Η οξεία αιμορραγία ανώτερου πεπτικού (ΟΑΑΠ) παραμένει ένα από τα πιο συχνά και επείγοντα περιστατικά που συνοδεύεται με αυξημένη νοσηρότητα και θνητότητα. Σκοπός της μελέτης είναι να δειχθούν αλλαγές στα κλινικο-επιδημιολογικά χαρακτηριστικά των ασθενών με ΟΑΑΠ την τελευταία δεκαετία. Συλλέχθηκαν δεδομένα από όλους τους ασθενείς που εισήχθησαν στα νοσοκομεία του Νομού Αχαΐας με ΟΑΑΠ από 1η Ιανουαρίου ως την 31η Δεκεμβρίου 2005 και έγινε αναδρομική σύγκριση με δεδομένα από ασθενείς που εισήχθησαν πριν 10 έτη στην ίδια περιοχή την περίοδο από 1η Ιανουαρίου ως τη 31η Δεκεμβρίου 1995. Η επίπτωση των ασθενών με ΟΑΑΠ και των πεπτικών ελκών και στις δυο περιόδους υπολογίσθηκε με βάση δεδομένων στοιχείων από την Εθνική Στατιστική Υπηρεσία. Παρατηρήθηκε μείωση στην επίπτωση των ασθενών με ΟΑΑΠ από 162,9/100.000 πληθυσμού το 1995, σε 108,2 /100.000 πληθυσμού (RR=0,49, CI 95%=0,37-0,63) το 2005 και στην επίπτωση των ασθενών με αιμορραγία από πεπτικό έλκος (ΑΠΕ) από 104,8 /100.000 πληθυσμού σε 72,5 /100000 (RR=0,49, CI 95%=0,35-0,68). Η μείωση αυτή οφειλόταν κυρίως στη μείωση της επίπτωσης των ασθενών με αιμορραγία από δωδεκαδακτυλικό έλκος (ΑΔΕ)(από 66,7ασθενείς/100.000 σε 35,5/100.000 πληθυσμού), ενώ η επίπτωση της αιμορραγίας από γαστρικά έλκη παρέμεινε στα ίδια επίπεδα (από 33,1 /100.000 σε 34,4 /100.000). Η μέση ηλικία των ασθενών αυξήθηκε από 59,4±17,1 έτη σε 66,1±16,1, p<0.0001, όπως και η συν-νοσηρότητα των ασθενών. Το ποσοστό χρήσης μη στεροειδών αντιφλεγμονωδών φαρμάκων (ΜΣΑΦ) σε αυτούς τους ασθενείς παρέμεινε σταθερό (49,3% vs 48,2%), ενώ η χρήση από του στόματος αντιπηκτικών και αντιαιμοπεταλιακών φαρμάκων αυξήθηκε σημαντικά (από 2,2% σε 6,8%, p=0,001 και από 1,2% σε 10,8%, p<0,0001 αντίστοιχα). Η συχνότητα υποτροπής αιμορραγίας σε ασθενείς με ΑΠΕ ,καθώς και η συχνότητα της επείγουσας χειρουργικής αιμόστασής τους μειώθηκαν σημαντικά (από 12% σε 5,9%, p=0,02 και από 8,9% σε 3,4%, p=0,009, αντίστοιχα). Δεν ανεβρέθηκε στατιστικά σημαντική διαφορά στην συνολική θνητότητα (3,9% το 1995 vs 6,5 % το 2005). Η επίπτωση της ΟΑΑΠ κατά την τελευταία δεκαετία μειώθηκε σημαντικά κυρίως λόγω της μείωσης της επίπτωσης των ασθενών με ΑΔΕ. Οι ασθενείς αυτοί είναι πιο ηλικιωμένοι με αυξημένα συνοδά νοσήματα, αλλά χωρίς να έχει μεταβληθεί στατιστικά η θνητότητά τους τα τελευταία δέκα έτη. / Acute upper gastrointestinal bleeding (AUGIB) remains a common medical emergency and an important cause of morbidity and mortality. The aim of this study was to evaluate changes in clinico-epidemiologic characteristics of patients who presented with AUGIB during the last 10 years. Data from all patients admitted with AUGIB in a defined geographical area in Greece from January 1 to December 31, 2005 (period B) were compared with retrospectively collected