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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
11

Arbetsterapeutens roll för personer med diagnosen myalgisk encefalomyelit/kroniskt trötthetssyndrom : En litteraturöversikt / The role of the Occupational Therapist for people diagnosed with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome : A literature overview

Andersson, Daniel, Hellmark, Emma January 2020 (has links)
Bakgrund: ME/CFS är en allvarlig, kronisk och komplex multisystemsjukdom som ofta och dramatiskt begränsar de drabbade personernas aktivitet. De vetenskapliga beläggen gällande effekten av interventioner riktade mot funktion och funktionsnedsättning är begränsade. Nuvarande kunskapsläge indikerar att arbetsterapeuten kan bidra i vården av personer med ME/CFS, men behov av vidare forskning finns. Syfte: Att med denna litteraturöversikt kartlägga och beskriva aktuell forskning gällande arbetsterapeutens roll för personer med diagnosen ME/CFS. Metod: Datainsamling för litteraturöversikten genomfördes baserat på utarbetade urvalskriterier i tre relevanta databaser; PubMed, CINAHL och PsycINFO och resulterade i tio artiklar, sju kvantitativa och tre kvalitativa studier. Studiernas kvalitet granskades och sedan utfördes en latent innehållsanalys. Resultat: Analysen resulterade i fyra kategorier: Att ge klientcentrerat stöd för strategier i aktivitet, Att justera terapeutiskt förhållningssätt vid aktivitetsanpassning, Att beakta gruppbehandlingens terapeutiska värde samt Att bidra till professionernas teamsamverkan. Slutsats: Arbetsterapeutens kompetens är ett viktigt bidrag i rehabiliteringen på grund av den komplexa aktivitetssituation som diagnosen innebär. / Background: ME/CFS is a serious, chronic and complex systemic disease which often and dramatically limits the activity of the affected. The existing scientific evidence of interventions regarding function and disability is limited. The current level of knowledge indicates that the occupational therapist can contribute to the care for people with ME/CFS, but there is a need for further research. Aim: The aim of this literature overview was to map out and describe current research regarding the role of the occupational therapist for people diagnosed with ME/CFS. Method: Data collection for the literature overview was conducted based on developed selection criterias in three relevant databases; PubMed, CINAHL and PsycINFO which resulted in ten articles, seven quantitative and three qualitative studies. The quality of the included studies were assessed and finally a latent content analysis was completed which resulted in four categories. Result: The content analysis resulted in four categories: to supply a client centered support for strategies in activity, to adjust therapeutic approach in occupational adaptation, to consider the therapeutic value of the group treatment, and to contribute to the professional team collaboration. Conclusion: The expertise of the occupational therapist is an important contribution to rehabilitation due to the complex occupational situation for people diagnosed with ME/CFS.
12

”Det värsta som har hänt, någonsin” -En kvalitativ studie om myalgisk encefalomyelit-sjukas situation samt om individuellt och institutionellt bemötande

