Objective: Dissecting aneurysms (DAs) of the vertebrobasilar territory manifesting with subarachnoid hemorrhage (SAH) are associated with significant morbi-mortality, especially in the case of re-hemorrhage. Sufficient reconstruction of the affected vessel is paramount, in particular, if a dominant vertebral artery (VA) is impacted. Reconstructive options include stent-assisted coiling and flow diversion (FD). The latter is technically less challenging and does not require catheterization of the fragile aneurysm. Our study aims to report a multicentric experience with FD for reconstruction of DA in acute SAH. Materials and Methods: This retrospective study investigated 31 patients (age: 30–78 years, mean 55.5 years) who had suffered from SAH due to a DA of the dominant VA. The patients were treated between 2010 and 2020 in one of the following German neurovascular centers: University Hospital Leipzig, Katharinenhospital Stuttgart, BG Hospital Bergmannstrost Halle/Saale, and Heinrich-Braun-Klinikum Zwickau. Clinical history, imaging, implanted devices, and outcomes were reviewed for the study. Results: Reconstruction with flow-diverting stents was performed in all cases. The p64 was implanted in 14 patients; one of them required an additional balloon expandable stent to reconstruct severe stenosis in the target segment. One case demanded additional liquid embolization after procedural rupture, and in one case, p64 was combined with a PED. Further 13 patients were treated exclusively with the PED. The p48MW-HPC was used in two patients, one in combination with two additional Silk Vista Baby (SVB). Moreover, one patient was treated with a single SVB, one with a SILK+. Six patients died [Glasgow Outcome Scale (GOS) 1]. Causes of death were periprocedural re-hemorrhage, thrombotic occlusion of the main pulmonary artery, and delayed parenchymal hemorrhage. The remaining three patients died in the acute–subacute phase related to the severity of the initial hemorrhage and associated comorbidities. One patient became apallic (GOS 2), whereas two patients had severe disability (GOS 3) and four had moderate disability (GOS 4). Eighteen patients showed a complete recovery (GOS 5). Conclusion: Reconstruction of VA-DA in acute SAH with flow-diverting stents is a promising approach. However, the severity of the condition is reflected by high overall morbi-mortality, even despite technically successful endovascular treatment.

Background and Purpose: Flow diversion is increasingly used as an endovascular treatment for intracranial aneurysms. In this retrospective multicenter study, we analyzed the safety and efficacy of the treatment of intracranial, unruptured, or previously treated but recanalized aneurysms using Flow Re-Direction Endoluminal Device (FRED) Jr with emphasis on midterm results. Materials and Methods: Clinical and radiological records of 150 patients harboring 159 aneurysms treated with FRED Jr at six centers between October 2014 and February 2020 were reviewed and consecutively included. Clinical outcome was measured by using the modified Rankin Scale (mRS). Anatomical results were assessed according to the O’Kelly-Marotta (OKM) scale and the Cekirge-Saatci Classification (CSC) scale. Results: The overall complication rate was 24/159 (16%). Thrombotic-ischemic events occurred in 18/159 treatments (11%). These resulted in long-term neurological sequelae in two patients (1%) with worsening from pre-treatment mRS 0–2 and mRS 4 after treatment. Complete or near-complete occlusion of the treated aneurysm according to the OKM scale was reached in 54% (85/158) at 6-month, in 68% (90/133) at 1-year, and in 83% (77/93) at 2-year follow-up, respectively. The rates of narrowing or occlusion of a vessel branch originating from the treated aneurysm according to the CSC scale were 11% (12/108) at 6-month, 20% (17/87) at 1-year, and 23% (13/57) at 2-year follow-up, respectively, with all cases being asymptomatic. Conclusions: In this retrospective multicenter study, FRED Jr was safe and effective in the midterm occlusion of cerebral aneurysms. Most importantly, it was associated with a high rate of good clinical outcome.

No description available.

No description available.