data from all patients admitted with AUGIB in the same area 10 years ago, from January 1 to December 31, 1995 (period A). The estimated incidence of AUGIB and peptic ulcer bleeding (PUB) in both periods was calculated using data from the population of this area according to the National Statistical Service. A reduction in the incidence of AUGIB from 162.9/100,000 population in 1995, to 108.2/100,000 population (rate ratio=0.49, confidence interval 95%=0.37-0.63) in 2005 and in the incidence of PUB from 104.8/100,000 population to 72.5/100,000 (rate ratio=0.49, confidence interval 95%=0.35-0.68) were, respectively, observed. This reduction was mainly due to the reduction in the incidence of duodenal ulcer bleeding (from 66.7 cases/100,000 to 35.5/100,000 population), whereas gastric ulcer bleeding incidence remained unchanged (33.1/100,000 vs. 34.4/100,000 cases). Mean age of patients increased from 59.4+/-17.1 years to 66.1+/-16.1, P<0.0001, and the patients' comorbidity. The percentage of NSAIDs' use remained stable (49.3% vs. 48.2%), whereas the use of oral anticoagulants and antiplatelets drugs increased significantly (from 2.2% to 6.8%, P=0.001 and from 1.2% to 10.8%, P<0.0001, respectively). Blood transfusion requirements per patient significantly decreased (from 2.5+/-2 to 2+/-2.4, P=0.009). The rate of rebleeding in PUB patients and emergency surgical hemostasis statistically decreased (from 12% to 5.9%, P=0.02 and from 8.9% to 3.4%, P=0.009, respectively). No significant difference in the overall mortality was observed (3.9% in 1995 vs. 6.5% in 2005). The incidence of AUGIB during the past 10 years significantly decreased, mainly due to the decline in the incidence of bleeding duodenal ulcers. Nowadays, patients are older with more comorbidities, but mortality remains unchanged.

Lower gastrointestinal bleeding (LGIB) can result in serious adverse events. Appropriate risk stratification of LGIB patients can improve their care. Previous risk scores to identify severe LGIB patients have limitations, therefore we developed clinical decision tool to accurately identify LGIB patients presenting to the emergency department (ED) who are at risk for 30-day adverse outcomes that would overcome these limitations. We conducted a health records review and compared two methods of regression analysis on our data in order to develop a clinical decision tool. We identified five risk factors that have a high sensitivity and good predictive value for identifying low risk LGIB patients: age ≥ 75 years, INR ≥2.0, hemoglobin ≤ 100 g/l, ongoing bleeding in the ED and a medical history of colorectal polyps. Future, large, prospective studies should be done to validate the results, after which implementation studies should be conducted.

