京都大学 / 新制・課程博士 / 博士(医学) / 甲第24802号 / 医博第4994号 / 新制||医||1067(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 石見 拓, 教授 近藤 尚己, 教授 湊谷 謙司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Background: Drugs are an important part of treating diseases but can also come with its risks. To reduce the risks, a system assisted pharmaceutical validation (SAPVAL) is being developed at Uppsala University Hospital. This will include the generation of alerts regarding different risks, sent to a clinical pharmacist who assesses whether the alerts should be forwarded to a physician or not. One of the risks included is QT prolongation, a relatively uncommon condition which however can result in sudden cardiac death. Aim: The aim was to map the management and the consequences of QT-related risk prescriptions and to determine the clinical relevance of QT-related alerts. Method: A retrospective cross-sectional study was performed at Uppsala University Hospital. It included the review of patients´ electronic health records (EHR) and determination of risk periods. The clinical relevance of the alerts was assessed by a physician and a developed flowchart. Results: 65 patients (age=71 ± 15 years, 54% women), and their 85 QT-related alerts were included, with a median risk period of 145 days. Within the risk period, 46 patients had an ECG taken with 35% having one or more prolonged QTc ≥ 480 ms. The risk of QT prolongation had been noticed or mitigated for 23% of the 65 patients. 89% of the alerts were concluded to be clinically relevant. Conclusion: The management and documentation of QT-related risks could be improved. It is also important to further study QT-related risk factors to better assess which patients are at the highest risk.

No description available.

Thesis (DMed (Medicine. Internal Medicine))--University of Stellenbosch, 2007. / Background Although great progress has been made in defining genes conferring the majority of genetic risk in Long QT Syndrome (LQTS) patients, there remains a substantial challenge to explain the widely observed variability in disease expression and phenotype severity, even among family members, sharing the same mutation. Identifying clinical and genetic variables capable of influencing/predicting the clinical phenotype of LQTS patients would allow a more accurate risk stratification, important for determining prognosis, selecting patients for the most appropriate therapy, and counseling asymptomatic mutation carriers (MCs). To address these questions an Italian LQT2 family and a South African Founder LQT1 population have been used. Methods and Results Italian LQT2 family. The proband, a 44-yr-old white woman, presented with ventricular fibrillation and cardiac arrest. Intermittent QT prolongation was subsequently observed and LQT2 was diagnosed following the identification of a missense KCNH2 mutation (A1116V). The proband also carried the common KCNH2 polymorphism K897T on the non-mutant allele. Relatives who carried A1116V without K897T were asymptomatic but some exhibited transient mild QTc prolongation suggesting latent disease. Expression studies in Chinese Hamster Ovary (CHO) cells, demonstrated that the presence of KCNH2-K897T is predicted to exaggerate the IKr reduction caused by the A1116V mutation. These data explain why symptomatic LQTS occurred only in the proband carrying both alleles. South African LQT1 population. The study population involved 320 subjects, 166 MCs and 154 non mutation carriers (NMCs). Off ß-blocker therapy, MCs had a wide range of QTc values (406-676 ms) and a QTc>500 ms was associated with increased risk for cardiac events (OR=4.22; 95%CI 1.12-15.80; p=0.033). We also found that MCs with a heart rate <73 bpm were at significantly lower risk (OR=0.23; 95%CI 0.06-0.86; p=0.035). In a subgroup of patients Baroreflex Sensitivity (BRS) was determined both in presence and absence of ß-blocker therapy. BRS, analyzed in subjects in the 2nd and 3rd age quartiles (age 26-47) to avoid the influence of age, was lower among asymptomatic than symptomatic MCs (11.8±3.5 vs 20.1±10.9 ms/mmHg, p<0.05). A BRS in the lower tertile carried a lower risk of cardiac events (OR 0.13, 95%CI 0.02-0.96; p<0.05). This study also unexpectedly determined that KCNQ1-A341V was associated with greater risk than that reported for large databases of LQT1 patients: A341V MCs were more symptomatic by age 40 (79% vs 30%) and became symptomatic earlier (7±4 vs 13±9 years), both p<0.001. Accordingly, functional studies of KCNQ1-A341V in CHO cells with KCNE1, identified a dominant negative effect of the mutation on wild-type channels. Conclusion Our findings indicate that risk stratification for LQTS patients must be more individually tailored and may have to take into account the specific mutation and probably additional clinical and genetic variables capable of influencing/predicting the clinical phenotype of LQTS patients. As a matter of fact, we have provided evidence that a common KCNH2 polymorphism may modify the clinical expression of a latent LQT2 mutation and the availability of an extended kindred with a common mutation allowed us to highlight that KCNQ1-A341V is associated with an unusually severe clinical phenotype and to identify two autonomic markers, HR and BRS, as novel risk factors.

