The clinical trial is the most import study for the development of successful novel drugs. The aim of this dissertation is to develop innovative statistical methods to overcome the three main obstacles in clinical trials: (1) lengthy trial duration and inaccurate maximum tolerated dose (MTD) in phase I trials; (2) heterogeneity in drug effect when patients are given the same prescription and same dose; and (3) high failure rates of expensive phase III confirmatory trials due to the discrepancy in the endpoints adopted in phase II and III trials. Towards overcoming the first obstacle, we originally develop a hybrid design for the time-to-event dose escalation method with overdose control using a normalized equivalent toxicity score (NETS) system. This hybrid design can substantially reduce sample size, shorten study length, and estimate accurate MTD by employing a parametric model and adaptive Bayesian approach. Toward overcoming the second obstacle, we propose a new approach to incorporate patients’ characteristic using our proposed design in phase I clinical trials which considers the personalized information for patients who participant in the trials. To conquer the third obstacle, we propose a novel two-stage screening design for phase II trials whereby the endpoint of percent change in of tumor size is used in an initial screening to select potentially effective agents within a short time interval followed by a second screening stage where progression free survival is estimated to confirm the efficacy of agents. These research projects will substantially benefit both cancer patients and researchers by improving clinical trial efficiency and reducing cost and trial duration. Moreover, they are of great practical meaning since cancer medicine development is of paramount importance to human health care.

Ikiteisminio tyrimo organizavimas – tai ne tik įstatymais apibrėžta procesinė veikla, bet ir įvairių bendravimo bei bendradarbiavimo veiksmų kompleksas, kuris gali būti paaiškintas remiantis kitų visuomenės mokslų žiniomis. Ikiteisminio tyrimo organizavimo, jam vadovavimo, kontroliavimo sistemą sudaro ikiteisminio tyrimo pareigūnas, prokuroras, ikiteisminio tyrimo teisėjas. Pagrindinis ikiteisminio tyrimo proceso organizatorius, vadovas ir kontrolierius - prokuroras. Ikiteisminio tyrimo pareigūnas (tyrėjas) privalo vykdyti visus prokuroro nurodymus bei jo nustatytu laiku pranešti apie ikiteisminio tyrimo eigą. Ikiteisminio tyrimo teisėjas atlieka tik jam priskirtus procesinius veiksmus ir tik gavęs prokuroro prašymą. Esminiai ikiteisminio tyrimo organizavimo principai: teisėtumas, vienasmeniškumas, veiksmų koordinavimas, mobilumas, intensyvumas, mokslo ir technikos panaudojimas, dinamiškumas ir vykdymo kontrolė bei uždaviniai skirti operatyviai ir išsamiai išaiškinti nusikalstamas veikas, sudaryti kiekvienoje byloje sąlygas teisingai taikyti įstatymą, kad kiekvienas nusikaltimą padaręs asmuo būtų teisingai nubaustas ir nė vienas nekaltas asmuo nebūtų patrauktas baudžiamojon atsakomybėn, užtikrinti nusikalstamą veiką padariusio asmens padarytos materialinės žalos atlyginimą arba ją atlyginti, sudaro vieną iš ikiteisminio tyrimo organizavimo pagrindų. Tačiau vienas svarbiausių, be ikiteisminio tyrimo organizavimo principų ir uždavinių, pagrindų yra procesinis, kurį sudaro... [toliau žr. visą tekstą] / Organization of the pre-trial investigation - is not only defined by law procedural activities but communication and cooperation between different set of operations which can be explained by other social science research organization of the pre-trial investigation, his leadership; the monitoring system consists of pre-trial investigation officer, prosecutor, investigating judge. The main organizer of investigative process, supervisor and controller - prosecutor. Pre-trial investigation officer (investigator) must comply with all instructions and prosecutor in due time to the pre-trial proceedings. The pre-trial judge assigned to him only by the proceedings and only after the prosecutor's request. Key pre-trial organization principles: legality, coordination, mobility, intensity of use of science and technology, dynamics and control performance as well as the targets for rapid and comprehensive interpretation of criminal offenses, consisting in each case for correct application of the law so that every offender would be justly punished and no innocent person is not prosecuted, to ensure the offender of material damages or compensation, is one of the pre-survey in the grounds. However, one of the most important, in addition to investigating the principles and objectives of the organization, the framework is procedural, which are the Republic of Lithuania Code of Criminal Procedure and other legislation. Proper pre-trial planning is essential in ensuring the success of the... [to full text]

