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no / One of the major shifts in the form and experience of contemporary family life has been the increasing insertion of the ‘expert’ voice into the relationship between parents and children. This paper focuses on an exploration of mothers’ engagement with advice around the combined measles, mumps and rubella (MMR) vaccine. Much of the previous literature utilises a ‘decision-making’ framework, based on ‘risk assessment’ whereby mothers’ decisions are conceptualised as rooted in complex belief systems, and supposes that that by gaining an understanding of these systems, beliefs and behaviour can be modified and uptake improved. However, less attention has been paid to the ways in which mothers negotiate such advice or the ways in which advice is mediated by positionings, practices and relationships. Analysis of data from a focus group with five mothers identified three themes: (i) Sourcing advice and information, (ii) Constructing ‘Mother knows best’ and (iii) Negotiating agency. Despite the trustworthiness of advice and information being questioned, an awareness of concerns about the MMR, and health professionals being constructed as remote, ultimate conformity to, and compliance with, the ‘system’ and ‘society’ were described as determining MMR ‘decisions’. / Full text was made available at the end of the publisher's embargo period: 1st Aug. 2015

The objective of this thesis is to design, analyze, and fabricate an innovative backpack energy harvester for human walking. To model human walking with backpack energy harvester, a simple dual-mass model has been developed and studied first. Dual-mass model for three types of distinct harvesters were investigated, pure damping, traditional rack pinion energy harvester and our MMR based energy harvester. A comparison in the output power and human comfort between the three types of harvesters is discussed. However, the dual-mass model could not effectively represent human walking in real situation with sinusoidal input, like M shaped Ground Reaction Force (GRF), vertical Center of Mass (COM) motion, etc. Thus, a bipedal walking model has been proposed to simulate human walking with backpack harvester. Experiments were conducted to compare power output and efficiency of MMR based backpack energy harvester with traditional rack pinion backpack energy harvester, and verify conclusions from the bipedal walking model that the proposed backpack energy harvester using mechanical motion rectifier (MMR) mechanism has larger power output than traditional backpack energy harvester at different walking speed. In human treadmill test, subjects were asked to wear the backpack frame which embedded with harvesters walking on a treadmill. Two walking speed, 3mph and 3.5mph, and four resistor values has been tested. The test results showed that the MMR based backpack energy harvester generated more power regardless of resistor values and walking speed. Up to 4.84W average power and instant power of 12.8W could be obtained while the subject walking on the treadmill at 3.5mph speed with MMR based backpack energy harvester. / Master of Science

Bakgrund: Långvarig smärta är vanligt förekommande och orsakar stort lidande. Multimodal rehabilitering (MMR) är en behandlingsmetod som erbjuds patienter med komplexa rehabiliteringsbehov. Behandlingsföljsamhet definieras hur väl patientens beteende överensstämmer med de rekommendationer patienten kommit överens med sin vårdgivare och har betydelse för behandlingsresultatet. Lite är känt idag om prognostiska faktorer för behandlingsföljsamheten vid MMR. Identifiering av hinder som kan förklara varför patienter inte slutför behandling är därför viktigt för att kunna optimera behandlingseffekterna. Syfte: Att undersöka vilka faktorer som hade betydelse för att inte fullfölja ett MMR 2 program hos patienter med komplex långvarig smärta. Metod: Projektet var en prospektiv kohortstudie. Studiepopulation var patienter mellan 18– 67 år med långvarig smärta, som påbörjade ett MMR program mellan 2009–2016, registrerade i det Nationella Registret över Smärtrehabilitering (NRS). Trettiosex variabler fanns tillgängliga, utfallsmåttet var fullfölja eller ej fullfölja MMR. För att identifiera variabler med störst betydelse för behandlingsföljsamhet skapades regressionsmodeller med logistisk regression. Modellens diskriminativa förmåga testades och goodness of fit bedömdes. Resultat: De tre viktigaste faktorerna som ökade odds för att inte slutföra MMR 2 var patienter med hög smärtintensitet, patienter i yngre ålderskategori och låg motivation. Modellens diskriminativa förmåga var undermålig, goodness of fit var inte signifikant. Slutsats: Modellen kan inte predicera utfall för enskilda individer men ger informationen om vilka faktorer som historiskt har varit viktiga. På sikt kan identifiering av faktorer som försämrar följsamheten