Le syndrome du QT long congénital (LQTS) est une canalopathie génétique, à l’origine de syncopes et mort subite. Le dépistage génétique identifie des variantes génétiques dans 50-70% des cas, suggérant l’implication d’autres gènes. Nous avons recueilli les caractéristiques des patients avec un LQTS à l’ICM, et recruté 12 patients avec un génotype négatif pour le LQTS pour un séquençage à haut débit des exons afin d’identifier de nouvelles variantes causales. Nous avons développé une approche analytique par étapes : (1) les gènes connus du, (2) les gènes dans des loci identifiés par des études d’association sur le QT, et (3) les gènes montrant la même variante chez plusieurs patients. L’analyse génétique a identifié de nouvelles variantes dans: (1) KCNJ2, ANK2 et AKAP9, et (2) dans NOS1AP. (3) Deux patientes avec des phénotypes semblables présentent la même variante homozygote dans TECRL, un nouveau gène candidat dont le rôle est inconnu. / Long QT syndrome (LQTS) is a channelopathy, causing syncope and sudden death. Genetic testing of individuals identifies genetic variants in up to 50-70% of cases, suggesting that additional genes may be involved. We have identified 50 patients with a diagnosis of LQTS at MHI, and recruited 12 patients reported negative for clinical testing of mutations in LQTS for a whole-exome next generation DNA sequencing approach in order to identify new variants and candidate genes. We have developed a stepwise analytic approach that focuses on (1) the known LQTS genes, (2) the genes in loci identified in genome-wide association studies of QT-interval, and (3) the loci showing variants across multiple patients. Our approach identified new variants in (1) KCNJ2, ANK2 and AKAP9, and (2) in NOS1AP. We identify 2 patients with a very similar phenotype with a homozygous variant in TECRL, an novel candidate gene with an unknown role in LQTS.

No description available.

Tolking och tillgodogörande av datastrukturer, organiserad information ochprogramkodsfiler förekommer frekvent i arbete med mjukvaruutveckling. Dennainformation är lagrad i textbaserad form och dess förståelse kräver stornoggrannhet och tidsinvestering från utvecklarens sida. I syfte att försöka förenklaprocessen beskriver detta examensarbete utvecklingen av en prototyp till ettverktygsprogram, vilket automatiserar tolkning av XML-data och källkodsfiler förprogrammeringsspråken C och C++. Programmet skapar och presenterar sedanen visuell graf av den undersökta strukturen. Algoritmen klarar av att presenteragodtyckligt stora XML-filer samt ett begränsat antal samtidigt inlästakällkodsfiler. Effekterna på tolkningens tidsåtgång och dess tillförlitlighet harutvärderats i en undersökning bland studenter inom mjukvaruutveckling.Resultatet visade på en viss mätbar ökning i antalet korrekta slutsatser somanvändaren drog efter att ha studerat datasammanhanget grafiskt jämfört meddess ursprungliga textform. Tidsåtgången mättes inte mer noggrant än subjektivthos användarna, av vilka en övervägande andel ansåg att tiden förkortades medden grafiska representationen till deras hjälp. Examensarbetet visar attanvändandet av detta eller motsvarande verktyg kan öka tillgodogörandet avdatastrukturer genom att både höja graden av tillförlitligheten hos dennainformation och samtidigt minska tidsåtgången. Däremot är den kvantifierbaravinsten av dessa resultat inte statistiskt säkerställd till en högre grad. / Interpretation and assimilation of data structures, organized information andsource code files are frequently occuring during software development. This kindof information is stored in text-based form and its understanding requires greatthoroughness and investment in time from the developer's part. This thesisdescribes the development of a utility program prototype, which automates theparsing of XML data and source code files from the programming languages Cand C++, in purpose of trying to simplify the interpretation process. The programcreates and presents a visual graph of the structure found, using an algorithmwhich can present arbitrary large XML files as well as a limited number ofconcurrent source code files. The effects on the interpretation time and itsreliablity has been evaluated in a survey among software development students.The result showed a certain increase in the number of correct conclusions fromthe participants' side after studying the visual representation compared to itsorignial text-based form. The amount of time used was not measured other thansubjectively by the users themselves, of which a predominant proportionconsidered a reduction in needed time when using the graphical representation.The thesis shows that the use of this or an equivalent utility can enhance theassimilation of data structures by increasing the rate of reliabilty whilesimultaneously decreasing the needed amount of time. Still, the quantifyable gainsof these results remains statistically largely uncertain.

