Made available in DSpace on 2015-07-22T20:49:30Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-10-26 / Objetivo: Avaliar em pacientes obesos mórbidos submetidos à derivação gástrica em Y de Roux com anel de contenção há mais de cinco anos: 1) o efeito a longo prazo da cirurgia nas comorbidades; 2) a relação deste efeito com o reganho de massa. Métodos: Foram estudados 140 pacientes (122 mulheres, média de idade de 41,4±10,6 (variação 19 a 62) anos, média de massa de 138,7±23,1 (variação 98 a 220) kg e média de IMC de 52,3±7,9 (variação 37 a 82) kg/m2 submetidos à derivação gástrica em Y de Roux com anel de contenção há cinco anos ou mais. Foram analisadas as seguintes comorbidades: diabetes tipo 2, hipertensão arterial, doença cardiovascular, dislipidemia, apnéia do sono, artropatia e infertilidade, e classificadas em Resolvida, Melhorada, Inalterada ou Piorada no momento de menor massa e no último seguimento. Resultados: Houve diferença significativa na variação da massa nos três momentos do estudo (inicial x mínimo, p<0.001; inicial x final, p<0.001; mínimo x final, p<0.001). Não houve variação do status obtido no momento de menor massa para diabetes tipo 2, doença cardiovascular e infertilidade. Hipertensão arterial mostrou discreta piora dos resultados, porém, sem significância estatística (p=0,8). Houve piora dos resultados para dislipidemia (p=0,012), apnéia do sono (p=0,046) e artropatia (p=0,007). Não há relação entre a variação do IMC e a evolução da comorbidade para infertilidade (p=0,71, massa mínima e p=0,42, massa final). Há relação direta entre a variação do IMC e a evolução das comorbidades para diabetes tipo 2 (p=0,013, massa mínima e p=0,014, massa final), hipertensão arterial (p=0,015, massa mínima e p=0,001, massa final) e doença cardiovascular (p=0,015, massa mínima e p=0,043, massa final). Há relação direta entre a variação do IMC e a evolução das comorbidades apenas no último seguimento para artropatia (p=0,096, massa mínima e p=0,0012, massa final), dislipidemia (p=0,054, massa mínima e p=0,015, massa final) e apnéia do sono (p=0,11, massa mínima e p=0,011, massa final). Conclusões: Em pacientes obesos mórbidos submetidos à derivação gástrica em Y de Roux com anel de contenção há mais de cinco anos: (1) Há manutenção do status obtido para o momento de menor massa para as comorbidades diabetes tipo 2, hipertensão arterial, doença cardiovascular e infertilidade, mas não para dislipidemia, apnéia do sono e artropatia; (2) A melhoria de todas as comorbidades avaliadas, com exceção da infertilidade, associou-se diretamente ao percentual de perda de massa corpórea. / BACKGROUND: Roux-en-Y gastric bypass (RYGB) is considered an effective therapy for weight loss although weight regain may be observed in a long-term follow-up. Obesity-related comorbidities are also well treated by RYGB due to weight loss and intestinal hormone changes. Few studies reported long-term status of comorbidities especially if weight regain is present. This study aims to analyze: (1) the resolution of obesity-related comorbidities after RYGB in a long-term follow-up and (2) its relationship to weight regain. METHODS: 140 patients (mean age 41, 18 male, mean body mass index (BMI) before operation 52 (range 39-82) kg/m2, mean BMI at nadir weight 29 (range 18-46) kg/m2, mean BMI at last follow-up 33 (range 19-49) kg/m2 were followed-up after RYGB for morbid obesity for at least 5 years (mean follow-up 90, range 60-155 months). Diabetes, cardiovascular disease, arterial hypertension, dyslipidemia, sleep apnea, arthropathy, and infertility were present when submitted to surgery in 26 (18%), 14 (10%), 88 (62%), 18 (13%), 83 (59%), 90 (64%), 9 (16%) patients; and in 6 (4%), 8 (5%), 38 (27%), 6 (4%), 45 (32%), 75 (53%), 7 (12%) patients at the Nadir weight, respectively. RESULTS: BMI was significantly different in the 3 periods. Comorbidities resolution was sustained in a long-term follow-up for diabetes, hypertension, cardiopathy and infertility. Comorbidities status was direct related to the % of weight loss for all comorbidities except infertility. CONCLUSION: Our results show that comorbidities remission after RYGB is sustained in the majority of patients in a long-term follow-up. Weight regain is linked to worse results for all comorbidities except infertility. / TEDE / BV UNIFESP: Teses e dissertações