bidra till att anpassa MMR program och därmed skapa bättre förutsättningar så att flera patienter fullföljer rehabiliteringen. / Background: Prolonged pain is common and causes great suffering. Multimodal rehabilitation (MMR) is a treatment method that is offered to patients with complex rehabilitation needs. Treatment adherence is defined how well the patient's behavior is consistent with the recommendations the patient has agreed with his / her health care provider and is of importance for the treatment outcome. Little is known today about prognostic factors for treatment adherence at MMR. Identification of obstacles that can explain why patients do not complete treatment is therefore important in order to be able to optimize the treatment effects. Purpose: To investigate which factors were important for the prognosis to not completing MMR 2 treatment in patients with complex long-term pain. Method: The project was a prospective cohort study. Study population were patients aged 18–67 years with long-term pain who started an MMR 2 program between 2009–2016, registered in the National Register for Pain Rehabilitation (NRS). Thirty-six variables were available, the outcome measure was to complete or not complete MMR. To identify variables with the greatest importance for treatment adherence, regression models were created with logistic regression. The model's discriminatory ability was tested, and goodness of fit was assessed Results: The three most important factors that increased odds of not completing MMR were high MPI-PI, patients in the younger age category and low motivation. The model's discriminatory ability was substandard, goodness of fit was not significant. Conclusion: The model cannot predict outcomes on individual level but provides information on which factors historically have been important. In the long term, identification of factors that impair adherence can contribute to adapting MMR programs and thereby create better conditions so that several patients complete the rehabilitation.

Colorectal carcinoma (CRC) is one of the most prevalent malignancies in the Czech Republic. In general, there are two molecular pathways leading to CRC: one is characterized by chromosomal instability, the other by the deficiency in DNA mismatch repair (MMR) genes. MutL homologue 1 (MLH1) gene, a member of the MMR gene-family, represents a key component of the MMR system, responsible for recognition of nucleotide mismatches occurring during DNA replication, and for the recruitment of repair proteins to correct the replication errors. According to literature, somatic mutations in MMR genes, and MLH1 in particular, hallmark sporadic, MMR deficient, CRC cases. We aimed at analyzing somatic events in MLH1 gene and the determination of microsatellite instability (MSI) status in 99 DNA samples from 96 patients with sporadic CRC. Mutations were screened by high resolution melting (HRM) curve analysis. Positive cases in each run were subsequently verified by automated sequencing. Mainly gene variants were found in MLH1 gene: We discovered two new variants, one in exon 2 at position c. 204 C>G, p. Ile68Met (98 C/C, 1C/G) and the other in exon 11 at position c. 973 C>T, p. Arg325Trp (98 C/C, 1 C/T). Only the latter variant c. 973 C>T was identified as somatic mutation. All other variants found in MLH1 gene...

Le syndrome de Lynch est une affection héréditaire autosomique dominante due à des mutations constitutionnelles des gènes du système de réparation de l'ADN (MLH1, MSH2 et MSH6). Depuis 20 ans le réseau français des laboratoires impliqués dans le syndrome de Lynch a identifié un total de 6687 variants. Sept cent sept d'entre eux, essentiellement des variants faux sens, restent encore des variants de signification inconnue (VSI), sans utilité pour le conseil génétique. Le but de notre étude était de développer un algorithme permettant de classer les variants de signification inconnue. Les critères utilisés étaient les données des analyses in silico, phénotypiques (ségrégation, critères d'Amsterdam), l'état de la fonction MMR (MisMatch Repair) dans les cellules tumorales, les tests fonctionnels et d'épissage, ainsi que les données publiées. Cet algorithme a été appliqué à l'ensemble des VSI de la base de données française et nous a permis de caractériser 370 variants . Les données ont été intégrées dans la base de données française UMD des gènes MMR afin d'être disponibles pour la communauté scientifique. Grace aux données collectées par le réseau, nous avons également pu caractériser le phénotype du syndrome de Lynch. Nous avons ainsi confirmé que le cancer du sein ne fait pas partie du spectre du syndrome de Lynch et que les formes de ce syndrome associées à une mutation du gène EPCAM n'entrainent qu'un risque très faible de cancers de l'endomètre, permettant ainsi d'adapter les recommandations de suivi dans cette situation.de l'endomètre, permettant