The field of guideline development has made considerable progress in the past twenty years, particularly after the introduction of GRADE in 2004. However, there are many shortcomings in current guideline development including failure to use GRADE, low quality systematic reviews, and excessive delays from the publication of practice changing evidence to new recommendations. The objective of this thesis is to describe the development of evidence-based recommendations, to document methodological issues that arose and describe how the research team addressed the questions, and to document how the ultimate guidelines contributed to optimization of treatment in clinical practice. The relevant guidelines address the issues of gastrointestinal bleeding prophylaxis and coronavirus disease 2019 (COVID-19). The thesis begins by presenting three methodological issues that arose during the planning and implementation of the guideline process and the initial process of how the research team addressed the challenges. The thesis subsequently presents a published paper that documents recommendations regarding gastrointestinal bleeding prophylaxis in critically ill patients. Then, this thesis presents a published systematic review and meta-analysis addressing efficacy and safety of corticosteroids in COVID-19 based on direct evidence from patients with COVID-19, and indirect evidence from acute respiratory distress syndrome, community-acquired pneumonia, severe acute respiratory syndrome, middle east respiratory syndrome and influenza. Further, the thesis includes a published paper describing recommendations regarding corticosteroids, convalescent plasma and antiviral drugs in COVID-19 on the basis of evidence available very early during the pandemic. This thesis ends by presenting how the methodological issues were ultimately addressed in the relevant guidelines, the importance of the guidelines themselves, and presents perspectives on future research and opportunities in guideline development. / Thesis / Candidate in Philosophy

Acute Upper Gastrointestinal Bleeding (AUGIB) accounts for 7000 deaths in the UK annually and is the single leading indication for transfusion of blood components. A large UK audit in 2007 reported high case fatality and rates of further bleeding. Since many deaths are determined by pre-existing co-morbidity, strategies to improve outcome should be targeted at preventable deaths and therefore focus upon improved control of haemorrhage and prevention of further bleeding, which are investigated in this thesis. Data for the analyses presented originate from the UK national audit of AUGIB, a laboratory study and a cross sectional survey. Five broad themes were investigated including service provision and timing of endoscopy, the use of transcatheter arterial embolisation (TAE) or surgery for refractory bleeding, the impact of coagulopathy on outcome, management of acute variceal haemorrhage (AVH) and haemostatic derangements after AVH, and the use of red blood cells (RBCs). Although there was no evidence of a “weekend effect” for mortality, earlier endoscopy (<12 hours) was associated with improved control of haemorrhage in higher risk patients compared to later endoscopy (>24 hours). TAE was an effective and safe modality for refractory bleeding, but the high post-surgical mortality (29%) raises questions about the appropriateness of case selection for surgery. Coagulopathy after non-variceal haemorrhage was associated with a 5-fold increase in risk-adjusted mortality. Further bleeding after AVH was strikingly high (26%) with notable deficiencies in the use of vasopressors, antibiotics and endotherapy. Global assessments of coagulation demonstrated that thrombin generation after AVH was normal, but clot strength was poor with excessive fibrinolysis. Platelets, fibrinogen and antifibrinolytics improved haemostasis ex vivo but coagulation factor transfusion had no effect. RBC transfusion practice is variable. This work on AUGIB provides new data highlighting areas of sub-optimal care, and informs both current practice and research questions for new interventional trials.