Since its appearance in Europe, the trial by jury had to travel a long path until it became the official procedure to try criminal cases in the United States. Although it was not really created with that specific purpose, over the years it experienced memorable moments in which it was granted with the prestige and value required to be inserted in the Constitution of that country, as a safeguard against the arbitrariness of the governmental power. Today, however, the great importance that it had in the past has significantly decreased. The needs and practices of a system with a particularly high rate of convictions have relegated and transformed it into a real endangered specie. The following article describes and explains its birth and rise, as well as its subsequent virtual disappearance due to the not so efficient as dangerous guilty pleas. / Desde su aparición en Europa, el juicio por jurados tuvo que recorrer un largo camino para convertirse en el método oficial de juzgamiento de casos penales en los Estados Unidos. A pesar de que no fue creado exactamente con esa finalidad, tuvo varios momentos memorables durante su desarrollo que le otorgaron el prestigio y valor necesarios para insertarse en la Constitución de ese país como una garantía frente al abuso del poder. Hoy, sin embargo, la gran importancia que alguna vez tuvo ha quedado atrás. Las necesidades y prácticas propias de un sistema con una altísima tasa de condenas han terminado por relegarlo, convirtiéndolo en una verdadera especie en peligro de extinción. El siguiente artículo describe y explica el nacimiento y auge de los juicios por jurados para causas penales y su posterior virtual desaparición a manos de los no tan eficientes como peligrosos acuerdos negociados de condena.

Le temps pénal, à la lumière de la pratique judiciaire sénégalaise révèle, à l'instar des législations progressistes, l'émergence d'un phénomène d'effritement de la loi procédurale face à un contentieux hétérogène complexifié par l'enchevêtrement d'éléments d'extranéité, des ramifications sous-régionales. Ces ingrédients, densément composites, ont fondamentalement désaxé la temporalité processuelle. Le dérèglement du temps pénal est la conséquence d'un pullulement de règles dérogatoires occasionnant un véritable millefeuille pénal. La pathologie de l'appareil judiciaire sénégalais est que la justice pénale s'enlise et reste peu lisible. Elle est empreinte d'inefficacité, de lenteurs endémiques. Cette étude est un réel prétexte, ayant permis d'indexer avec vigueur les lacunes saillantes d'une règle procédurale importée et fragmentée. À cet égard, il est nécessaire de cristalliser l'attention sur l'improductivité des réformes ponctuelles et contingentes, proposer une issue à ce labyrinthe procédural et poser le soubassement d'un humanisme pénal, fondé sur le consensualisme clé de voûte de la nouvelle figure du procès pénal. Ce processus de déjudiciarisation conforte la priorisation de la modulation du temps de la réponse pénale comme vecteur de qualité de la justice. L'édification d'une charpente d'une nouvelle politique criminelle passe par un modèle de droit processuel plus lisible, performant qui recentre l'idéal de justice pénale sur un mode de traitement de l'infraction plus cohérent en phase avec les exigences de droits de l'homme pour remplir les fonctions essentielles d'une justice juste et équitable. / Penal time, in the light of the Senegalese legal practice reveals, following the example of liberal legislations, the emergence of a phenomenon of flaking of the procedural law vis-a-vis a heterogeneous litigation made more complex by the tangle of extraneous elements, sub-regional ramifications. These ingredients that have basically offset procedural temporality, call undoubtedly for a differentia processing of the infringement. The deregulation of the penal time is the consequence of a proliferation of derogatory rules causing a true penal cream slice. The pathology of the Senegalese legal apparatus is that criminal justice is getting stuck and remains not very readable This study is a real pretext, having made it possible to stress with strength the salient gaps of an imported and split up procedural law. In this respect, it was of a burning need to focus the attention on the unproductiveness of the specific and contingent reforms, by suppressing the culture of slowness, proposing a solution to this procedural labyrinth and posing obviously the base of a penal humanism based on the consent, the keystone of the new face of the criminal trial. The construction of a frame for a new criminal policy passes by a model of more readable, efficient procedural law which focuses the ideal of criminal justice on a more coherent mode of management of the infringement in tune with the requirements of human rights to fulfill the essential functions of a fair and equitable justice law.