ainsi d'adapter les recommandations de suivi dans cette situation. / Lynch syndrome is a frequent cancer predisposition with an autosomal dominant mode of inheritance and caused by heterozygous germ line mutations in one of the major DNA mismatch repair (MMR) genes (MLH1, MSH2 and MSH6). For 20 years, the French laboratories network involved in Lynch syndrome identified a total of 6687 variations. Among them, 707, mainly missense variations, remained variants of uncertain significance (VUS), thus could not be used for reliable genetic counseling. The aim of our study was to develop an algorithm able to classify VUS, according to the international consensus (IARC). This algorithm was constructed based on criteria usually required for genetic characterization such as in silico analysis, phenotypical data (segregation, Amsterdam criteria's), MMR status in tumor cells, functional assays, splicing analyses and published data. Data were registered in the French database. As a result of this work, we were able to classify 370 variants of the 707 (52,3%). As part of this work, we also analyzed phenotypical data of patients with Lynch syndrome and showed that breast cancer can definitively be excluded from the spectrum of Lynch-related cancers, and that EPCAM mutations, which may lead to Lynch syndrome, are associated with a very low incidence of endometrial cancer and have probably to be considered as an allelic disease with specific clinical recommendations.

L’instabilité des séquences répétées microsatellites du génome (courtes répétitions en tandem d’un à cinq nucléotides) est une conséquence de l’inactivation du système MMR (MisMatch Repair), en charge de la réparation des erreurs produites au cours de la réplication de l’ADN. Cette instabilité est associée à un processus de transformation cellulaire original, observé chez l’homme dans des pathologies tumorales fréquentes, nommées MSI (pour Microsatellite Instability). Les localisations primaires les plus fréquentes de ces tumeurs sont le côlon, l’endomètre et l’estomac. Elles peuvent avoir une origine héréditaire (prédisposition familiale ; syndrome de Lynch et apparentés), mais sont dans la majorité des cas de survenue sporadique. La transformation des cellules MMR-déficientes s’observe dans le contexte de l’accumulation de nombreuses mutations somatiques dans l’ADN tumoral. Certaines ont un caractère oncogénique en favorisant la troncature et la perte de fonction de gènes suppresseurs de tumeur ou apparentés, impliqués dans des voies de signalisations diverses et qui contiennent des microsatellites codants (mutations indels d’une à deux paires de base, décalant le cadre de lecture, fréquemment rapportées dans ces tumeurs). Les travaux présentés dans le cadre de mon doctorat visent à mieux comprendre le rôle de l’instabilité microsatellitaire dans la tumorigenèse MSI. Ils s’inscrivent dans le contexte du décryptage et de l’analyse des données de séquençage d’exome de 47 cancers colorectaux primitifs MSI. Dans le contexte d’un niveau élevé d’instabilité génomique caractérisant ces tumeurs, la mise au point par mon laboratoire d’accueil de modèles probabilistes a permis de dresser une liste restreinte de gènes, remarquables par le fait qu’ils sont affectés par des mutations somatiques dont les fréquences sont exceptionnellement élevées ou basses dans l’ADN tumoral. Sous l’hypothèse que de tels évènements somatiques affectent des gènes clés de la tumorigenèse MSI colique, j’ai focalisé mes recherches sur les gènes dont les altérations sont peu fréquentes. Brièvement, j’ai pu démontrer le caractère délétère d’un petit nombre d’altérations microsatellitaires codantes dont la survenue semble soumise à une pression de sélection négative (N=13). Mes résultats indiquent que ces mutations semblent fragiliser le phénotype tumoral des cellules dans lesquelles elles surviennent, la perte de fonction des gènes qu’elles affectent conduisant à diverses conséquences délétères en fonction du gène candidat (e.g. sensibilisation à la mort cellulaire, perte des capacités proliférative et migratoire, ralentissement de la croissance tumorale). Ces résultats rapportent pour la première fois et à grande échelle, la sélection négative de mutations dans des tumeurs à forte instabilité génomique MSI. Ils ouvrent de nouvelles voies pour la compréhension de ce mode particulier de transformation cellulaire, et sont potentiellement d’intérêt pour la mise au point de thérapies personnalisées pour les patients. / Since the discovery of a link between mismatch repair (MMR) deficiency and cancer, microsatellite instability (MSI) is thought as a process underlying cell transformation and tumour progression and invasion. MSI tumours are a subset of frequent human neoplasms, both inherited and sporadic, associated with several primary locations (colon, stomach, endometrium…). In MMR-deficient cells, MSI generates