Contexto: A hemorragia digestiva alta (HDA) resulta em 200 a 300 mil internações por ano nos Estados Unidos, com uma mortalidade de 2,5% a 10%. A úlcera péptica representa a causa mais comum de HDA, correspondendo por um terço a metade de todos os casos. Apesar das melhorias na compreensão de sua etiologia, a incidência de sangramento da úlcera péptica, sua complicação mais comum, não se alterou nas últimas décadas. A terapia endoscópica para HDA pode reduzir drasticamente o risco de ressangramento ou sangramento contínuo, a necessidade de cirurgia de urgência, o número de unidades de concentrado de hemácias para transfusão, o tempo de internação hospitalar e a mortalidade. O tratamento endoscópico da úlcera hemorrágica já percorreu um longo caminho desde injeções de adrenalina e outras soluções, o uso da termocoagulação, até a aplicação de dispositivos mecânicos, como o clipe metálico e a ligadura elástica. Objetivo: Permanece por esclarecer qual é a modalidade endoscópica (ou combinação de modalidades) que apresenta os melhores resultados no tratamento da hemorragia digestiva decorrente da úlcera péptica. Portanto, o objetivo desta revisão sistemática é comparar as diferentes modalidades de tratamento endoscópico da HDA decorrente da úlcera péptica, utilizando ensaios clínicos randomizados. Fontes de dados: Os estudos foram identificados através de pesquisa em bases de dados eletrônicas e listas de referência de artigos. As bases de dados pesquisadas foram Medline, Embase, Cochrane, LILACS, Dare e CINAHL. Critérios de elegibilidade de estudo, participantes e intervenções: Os estudos selecionados foram os ensaios clínicos randomizados comparando as diferentes modalidades endoscópicas para o tratamento de pacientes com hemorragia digestiva alta causada por úlcera péptica. Os estudos incluídos avaliaram técnicas endoscópicas contemporâneas de hemostasia: terapia de injeção endoscópica (todas as soluções, simples ou múltiplas), termocoagulação (heater probe, coagulação com plasma de argônio, coagulação com micro-ondas, eletrocoagulação monopolar, bipolar e multipolar), aplicação de clipes metálicos e tratamento combinado. Os desfechos avaliados foram as taxas de hemostasia inicial, ressangramento, cirurgia de urgência e de mortalidade. Avaliação de vieses: Ao nível de cada estudo, os revisores determinaram a adequação da randomização e da alocação; cegamento de pacientes, profissionais de saúde, coletores de dados e avaliadores de resultados; bem como o relato e a extensão das perdas de seguimento. Também foi avaliado se as técnicas de hemostasia endoscópica foram devidamente descritas e, se os desfechos foram adequadamente definidos em cada estudo. A análise de sensibilidade foi realizada quando a heterogeneidade (I2) foi superior a 50% e uma nova meta-análise foi calculada excluindo o(s) estudo(s) discrepante(s). Uma análise adicional foi realizada em cada comparação, incluindo apenas os ensaios de qualidade metodológica mais elevada. Resultados principais: Um total de 28 ensaios clínicos randomizados (envolvendo 2988 pacientes) foram avaliados nesta revisão, eles foram divididos em sete grupos de comparação de acordo com as modalidades estudadas em cada estudo. A terapia de injeção endoscópica como modalidade única foi inferior à sua combinação com o clipe metálico e com a termocoagulação na avaliação de taxa de ressangramento (diferença dos riscos [DR] = -0,10, intervalo de confiança de 95% [IC95%] = -0,18 a -0,03 e [DR] = -0,08, [IC95%] = -0,14 a -0,02, respectivamente) e na necessidade de cirurgia de urgência ([DR] = -0,11, [IC95%] = -0,18 a -0,04 e [DR] = -0,06, [IC95%] = -0,12 para -0,00, respectivamente). A aplicação de clipes metálicos foi superior à terapia de injeção endoscópica na avaliação da taxa de ressangramento ([DR] = -0,13, [IC95%] = -0,19 para -0,08), e os resultados da comparação entre a aplicação de clipes metálicos como monoterapia e a sua combinação com a terapia de injeção endoscópica não apresentaram diferenças estatísticas. A comparação entre o clipe metálico e a termocoagulação encontrou uma considerável heterogeneidade entre as intervenções utilizadas em cada estudo e nos resultados encontrados das meta-análises. A comparação da termocoagulação com a terapia de injeção endoscópica não evidenciou qualquer diferença estatística entre as modalidades, e a combinação delas é superior à técnica de termocoagulação sozinha ao avaliar a taxa de ressangramento ([DR] = -0,11, [IC95%] = -0,21 para - 0,02). Conclusões: A terapia de injeção endoscópica não deve ser empregada isoladamente. A aplicação de clipes metálicos é superior à terapia de injeção endoscópica, e a associação da injeção endoscópica não