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Cited in almost all inspections of the pharmaceutical industry, data integrity is an essential subject. Data, metadata, GxP data, audit trail, data life cycle, this thesis presents the general concepts, realizes the state of the art in terms of legislation to date and reviews the practical approaches allowing the industrialist to achieve compliance., Citée dans pratiquement toutes les inspections de l’industriel pharmaceutique, l’intégrité des données ou data integrity en anglais est un sujet incontournable. Donnée, métadonnée, données BPx, audit trail, cycle de vie de la donnée, cette thèse présente les notions générales, réalise l’état de l’art en termes de législation à date et revient sur les approches pratiques permettant à l’industriel d’atteindre la conformité.

Chronic nonbacterial osteomyelitis (CNO) is an auto-inflammatory bone disorder with a wide spectrum of clinical manifestations, from unifocal to multifocal lesions. When it manifests with multifocal lesions, it is also referred to as chronic recurrent multifocal osteomyelitis (CRMO). CNO/CRMO can affect all age groups, with the pediatric population being the most common. Patients may present with systemic inflammation, but there is no pathognomonic laboratory finding. Magnetic resonance imaging (MRI) is the gold standard radiological tool for diagnosis. In the absence of validated diagnostic criteria, CNO/CRMO remains an exclusion diagnosis. Bone biopsy does not show a specific disease pattern, but it may be necessary in unifocal or atypical cases to differentiate it from malignancy or infection. First-line treatments are non-steroidal anti-inflammatory drugs (NSAIDs), while bisphosphonates or TNF-α blockers can be used in refractory cases. The disease course is unpredictable, and uncontrolled lesions can complicate with bone fractures and deformations, underlying the importance of long-term follow-up in these patients.

Background Deficiency of the natural antagonist of interleukin-1 was first described in 2009 and so far 20 patients has been reported. In Brazil just two cases have been reported both carrying the same homozygous 15 bp deletion. Blocking interleukin-1 has changed rate survival for DIRA patients. The use of anakinra and rilonacept has been reported safe and efficient, whereas the selective blockade of interleukin-1 beta, using the monoclonal antibody canakinumab has been reported in a single case only. Case presentation Here we report a case of a 7 years old Brazilian boy that presented with recurrent episodes of systemic inflammation with severe disabling osteomyelitis with mild pustular skin rash. A Next Generation Sequencing gene panel allowed to detect two pathogenic mutations in the IL1RN gene, described in compound heterozygosity. Corticosteroids was effective in controlling inflammation and anti-IL1 beta blocker triggered disease flare. Complete clinical control could be achieved using IL-1 receptor antagonist. Conclusions DIRA is a severe, life threatening autoinflammatory condition with low numbers of patients described all over the world. The mutation p.Asp72_Ile76del in IL1RN is presented in all Brazilian DIRA patients already described and p.Q45* (rs1019766125) is a new mutation affecting the IL1RN gene. Following the pathogenesis of DIRA, blocking both subunits of interleukin one as well as antagonizing the receptor using anakinra or rilonacept seems to be effective. There is just one report using canakinumab for the treatment of DIRA and this is the first report of disease flare using this drug.

Chronic nonbacterial osteomyelitis (CNO) is an auto-inflammatory bone disorder with a wide spectrum of clinical manifestations, from unifocal to multifocal lesions. When it manifests with multifocal lesions, it is also referred to as chronic recurrent multifocal osteomyelitis (CRMO). CNO/CRMO can affect all age groups, with the pediatric population being the most common. Patients may present with systemic inflammation, but there is no pathognomonic laboratory finding. Magnetic resonance imaging (MRI) is the gold standard radiological tool for diagnosis. In the absence of validated diagnostic criteria, CNO/CRMO remains an exclusion diagnosis. Bone biopsy does not show a specific disease pattern, but it may be necessary in unifocal or atypical cases to differentiate it from malignancy or infection. First-line treatments are non-steroidal anti-inflammatory drugs (NSAIDs), while bisphosphonates or TNF-α blockers can be used in refractory cases. The disease course is unpredictable, and uncontrolled lesions can complicate with bone fractures and deformations, underlying the importance of long-term follow-up in these patients.