[pt] Aneurisma arterial é definido como uma dilatação excessiva do diâmetro normal de uma artéria. O aneurisma da aorta ascendente é geralmente assintomático, portanto, é frequentemente identificado acidentalmente durante exames de imagem de rotina. Após a identificação do aneurisma, caso não haja indicação cirúrgica, o paciente deve ser acompanhado de maneira adequada, pois a ruptura arterial pode ser fatal. A influência do fluxo sanguíneo no remodelamento aórtico é uma importante área de investigação. O objetivo deste estudo é identificar padrões hemodinâmicos em aneurismas de aorta ascendente que possam estar relacionados com o aumento do aneurisma. Cada paciente do estudo foi avaliado em dois momentos distintos. Um modelo tridimensional do aneurisma de aorta ascendente foi gerado para cada paciente a partir de exames de angiotomografia de aorta. O padrão de fluxo foi determinado numericamente com a utilização de um software comercial. Foi demonstrado que o ângulo entre a entrada do fluxo principal e o tronco braquiocefálico pode induzir a uma incidência de um jato incidente na parede da aorta, ocasionado áreas de recirculação na região posterior do jato, além de altos valores de pressão e tensão cisalhante. Os presentes achados hemodinâmicos podem estar relacionados com o remodelamento da aorta ascendente. / [en] Arterial aneurysmal is defined as an excessive dilation of the normal diameter of an artery. Ascending aortic aneurysm is generally asymptomatic, so it is often accidentally identified during routine imaging examinations. After the aneurysm has been identified, if there is no surgical indication, the patient should be followed adequately, since arterial rupture can be fatal. The influence of blood flow on aortic remodeling is an important area of investigation. The aim of this study is to identify hemodynamic patterns in ascending aortic aneurysms that may be related to aneurysm enlargement. Each patient in the study was evaluated at two different times. A three-dimensional model of the ascending aortic aneurysm was generated for each patient from aortic angiotomography examinations. The flow field was numerically determined with a commercial software. It has been shown that the angle between the entrance of the main flow and the brachiocephalic trunk can induce an incident jet on the aortic wall, causing areas of recirculation in the posterior region of the jet, besides high values of pressure and wall shear stress. The present hemodynamics findings may be related to remodeling of the ascending aorta.

Extracellular matrix (ECM) is a key component and regulator of many biological tissues. Several cardiovascular pathologies are associated with significant changes in the composition of the matrix. Better understanding of these pathologies and the physiological phenomenon behind their development depends on reliable methods that can measure and characterize ECM content and structure. In this dissertation, infrared spectroscopic methodologies are developed to study the changes in extracellular matrix of cardiovascular tissue in two cardiovascular pathologies; myocardial infarction and abdominal aortic aneurysm. The specific aims of this dissertation were: 1. To develop a Fourier transform infrared imaging spectroscopy (FT-IRIS) methodology for creating distribution maps of collagen in remodeled cardiac tissue sections after myocardial infarction, and to quantitatively compare maps created by FT-IRIS with conventional staining techniques. 2. To develop an FT-IRIS method to assess elastin and collagen composition in the aortic wall. This will be accomplished using ex vivo animal aorta samples, where the primary ECM components of the wall will be systematically enzymatically degraded. 3. To apply the newly developed FTIR imaging methodology to evaluate changes in the primary ECM components (collagen and elastin) in the wall of human AAA tissues. The infrared absorbance band centered at 1338 cm-1, was used to map collagen deposition across heart tissue sections of a rat model of myocardial infarction, and was correlated strongly in the size of the scar (R=0.93) and local intensity of collagen deposition (R=0.86). In enzymatically degraded pig aorta samples, as a model of ECM degradation in abdominal aortic aneurysm (AAA), partial least squares (PLS) models were created to predict collagen and elastin content in aorta based on collected FTIR spectra and biochemically measured values. PLS models based on FT-IRIS spectra were able to predict elastin and collagen content of the samples with strong correlations (R2=0.90 and 0.70 respectively). Elastin content prediction from IFOP spectra was successful through a PLS regression model with high correlation (R2=0.81). The PLS regression coefficient from the FT-IRIS models were used to map collagen and elastin human AAA biopsy tissue sections, creating a similar map of each component compared to histologically stained images. The mean value of collagen deposition in each tissue was calculated for 13 pairs of AAA samples where stress had been calculated using finite element modeling. In most pairs with stress values higher than 5 N/m2, collagen content was lower in the sample with higher stress value. Collagen maturity had a weak negative correlation (R=-0.35) with collagen content in these samples. These results confirm that infrared spectroscopy is a powerful tool that can be applied to replace or complement conventional methods such as histology and biochemical analysis to characterize ECM components in cardiovascular tissues. Furthermore, infrared spectroscopy has the potential for translation to a clinical environment to examine ECM changes in aorta in a minimally invasive fashion using fiber optic technology. / Mechanical Engineering