melhora a eficácia hemostática do uso isolado do clipe metálico. Como modalidade única, uma técnica de termocoagulação tem uma eficácia hemostática semelhante à terapia de injeção endoscópica, e estas modalidades combinadas parecem ser superiores à técnica de termocoagulação sozinha. Portanto, recomendamos a aplicação de clipes metálicos ou o uso combinado de uma terapia de injeção endoscópica com um método de termocoagulação para o tratamento de pacientes com hemorragia digestiva alta por úlcera péptica / Background: Upper Gastrointestinal bleeding (UGIB) results in 200,00 to 300,000 hospital admissions annually in the United States, with a mortality of 2,5% to 10%. Peptic ulcer disease represents the most common cause of UGIB, accounting for a third to a half of all episodes. Despite improvements in the understanding of its etiology, the incidence of bleeding from peptic ulcer disease, the most common complication, has not changed. Endoscopic therapy for active UGIB can dramatically reduce the risk of rebleeding or continued bleeding, the need for surgery, the number of units of packed erythrocytes required for transfusion, the length of hospital stay and mortality. Endoscopic treatment for ulcer bleeding has come a long way from injections of epinephrine and other solutions, the use of thermocoagulation, to the application of mechanical devices such as hemoclips and banding ligator. Objective: It remains unclear which is the endoscopic modality (or combination of modalities) that presents the best results in the treatment of peptic ulcer bleeding. Therefore, the objective of this systematic review is to compare the different modalities of endoscopic hemostatic therapy, using randomized clinical trials. Data sources: Studies were identified by searching electronic databases and scanning reference lists of articles. The searched databases were Medline, Embase, Cochrane, LILACS, DARE and CINAHL. Study eligibility criteria, participants and interventions: The studies selected were the randomized clinical trials comparing different endoscopic modalities for the treatment of patients presenting with acute upper gastrointestinal bleeding caused by peptic ulcer disease. The included trials assessed contemporary endoscopic hemostatic techniques: endoscopic injection therapy (all injectates, single or multiple), thermal coagulation (heater probe, argon plasma and microwave coagulation, monopolar, bipolar and multipolar electrocoagulations), hemoclip placement and combination treatment. The outcomes measured were the rates of initial hemostasis, rebleeding, emergency surgery and overall mortality. Risk of bias assessment: At the study level, the reviewers determined the adequacy of randomization and concealment of allocation; blinding of patients, of health care providers, of data collectors, and of outcome assessors; and the correct report and extent of loss to follow-up. It was also evaluated whether the endoscopic hemostatic techniques were properly described and if the outcomes were appropriately defined in each study. A sensitivity analysis was held when the heterogeneity (I2) was over 50% and a new meta-analysis was calculated excluding the outlier(s). An additional analysis was made at each comparison, including only the higher methodological quality trials. Main results: A total of 28 trials, involving 2988 patients were evaluated in this review, they were divided into seven comparison groups according to the modalities studied in each trial. Injection Therapy as single modality was inferior to its combination with Hemoclip and with Thermal Coagulation Therapy when evaluating rebleeding rate (risk difference [RD] = -0.10, 95% confidence interval [95%CI] = -0.18 to -0.03 and [RD] = -0.08, [95%CI] = -0.14 to -0.02, respectively) and need for emergency surgery ([RD] = -0.11, [95%CI] = -0.18 to -0.04 and [RD] = -0.06, [95%CI] = -0.12 to -0.00, respectively). Hemoclip was superior to Injection Therapy in the evaluation of rebleeding rate ([RD] = -0.13, [95%CI] = -0.19 to -0.08), and the results of the comparison between Hemoclip alone versus its combination with Injection Therapy did not present any statistical differences. The comparison between Hemoclip and Thermal Coagulation encountered a considerable heterogeneity between the trials in the interventions used and in the results found. The comparison of Thermal Coagulation versus Injection Therapy did not