OBJECTIVES The aim of this analysis was to assess the 7-year long-term safety and effectiveness of a randomized comparison of percutaneous coronary intervention (PCI) with sirolimus-eluting stents (SES) versus minimally invasive direct coronary artery bypass (MIDCAB) surgery for the treatment of isolated proximal left anterior descending lesions. BACKGROUND Long-term follow-up data comparing PCI by SES and MIDCAB surgery for isolated proximal left anterior descending lesions are sparse. METHODS Patients were randomized either to PCI with SES (n ¼ 65) or MIDCAB (n ¼ 65). Follow-up data were obtained after 7 years with respect to the primary composite endpoint of death, myocardial infarction, and target vessel revas- cularization. Angina was assessed by the Canadian Cardiovascular Society classification and quality of life with Short Form 36 and MacNew quality of life questionnaires. RESULTS Follow-up was conducted in 129 patients at a median time of 7.3 years (interquartile range: 5.7, 8.3). There were no significant differences in the incidence of the primary composite endpoint between groups (22% PCI vs. 12% MIDCAB; p ¼ 0.17) or the endpoints death (14% vs. 17%; p ¼ 0.81) and myocardial infarction (6% vs. 9%, p ¼ 0.74). However, the target vessel revascularization rate was higher in the PCI group (20% vs. 1.5%; p < 0.001). Clinical symptoms and quality of life improved significantly from baseline with both interventions and were similar in magnitude between groups. CONCLUSIONS At 7-year follow-up, PCI by SES and MIDCAB in isolated proximal left anterior descending lesions yielded similar long-term outcomes regarding the primary composite clinical endpoint and quality of life. Target vessel revascularization was more frequent in the PCI group. (Randomied Comparison of Minimally Invasive Direct Coronary Artery Bypass Grafting and Percutaneous Coronary Intervention With Drug-Eluting Stents in Patients With Proximal Stenosis of the Left Anterior Descending Coronary Artery; NCT00299429) (J Am Coll Cardiol Intv 2014;-:-–-) © 2014 by the American College of Cardiology Foundation.

Einleitung Die aneurysmale Subarachnoidalblutung und ihre Komplikationen stellen eine akut lebensbedrohliche Erkrankung dar. Aufgrund einer hohen Letalität und Morbidität sowie zahlreichen, nicht modifizierbaren Risikofaktoren und fehlenden eindeutigen Präventionsmaßnahmen bleibt diese Krankheit eines der aktuellen Themen der Neurochirurgie. Ziel Ziel dieser Studie ist der Vergleich der Behandlungsergebnisse von Patienten mit aneurysmaler SAB im Klinikum Chemnitz mit aktuellen Literaturdaten. Material und Methode In dieser Arbeit wurden die Daten von insgesamt 200 Patienten mit aneurysmaler Subarachnoidalblutung retrospektiv zusammengefasst. Es wurde eine Populationsanalyse zusammen mit einer Analyse der Korrelationen zwischen verschiedenen Ausgangs- und Verlaufsparametern mit dem allgemeinen Outcome und der Mortalität durchgeführt. Zusätzlich erfolgte eine Follow-up-Analyse der Mortalität und Morbidität bei 108 Patienten. Im statistischen Modell wurden eine Uni- und Bivariatanalyse sowie binäre und multinomiale logistische Regression angewendet. Kaplan-Meier-Kurven in Verbindung mit Cox-Regressionsanalysen wurden zur Beurteilung der Mortalität eingesetzt. Die Ergebnisse wurden mit Literaturdaten verglichen. Das Votum der Ethikkommission der TU Dresden liegt vor (EK 181052014 vom 15.09.2014). Ergebnisse Von 200 Patienten mit einem Durchschnittsalter von 52 J (20-82 J, Medianalter 51 ± 13,6 J) waren 69 Patienten männlich (34,5 %), 131 – weiblich (65,2 %). Das männlich : weiblich Verhältnis betrug 1:1,9. Der klinische Schweregrad der Patienten bei Aufnahme wurde durch die WFNS- und die HH-Skalen evaluiert. Zusätzlich wurden die BNI- und Fisher-Skalen zwecks Evaluation des radiologischen Schweregrades der aSAB eingesetzt. Die Patientendistribution anhand der WFNS-Skala war: WFNS °I – 42,0 %, WFNS °II – 10,0 %, WFNS °II – 16,5 %, WFNS °IV – 22,5%, WFNS °V – 9,0 %. Die Verteilung der Patienten durch die HH-Skala war vergleichbar. 14,5 % der Patienten hatten eine BNI 1, 41,5 % - BNI 2, 32,0 % – BNI 3, 10,5 % - BNI 4, 1,5 % - BNI 5 Blutung. Bei 5,5 % der Patienten lag eine Fisher 1, 10,5 %– Fisher 2, 28,0% - Fisher 3 und 56,0 % - Fisher 4 SAB vor. 77,5 % der Aneurysmata waren klein (<11mm), 18,5 % - groß (11-25mm), 4 % - Giant (>25mm). Die Aneurysmen war meist im Bereich der Acom (41,5 %) und MCA (36,5 %) lokalisiert. Insgesamt 94,5 % der Aneurysmen gehörten zur vorderen Zirkulation. Die primäre Mortalitätsrate betrug 14,5 %. 