Foundation, Implementation and Evaluation of the MorphoSaurus System: Subword Indexing, Lexical Learning and Word Sense Disambiguation for Medical Cross-Language Information Retrieval

Im medizinischen Alltag, zu welchem viel Dokumentations- und Recherchearbeit gehört, ist mittlerweile der überwiegende Teil textuell kodierter Information elektronisch verfügbar. Hiermit kommt der Entwicklung leistungsfähiger Methoden zur effizienten Recherche eine vorrangige Bedeutung zu. Bewertet man die Nützlichkeit gängiger Textretrievalsysteme aus dem Blickwinkel der medizinischen Fachsprache, dann mangelt es ihnen an morphologischer Funktionalität (Flexion, Derivation und Komposition), lexikalisch-semantischer Funktionalität und der Fähigkeit zu einer sprachübergreifenden Analyse großer Dokumentenbestände. In der vorliegenden Promotionsschrift werden die theoretischen Grundlagen des MorphoSaurus-Systems (ein Akronym für Morphem-Thesaurus) behandelt. Dessen methodischer Kern stellt ein um Morpheme der medizinischen Fach- und Laiensprache gruppierter Thesaurus dar, dessen Einträge mittels semantischer Relationen sprachübergreifend verknüpft sind. Darauf aufbauend wird ein Verfahren vorgestellt, welches (komplexe) Wörter in Morpheme segmentiert, die durch sprachunabhängige, konzeptklassenartige Symbole ersetzt werden. Die resultierende Repräsentation ist die Basis für das sprachübergreifende, morphemorientierte Textretrieval. Neben der Kerntechnologie wird eine Methode zur automatischen Akquise von Lexikoneinträgen vorgestellt, wodurch bestehende Morphemlexika um weitere Sprachen ergänzt werden. Die Berücksichtigung sprachübergreifender Phänomene führt im Anschluss zu einem neuartigen Verfahren zur Auflösung von semantischen Ambiguitäten. Die Leistungsfähigkeit des morphemorientierten Textretrievals wird im Rahmen umfangreicher, standardisierter Evaluationen empirisch getestet und gängigen Herangehensweisen gegenübergestellt

Exploring the role of mitochondria in the changes seen in overall skeletal muscle health associated with ageing and cancer

Purpose: Pathological and age-related declines in both physical fitness and muscle function are well established; however, the role mitochondrial function plays in these changes is less understood. With low skeletal muscle mass and function associated with poorer surgical outcomes, treatments and interventions that can limit the decrease in muscle mass and function seen in the elderly, known as sarcopenia, and in those with cancer, known as cancer cachexia, is vital. Methods: A systematic review and meta-analysis was conducted to determine the impact of sarcopenia on overall and disease-free survival in patients with locally advanced rectal cancer. In addition, young and older healthy volunteers were recruited to determine links between advancing age and declines in global physical fitness and muscle function, as well as investigate if similar declines in mitochondrial function occur. Results: Our systematic review and meta-analysis established that pre-existing sarcopenia was associated with shorter overall and disease-free survival in patients with locally advanced rectal cancer. Within our healthy volunteer cohort, age significantly impacted global physical function (HGS, 1-RM and VO2max) and measures of muscle architecture, with reduced status in older adults. Conversely, mitochondrial function was not different between the age-groups. Conclusions: There is clearly an age-related decline in global physical fitness and muscle function, however it remains unknown to what degree mitochondrial function is implicated in these changes. With sarcopenia and cachexia both having a negative impact on various prognostic outcomes, interventions such as exercise training regimes show promising results in improving cardiovascular fitness and muscle mass/ function in both elderly and cancer patients undergoing surgery. Despite this, if or how these interventions may modify any mitochondrial dysfunction that may exist, especially in cancer patients undergoing neoadjuvant treatment prior to surgery is wholly unknown. More research is required to understand the complex relationship between mitochondrial function and the changes seen in the skeletal muscle of both the elderly and cancer patients

Pre-mRNA splicing manipulation via Antisense Oligomers

Duchenne muscular dystrophy (DMD), the most common lethal neuromuscular disease in childhood, arises from protein-truncating mutations in the dystrophin gene. A deficiency in dystrophin leads to loss of the dystrophin associated protein complex (DAPC), which in turn, renders muscle fibres vulnerable to injury, and eventually leads to muscle loss, necrosis and fibrosis. Although, the dystrophin gene was identified nearly two decades ago, and extensive research has been directed at finding a therapy for DMD, to date, there is still no effective treatment available. One promising molecular approach to treat DNID is antisense oligomer (AO) induced splice intervention. AOs were most widely used to induce RNaseH-mediated gene transcript degradation, however, the development of different backbone chemistries heralds a new generation of AOs that can modify gene transcript splicing patterns. Application of AOs to the dystrophin pre-mRNA to influence exon selection and induce shortened, in-frame dystrophin isoforms is being vigorously pursued. The majority of the work presented here explores the concept of personalised therapies for DMD, whereby oligomers are designed to specifically target individual mutations. The importance of AO-optimisation to obtain AOs capable of inducing efficient dual exon skipping in an established animal model of muscular dystrophy (4CV mouse), which carries a DMD-causing mutation in exon 53, is demonstrated. Removal of both exons 52 and 53 was required to by-pass the mutation, maintain the reading frame and restore dystrophin expression. One of the major challenges of AO-induced splice intervention for therapeutic purposes will be the design and development of clinically relevant oligomers for many different mutations. Various models, including cells transfected with artificial constructs and mice carrying a human dystrophin transgene, have been proposed as tools to facilitate oligomer design for splice manipulation. This thesis investigates the relevance of using mouse models to design AOs for human application, and also explores the use of cultured human myoblasts, from both unaffected humans and a DMD patient, as a means of establishing the most effective therapeutic compound. In addition to induction of exon skipping, the applicability of AOs to promote exon inclusion, by masking possible intronic silencing motifs of survival motor neuron (SMN) pre-mRNA in cultured fibroblasts from a spinal muscular atrophy (SMA) patient, is investigated. This study provides additional information about a novel oligomer target site that could be used in combination with previously identified splice silencing motifs for a molecular therapeutic approach to SMA, and may perhaps open up new avenues of treatment for other genetic disorders, where oIigomers could be used to induce exon inclusion