Karlsson, Rebecka January 2021 (has links)
In 2020, many Swedes were infected by the COVID-19 virus. The individuals who now suffer from post-COVID conditions have symptoms that resemble the neurological disorder myalgic encephalomyelitis (ME). ME is predicted to increase in the aftermath of the pandemic. Both post-Covid and ME patients commonly encounter misunderstandings, a lack of treatment options and experience difficulties with the Swedish Social Insurance Agency. The purpose of this study is to examine how patients with ME experience their condition to affect the relationships to people in their everyday life and the reception from the health care system as well as the Swedish Social Insurance Agency. The study also examines important factors in coping with the condition. Previous research on the disorder shows difficulties with getting diagnostic legitimacy, a drastically diminished social life, stigma and traumatic experiences with the Swedish Social Insurance Agency. This study is based on six semi-structured video interviews with people who have ME. The analysis of the results has its foundation in Goffman’s dramaturgical theory and his concept of stigma. It further draws on Elias’ and Scotson’s explanation of moral differentiation and Antonovsky’s determining factors of coping with traumatic events. The empiric material shows that having ME leads to a diminished group of friends, which seems to affect the young participants the most. They are also more prone to stigmatization by superficial acquaintances and new contacts. A shared experience among the participants is stigmatization in primary care, which also complicates their encounters with the Swedish Social Insurance Agency. Emotional, practical and financial support make it easier to handle the situation. When needed, it is essential to be able to rest. The situation also becomes easier to handle if the individual is able to create meaning from the new life circumstances. / 2020 smittades många svenskar av covid-19. De individer som drabbats av långtidscovid har en symptombild som liknar den neurologiska sjukdomen myalgisk encefalomyelit (ME). En sjukdom som förutspås öka i spåren av pandemin. Båda dessa patientgrupper möts av oförståelse, brist på behandlingsalternativ och problem med Försäkringskassan. Denna studie ämnar undersöka hur ME-sjuka upplever att sjukdomen påverkar relationen till de människor individen möter i vardagen samt bemötandet från vård och Försäkringskassan. Den fokuserar även på vad som är viktigt för individens hantering av situationen som sjuk. Tidigare forskning om sjukdomen visar på problem med diagnostisk legitimitet, krympta sociala nätverk, stigmatisering och traumatiserande behandling av Försäkringskassan. Studien är baserad på 6 semistrukturerade videointervjuer med ME-patienter. Resultaten har analyserats utifrån Goffmans dramaturgiska perspektiv samt teori om stigma. Vidare används Elias och Scotsons beskrivning av moralisk differentiering samt de faktorer Antonovsky uppger som avgörande för att hantera traumatiska händelser. Empirin visar att ME leder till en reducerad vänskapskrets, vilket de unga lider mest av. Unga är i större mån även utsatta för stigmatisering av ytliga bekanta och nya kontakter. Samtliga deltagare upplever stigmatisering inom primärvården, vilket bidrar till en komplicerad ärendeprocess hos Försäkringskassan. Hanteringen av situationen som sjuk främjas av emotionellt, praktiskt och ekonomiskt stöd, möjlighet att vila samt att utifrån nya förutsättningar finna mening i livet.
13

Narratives of young people living with a diagnosis of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)

Solomons, Wendy January 2016 (has links)
CFS/ME (Chronic Fatigue Syndrome/Myalgic Encephalomyelitis) is a distressing and potentially debilitating condition. It can also be understood as a contested condition, surrounded by controversy about its nature, causes and treatment. Previous research indicates that those affected experience this climate of contestation as a troubling and discrediting assault, not only on the nature of their condition, but also on their identities. However, little attention has been paid to the voices of young people living with CFS/ME. This thesis extends a relatively small literature in new directions, focusing a constructionist, discursive narrative lens on the accounts of ten young people (aged 13-18) living with a diagnosis of CFS/ME. Narratives constructed during repeated interviews over a year, and drawing on multimodal materials collected by participants over that period, were analysed for their content, structure and performance, with reference to the local and broader contexts of their production. This analysis demonstrates that teenagers construct rich, multi-layered narratives with the potential to enhance understanding of their situation and broader features of the social world. As they speak of the onset of illness, attempts to live with enduring, unpredictable symptoms and their psychosocial consequences, and (for some) the possibility of 'moving on' from the worst of illness, this analysis throws new light on how young people's narratives can be understood as simultaneously constructing the condition ('M.E.') and the identities of those involved ('me' and others), in ways that engage with, reflect and resist prevailing discourses. It is argued that the discursive contexts of CFS/ME and adolescence raise particular challenges for young people as they try to construct credible narratives that convey the full extent of their difficulties, while resisting stigmatising identities (eg, as 'complaining', 'lazy' or otherwise 'not normal'). This analysis highlights implications for them, their families and those who work professionally with them; and for the ongoing social construction of CFS/ME in young people.
14

Citometria de fase sólida aplicada ao teste de esterilidade do produto Cloreto de Sódio 0,9% Solução Injetável / Solid-Phase Cytometry applied to sterility test for Sodium chloride 0.9% Injectable Solution Product