21,5% der Patienten hatten einen mRS von 0-1 bei Entlassung, 26,0 % - einen mRS 2-3, 38,0 % - einen mRS 4-5. Die mittlere Follow-up-Dauer betrug 71,3 ± 43,2 Monate (Spannweite 2-168 Monate). Von den initial Überlebenden und im Follow-up eingeschlossenen Patienten sind 10,2 % im Verlauf verstorben. 48,1 % hatten einen mRS 0-1, 30,6% mRS 2-3, 11,1 % - mRS 4-5. Diskussion Das Outcome der Patienten mit einer aSAB trägt einen multifaktoriellen Charakter. Die wesentlichen Prädiktoren des Outcomes sind das Alter, der klinische und radiologische Schweregrad der Blutung, die Notwendigkeit der Versorgung eines posthämorrhagischen Hydrozephalus (temporäre und dauerhafte CSF-Ableitung), ein Vasospasmus, DIND und Entgleisun-gen im Serum-Natrium-Spiegel. Die Mortalitätsrate bei der primären Versorgung der Patienten mit einer aSAB in unserer Ko-horte ist um etwa 5 % niedriger als in der Literatur angegeben. Die Mortalitätsrate steigert sich allmählich während der ersten 3 Wochen. Sie wird im Wesentlichen vom Patientengeschlecht, dem klinischen und radiologischen Schweregrad der Blutung, der Notwendigkeit einer Akutversorgung eines aufgetretenen Hydrozephalus, einem Vasospasmus, Entgleisungen im Serum-Natrium-Spiegel sowie der Notwendigkeit einer CSF-Dauerableitung beeinflusst. Die Notwendigkeit einer CSF-Außenableitung bei Aufnahme korreliert mit einem schlechten Zustand der Patienten bei Entlassung und im Follow-up. Der Vasospasmus ist ein unabhängiger Prädiktor eines primär schlechten Outcomes und einer hohen Mortalität, zeigt sich aber als nicht signifikanter Faktor im Langzeit-Follow-up. Die Shuntpflicht ist bei Patienten mit Elektrolytentgleisungen, beidseitigen EVDs und DIND 3-4fach erhöht, beeinflusst jedoch nur die primäre Morbidität/Mortalität. Entgleisungen im Serum-Natrium-Spiegel zeigten sich als unabhängiger Prädiktor eines schlechten Outcomes und erhöhter Mortalität sowohl während des stationären Aufenthaltes, als auch im Langzeit-Follow-up. Die Notwendigkeit einer dekompressiven Kraniektomie wiederspiegelt sich in einem niedrigen BI der Patienten im primären Outcome und ist Prädiktor eines schlechten Outcomes und erhöhter Mortalität im Langzeit-Follow-up.:Verzeichnis der Abkürzungen 5 Kapitel 1: Grundlagen 6 1.1. Einleitung 6 1.2. Definition und Epidemiologie 7 1.3. Ätiologie 8 1.4. Pathogenese 9 1.5. Klinische Manifestation 11 1.6. Diagnostik 13 1.7. Therapie des rupturierten Aneurysmas 15 1.8. Therapie der Komplikationen nach aneurysmaler Subarachnoidalblutung 17 Kapitel 2: Methodik 19 2.1. Allgemein 19 2.2. Patientengut, Aufnahmezustand und Aneurysmacharakterisierungen 20 2.3. Therapie und Krankheitsverlauf 21 2.4. Outcome 22 2.5. Evaluation des aktuellen Zustandes der Patienten 23 2.6. Datenschutz und Statistisches Modell 24 Kapitel 3: Ergebnisse 25 3.1. Populationsanalyse, Ein- und Ausschlusskriterien 25 3.2. Schwere der Subarachnoidalblutung 26 3.3. Charakteristika der rupturierten Aneurysmen 27 3.4. Primäres Outcome 29 3.5. Outcome im Langzeit-Follow-up 31 3.6. Mortalität 33 3.7. Therapiedauer, Hydrozephalus, Elektrolytentgleisungen 36 3.8. DIND und Vasospasmus 38 3.9. Therapieassoziierte Komplikationen und Folgeoperationen 39 Kapitel 4: Diskussion 40 4.1. Mortalität 40 4.2. Outcome 43 4.3. Versorgungspflichtiger Hydrozephalus und Outcome 44 4.4. Vasospasmus, DIND, Elektrolytentgleisungen und Outcome 45 4.5. Limitationen der Studie 47 4.6. Schlussfolgerungen 48 Zusammenfassung 49 Summary 52 Literaturverzeichnis 55 Anlage 1 64 Anlage 2 66 Anlage 3 67 Anlage 4 68 Anlage 5 69 Anhang 1: Mortalitätsdynamik während des stationären Aufenthaltes 72 Anhang 2: Mortalitätsdynamik im Follow-up 74 Anhang 3: Die Abhängigkeit des Outcomes von verschiedenen Faktoren 75 Danksagung 78

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Contexte : De nos jours, la survie à 5 ans des enfants atteints d’un cancer dépasse les 80% en France, ce qui correspond à plus de 50 000 adultes guéris d’un cancer pédiatrique, mais la prévalence des complications à long terme dépasse 60% après un suivi de 30 ans. Dans cette thèse, nous nous sommes intéressés à deux problème de santé distincts : l’un grave et mortel, qui est le risque de cancer secondaire du sein – l’autre, morbide, altérant la qualité de vie et multifactoriel, qui est le risque d’une petite taille à l’âge adulte. Méthodes : L’approche fut différente, essentiellement descriptive avec une analyse de terrain, puis interventionnelle avec la mise en place d’un programme national de dépistage dans une population ciblée pour le cancer