Exploring the role of mitochondria in the changes seen in overall skeletal muscle health associated with ageing and cancer

Purpose: Pathological and age-related declines in both physical fitness and muscle function are well established; however, the role mitochondrial function plays in these changes is less understood. With low skeletal muscle mass and function associated with poorer surgical outcomes, treatments and interventions that can limit the decrease in muscle mass and function seen in the elderly, known as sarcopenia, and in those with cancer, known as cancer cachexia, is vital. Methods: A systematic review and meta-analysis was conducted to determine the impact of sarcopenia on overall and disease-free survival in patients with locally advanced rectal cancer. In addition, young and older healthy volunteers were recruited to determine links between advancing age and declines in global physical fitness and muscle function, as well as investigate if similar declines in mitochondrial function occur. Results: Our systematic review and meta-analysis established that pre-existing sarcopenia was associated with shorter overall and disease-free survival in patients with locally advanced rectal cancer. Within our healthy volunteer cohort, age significantly impacted global physical function (HGS, 1-RM and VO2max) and measures of muscle architecture, with reduced status in older adults. Conversely, mitochondrial function was not different between the age-groups. Conclusions: There is clearly an age-related decline in global physical fitness and muscle function, however it remains unknown to what degree mitochondrial function is implicated in these changes. With sarcopenia and cachexia both having a negative impact on various prognostic outcomes, interventions such as exercise training regimes show promising results in improving cardiovascular fitness and muscle mass/ function in both elderly and cancer patients undergoing surgery. Despite this, if or how these interventions may modify any mitochondrial dysfunction that may exist, especially in cancer patients undergoing neoadjuvant treatment prior to surgery is wholly unknown. More research is required to understand the complex relationship between mitochondrial function and the changes seen in the skeletal muscle of both the elderly and cancer patients

Evaluation of the Oregon Medicaid Proposal

This report discusses the Oregon legislature that passed the Oregon Basic Health Services Act in 1989, which established three mechanisms for increasing access to health insurance

Special Topics in Information Technology

This open access book presents outstanding doctoral dissertations in Information Technology from the Department of Electronics, Information and Bioengineering, Politecnico di Milano, Italy. Information Technology has always been highly interdisciplinary, as many aspects have to be considered in IT systems. The doctoral studies program in IT at Politecnico di Milano emphasizes this interdisciplinary nature, which is becoming more and more important in recent technological advances, in collaborative projects, and in the education of young researchers. Accordingly, the focus of advanced research is on pursuing a rigorous approach to specific research topics starting from a broad background in various areas of Information Technology, especially Computer Science and Engineering, Electronics, Systems and Control, and Telecommunications. Each year, more than 50 PhDs graduate from the program. This book gathers the outcomes of the best theses defended in 2021-22 and selected for the IT PhD Award. Each of the authors provides a chapter summarizing his/her findings, including an introduction, description of methods, main achievements and future work on the topic. Hence, the book provides a cutting-edge overview of the latest research trends in Information Technology at Politecnico di Milano, presented in an easy-to-read format that will also appeal to non-specialists

Three studies of spine disorders: cost-utility of cognitive behavioral therapy; classification of incident cases; and distribution of treatment cost

Thesis (Ph.D.)--Boston UniversityWe performed three distinct studies of low back pain treatment using a generalizable database of medical and pharmaceutical claims paid by multiple commercial payers. Objectives: (1) Evaluate the cost-utility, from the US commercial payer perspective, of Cognitive Behavioral Therapy (CBT) to manage chronic non-specific low back pain (LBP); (2) Identify unique subgroups ofpeople with incident LBP based on health care utilization; (3) Specify the distribution of costs for people with intervertebral disc herniation (IDH). Methods: (1) We constructed and validated a Markov model with 1-year and 10-year time horizons. We applied rates of service utilization and recovery from a randomized controlled trial assessing CBT to treat chronic LBP, estimated standardized costs from the claims database, and derived utilities and recurrence rates from the literature. (2) Using Latent Class Analysis, we identified four subgroups (classes) ofpeople with LBP based on utilization over 27 months (9 quarters). We modeled increasing numbers of classes and service combinations to build the final model. (3) We compared empirical cost data to four candidate distributions. Results: (1) The incremental cost-utility of CBT, compared to education, was $7197 per QALY in the first year and$5833 per QALY over ten years. (2) We identified four mutually exclusive subgroups ofpatients. Two groups were very likely to receive services in each quarter (Pr>0.70 for 7% and >0.40 for 33%), implying continuing symptoms or frequent relapse. The extremely high utilization group (8%) had >85% likelihood of receiving services, >70% painkillers, in each quarter after the first. Differences in types of service received imply the groups were characterized by pain or disability. Just over half the patients recovered, not receiving services after the frrst quarter. (3) Lognormal distribution fit costs of iDH more closely than Weibull, Gamma, or Exponential. Results for all studies were robust across numerous sensitivity analyses. Conclusions: (1) CBT is a cost-effective approach to managing NSLBP among commercial health plans members, regardless of plan structure. (2) Almost half of people with low back pain are at high risk of continuing symptoms or repeated relapse over 27 months. (3) Costs for IDH follow a Lognormal distribution