hundreds of frameshift mutations in genes (MSI Target Genes, MSI-TGs) containing coding microsatellite sequences (e.g. -1/+1 bp, insertions/deletions, i.e. indels). Some of these mutations affect genes with a role in human carcinogenesis and are thus expected to promote the MSI-driven tumorigenic process. During my PhD, I aimed to decipher the role of MSI in colon tumorigenesis. I exploited exome-sequencing data available in my lab that were generated from the analysis of a series of 47 human MSI primary colorectal cancer (CRC). Through biostatistics analysis and mathematical models that we designed to interpret mutation rates in the context of the high background for instability characterizing MSI in CRC, we identified a few microsatellites containing genes coding mutations that were negatively selected in MSI colon tumours (N=13). Under the hypothesis that these events may have a negative impact in colon tumorigenesis, I demonstrated that the silencing of these MSI target genes (siRNA/shRNA) was deleterious for MSI cancer cells using in vitro and in vivo models (impairment of proliferation and/or migration and/or response to chemotherapy and/or tumour growth) (Jonchère*, Marisa*, Greene* et al., submitted).

La inestabilidad de microatélites (MSI) está presente en diferentes tipos tumorales. Generalmente se explica por metilación del promotor de MLH1 o mutaciones germinales en los genes de reparación mismatch repair (MMR) del ADN, causando el conocido síndrome de Lynch. Recientemente, con el cribado universal se ha dado a conocer que un gran porcentaje de tumores con sospecha de síndrome de Lynch, no presentan estas mutaciones. Hasta la fecha, la hipótesis más aceptada para explicar este fenómeno conocido como síndrome Lynch-like, es la doble inactivación de estos genes a nivel somático. Aun así, estos pacientes presentan cáncer colorectal y otros tumores a edades tempranas y en muchos casos, se acompaña de una historia familiar de cáncer colorectal, que sugiere un origen hereditario. Objetivos: Elucitar las bases moleculares responsables de la pérdida de función del sistema MMR en casos de sospecha de Síndrome de Lycnh sin mutaciones germinales en estos genes. Estudio germinal: Identificar nuevas mutaciones germinales en genes reparadores del ADN que puedan estar implicadas en el desarrollo de inestabilidad de microsatélites. Estudio somático: Realizar una caracterización molecular de los tumores con MSI para identificar los eventos moleculares que pueden impactar el comportamiento tumoral y el manejo clínico. Materiales y métodos: Se analizó el exoma germinal de 100 muestras de pacientes Lynch-like y 30 Lynch. Adicionalmente se secuenciaron 37 tumores Lynch-like, 25 Lynch y se utilizó la información de 31 MSI/BRAF del TCGA. Las muestras fueron secuenciadas en Illumina HiSeq y analizadas en un High-performance computer siguiendo los estándares del Yale Center for Genome Analysis (YCGA). Resultados: Estudio germinal: Entre los Lynch-like encontramos 7 Lynch no identificados previamente. El 50% del MSI detectado en Lynch-like podía explicarse por dobles inactivación de los mismos a nivel somático. Además entre los Lynch-like encontramos 15 variantes germinales patogénicas que podían explicar la inestabilidad genética. Dos de ellas con inactivación del otro alelo a nivel somático. Además demostramos que la inactivación de un solo alelo es suficiente para tener un fenotipo deficiente. Estudio somático: no todos los tumores clasificados como MSI por MSI-PCR son presentan esta inestabilidad a nivel global. Al analizar diferentes tumores MSI descubrimos dos clústeres bien diferenciados en base a los perfiles mutacionales detectados. Buscamos mutaciones en genes reparadores y de predisposición al cáncer que pudieran estar marcando esas diferencias en las signatures. Discusión y conclusiones: Estudio germinal: Este estudio confirma el enriquecimiento existente en variantes germinales en los genes reparadores del ADN en pacientes con Síndrome Lynch-like. Variantes en estos genes, conferirían una deficiencia media heredada que promovería y podría inducir una inestabilidad genómica con el paso del tiempo. LA identificación de la variante en RECQL5 como potencial mutación asociada a un fenotipo de cáncer colorrectal familiar. Lynch-like es un grupo heterogéneo a nivel genético, con la característica común de ser MSI. Los tumores Lynch-like pueden ser causados por doble inactivación somática u otros defectos en otros genes reparadores. Además, el grupo incluye Lynch no identificados por los métodos de detección actuales. Estudio somático: Este estudio proporciona un valorable nueva perspectiva en los tumores con deficiencia en el sistema MMR. Muestra la correlación entre los diferentes niveles de MSI global y los perfiles mutacionales y clínicos, lo cual puede tener grandes implicaciones a nivel de diagnóstico y tratamiento de los pacientes.