du sein secondaire – et analytique avec élaboration d’un modèle de prédiction du risque pour le risque d’une petite taille à l’âge adulte. La population étudiée fut en majeure partie celle de la cohorte française FCCSS, qui sont des adultes guéris d’un cancer pédiatrique solide et traités avant 2000, à laquelle se sont associés quelques centres pour la partie sur le cancer du sein.Résultats : Peu de femmes guéries d’un cancer dans l’enfance et dont le traitement comportait entre autres de la radiothérapie bénéficiaient d’un dépistage (21,2% et 15,4% avec des examens radiologiques). Une proportion importante de carcinomes infiltrants étaient agressifs avec 29% de tumeurs triple négatives. Sur un plan interventionnel, le programme DeNaCaPST a débuté il y a 18 mois et a été confronté au problème du suivi, et de la transition de ces adultes guéris. Concernant le risque de petite taille adulte, nous avons pu préciser que de faibles doses de radiothérapie reçues par l’hypophyse étaient un facteur de risque significatif, que ce risque augmentait avec la dose, qu’un grand champ sur la colonne était également un paramètre important. Etre petit et être jeune au diagnostic du cancer pédiatrique étaient deux facteurs de risque supplémentaires. Par ailleurs, nous avons découvert l’impact de deux molécules de chimiothérapie de la famille des alkylants : le busulfan et la lomustine. Conclusion : Les cancers du sein secondaires rappellent ceux survenant chez les femmes ayant une mutation constitutionnelle BRCA (âge de survenue, incidence cumulée à 50 ans, agressivité des cancers, taux de bilatéralité), ce qui a justifié l’élaboration d’un programme national, inspiré de celui pour les femmes à haut risque du fait d’une mutation génétique pour que « à risque égale, un dépistage égal ». Le réseau de prise en charge nécessaire se met progressivement en place, nécessitant plusieurs amendements au programme. Concernant le risque de petite taille à l’âge adulte, d’autres études sont nécessaires pour confirmer nos découvertes. / Background: Today, the five-year survival rate of children with cancer in France is over 80%, which corresponds to more than 50,000 adults cured of pediatric cancer, but the prevalence of long-term complications exceeds 60% after a 30-year follow-up. In this thesis, we focused on two distinct health problems: one serious and fatal, which is the risk of secondary breast cancer - the other morbid, affecting quality of life and multifactorial, which is the risk of a small height in adulthood. Methods: The approach was different, essentially descriptive with field analysis, followed by intervention with the implementation of a national screening program in a targeted population for secondary breast cancer - and analytical with the development of a risk prediction model for small height risk in adulthood. The population studied was mainly that of the French FCCSS cohort, which are adults cured of childhood solid cancer and treated before 2000, with which some centres have joined for the breast cancer part. Results: Few women cured of childhood cancer and whose treatment included radiotherapy were screened (21.2% and 15.4% with radiological examinations). A significant proportion of infiltrating carcinomas were aggressive with 29% of triple negative tumors. On an intervention level, the DeNaCaPST program began 18 months ago and faced the problem of follow-up and transition of these survivors.Concerning the risk of small adult size, we were able to specify that low doses of radiotherapy received by the pituitary gland were a significant risk factor that this risk increased with the dose, that a large field on the spine was also an important parameter. Being small and being young at diagnostic of childhood cancer were two additional risk factors. In addition, we discovered the impact of two chemotherapy molecules from the alkylant family: busulfan and lomustine. Conclusion: Secondary breast cancers are reminiscent of those occurring in women with a BRCA constitutional mutation (age of onset, cumulative incidence at 50 years, aggressiveness of cancers, bilaterality rate), which justified the development of a national program, inspired by that for women at high risk due to a genetic mutation so that "equal risk, equal screening". The necessary care network is gradually being set up, requiring several amendments to the program. Regarding the risk of small height in adulthood, further studies are needed to confirm our findings.