evidence any statistical difference between the modalities, and the combination of these is superior to the Thermal Coagulation alone when evaluating rebleeding rate ([RD] = -0.11, [95%CI] = -0.21 to -0.02. Conclusions: Injection therapy should not be used as single modality. The application of Hemoclip is superior to injection therapy, and the combined application of an injectate does not improve the hemostatic efficacy of the use of Hemoclip alone. As single modality, a thermal coagulation technique has a similar hemostatic efficacy as injection therapy, and these combined modalities appear to be superior to thermal coagulation technique alone. Therefore, we recommend the application of Hemoclips or the combined use of an Injection Therapy with a Thermal Coagulation method for the treatment of patients presenting with acute peptic ulcer bleeding

Contexto: A hemorragia digestiva alta (HDA) resulta em 200 a 300 mil internações por ano nos Estados Unidos, com uma mortalidade de 2,5% a 10%. A úlcera péptica representa a causa mais comum de HDA, correspondendo por um terço a metade de todos os casos. Apesar das melhorias na compreensão de sua etiologia, a incidência de sangramento da úlcera péptica, sua complicação mais comum, não se alterou nas últimas décadas. A terapia endoscópica para HDA pode reduzir drasticamente o risco de ressangramento ou sangramento contínuo, a necessidade de cirurgia de urgência, o número de unidades de concentrado de hemácias para transfusão, o tempo de internação hospitalar e a mortalidade. O tratamento endoscópico da úlcera hemorrágica já percorreu um longo caminho desde injeções de adrenalina e outras soluções, o uso da termocoagulação, até a aplicação de dispositivos mecânicos, como o clipe metálico e a ligadura elástica. Objetivo: Permanece por esclarecer qual é a modalidade endoscópica (ou combinação de modalidades) que apresenta os melhores resultados no tratamento da hemorragia digestiva decorrente da úlcera péptica. Portanto, o objetivo desta revisão sistemática é comparar as diferentes modalidades de tratamento endoscópico da HDA decorrente da úlcera péptica, utilizando ensaios clínicos randomizados. Fontes de dados: Os estudos foram identificados através de pesquisa em bases de dados eletrônicas e listas de referência de artigos. As bases de dados pesquisadas foram Medline, Embase, Cochrane, LILACS, Dare e CINAHL. Critérios de elegibilidade de estudo, participantes e intervenções: Os estudos selecionados foram os ensaios clínicos randomizados comparando as diferentes modalidades endoscópicas para o tratamento de pacientes com hemorragia digestiva alta causada por úlcera péptica. Os estudos incluídos avaliaram técnicas endoscópicas contemporâneas de hemostasia: terapia de injeção endoscópica (todas as soluções, simples ou múltiplas), termocoagulação (heater probe, coagulação com plasma de argônio, coagulação com micro-ondas, eletrocoagulação monopolar, bipolar e multipolar), aplicação de clipes metálicos e tratamento combinado. Os desfechos avaliados foram as taxas de hemostasia inicial, ressangramento, cirurgia de urgência e de mortalidade. Avaliação de vieses: Ao nível de cada estudo, os revisores determinaram a adequação da randomização e da alocação; cegamento de pacientes, profissionais de saúde, coletores de dados e avaliadores de resultados; bem como o relato e a extensão das perdas de seguimento. Também foi avaliado se as técnicas de hemostasia endoscópica foram devidamente descritas e, se os desfechos foram adequadamente definidos em cada estudo. A análise de sensibilidade foi realizada quando a heterogeneidade (I2) foi superior a 50% e uma nova meta-análise foi calculada excluindo o(s) estudo(s) discrepante(s). Uma análise adicional foi realizada em cada comparação, incluindo apenas os ensaios de qualidade metodológica mais elevada. Resultados principais: Um total de 28 ensaios clínicos randomizados (envolvendo 2988 pacientes) foram avaliados nesta revisão, eles foram divididos em sete grupos de comparação de acordo com as modalidades estudadas em cada estudo. A terapia de injeção endoscópica como modalidade única foi inferior à sua combinação com o clipe metálico e com a termocoagulação na avaliação de taxa de ressangramento (diferença dos riscos [DR] = -0,10, intervalo de confiança de 95% [IC95%] = -0,18 a -0,03 e [DR] = -0,08, [IC95%] = -0,14 a -0,02, respectivamente) e na necessidade de cirurgia de