Silva, Gisele Badauy Lauria 22 June 2015 (has links)
Submitted by Erika Demachki (erikademachki@gmail.com) on 2017-05-05T18:49:22Z No. of bitstreams: 2 Dissertação - Gisele Badauy Lauria Silva - 2015.pdf: 2934917 bytes, checksum: 7660d0a89305d09f8d7a2fe77bda401e (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-05-10T13:35:58Z (GMT) No. of bitstreams: 2 Dissertação - Gisele Badauy Lauria Silva - 2015.pdf: 2934917 bytes, checksum: 7660d0a89305d09f8d7a2fe77bda401e (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-05-10T13:35:59Z (GMT). No. of bitstreams: 2 Dissertação - Gisele Badauy Lauria Silva - 2015.pdf: 2934917 bytes, checksum: 7660d0a89305d09f8d7a2fe77bda401e (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2015-06-22 / The sterility test is a test that certificate the absence of viable microorganisms in pharmaceutical raw materials, drugs and medical device. The Solid Phase Cytometry method (SFC) is based on the detection of viable cells through the use of viability markers reagents, that permeate the cell membrane and are cleaved by nonspecific esterase enzymes, forming the fluorochromes that are detected by ChemScan RDI® equipment. It is a fast and innovative method for the sterile injecting drugs area. The objective of the study was to evaluate and validate this technology applied to the sterility test, of the product Sodium Chloride (NaCl) 0.9% Injectable Solution, using the ChemScan RDI® equipment (CS RDI®). Eight microorganisms were evaluated, being six compendial (Clostridium sporogenes NCTC 12935 (ATCC 11437), Pseudomonas aeruginosa NCTC 12924 (ATCC 9027), Staphylococcus aureus NCTC 10788 (ATCC 6538), Bacillus subtilis NCTC 10400 (ATCC 6633), Aspergillus brasiliensis NCPF 2275 (ATCC 16404) and Candida albicans NCPF 3179 (ATCC 10231)) and two "in house” microorganisms, obtained from bioburden monitoring of pre sterilization (Micrococcus luteus and Staphylococcus epidermidis). The Solid Phase Cytometry methodology through logistic regression statistical analysis and Chi-square test, showed to be more rapid than the sterility test by membrane filtration (MF) for all tested microorganisms, reducing the analysis time from 14 days to about 3 hours. The method was validated by the use of qualitative parameters: specificity, limit of detection and robustness. / O teste de esterilidade é um ensaio que certifica a ausência de micro-organismos viáveis em insumos farmacêuticos, medicamentos e produtos para saúde. A Citometria de Fase Sólida (CFS) é um método rápido e inovador para a área de medicamentos estéreis injetáveis e é fundamentado na detecção de células viáveis através da utilização de reagentes marcadores de viabilidade, que permeiam a membrana celular e são clivados por enzimas esterases não específicas, formando o fluorocromo, que são detectados pelo equipamento ChemScan RDI®. O objetivo do estudo foi avaliar e validar esta tecnologia aplicada para o teste de esterilidade, no produto Cloreto de Sódio (NaCl) 0,9% Solução Injetável, utilizando o equipamento ChemScan RDI® (CS RDI®). Os micro-organismos padrões utilizados para os testes foram Clostridium sporogenes NCTC 12935 (ATCC 11437), Pseudomonas aeruginosa NCTC 12924 (ATCC 9027), Staphylococcus aureus NCTC 10788 (ATCC 6538), Bacillus subtilis NCTC 10400 (ATCC 6633), Aspergillus brasiliensis NCPF 2275 (ATCC 16404) e Candida albicans NCPF 3179 (ATCC 10231), e dois micro-organismos “in house” obtidos do monitoramento da biocarga pré esterilização, o Micrococcus luteus e Staphylococcus epidermidis. O método de Citometria de Fase Sólida mostrou-se significativamente mais rápido em relação ao teste de esterilidade por filtração em membrana (FM) para todos os micro-organismos testados, reduzindo o tempo de análise de 14 dias para aproximadamente 3 horas. O método foi validado por meio da utilização dos parâmetros qualitativos: especificidade, limite de detecção e robustez.
15

"Vad jag än gör så kostar det..." : Upplevelsen och erfarenheten av ansträngningsutlöst försämring hos personer med Myalgisk Encefalomyelit/Kroniskt Trötthetssyndrom: En empirisk studie baserad på bloggar / “Whatever I do has a price...” : The experiences and perceptions of post-exertional malaise in people with Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome: A qualitative empirical study.