Vorliegende Dissertation untersucht den Einfluss einer leichtgradigen Subarachnoidalblutung (SAB, Hunt & Hess Grad 1-2) auf das Outcome der Patienten nach Clipping intrakranieller Aneurysmen im Vergleich zu elektivem Clipping unrupturierter Aneurysmen. Es wurden insgesamt 588 Patienten aus dem Zeitraum zwischen 2009 und 2020 eingeschlossen (458 Patienten mit einer SAB, darunter 104 Patienten mit einer SAB Hunt & Hess Grad 1-2 und Clipping; 130 Patienten mit elektivem Clipping). Eine Populationsanalyse, Dokumentation des Therapieverlaufs und Evaluation des Outcomes der Patienten zum Entlassungszeitpunkt erfolgte retrospektiv anhand der Patientenakten. Nach etwa 6 Jahren im Median erfolgte eine erneute Abfrage der Lebensqualität bei 53 SAB-Patienten und 67 elektiv geclippten (EC) Patienten via Telefoninterview. Das Outcome der Patienten wurde mittels Glasgow Outcome Scale Extended (GOSE), Modified Rankin Scale (mRS), dem Score der World Federation of Neurosurgical Societies (WFNS), dem Barthel Index und dem Short Form 36 – Fragebogen erfasst. Eine statistische Analyse der Einflussfaktoren auf das Outcome der Patienten erfolgte sowohl uni- als auch multivariat mittels Pearson-Chi-Quadrat Test, Mann-Whitney-U Test und Kruskal-Wallis Test. Die Ergebnisse der vorliegenden Studie zeigten einen signifikanten Unterschied im kurzfristigen, sowie langfristigen Outcome der untersuchten Patienten in mehreren Scores. So erreichten unter den elektiv geclippten Patienten zum Entlassungszeitpunkt in der GOSE (7-8 Punkte) und in der mRS (0-1 Punkt) jeweils etwa 70% der Patienten ein sehr gutes Outcome, wohingegen dies für die Patienten mit leichtgradiger aSAB nur für etwa 40% der Patienten galt (p = < 0,001). Auch im Follow-up konnten diese Ergebnisse bestätigt werden (GOSE 7-8 Punkte: 74,6% vs. 54,7%, p = 0,022). Im Score der WFNS zeigte sich dieser Unterschied unmittelbar postoperativ weniger deutlich (93,8% vs. 80,8%). Beide Patientengruppen gaben die meisten Beschwerden aufgrund physischer Einschränkungen und Schmerzen an, während sie sich aufgrund mangelnder Energie und emotionaler Probleme am wenigsten belastet fühlten. Die mediane Zeit bis zur erneuten Aufnahme der Berufstätigkeit betrug in beiden Gruppen etwa ein halbes Jahr. Unerwünschte Ereignisse im Verlauf wurden seltener unter den EC Patienten dokumentiert, darunter die Entwicklung eines Hydrocephalus (1,5% vs. 48,1%) und Vasospasmen (10% vs. 41,3%) (p = < 0,001). Dagegen stellte das Vorliegen eines Hydrocephlaus für die SAB-Patienten einen unabhängigen Risikofaktor für ein schlechteres Outcome in der GOSE dar (HR 8,026, p = 0,010). Nebenbefundlich wiesen die EC Patienten im Durchschnitt mit 58,2 Jahren ein um 5,3 Jahre signifikant höheres Lebensalter auf als die SAB-Patienten. Ein steigendes Lebensalter erwies sich dabei in beiden Gruppen als unabhängiger Risikofaktor für ein schlechtes Outcome im alltäglichen Leben (GOSE 1-4 Punkte) (SAB: HR 0,924, p = 0,017, EC: HR 0,790, p = 0,049). In beiden Gruppen zeigte sich ein Geschlechterverhältnis von 2:1 Frauen zu Männern, wobei das weibliche Geschlecht für EC Patienten ebenfalls als unabhängiger Risikofaktor für ein schlechteres Outcome in der GOSE (1-4 Punkte) galt. Diese Patientengruppe erreichte außerdem weniger Punkte im SF 36 – Fragebogen mit steigendem Aneurysmavolumen sowohl für ihre körperliche (HR 0,949, p = 0,006), als auch für ihre mentale Gesundheit (HR 0,955, p = 0,015). Abschließend konnten unter den EC Patienten vermehrt Nebendiagnosen dokumentiert werden, darunter am häufigsten ein arterieller Hypertonus (71,5% vs. 45,2%) und Nikotinabusus (37,7% vs. 14,4%). Als unabhängige Risikofaktoren für ein schlechteres Outcome (GOSE 1-4 Punkte) konnten allerdings für diese Patienten ein Diabetes mellitus (HR 6,795, p = 0,022) und eine Niereninsuffizienz (HR 7,304, p = 0,027) evaluiert werden. Das Outcome der Patienten nach neurochirurgischem Clipping wird maßgeblich durch das Vorhandensein einer leichtgradigen SAB beeinflusst. Patienten mit einem Blutungsereignis zeigen auch im späteren Verlauf nach mehreren Jahren noch häufiger kognitive und körperliche Einschränkungen als elektiv geclippte Patienten. Dabei scheinen vor allem ein höheres Lebensalter, das weibliche Geschlecht und die Entwicklung unerwünschter Ereignisse im Therapieverlauf einen signifikanten Einfluss auf die Lebensqualität der Patienten zu nehmen. Komorbiditäten der Patienten, sowie die Anzahl und Lokalisation der Aneurysmen zeigten dagegen keinen relevanten Einfluss auf das Outcome der Patienten.:Abkürzungsverzeichnis I Abbildungsverzeichnis II Tabellenverzeichnis III Inhaltsverzeichnis IV 1 Einleitung 1 1.1 Definition und Inzidenz 1 1.2 Pathophysiologie und Risikofaktoren 5 1.3 Klinische Symptomatik und Diagnostik 7 1.4 Therapie von intrakraniellen Aneurysmen 11 1.5 Patientenoutcome 16 2 Methoden 17 2.1 Patientengut 17 2.2 Datenerhebung 18 2.3 Statistische Auswertung 23 3 Ergebnisse 24 3.1 Populationsanalyse 24 3.2 Patientenstatus bei Aufnahme 26 3.3 Charakteristika der Aneurysmen 29 3.4 Primäres Outcome 30 3.5 Outcome im Langzeit-Follow-up 35 4 Diskussion 38 4.1 Einfluss von Alter und Geschlecht auf das Outcome 44 4.2 Einfluss der Nebendiagnosen auf das Outcome 48 4.2.1 Nikotinabusus 48 4.2.2 arterieller Hypertonus 49 4.2.3 Diabetes mellitus 50 4.2.4 Niereninsuffizienz 51 4.2.5 koronare Herzkrankheit 52 4.3 Einfluss der Aneurysmencharakteristik auf das Outcome 54 4.4 Einfluss der unerwünschten Ereignisse auf das Outcome 58 4.4.1 Hydrocephalus 58 4.4.2 Vasospasmus und Infarkt 59 4.4.3 Hirnödem 60 4.4.4 Restperfusion des Aneurysmas und Nachblutungen 61 4.5 Limitationen der Studie 64 5 Zusammenfassung 65 6 Summary 67 7 Literaturverzeichnis 69 8 Anhang 84 8.1 Glasgow Outcome Scale Extended Fragebogen 84 8.2 Barthel Index 87 8.3 Short Form 36 – Fragebogen 89 Anlage 1: Erklärungen zur Eröffnung des Promotionsverfahrens 95 Anlage 2: Bestätigung über Einhaltung der aktuellen gesetzlichen Vorgaben 96