Multiple myeloma is an hematological malignancy that is still incurable to this day, but whose treatments have considerably evolved over the last two decades. Daratumumab, an anti-CD38 monoclonal antibody, has demonstrated a significant efficacy in terms of survival, and its indications will involve an increasing number of patients. But its use also causes troubles in follow-up, by interfering with interpretation of several biological tests. In particular, its detection on serum protein electrophoresis and immunofixation electrophoresis which are key monitoring assays may lead to mask a Complete Response. A semi-automated test named Hydrashift 2/4 Daratumumab® was marketed by Sebia company, enabling to remove interference on immunofixation electrophoresis by modifying the electrophoretic mobility of Daratumumab. In order to evaluate this assay, we tested the Hydrashift on a cohort of patients from clinical hematology department of the University Hospital of Bordeaux. We analyzed the kinetics of appearance of interference during the therapeutic sequence. Our study confirms the usefulness of Hydrashift for the interpretation of immunofixation electrophoresis in patients treated with Daratumumab. A decision-making algorithm for prescribing this test is proposed for an appropriate use in daily practice, thus warranting in all circumstances a reliable assessment of response to treatment in the follow-up of these myelomas., Le myélome multiple est une hémopathie maligne actuellement toujours incurable, mais dont les traitements ont considérablement évolué au cours des deux dernières décennies. Le Daratumumab, anticorps monoclonal anti-CD38, a montré une efficacité significative en termes de survie, et ses indications vont concerner un nombre croissant de patients. Mais son utilisation engendre aussi des difficultés dans le suivi, en interférant dans l’interprétation de plusieurs examens biologiques. En particulier, sa détection sur les examens incontournables de suivi, électrophorèse et immunofixation des protéines sériques, peut amener à méconnaître une Réponse Complète. Un test semi-automatisé a été commercialisé par la société Sebia sous le nom d’Hydrashift 2/4 Daratumumab® permettant de lever l’interférence sur l’immunofixation en modifiant la mobilité électrophorétique du Daratumumab. Afin d’évaluer la technique, nous avons testé l’Hydrashift sur une cohorte de patients du service d’hématologie clinique du CHU de Bordeaux. Nous avons analysé la cinétique d’apparition de l’interférence au cours de la séquence thérapeutique. Notre étude confirme l’utilité de l’Hydrashift pour l’interprétation des immunofixations de patients traités par Daratumumab. Un algorithme décisionnel de la prescription de ce test est proposé pour son utilisation adaptée en pratique quotidienne garantissant ainsi une évaluation fiable, en toutes circonstances, de la réponse au traitement dans le suivi de ces myélomes.

At some point during a creative action something clicks, suddenly the prospective problem solver just knows the solution to a problem, and a feeling of joy and relief arises. This phenomenon, called Eureka experience, insight, Aha moment, hunch, epiphany, illumination, or serendipity, has been part of human narrations for thousands of years. It is the moment of a subjective experience, a surprising, and sometimes a life-changing event. In this thesis, I narrow down this moment 1. conceptually, 2. experientially, and 3. temporally. The concept of emerging solutions has a multidisciplinary background in Cognitive Science, Arts, Design, and Engineering. Through the discussion of previous terminology and comparative reviews of historical literature, I identify sources of ambiguity surrounding this phenomenon and suggest unifying terms as the basis for interdisciplinary exploration. Tracking the experience based on qualitative data from 11 creative practitioners, I identify conflicting aspects of existing models of creative production. To bridge this theoretical and disciplinary divide between iterative design thinking and sequential models of creativity, I suggest a novel multi-layered model. Empirical support for this proposal comes from Dira, a computer-based open-ended experimental paradigm. As part of this thesis I developed the task and 40 unique sets of stimuli and response items to collect dynamic measures of the creative process and evade known problems of insightful tasks. Using Dira, I identify the moment when solutions emerge from the number and duration of mouse-interactions with the on-screen elements and the 124 participants’ self-reports. I provide an argument for the multi-layered model to explain a discrepancy between the timing observed in Dira and existing sequential models. Furthermore, I suggest that Eureka moments can be assessed on more than a dichotomous scale, as the empirical data from interviews and Dira demonstrates for this rich human experience. I conclude that the research on insight benefits from an interdisciplinary approach and suggest Dira as an instrument for future studies.

There is a need for quantitative CT data in radiation therapy. Currently there are only few algorithms that address this issue, for instance the commercial DirectDensity algorithm. In scientific literature, an example of such an algorithm is DIRA. DIRA is an iterative model-based reconstruction method for dual-energy CT whose goal is to determine the material composition of the patient from accurate linear attenuation coefficients. It has been implemented in a two dimensional geometry, i.e., it could process axial scans only. There was a need to extend DIRA so that it could process projection data generated in helical scanning geometries. The newly developed algorithm (DIRA-3D) implemented (i) polyenergetic semi-parallel projection generation, (ii) mono-energetic parallel projection generation and (iii) the PI-method for image reconstruction. The computation experiments showed that the accuracies of the resulting LAC and mass fractions were comparable to the ones of the original DIRA. The results converged after 10 iterations.

