~16,000 unique amiRNAs was passaged in pancreatic cancer cell lines to enrich for sequences that could enhance OV replication. An amiRNA that improves PC cell killing when expressed from an OV was identified. Target identification of this amiRNA (amiR-4) revealed ARID1A as a key player in resistance to OV therapy in pancreatic cancers. This target is of particular interest, since its downregulation acts in a synthetic lethal fashion with inhibition of the EZH2 methyltransferase. Combining VSV51-amiR-4 with a small molecule inhibitor of EZH2 enhances PC cell death. Moreover, amiR-4 is packaged in cancer cell-secreted EVs which can reach neighboring naïve cells to sensitize them to EZH2 inhibition-mediated cell death and to spread the OV-mediated tumor killing effect throughout the tumor. This data translates into tumor debulking and survival in animal models of highly aggressive PC. This work not only broadens our knowledge on the resistance of select tumors to oncolytic virotherapy and the EV-mediated bystander killing effect in OV-infected tumors, but it also establishes OVs as a novel tool to produce anti-cancer therapeutic EVs in situ to improve therapeutic gain. Ultimately, our work provides new hope for a cure to the grim disease that is PC.

Lethality of aggravated assaults has long been discussed in terms of weapons used, location of assault, demographics of victims, and regions of the US in which the assault occurred. However, dating back to the 1950s, medical response times have been discussed as a mediating factor, but minimally explored in analyses. The current study assesses the lethality of shootings with a primary focus on emergency medical and police response times in New Orleans, LA. Along with routine activities and social disorganization indicators, 102 shootings that occurred in 3 months are analyzed to establish response time patterns of lethality. Results indicate that neither medical nor police response times impact the odds of a victim surviving a shooting, but instead, it is the days on which the violent encounters occur and the socioeconomic characteristics of the neighborhood that have a stronger influence on life or death, although not statistically significant. Limitations and future research directions are discussed.

The current study examines firearms’ impact on the relationship between illegal drug markets and homicide. At the county-level, Iowa and Virginia are analyzed using crime data from the National Incident Based Reporting System. More specifically, gun availability is tested as a mediator for county drug crime rates and homicide counts. Variable selection and prediction is based on routine activity and social disorganization theories. I argue that social disorganization allows the context for which criminal opportunity presents itself through routine activities. I posit gun availability mediates a positive relationship between illegal drug markets and homicide, with differences between urban and rural communities

Utilizing a Criminal Event Perspective, the analyses of this dissertation test a variety of relationships to the dependent variable: the Criminal Lethality Index. Data from the National Incident-Based Reporting System, the Census and American Community Survey, the American Trauma Society, and data derived from the Census’s mapping TIGER files are combined to create a database of 190 cities. This database is used to test road network connectivity (Gama Index), medical resources, criminal covariates and Social Disorganization variables in relation to a city’s Criminal Lethality Index. OLS regression demonstrates a significant and negative relationship between a city’s Gama Index and its Criminal Lethality Index. In addition, percent male, percent black, median income and percent of the population employed in diagnosing and treating medical professions were all consistently positively related to Criminal Lethality. The percent of males 16 to 24, percent of single parent households, and Concentrated Disadvantage Index were all consistently and negatively related to Criminal Lethality. Given these surprising results, additional diagnostic regressions are run using more traditional dependent variables such as the number of murders in a city and the proportion of aggravated assaults with major injuries per 100,000 population. These reveal the idiosyncratic nature of utilizing the Criminal Lethality Index. This dependent variable has proven useful in some circumstances and counterintuitive in others. The source of the seemingly unintuitive results is the fact that certain factors only reduce murders but many factors impact both murder and aggravated assaults, thereby creating difficultly when trying to predict patterns in Criminal Lethality

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