Introduction: Temporary QT-interval prolongation following intracranial hemorrhage and hydrocephalus has been repeatedly reported in adults. Case: We report a case of excessive QT prolongation with sudden bradycardia resulting in 2:1 atrioventricular conduction in a preterm infant most likely associated with a congenital hydrocephalus. Pathomechanisms are discussed. Conclusion: Congenital hydrocephalus predisposes to excessive QT prolongation in preterm infants.

At present, doctors are not consistent in the way they set the QTc interval in the recovery phase. The main goal of this study was to screen healthy subjects in the two different exercise stress tests and to compare the obtained data from both tests. We wanted to explore whether the heart rate and the QTc interval differs from each other when performed in two different body positions during the recovery phase. The main purpose was to present evidence that would prove or disprove a hypothesis that the figures differ in the different body positions. In the theoretical part we submitted the main information about the heart rate, the QT interval and the relationship between them. We compared the behaviour of the obtained data during the exercise and during the recovery phase. We described the causes of the QTc prolongation and how it is related to the cardiac arrhythmias. In the practical part we examined 20 healthy subjects. Each of them underwent two exercise stress tests on the bicycle ergometer, up to the subjective maximum level of the exercise intensity. The subjects then recovered in two different positions. The first one was a supine position. The second rest position was on the bicycle ergometer set to very low intensity. We found out that the 4-minute recovery phase, the most important for...

På CBH (Skolan för kemi, bioteknologi och hälsa) har en mikro-CT utvecklats, men med förbättringspotential gällande användbarheten. Målet med kandidatexamensarbetet var att förbättra mjukvaran genom att automatisera tre olika aspekter av manuell datahantering: Dels att placera filerna i en mapp med namn kopplat till valda bildtagningsinställningar. Dels att kopiera data via SCP mellan två datorer kopplade till mikro-CT:n. Samt att radera kopierade data från disken som preliminärt sparar filerna. För att möjliggöra en automatisk dataöverföring implementerades ett SSH-nyckelpar med publik nyckelautentisering mellan de två datorerna. Till den befintliga mjukvaran tillades ett skript samt en klass med handhavande över de tre automatiseringsaspekterna. Genom användargränssnittet hämtar klassen inledningsvis information om bildtagningsinställningarna till mappnamnet och när bildtagningen är klar anropar programkoden skriptfilen som utför SCP-kopieringen. Därefter kontrolleras att inga data gått förlorade under överföringen, varefter en radering av de kopierade filerna utförs på den ursprungliga disken. Den nya klassen förbättrar mikro-CT:ns användarvänlighet och underlättar hanteringen av data efter en bildtagning. / At CBH (The School of Engineering Sciences in Chemistry, Biotechnology and Health) a micro-CT has been developed, but the system has potential improvement regarding the usability. The purpose of this bachelor’s thesis was to improve the software by automatizing three aspects of manual data handling: Firstly to place the data in a folder with a name related to the obtained acquisition settings. Secondly to transfer files through SCP between the two computers connected to the micro-CT. Lastly to delete the copied data from the disk that initially saves the files. In order to automate the data transfer an SSH key pair with public key authentication was implemented between the two computers. To the existing software a script as well as a class controlling the three automation aspects were added. From the user interface, the class initially retrieves information about the acquisition settings to the folder name and when the acquisition is complete, the program code calls the script file that performs the SCP transfer. Afterwards a verification is made that no data was lost during the transfer, after which a deletion of the copied files is performed on the original disk. The new class improves the usability of the micro-CT and facilitates the handling of data after an acquisition.