Les progrès thérapeutiques ont conduit à une augmentation de la survie à 5 ans des enfants traités pour un un cancer et qui dépasse actuellement 80%. En France il a été estimé que 50 000 adultes guéris d’un cancer pédiatrique, mais la prévalence des complications à long terme causées par la maladie et par ses traitement dépasse 60% après un suivi de 30 ans. L’objectif général de cette thèse était de faire avancer les connaissances actuelles sur la mortalité et la morbidité à long terme liées aux cancers pédiatriques.Avec les données de la cohorte FCCSS (French Childhood Cancer Survivor Study) qui inclut des sujets ayant été traités pour entre 1946 et 2000 pour un cancer pédiatrique solide, nous avons observé que le risque de mortalité chez ces patients demeure plus élevé que la population générale même à plus de 40 ans après le diagnostic de leur premier cancer. D’autre part, la mortalité liée plus aux effets à long terme des traitements anticancéreux, plus spécifiquement les seconds cancers et maladies circulatoires, a significativement baissé parmi les sujets traités plus récemment.Par ailleurs, nous avons aussi confirmé le rôle des anthracyclines dans la survenue de l’insuffisance cardiaque et montré que la fraction du volume médian du cœur ayant reçu 30 Gray était beaucoup plus élevés chez les sujets ayant développé une insuffisance cardiaque par rapport aux autres. Nous avons aussi observé que des faibles volumes du cœur (10% du volume du ventricule gauche) ayant reçus ≥30 Gy sont associés à un risque élevé de développer une insuffisance cardiaque. Cette étude est la première à rapporter une relation dose-effet basée sur des indicateurs dose-volume et ces résultats peuvent être utilisés dans la pratique clinique couranteNos travaux ont aussi montré que les patients ayant subi une néphrectomie unilatérale étaient à risque de développer une maladie rénale chronique à très long terme. L’effet de la dose de radiation reçue aux reins différait selon si les patients ayant subi une néphrectomie unilatérale ou non . En effet, une dose au seul rein même <5Gy était associée à un risque élevé de dysfonctionnement rénal. Par ailleurs, grâce aux données du registre REIN, nous avons pu montrer que l’incidence de l’insuffisance rénale terminale liée aux anticancéreux était en train d’augmenter au fil des années. Cependant ces patients étaient moins inscrits en liste d'attente comparés à d’autres malades rénaux et avaient par conséquent un accès très limité à la transplantation rénale.En conclusion, le travail effectué courant cette thèse pourrait aider à identifier les patients à risque accru de complications tardives majeures liées aux traitements anticancéreux. Nos résultats pourraient être utilisés dans la pratique clinique courante pour l’adaptation de la prise en charge thérapeutique des enfants atteints de cancer et pour les recommandations de leurs suivi à long terme. / Advances in treatment have increased the overall 5-year survival rate for childhood cancers to approximately 80%. In France, it estimated that about 50,000 adults have survived childhood cancer. However, previous studies have demonstrated that by the second decade of life, more than 60% of survivor of childhood malignancies (CCS) will suffer from at least one chronic disease related to the treatment they have received.The general objective of this thesis was to advance knowledge about the very long morbidity associated with childhood cancer, with the ultimate target to improve both the long term outcome and quality of life of survivors.Using data from the French Childhood Cancer Survivor Study (FCCSS) cohort, which includes patients treated for a solid pediatric malignancy between 1942 and 2000, we found that that mortality among CCS remained higher than the general population even after more than 40 years of the primary cancer diagnosis. A major finding of this study was that mortality attributed to adverse effects of cancer treatments (secondary primary neoplasm and circulatory disease) declined among patients treated in more recent treatment periods. We also conducted a case control study nested in the FCCSS cohort and further affirmed the role of anthracycline in the occurrence of heart failure. We demonstrated that the median heart volume that received at least 30Gy was higher among heart failure cases and that exposing small volumes of the heart (10% of the volume of the left ventricle) to at least 30Gy was associated with an elevated risk of cardiac failure. This study was the first to derive a dose response relationship based on dose-volume metrics which can be used in current clinical practice.Our results also showed that unilateral nephrectomy was associated with a high risk of renal impairment. The effect of radiation dose to the kidneys was also different among nephrectomized patients for whom any exposure to radiation was associated with an elevated risk of chronic kidney disease even at doses less than 5 Gy.Furthermore, data from the renal epidemiology and information network (REIN) registry allowed us to investigated ESKD (end stage kidney disease) related to nephrotoxic chemotherapy and/or radiation. Our registry-based study showed that ESKD related to nephrotoxic cancer treatment has been steadily increasing over the past decade in the French population. These patients experienced a much lower rate of wait-listing than matched controls with other causes of ESKD, despite similar survival on dialysis.To conclude the results of this thesis are useful to identify survivors of childhood malignancies who are at risk of developing severe long term adverse effects related to the treatment of their primary cancer. Our results could be applied in current clinical practice to help adapt current treatment strategies and improve the long-term follow-up recommendations of childhood cancer survivors.