Dardani, Vedije, Lindgren, Sara, Svensson, Evelina January 2021 (has links)
Inledning: Myalgisk encefalomyelit/kroniskt trötthetssyndrom (ME/CFS) kännetecknas som en inflammation i hjärna och ryggmärg och karakteriseras framför allt av ihållande utmattning. Sjukdomen är ingen kultursjukdom eller lokal företeelse utan den förekommer i diverse åldrar, länder och sociala grupper. Ansträngningsutlöst försämring (PEM) är ett kardinalsymtom för sjukdomen. PEM kännetecknas av en förvärring av symtom efter rörelse, ortostatisk eller neuromuskulär stress och/eller kognitiv aktivitet. Syfte: Syftet var att beskriva upplevelsen och erfarenheten av ansträngningsutlöst försämring (PEM) hos personer med ME/CFS. Metod: En kvalitativ empirisk studie baserad på bloggar med deduktiv ansats. Livsvärldsteorin användes som en teoretisk referensram. Resultat: Resultatet visade att personer med ME/CFS beskrev PEM som en påfrestande och dramatisk upplevelse och att det krävdes ständiga anpassningar för att undvika försämringen. Situationen förvärrades ytterligare av ett bristfälligt och empatilöst bemötande inom sjukvården. Slutsats: På grund av känslighet för stimuli behöver varje handling gentemot personer med diagnosen ME/CFS reflekteras över huruvida den är till nytta eller till skada. För att förhindra PEM måste vården anpassas utifrån individuella ansträngningströsklar hos varje enskild person. Vidare forskning behövs om vilka förändringar som krävs för att säkerställa högkvalitativ omvårdnad. / Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized as inflammation of the brain and spinal cord and is characterized above all by persistent fatigue. The disease ME/CFS is not a cultural disease or a local phenomenon and It occurs in various ages, countries and social groups. PEM is characterized by an exacerbation of symptoms after movement, orthostatic or neuromuscular stress and / or cognitive activity. Purpose: The aim of this study was to describe the experiences and the perceptions of post-exertional malaise (PEM) in people with ME/CFS. Method: The study was a qualitative empirical study with a deductive approach based on blogs. Lifeworld was used as a theoretical framework. Result: The results showed that people with ME / CFS described PEM as a stressful and dramatic experience and that constant adjustments were required to avoid this deterioration. The situation was further aggravated by a deficient and unempathetic response in healthcare. Conclusion: Due to abnormal sensitivity to stimuli, each intervention for persons diagnosed with ME / CFS needs to be reflected on whether it is beneficial or harmful. To prevent PEM, healthcare must be adjusted based on the individual effort thresholds of each person. Further research is needed on what improvements are required to ensure high-quality nursing.
16

The Integrity of the circadian time-keeping system in chronic fatigue syndrome.

Tooley, Gregory Allan, mikewood@deakin.edu.au January 2000 (has links)
Chronic Fatigue Syndrome (CFS) is a debilitating condition in which severe, ongoing fatigue is the most prominent of a complex of somatic, psychological and neuropsychological symptoms. The aetiology of CFS remains uncertain and, to date, efforts to distinguish a clear pathophysiological profile for the disorder have been unsuccessful. Current evidence suggests that, rather than being a discrete disease entity with a single cause, CFS is a clinical condition resulting from the interaction of a number of pathophysiological factors, including acute infections, stress and psychiatric disorder. Recently, there has been some interest in the proposition that disordered circadian time-keeping may contribute to the development and/or course of the illness. The rationale for the investigation of circadian factors in CFS is based on the fact that disorders known to be associated with circadian dysregulation, such as jet lag and shiftwork related syndromes have a high degree of symptomatological overlap with CFS. Also, the presence of circadian disturbance could account, in part, for other phenomenological aspects of CFS, including the high rates of comorbid affective disturbance, and the reports of low-level immune dyregulation among sufferers. While several recent studies have produced some evidence of chronobiological dysregulation in CFS patients, much work remains before conclusions can be drawn about the presence, nature and clinical significance of circadian disturbance in CFS. This thesis describes a series of studies that were designed to systematically investigate: 1. whether CFS is associated with a state of circadian dysregulation, and 2. whether circadian dysregulation contributes significantly to the symptomatology of CFS. The first of the 5 studies reported here compared the circadian patterns of sleep-activity of CFS sufferers with those of healthy controls. Results indicated that CFS patients' sleep-activity cycles were significantly phase delayed compared to controls, and that some aspects of their circadian profiles of sleep-activity were related to some measures of sleep-disturbance and well-being. Studies 2 and 3 investigated the relationship between rhythms of sleep-wake and core temperature in CFS patients and healthy controls. The major finding from these studies was that sleep-wake and core temperature rhythms appear to be less effectively synchronised. Further evidence was collected that suggested that there was a relationship between circadian parameters and symptom measures in the CFS group. While this indicated that circadian dysregulation is linked in some way to the symptoms of CFS, assessment of the actual clinical significance of circadian disturbances required the use of a prospective methodology. The final two studies, therefore, report on a placebo-controlled trial of clinical interventions that were designed to restore circadian integrity to CFS patients, in order to see whether this would lead to a reduction in symptom number or severity. Results indicated that, although patients experienced improvements across a range of measures of symptoms and functional capacity, these were small in magnitude, of unlikely clinical significance, and no greater, in general, to improvements reported by patients who underwent placebo treatment. These results, along with those of the earlier studies, are discussed with respect to their implications regarding the presence and significance of circadian dysregulation. It is concluded that, while they provide evidence that CFS is associated with a degree of both internal and external circadian desynchrony, these findings suggest that circadian dysregulation is likely to be only a peripheral, contributor to the processes that generate and maintain the symptom complex. These findings are discussed with respect to how they contribute to our overall understanding of this multi-dimensional condition, and the implications they have for the continuing effort to investigate the causes and treatment of CFS.
17