This thesis consists of four self-contained papers. Essay I (with Linuz Aggeborn): Fluoridation of the drinking water is a public policy whose aim is to improve dental health. Although the evidence is clear that fluoride is good for dental health, concerns have been raised regarding potential negative effects on cognitive development. We study the effects of fluoride exposure through the drinking water in early life on cognitive and non-cognitive ability, education and labor market outcomes in a large-scale setting. We use a rich Swedish register dataset for the cohorts born 1985-1992, together with drinking water fluoride data. To estimate the effects, we exploit intra-municipality variation of fluoride, stemming from an exogenous variation in the bedrock. First, we investigate and confirm the long-established positive relationship between fluoride and dental health. Second, we find precisely estimated zero-effects on cognitive ability, non-cognitive ability and education for fluoride levels below 1.5 mg/l. Third, we find evidence that fluoride improves later labor market outcomes, which indicates that good dental health is a positive factor on the labor market. Essay II: I study the associations between cognitive and non-cognitive abilities and mortality using a population-wide dataset of almost 700,000 Swedish men born between 1950 and 1965. The abilities were measured at the Swedish military enlistment at age 18-20. In addition, I investigate if income and education are good proxies for the abilities. The results suggest that both cognitive and non-cognitive abilities are strongly associated with mortality, but that non-cognitive ability is a stronger predictor. The associations are only partly mediated through income and education. For middle and high income earners and individuals with a college education there are no associations with mortality. However, for low income earners and individuals without a college education, both abilities are strongly associated with mortality. The associations are mainly driven by the bottom of the distributions. Essay III (with Matz Dahlberg, Kevin Mani and Anders Wanhainen): We examine how health information affects individuals' well-being using a regression discontinuity design on data from a screening program for an asymptomatic disease, abdominal aortic aneurysm (AAA). The information provided to the individuals is guided by the measured aorta size and its relation to pre-determined levels. When comparing individuals that receive information that they are healthy with those that receive information that they are in the risk zone for AAA, we find no effects. However, when comparing those that receive information that they have a small AAA, and will be under increased surveillance, with those who receive information that they are in the risk zone, we find a weak positive effect on well-being. This indicates that the positive information about increased surveillance may outweigh the negative information about worse health. Essay IV: I estimate the effect of SSRI antidepressants on the risk of mortality for myocardial infarction (MI) patients using Propensity Score Matching on individual health variables such as pharmaceutical drug prescription, patient history and severity of the MI. The effect of antidepressants on mortality is a heavily debated topic. MI patients have an elevated risk of developing depression, and antidepressants are among the most common treatments for depression and anxiety. However, there are indications that some classes of antidepressants may have drug-induced cardiovascular effects and could be harmful for individuals with heart problems, but there is a lack of large-scale studies using credible identification strategies. My findings indicate no increased risk of two-year mortality for MI patients using SSRI. The results are stable for several specifications and robustness checks.