Objective Chronic non-bacterial osteomyelitis CNO is an inflammatory disorder of the musculoskeletal system with unknown etiology. In addition to bone inflammation, patients may present with inflammatory involvement of other tissues including, e.g.,skin. Recently, a novel syndrome due to deficiency of interleukin-1 receptor antagonist (IL1RN), DIRA has been identified. Clinically the syndrome is characterized by neonatal onset of pustular dermatosis, periostitis and chronic sterile multifocal osteomyelitis, strongly resembling CNO. Homozygous mutations of IL1RN have been identified and resulted in a truncated protein that is not secreted, hence leaving the action of interleukin-1 unopposed. Methods Because of similar clinical, radiological and histological features of CNO and DIRA, we hypothesized that both disorders might share a common autoinflammatory process. Thus, we searched for the presence of mutations in the interleukin-1 receptor antagonist gene in 60 patients diagnosed with CNO. Results In one patient with chronic multifocal osteomyelitis a heterozygous missense variant: c.281G>T (p.Cys94Phe) was detected. In the other patients only frequent polymorphisms were found. Conclusion Our findings were not able to confirm mutations in IL1RN being an important contributing factor to the pathogenesis of CNO.

WOS: 000463332100020, PubMed ID: 30968643, Autoinflammatory diseases can cause severe inflammation in bone and skin such as neonatal-onset multisystem inflammatory disease (NOMID), Majeed syndrome, interleukin-36 receptor antagonist deficiency (DITRA) and deficiency of interleukin-1 (IL-1) receptor antagonist (DIRA) syndrome. Here we report a five-year old boy who was admitted to the hospital with pustular skin lesions and fever in the first month of his life. Molecular analysis of IL1RN gene revealed a single homozygous C nucleotide deletion at nucleotide position 396 (p.Thr133Profs*118). The novel p.Thr133Profs*118 mutation found in our study caused frameshift mutation and as a result, the respective protein is most likely non-functional. The patient, who received a variety of treatments for various preliminary diagnoses until the final diagnosis (DIRA), was treated with recombinant IL-1Ra, anakinra, and experienced significant clinical improvement.

Sterile bone inflammation is the hallmark of autoinflammatory bone disorders, including chronic nonbacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO). Autoinflammatory osteopathies are the result of a dysregulated innate immune system, resulting in immune cell infiltration of the bone and subsequent osteoclast differentiation and activation. Interestingly, autoinflammatory bone disorders are associated with inflammation of the skin and/or the intestine. In several monogenic autoinflammatory bone disorders mutations in disease-causing genes have been reported. However, regardless of recent developments, the molecular pathogenesis of CNO/CRMO remains unclear. Here, we discuss the clinical presentation and molecular pathophysiology of human autoinflammatory osteopathies and animal models with special focus on CNO/CRMO. Treatment options in monogenic autoinflammatory bone disorders and CRMO will be illustrated.

The thesis deals with subsemigroups of (Nm 0 , +), a special discussion is later devoted to the cases m = 1, m = 2 and m = 3. We prove that a subsemigroup of Nm 0 is finitely generated if and only if its generated cone is finitely generated (equivalently polyhedral) and we describe basic topological properties of such cones. We give a few examples illustrating that conditions sufficient for finite generation in N2 0 can not be easily trans- ferred to higher dimensions. We define the Hilbert basis and the related notion of Carathéodory's rank. Besides their basic properties we prove that Carathédory's rank of a subsemigroup of Nm 0 , m = 1, 2, 3, is less than or equal to m. A particular attention is devoted to the subsemigroups containing non-trivial subsemigroups of "subtractive" elements.

Objective Chronic non-bacterial osteomyelitis CNO is an inflammatory disorder of the musculoskeletal system with unknown etiology. In addition to bone inflammation, patients may present with inflammatory involvement of other tissues including, e.g.,skin. Recently, a novel syndrome due to deficiency of interleukin-1 receptor antagonist (IL1RN), DIRA has been identified. Clinically the syndrome is characterized by neonatal onset of pustular dermatosis, periostitis and chronic sterile multifocal osteomyelitis, strongly resembling CNO. Homozygous mutations of IL1RN have been identified and resulted in a truncated protein that is not secreted, hence leaving the action of interleukin-1 unopposed. Methods Because of similar clinical, radiological and histological features of CNO and DIRA, we hypothesized that both disorders might share a common autoinflammatory process. Thus, we searched for the presence of mutations in the interleukin-1 receptor antagonist gene in 60 patients diagnosed with CNO. Results In one patient with chronic multifocal osteomyelitis a heterozygous missense variant: c.281G>T (p.Cys94Phe) was detected. In the other patients only frequent polymorphisms were found. Conclusion Our findings were not able to confirm mutations in IL1RN being an important contributing factor to the pathogenesis of CNO.