Signing with Codes

Mas??rov??, Zuzana January 2014 (has links)
Code-based cryptography is an area of classical cryptography in which cryptographic primitives rely on hard problems and trapdoor functions related to linear error-correcting codes. Since its inception in 1978, the area has produced the McEliece and the Niederreiter cryptosystems, multiple digital signature schemes, identification schemes and code-based hash functions. All of these are believed to be resistant to attacks by quantum computers. Hence, code-based cryptography represents a post-quantum alternative to the widespread number-theoretic systems. This thesis summarizes recent developments in the field of code-based cryptography, with a particular emphasis on code-based signature schemes. After a brief introduction and analysis of the McEliece and the Niederreiter cryptosystems, we discuss the currently unresolved issue of constructing a practical, yet provably secure signature scheme. A detailed analysis is provided for the Courtois, Finiasz and Sendrier signature scheme, along with the mCFS and parallel CFS variations. Finally, we discuss a recent proposal by Preetha et al. that attempts to solve the issue of provable security, currently failing in the CFS scheme case, by randomizing the public key construct. We conclude that, while the proposal is not yet practical, it represents an important advancement in the search for an ideal code-based signature scheme.
18

Introduction of the Debye media to the filtered finite-difference time-domain method with complex-frequency-shifted perfectly matched layer absorbing boundary conditions

Long, Zeyu January 2017 (has links)
The finite-difference time-domain (FDTD) method is one of most widely used computational electromagnetics (CEM) methods to solve the Maxwell's equations for modern engineering problems. In biomedical applications, like the microwave imaging for early disease detection and treatment, the human tissues are considered as lossy and dispersive materials. The most popular model to describe the material properties of human body is the Debye model. In order to simulate the computational domain as an open region for biomedical applications, the complex-frequency-shifted perfectly matched layers (CFS-PML) are applied to absorb the outgoing waves. The CFS-PML is highly efficient at absorbing the evanescent or very low frequency waves. This thesis investigates the stability of the CFS-PML and presents some conditions to determine the parameters for the one dimensional and two dimensional CFS-PML.The advantages of the FDTD method are the simplicity of implementation and the capability for various applications. However the Courant-Friedrichs-Lewy (CFL) condition limits the temporal size for stable FDTD computations. Due to the CFL condition, the computational efficiency of the FDTD method is constrained by the fine spatial-temporal sampling, especially in the simulations with the electrically small objects or dispersive materials. Instead of modifying the explicit time updating equations and the leapfrog integration of the conventional FDTD method, the spatial filtered FDTD method extends the CFL limit by filtering out the unstable components in the spatial frequency domain. This thesis implements filtered FDTD method with CFS-PML and one-pole Debye medium, then introduces a guidance to optimize the spatial filter for improving the computational speed with desired accuracy.
19

Narratives of parents living with a child affected by chronic fatigue syndrome/myalgic encephalomyelitis