Syftet med denna studie var att utvärdera behandling med hjälp av elektropalatografi (EPG) och portabel träningsenhet (PTU) hos en person med kvarstående artikulationsproblem. Försökspersonen var en vuxen man med medfödd hemifacial mikrosomi och mikrognati som tidigare genomfört konventionell talträning. En kvasiexperimentell, prospektiv, kontrollerad single subjekt A-B-A design användes. Försökspersonen hade vid träningsstart en tillbakadragen artikulation av /t/ och /d/ till velart/uvulart artikulationsställe med kvarstående svårighet att göra sitt tal förståeligt för sina samtalspartners.  Behandlingseffekten utvärderades genom instrumentell EPG analys av /t/ i enstaka ord före och efter behandling. Analysen visade signifikanta behandlingsresultat där en fortgående förbättring av produktionen av /t/ i medial och final position skedde även fyra år efter avslutad behandling. Perceptuell lyssnarbedömning av tränade och otränade lyssnare uppvisade signifikant förbättrad skattning av t-likhet av målljudet /t/ i medial och final position över tid. Ett mycket svagt samband sågs mellan perceptuell skattning av t-likhet och de analyserade EPG-värdena. Lyssnarskattningen av spontantalet visade en förbättring av förståelighet vid kontroll 4 år efter avslutad träning. Utvärderingen bekräftar tidigare forskning och visar att talträning med EPG är ett effektivt sätt att ge visuell återkoppling i försök att etablera ett korrekt artikulationsmönster, förbättrat tal och ökad förståelighet. Detta provades i föreliggande studie och även om resultaten inte var entydiga, antyddes att metoden kan vara långsiktigt framgångsrik vid sedan lång tid väl etablerade talavvikelser utan tecken på förändring spontant eller efter tidigare träning utan visuell återkoppling. En viktig erfarenhet är således att planera långsiktigt och invänta automatisering av nya artikulationsrörelser som har lång etableringsfas. Träning med EPG föreslås kunna erbjudas vuxna personer med kvarstående artikulationsavvikelser där konventionell träning inte har kunnat ge önskvärda resultat. Nyckelord: Elektropalatografi, behandlingseffekt, hemifacial mikrosomi, artikulationsstörning, långtidsuppföljning, förståelighet / The aim of this study was to evaluate speech therapy using electropalatography (EPG) and portable training unit (PTU) in a subject with persistent articulation errors. The participant was a male adult with congenital hemifacial microsomia and micrognathia who previously had received conventional speech therapy. The subject had a retracted, velar/ uvular articulation of dental plosives with difficulty making speech understandable to listeners. A quasi-experimental prospective, controlled single-subject ABA design was used. Treatment efficacy was assessed by instrumental EPG analysis of  /t/ in single words before and after treatment and showed significant treatment results with a continuing improvement in the production of  /t/ in medial and final position even four years after completion of treatment. Perceptual listen assessment of trained and untrained listeners showed significantly improved estimation of the target /t/ in medial and final position over time. A very weak association was found between the perceptual estimation of t-likeness and the analyzed EPG values. Listener rating of spontaneous speech showed an improvement in intelligibility 4 years after completing training. The evaluation confirms previous research showing that speech therapy with EPG seems effective for providing visual feedback in the attempt to establish a correct articulation pattern, improved speech and enhanced intelligibility. This was investigated in the present study and although the results were not unambiguous, it was indicated that the method can be successful at long persisting well established articulation errors without signs of spontaneous change or after previous training without visual feedback. An important experience is to plan long term and wait for the automation of the new articulation movements that have a long establishment phase. Training with EPG is proposed to be offered to adults with persistent articulation disorders for which conventional therapy has been unable to provide desirable results. Keywords:  Electropalatography, treatment effect, hemifacial microsomia, articulation disorder, long- term follow- up, intelligibility

Introduction - Quel est le modèle de suivi à long terme adapté aux attentes et besoins des jeunes adultes guéris d’un cancer dans l’enfance ? Méthode - Cette étude a pour objectif d’évaluer l’impact sur la santé de jeunes adultes guéris d’un cancer pédiatrique d’un modèle de suivi associant auto-questionnaire et consultation médicale. De jeunes adultes ayant eu un cancer entre 1987 et 1992 en Rhône-Alpes-Auvergne ont été vus en consultation médicale et psychologique de Suivi A Long Terme (SALTO), précédée et suivie d’un auto-questionnaire. De plus, la capacité d’adaptation de leur système nerveux autonome (SNA) a été évaluée afin de déterminer les caractéristiques des sujets dont le SNA était altéré. Résultats - 207 jeunes adultes ont rempli un questionnaire pré-consultation et 197 ont déclaré avoir de nombreuses séquelles, en moyenne 3,4 séquelles, ce qui a été