urgência ([DR] = -0,11, [IC95%] = -0,18 a -0,04 e [DR] = -0,06, [IC95%] = -0,12 para -0,00, respectivamente). A aplicação de clipes metálicos foi superior à terapia de injeção endoscópica na avaliação da taxa de ressangramento ([DR] = -0,13, [IC95%] = -0,19 para -0,08), e os resultados da comparação entre a aplicação de clipes metálicos como monoterapia e a sua combinação com a terapia de injeção endoscópica não apresentaram diferenças estatísticas. A comparação entre o clipe metálico e a termocoagulação encontrou uma considerável heterogeneidade entre as intervenções utilizadas em cada estudo e nos resultados encontrados das meta-análises. A comparação da termocoagulação com a terapia de injeção endoscópica não evidenciou qualquer diferença estatística entre as modalidades, e a combinação delas é superior à técnica de termocoagulação sozinha ao avaliar a taxa de ressangramento ([DR] = -0,11, [IC95%] = -0,21 para - 0,02). Conclusões: A terapia de injeção endoscópica não deve ser empregada isoladamente. A aplicação de clipes metálicos é superior à terapia de injeção endoscópica, e a associação da injeção endoscópica não melhora a eficácia hemostática do uso isolado do clipe metálico. Como modalidade única, uma técnica de termocoagulação tem uma eficácia hemostática semelhante à terapia de injeção endoscópica, e estas modalidades combinadas parecem ser superiores à técnica de termocoagulação sozinha. Portanto, recomendamos a aplicação de clipes metálicos ou o uso combinado de uma terapia de injeção endoscópica com um método de termocoagulação para o tratamento de pacientes com hemorragia digestiva alta por úlcera péptica / Background: Upper Gastrointestinal bleeding (UGIB) results in 200,00 to 300,000 hospital admissions annually in the United States, with a mortality of 2,5% to 10%. Peptic ulcer disease represents the most common cause of UGIB, accounting for a third to a half of all episodes. Despite improvements in the understanding of its etiology, the incidence of bleeding from peptic ulcer disease, the most common complication, has not changed. Endoscopic therapy for active UGIB can dramatically reduce the risk of rebleeding or continued bleeding, the need for surgery, the number of units of packed erythrocytes required for transfusion, the length of hospital stay and mortality. Endoscopic treatment for ulcer bleeding has come a long way from injections of epinephrine and other solutions, the use of thermocoagulation, to the application of mechanical devices such as hemoclips and banding ligator. Objective: It remains unclear which is the endoscopic modality (or combination of modalities) that presents the best results in the treatment of peptic ulcer bleeding. Therefore, the objective of this systematic review is to compare the different modalities of endoscopic hemostatic therapy, using randomized clinical trials. Data sources: Studies were identified by searching electronic databases and scanning reference lists of articles. The searched databases were Medline, Embase, Cochrane, LILACS, DARE and CINAHL. Study eligibility criteria, participants and interventions: The studies selected were the randomized clinical trials comparing different endoscopic modalities for the treatment of patients presenting with acute upper gastrointestinal bleeding caused by peptic ulcer disease. The included trials assessed contemporary endoscopic hemostatic techniques: endoscopic injection therapy (all injectates, single or multiple), thermal coagulation (heater probe, argon plasma and microwave coagulation, monopolar, bipolar and multipolar electrocoagulations), hemoclip placement and combination treatment. The outcomes measured were the rates of initial hemostasis, rebleeding, emergency surgery and overall mortality. Risk of bias assessment: At the study level, the reviewers determined the adequacy of randomization and concealment of allocation; blinding of patients, of health care providers, of data collectors, and of outcome assessors; and the correct report and extent of loss to follow-up. It was also evaluated whether the endoscopic hemostatic techniques were properly described and if the outcomes were appropriately defined in each study. A sensitivity analysis was held when the heterogeneity (I2) was over 50% and a new meta-analysis was calculated excluding the outlier(s). An additional analysis was made at each comparison, including only the higher