Payne, Rosalind January 2017 (has links)
Background and Aims: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) remains a poorly understood condition, shrouded by debate, stigma, and uncertainty. Unsurprisingly, the little available research suggests that caring for a Child or Young Person (CYP) affected by the condition can be extremely challenging. While the majority of available literature is quantitative in nature, there is some qualitative research examining the impact of having a CYP with CFS/ME on parents. However, there currently appear to be no studies examining the narratives of parents living with a CYP with CFS/ME. Therefore, this research aimed to hear how parents narrate their experiences of living with a CYP affected by CFS/ME, paying attention to how they construct their identity, and the contested condition. Methodology: This research drew on a qualitative approach that explored the narratives of the participants. A purposive sample of five parents of CYP affected by CFS/ME (5 mothers) was recruited for a single semi-structured interview. The interviews were audio-recorded, transcribed, and analysed using a narrative approach to explore what participants said and how they narrated their accounts. This was then situated within the social and cultural contexts that shaped them. Analysis and Findings: Multiple readings of the narratives allowed me to develop a summary of each individual's narrative account. These were presented, after which similarities and differences across narratives were considered. Analysis identified six areas of collective focus: 'stories of onset and diagnosis', 'stories of battle', 'stories of finding the person/people who can help', 'stories of impact', 'stories of seeking social support', and 'stories of coping and adjustment'. Participants' narratives were heavily influenced by dominant societal discourses surrounding CFS/ME and motherhood, and could be seen as a response to these narratives. Consequently, participants offered particular constructions of the condition, themselves, their CYP, and others that they had come into contact with. These findings are discussed with reference to their potential bearing for clinical practice, strengths and limitations of the methodology, and directions for future research.
20

Investigating transcription, replication and chromatin structure in determining common fragile site instability

Boteva, Lora January 2017 (has links)
Common fragile sites are a set of genomic locations with a propensity to form lesions, breaks and gaps on mitotic chromosomes upon induction of replication stress. While the exact reasons for their fragility are unknown, CFS display instability in a cell-type specific manner, suggesting a substantial contribution from an epigenetic component. CFSs also overlap with sites of increased breakage and deletions in tumour cells, as well as evolutionary breakpoints, implying that their features shape genome stability in vivo. Previously, factors such as delays in replication timing, low origin density and transcription of long genes have been implicated in instability at CFS locations but comprehensive molecular studies are lacking. Chromatin structure, an important factor that fits the profile of cell-type specific contributor, has also not been investigated yet. Throughout their efforts to determine the factors that lead to the appearance of CFS lesions, investigators have focused on a single component at a time, potentially missing out complex interactions between cellular processes that could underlie fragility. Additional difficulties come from the cell-type specificity of CFS breakage: it indicates that only cell type-matched data would be informative, limiting the scope for studies using publicly available data. To perform a comprehensive study defining the role of different factors in determining CFS fragility, I explored replication timing, transcriptional landscapes and chromatin environment across a number of CFSs in two cell types exhibiting differential CFS breakage. Initially, I characterised the patterns of CFS fragility in the two cell types on both the cytogenetic and the molecular level. I then used a FISH-based technique to investigate the process of mitotic compaction at active CFS sites and found that the cytogenetically fragile core of these sites sits within larger regions which display a tendency to mis-fold in mitosis. The aberrant compaction of these regions could be observed on cytogenetically normal metaphase chromosomes, suggesting that finer scale abnormalities in chromosome structure underlie the cytogenetically visible breaks at fragile sites. I also investigated the links between transcription of long genes and CFS fragility using two approaches: I quantified levels of expression across all fragile sites using RNA-seq and modified transcription at a single active CFS using the CRISPR genome engineering methodology. My results indicate a complex interplay between transcription and CFS fragility: no simple linear correlation can be observed, but an increase of transcriptional levels at the active CFS led to a corresponding increase in fragility. To investigate the influence of the cell type specific replication programme and replication stress on CFS instability, I mapped replication timing genome-wide in unperturbed cells and under conditions of replication stress in both cell types. I found that replication stress induces bi-directional changes in replication timing throughout the genome as well as at CFS regions. Surprisingly, the genomic regions showing the most extreme replication timing alterations under replication stress do not overlap with CFS, implying that CFS instability is not fully explained by replication delays as previously suggested. Instead, I observed a range of replication-stress induced timing changes across CFS regions: while some CFSs appear under-replicated, others display switches to both earlier and later replication as well as differential recruitment of both early and late origins, implying that dis-regulation of replication timing and origin firing, rather than simply delays, underlie the sensitivity to CFS regions to replication stress. Finally, I investigated large-scale chromatin states at two active CFSs throughout S phase and into G2, the cell cycle stages most relevant stage for CFS breakage. I found that changes in large-scale chromatin architecture accompany the replication timing shifts triggered by replication stress, raising the possibility that such alterations contribute to instability. In conclusion, I assessed the influence of multiple relevant factors on CFS fragility. I found that bi-directional replication timing changes and alterations in interphase chromatin structure are likely to play a role, converging to promote mitotic folding problems which ultimately result in the well-described cytogenetic lesions on metaphase chromosomes and genomic instability.

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