IEEE 802.16標準中有所謂Mobile Multi-hop Relay（MMR）的概念，然而基地台覆蓋範圍不足及遮蔽效應等問題尚待解決，因此在IEEE 802.16j標準中提出Relay Station（RS）以提升網路傳輸量並增進無線通訊品質。在MMR中由於多了中繼傳輸站來傳遞資料，因此需要有較多的連線頻道，此外也不能保證所有頻道都處於良好狀態，所以會有很高的機率造成資料傳送失敗。混和自動重傳要求（Hybrid Automatic Repeat reQuest, HARQ）的提出便是用來保證資料傳遞成功的機制。HARQ在IEEE 802.16-2004就已被提出，然而我們發現該HARQ機制在802.16j中是不具效率的，而且也並無法確保QoS（Quality of Service）的要求。在本論文中我們改善Chen[4]所提出的Dynamic Pre-allocation HARQ（DP-HARQ）機制，藉由考慮slot分配不足及封包發生非連續錯誤時造成延遲時間增加等問題，並加入具服務品質感知（QoS aware）的機制，以降低整體延遲時間（delay）並能有效提高吞吐量（throughput）。最後，我們以具二個hop以上的模擬環境，證明我們所提出的方法優於802.16j的HARQ機制及Chen[4]的方法。 / Mobile Multihop Relay (MMR) had already been defined in IEEE 802.16 network. The major purpose of MMR is to efficiently extend the coverage of a base station and to solve the shadow fading problem. The Relay Station (RS) defined in IEEE 802.16j is thus proposed to fulfill these goals. Because of the MMR Relay Station, we need more channels to transmit packets. However we cannot guarantee that all chaneels are in good condtion, there might be a high probability of failure transmission. The Hybrid Automatically Repeat reQuest (HARQ) mechanism is therefor proposed to ensure the successful transmission. The HARQ proposed in IEEE 802.16-2004 is not sufficient in 802.16j. Besides it can not help to meet QoS (Quality of Service) requirements. In this reserch we improve Chen’s [4] Dynamic Pre-allocation HARQ (DP-HARQ) mechanism by considering some problems like lack of slot allocation and packet transmission failure with non-continuous error, etc. We add the QoS aware mechanism to reduce the overall delay time and improve the throughput effectively. Finally, we simulate three hops environment and show that our method outperforms both the standard IEEE 802.16j the HARQ mechanism and Chen’s [4] method.

Chronic Myeloid Leukemia is a kind of blood cancer with around 1 incidence per 100 000 persons/year. After the development of an effective treatment, imatinib, in the late 1990:s, the survival percentage has increased drastically. The high survival has turned the attention to different kinds of treatment responses, which in turn are good prognostic factors to future health status. In this thesis, the focus is on whether or not the patient has achieved a so called major molecular response after 12 month, or not. More precisely, the aim is to find prognostic factors to the 12 month response. In order to find prognostic factors for this binary response variable, a multivariate logistic regression analysis is conducted, with the goal of finding a parsimonious logistic model that describes the data. The analysis is done from a merged dataset from three earlier studies. The prognostic factors in the final model are treatment, 3 month response, and enlarged spleen. However, the residual analysis indicates that the model is incomplete, implying that further research needs to be done.