De toutes les judiciarisations, le procès civil en contrefaçon est l’un de ceux qui durant ces dernières années a pris le plus d’ampleur, car au-delà de l’atteinte que le fléau de la contrefaçon porte aux monopoles d’exploitation, il rejaillit aussi sur tous les secteurs de notre économie, à savoir les emplois, la santé, la sécurité des consommateurs ou bien encore l’investissement. C’est par l’analyse du rôle que les acteurs ont à tenir dans le procès civil en contrefaçon, que l’on se propose d’étudier la singularité de ce procès au regard du droit commun procédural et d’envisager une possible théorie du procès civil en contrefaçon. Les recherches s’attachent alors à effectuer, tout d’abord, une analyse approfondie de la charge des parties dans le procès civil en contrefaçon ; l’enjeu est de mettre ici en évidence le pouvoir particulier d’impulsion des parties en identifiant les facteurs de divergence ou d’unité de la matière. Parallèlement à l’examen de ce pouvoir d’initiative, il s’agit aussi de mettre l’accent sur les mesures auxiliaires originales, telles que la saisie-contrefaçon ou la retenue en douane ouvertes aux parties afin de leur permettre de mieux prouver ou de mieux anticiper le procès au fond, sans forcément rompre l’équilibre procédural des droits entre les parties. Le sujet nous emmène, ensuite, à mettre à jour l’office du juge dans le procès civil en contrefaçon. Assurément, après que la préparation et l’initiative de l’instance en contrefaçon aient été laissées à la diligence des parties, c’est en effet au juge étatique qu’il appartient de « prendre la main » sur le procès et il convient alors d’étudier sa compétence dérogatoire en matière de contrefaçon, compétence qui se révèle tantôt concentrée, tantôt éclatée en cas de conflit de juridictions, tantôt concurrencée aussi par un juge « privé ». La réflexion conduit in fine à rechercher si le pouvoir qu’a le juge de trancher le litige, en allouant des dommages et intérêts ou en réintégrant la victime dans l’intégralité de son droit de propriété, témoigne ou non de la nature hybride des droits de propriété intellectuelle dépassant la simple sphère privative pour rejoindre une autre dimension plus largement collective. Telles sont les pistes de réflexion menant à l’édification d’un régime commun procédural. / In all trials, the civil lawsuit for counterfeiting is one of those which is on the increase because, beyond violate a monopoly, the counterfeiting also spills over into all sectors of our economy, ie employment, health, consumer safety or even investment. It’s by analyzing the role that players have in the civil lawsuit for imitation, we will study the specific feature of this case compared with the procedural law and we will consider a possible theory of civil trial for counterfeiting. The research lead to make, first of all, a thorough analysis of the burden of the parties in the civil lawsuit for imitation. The challenge is to highlight the particular impetus of the parties by identifying divergence factors or convergence about the subject. We have also to stress that the original auxiliary measures allow the parties to better prove or to anticipate the trial without break necessarily the procedural balance. Afterwards, we have to study the role of the judge in the civil lawsuit for counterfeiting. Indeed, after the parties have prepared and taken legal action, the judge has to "take over" the trial and it’s then necessary to examine its derogatory competence, which is sometimes concentrated, sometimes exploded in a conflict of jurisdictions, sometimes challenged by a "private" judge. Finally the subject leads to determine if the judge’s power, allocating damages for example, show the dual prism of intellectual property law wich overstep the private monopoly to belong to a wider collective dimension. These are the lines of thought leading to the building of a common procedural regime.

No description available.

Many Syrian refugees residing in Germany have been exposed to traumatizing events, while treatment options are scarce. Therefore, the self-help app “Sanadak” was developed to target post-traumatic stress in Syrian refugees. We aimed to inspect the recruitment and baseline characteristics of the participants in the trial, which is conducted to evaluate the app. Analyses were based on the recruitment sample (n = 170) and the trial sample (n = 133). Data were collected during structured face-to-face interviews in the Arabic language. Targeted outcomes included post-traumatic stress (primary; Post-traumatic Diagnostic Scale for DSM-5/PDS-5) and depressive symptoms, anxiety, resilience, among others (secondary). Recruited individuals were M = 32.8 (SD = 11.2, range = 18–65) years old; 38.8% were women. The average PDS-5 score was 23.6 (SD = 13.2) regarding trauma exposure, which was most frequently related to experiencing military- or combat-related events (32.9%). Moreover, 46.5% had major depression and 51.8% showed low resilience. Anxiety was present in 40.6% of the trial participants. Psychological distress was high in Syrian refugees residing in Germany, enrolled in a trial targeting post-traumatic stress. This underlines the need for intervention. Our results provide important figures on the mental health of a not well-studied population group in Germany.