confirmé par l’observation médicale faite chez les 150 consultants (2,6 séquelles observées/sujet). Après la consultation, près de 70% des sujets ont modifié leur nombre de séquelles déclarées. Aucune caractéristique particulière n’a pu être clairement mise en évidence quant aux personnes ayant une capacité de régulation du SNA altérée mais une relation significative a été établie entre SNA altéré et observation d’une séquelle cardiovasculaire (P=0,049). Une enquête de satisfaction a montré une opinion très favorable à la consultation SALTO. Environ 80% des sujets présentant un trouble psychiatrique au moment de la consultation ne bénéficiaient d’aucun suivi psychologique.Conclusion - Un suivi à long terme des jeunes adultes guéris d’un cancer dans l’enfance est nécessaire, faisable et répond à une demande réelle / Introduction - What is the model of long-term follow-up adapted to the expectations and needs of youngadults cured of a childhood cancer? Method – The aim of this study was to estimate the impact of a long-term follow-up care (LTFU) associated self-questionnaire and medical consultation, on the health of young adult survivors of childhood cancer. Young adults with childhood cancer between 1987 and 1992 in Rhône-Alpes-Auvergne were seen during a LTFU medical and psychological consultation (SALTO), which was preceded and followed by a self-questionnaire. Furthermore, the capacity of adaptation of their autonomous nervous system (ANS) was estimated to determine the characteristics of the subjects whose ANS was altered. Results - 207 young adults completed a questionnaire before consultation and 197 of them declared having sequalae, on average each self-reported 3.4 late effects, which was confirmed by a medical observation made at 150 consultations (mean 2.6 observed late effects/subject). After the consultation, about 70 % of the subjects modified their number of self-reported late effects. No particular characteristic was clearly highlighted in people with an altered capacity of ANS regulation but a significant relationship was established between altered ANS and cardiovascular complication (P=0,049). A satisfaction survey showed a very favorable opinion about the SALTO consultation. Approximately 80% of the subjects presenting a psychiatric disorder at the time of the consultation had received no psychological follow-up at this time. Conclusion - Long-term follow-up of young adult survivors of a childhood cancer is necessary, feasible and answers a real need

Polycystic ovary syndrome (PCOS) is a complex clinical condition characterized by hyperandrogenism and chronic oligo/anovulation. Infrequent ovulation and metabolic alterations in women with PCOS are associated with subfertility and probably increased miscarriage rates compared with normal fertile women. The overall risk of developing type 2 diabetes and impaired glucose tolerance (IGT) is three- to sevenfold higher in PCOS women, and the onset of glucose intolerance seems to occur at an earlier age than in healthy controls. Women with PCOS also have several risk factors for cardiovascular disease, although it is unclear whether they actually experience more cardiovascular events than other women. Very few studies assessing the long-term reproductive and metabolic consequences in older women with previously confirmed PCOS have been conducted. In this long-term follow-up of women with PCOS, 84 women with a diagnosis of PCOS between 1987 and 1995 and age at the follow-up &gt; 35 years and an age-matched population-based group of control women participated. Data on reproductive outcome, ovarian reserve, endothelial function, insulin sensitivity and beta-cell function were collected. According to our results most women with PCOS had given birth and the rate of spontaneous pregnancies was relatively high. The rate of miscarriages was not increased in PCOS patients and the ultrasound findings together with increased levels of anti-müllerian hormone suggested that their ovarian reserve is superior to women of similar age. PCOS women displayed signs of endothelial dysfunction, but this was largely due to the increased prevalence of independent risk factors for cardiovascular disease such as increased BMI, triglycerides and blood pressures. IGT and type 2 diabetes occurred more often in PCOS women. Free androgen levels and beta-cell function decreased over time whereas insulin sensitivity remained unchanged. Obesity at young age and progressive weight-gain rendered them more prone to be insulin resistant at the follow-up. Beta-cell function was increased in PCOS women in comparison with control subjects but declined over time. Independent of PCOS phenotype at the index assessment and persistence of PCOS symptoms at the follow-up investigation, premenopausal women with PCOS had lower insulin sensitivity and increased beta cell function in comparison with control subjects. Conclusion: The long-term reproductive outcomes of PCOS are similar compared to women with normal ovaries. Although symptoms and androgen levels are normalized over time, women with PCOS continue to display reduced insulin sensitivity and increased beta-cell function and they also have an increased risk of IGT and type 2 diabetes.