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease with mean age of 59 years. SAH accounts for 5% of all stroke and more than one quarter of potential life years lost through stroke. With the advanced neurosurgical methods of today two thirds of the patients survive. We know, however, that various cognitive, psychiatric and physical impairments are common that affect quality of life, social life, and the ability to work in the aftermath of SAH. The overall aim constituting this PhD dissertation is to better understand some of the challenges often faced by those surviving SAH. Two SAH patient cohorts have been studied. The first followed 96 consecutively included patients during the first year after ictus. Spasticity and cognitive impairment was assessed after 6 months and the Swedish stroke register follow-up form was used to investigate family support and the use of medical and social services. Return to work was assessed at 12 months. The second cohort assessed attention deficits using the test of variables of attention (T.O.V.A.) at 7 months after ictus in 19 patients with moderate to good recovery. Spasticity was just as common in our SAH patients as after other stroke, though it was rarely treated pharmacologically. By assessing cognitive impairment at 6 months after ictus using the Montreal cognitive assessment, 68% of the patients could be correctly predicted as having returned/not returned to work at 12 months. Seventeen percent of the patients had not had a follow-up appointment 6 months after ictus. These patients were older, more often living alone, had a lower quality of life, more depressive symptoms and more cognitive impairment compared to those having had a follow-up appointment. Twenty percent had had a follow-up in primary care. Seventy-eight percent of those with moderate to severe disability were living in their own accommodations. Fifty-eight percent of the patients had attention deficits. Challenges after SAH were common and often dealt with in the home environment of the patients. The results of this thesis highlight the importance of assisting the patients and their relatives in their struggle back to life after SAH.

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