<p><strong>Background and objectives</strong></p> <p>We investigate three issues related to the adjustment for baseline covariates in late phase clinical trials: (1) the analysis of correlated outcomes in multicentre RCTs, (2) the assessment of the probability and implication of prognostic imbalance in RCTs, and (3) the adjustment for baseline confounding in cohort studies.</p> <p><strong>Methods</strong></p> <p>Project 1: We investigated the properties of six statistical methods for analyzing continuous outcomes in multicentre randomized controlled trials (RCTs) where within-centre clustering was possible. We simulated studies over various intraclass correlation (ICC) values with several centre combinations.</p> <p>Project 2: We simulated data from RCTs evaluating a binary outcome by varying risk of the outcome, effect of the treatment, power and prevalence of a binary prognostic factor (PF), and sample size. We compared logistic regression models with and without adjustment for the PF, in terms of bias, standard error, coverage of confidence interval, and statistical power. A tool to assess sample size requirement to control for chance imbalance was proposed.</p> <p>Project 3: We conducted a prospective cohort study to evaluate the effect of tuberculosis (TB) at the initiation of antiretroviral therapy (ART) on all cause mortality using Cox proportional hazard model on propensity score (PS) matched patients to control for potential confounding. We assessed the robustness of results using sensitivity analyses.</p> <p><strong>Results and conclusions</strong></p> <p>Project 1: All six methods produce unbiased estimates of treatment effect in multicentre trials. Adjusting for centre as a random intercept leads to the most efficient treatment effect estimation, and hence should be used in the presence of clustering.</p> <p>Project 2: The probability of prognostic imbalance in small trials can be substantial. Covariate adjustment improves estimation accuracy and statistical power, and hence should be performed when strong PFs are observed.</p> <p>Project 3: After controlling for the important confounding variables, HIV patients who had TB at the initiation of ART have a moderate increase in the risk of overall mortality.</p> / Doctor of Philosophy (PhD)

The sexual offences that are committed by adolescents lately are of a great concern, particularly in the Mafikeng area. The record shows that adolescents are arrested daily for committing criminal offences. Despite the measures that are taken by the government in developing the young people to be the generation that would be tomorrow’s future leaders, others turn to not taking the opportunity with both hands but rather engaging in criminal activities. The office record also shows that adolescents’ cases that are assessed by the Probation officers in Mafikeng are mostly of sexual offences. In every assessment the child offender is expected to be accompanied by the parent/s. In most instances the parent/s indicates to be not aware of what influences the child to act against the law by committing a sexual offence. The role of the family is to provide care, support and guidance towards the child. It becomes difficult for the Probation officers to assist the child in such case if the parent/s does not know the causal factor of his/her child’s negative act, since they are seen to be the child’s primary care giver. In South Africa sexual offence is seen to be serious offence before the court of law that falls under schedule 3 offences. The research was conducted among the adolescents who were found to have committed sexual offences in Mafikeng area. The aim of the research was to gain information on factors that contribute to adolescents to commit sexual crimes. The objective for this research was to explore the factors that contribute to adolescents committing a sexual crime and formulate recommendations for social workers and parents/guardians in preventing adolescents from committing sexual crimes in the Mafikeng area. An empirical study was conducted using a qualitative approach. A self-administered schedule was used to evaluate the factors that contribute to adolescents committing sexual crimes by means of interviews with each adolescent who has been found to have committed sexual offences. It is evident from the data collected from the research that the main factors that influence adolescents to commit sexual offences in Mafikeng are substance abuse, failure to attend school and lack of parental supervision. It takes a village to raise a child, from these findings it is clear that an integrated service approach has to be adopted in addressing the challenge, i.e. parents should start to play their role in providing care and support for their children. There has to be good relationships between the community and government departments as well as NGO’s in dealing with moral decay. / MSW (Forensic Practice), North-West University, Potchefstroom Campus, 2014

In this paper, a rheumatoid arthritis (RA) medicine clinical dataset with an ordinal response is selected to study this new medicine. In the dataset, there are four features, sex, age,treatment, and preliminary. Sex is a binary categorical variable with 1 indicates male, and 0 indicates female. Age is the numerical age of the patients. And treatment is a binary categorical variable with 1 indicates has RA, and 0 indicates does not have RA. And preliminary is a five class categorical variable indicates the patient’s RA severity status before taking the medication. The response Y is 5 class ordinal variable shows the severity of patient’s RA severity after taking the medication. The primary aim of this study is to determine what factors play a significant role in determine the response after taking the medicine. First, cumulative logistic regression is applied to the dataset to examine the effect of various factors on ordinal response. Secondly, the ordinal response is categorized into two classes. Then logistic regression is conducted to the RA dataset to see if the variable selection would be different. Moreover, the shrinkage methods, elastic net and lasso are used to make a variable selection on the RA dataset of two-class response for the purpose of adding penalization to increase the model’s robustness.The four model results were compared at the end of the paper. From the comparison result, logistic regression has a better performance on variable selection than the other three approaches based on P-value.