Fear is an innate emotion and an adaptive response to provide protection from potential harm. When fear is excessive and out of proportion in relation to the confronted situation, it can lead to the development of an anxiety disorder. Many individuals feel anxious at some point, but not all experience clinical anxiety or meet the diagnostic criteria of an anxiety disorder. Still, anxiety disorders are the most prevalent form of psychiatric disorder in the general population. More often than not people suffering from one anxiety disorder also present other psychiatric conditions. As of today, cognitive and behavioural treatments have been tested and found to positively affect anxiety disorders, making them the treatment of choice. Nevertheless, many patients do not seek or receive adequate treatment. One common critique of the research trials from which the recommendations for treatments stem is the use of a single protocol targeting only one diagnosis. This is because many people suffer from comorbidities. Another problem connected to the recommendation that cognitive behavioural therapy (CBT) should be the treatment of choice for anxiety disorders is the lack of therapists with adequate training. One possible way of dealing both with the shortcoming of therapists and making CBT more accessible is the use of the Internet. Internet-based CBT (ICBT) has been tested in numerous trials during the last 15 years, showing positive outcomes for a large variety of disorders. Many ICBT trials also make use of a single protocol. Another way of dealing with comorbidities might be to tailor the treatment to let characteristics and preferences of the patient guide the design of the protocol. Little is known about possible effects of tailoring the ICBT, the effects of therapeutic relationships in ICBT, and the effectiveness and cost-effectiveness of these treatments. This thesis is based on three studies on two separate randomized controlled trials (RCTs) using the same set of modules accessible for the tailored protocol. Study I was an RCT investigating treatment effects up to two-year after completion, showing favourable outcomes of the treatment in a self-recruited sample at all measure points. Study II was a secondary analysis exploring possible relations between working alliance and treatment outcome for participants in the treatment group recruited for Study I indicating that working alliance predict outcome in this tailored treatment. The second RCT was an effectiveness trial (Study III) analysing treatment effects and cost-effectiveness of the treatment up to one year post treatment in a primary-care population. This study showed positive treatment effects both regarding symptom reduction and cost-effectiveness, and that effects were sustained at one year post treatment. Conclusions drawn from these studies are that individually tailored ICBT seems to be a feasible approach for patients with anxiety disorders regardless of comorbidities, and a responsible choice in terms of societal costs. / Rädsla är en medfödd känsla och en adaptiv respons för att skydda organismen från potentiell skada. När rädslan blir överdriven och oproportionerlig i relation till den konfronterade situationen, kan det leda till utvecklandet av ångestsyndrom. Många personer upplever någon gång ångest, men inte alla upplever klinisk ångest eller uppfyller de diagnostiska kriterierna för något ångestsyndrom. Trots detta är ångest det vanligaste psykiatriska tillståndet i befolkningen i stort och oftast uppfyller personer som lider av ett ångestsyndrom även andra  psykiatriska tillstånd. Till dags dato har både kognitiva och beteendeinriktade behandlingar testats och visat sig verksamma vid ångestproblem, vilket gjort dem till de behandlingar som rekommenderas för dessa tillstånd. Trots god effekt av behandling söker många patienter ändå inte hjälp, alternativt erhåller inte adekvat behandling. En vanlig kritik mot den forskning från vilka behandlingsrekommendationerna för ångestsyndrom stammar är att många använt en manual eller ett protokoll som riktar sig mot bara en diagnos. Detta på grund av den stora komorbiditeten. Ett annat problem kopplat till rekommendationerna att kognitiv beteendeterapi (KBT) ska vara förstahandsval vid behandling av ångest är bristen på behandlare med adekvat utbildning. Ett möjligt sätt att göra KBT mer tillgängligt är att använda Internet. Internet- förmedlad KBT (IKBT) har prövats i ett stort antal studier de senaste 15 åren dessa har visat positiva resultat vid ett stort antal psykiatriska tillstånd. Flertalet av dessa studier har dock använt ett enda behandlingsprotokoll. En annan möjlighet att hantera komorbiditet kan vara att skräddarsy behandlingen för att låta patientens egenskaper och preferenser vara med och styra utformningen av behandlingsprotokollet. Möjliga effekter av att skräddarsy IKBT är relativt lite undersökt, likaså effekterna av terapeutiska relationer i IKBT samt klinisk effektivitet och kostnadseffektiviteten för dessa behandlingar. Denna avhandling bygger på tre studier från två randomiserade kontrollerade studier med samma uppsättning av moduler tillgängliga för att skräddarsy behandlingsprotokollen. I Studie I undersöktes behandlingseffekter upp till två år efter avslutad behandling i en självrekryterad grupp patienter. Studie II var en sekundäranalys av behandlingsgruppen från Studie I där eventuella samband mellan arbetsallians och behandlingsresultat undersöktes. Den andra randomiserade kontrollerade studien var en prövning av huruvida denna behandling var effektiv för en klinisk population (Studie III) rekryterad via primärvården. Förutom behandlingseffekter undersöktes även kostnadseffektiviteten upp till ett år efter behandlingsavslut. De slutsatser som dras utifrån dessa studier är att skräddarsydd IKBT verkar vara en framkomlig väg för patienter med ångest oavsett komorbiditet, att arbetsalliansen kan vara en faktor som påverkar utfallet, samt att det är ett ansvarsfullt val vad gäller samhälleliga kostnader.