methodological quality trials. Main results: A total of 28 trials, involving 2988 patients were evaluated in this review, they were divided into seven comparison groups according to the modalities studied in each trial. Injection Therapy as single modality was inferior to its combination with Hemoclip and with Thermal Coagulation Therapy when evaluating rebleeding rate (risk difference [RD] = -0.10, 95% confidence interval [95%CI] = -0.18 to -0.03 and [RD] = -0.08, [95%CI] = -0.14 to -0.02, respectively) and need for emergency surgery ([RD] = -0.11, [95%CI] = -0.18 to -0.04 and [RD] = -0.06, [95%CI] = -0.12 to -0.00, respectively). Hemoclip was superior to Injection Therapy in the evaluation of rebleeding rate ([RD] = -0.13, [95%CI] = -0.19 to -0.08), and the results of the comparison between Hemoclip alone versus its combination with Injection Therapy did not present any statistical differences. The comparison between Hemoclip and Thermal Coagulation encountered a considerable heterogeneity between the trials in the interventions used and in the results found. The comparison of Thermal Coagulation versus Injection Therapy did not evidence any statistical difference between the modalities, and the combination of these is superior to the Thermal Coagulation alone when evaluating rebleeding rate ([RD] = -0.11, [95%CI] = -0.21 to -0.02. Conclusions: Injection therapy should not be used as single modality. The application of Hemoclip is superior to injection therapy, and the combined application of an injectate does not improve the hemostatic efficacy of the use of Hemoclip alone. As single modality, a thermal coagulation technique has a similar hemostatic efficacy as injection therapy, and these combined modalities appear to be superior to thermal coagulation technique alone. Therefore, we recommend the application of Hemoclips or the combined use of an Injection Therapy with a Thermal Coagulation method for the treatment of patients presenting with acute peptic ulcer bleeding

Chapter 1. Deciphering the toxicity of Helicobacter pylori clinical isolates from gastric diseases patients using MALDI-TOF/MS and multivariate analysis. Helicobacter pylori (H. pyloyi) infection is associated with gastric diseases such as gastric polyp, chronic gastritis, gastric ulcer, gastric cancer, etc. In fact, most of the people infected not have the symptoms of gastric diseases due to the high degree of variability of gene with H. pyloyi and the specific immune responses of the hosts. In order to investigate the relationship between H.pylori and gastric diseases, the clinical strains of H. pylori isolated from patients from nine gastric diseases were extracted from the optimized extraction and analysis by MALDI-TOF/MS, then the high reproducible spectra were combined with multivariate statistical analysis including Principal Component Analysis (PCA), Hierarchical Cluster Analysis (HCA), Discriminant Analysis (DA) . In the result of PCA, there is no specific potential marker to discriminate the clinical strains to nine gastric diseases. In the result of HCA, the strains from different gastric diseases were clustered together means they have the similarity of the protein and metabolite. In the result of DA, the strains from gastric and non-gastric cancer were discriminanted by the discriminant function composed of thirty-eight discriminant variables in the spectra. This discriminant function would be confirmed by other clinical strains isolated from gastric diseases patients in the future and then would help to predict the the similarity of the protein and metabolite of the strains isolated from the gastric diseases patients whether gastric cancer or not. Chapter 2. Biomarker discovery in the stools of gastric cancer patients using MALDI-TOF/MS. According to the statistics of Republic 100 years from the Department of Health, cancer was the first of the ten lesding to death. With the modern change of eatiog habbits, gastrointestinal cancer has increased steadily. Gastrointestinal cancer accompanied occult gastrointestinal bleeding, and it is commonly detected by the fecal occult blood test (FOB). FOB including Guaiac-based fecal occult-blood test and immunochemical tests. Guaiac-based fecal occult-blood tests make use of the pseudoperoxidase activity of heme, and the reagent turns blue after oxidation by oxidants or peroxidases in the presence of an oxygen donor such as hydrogen peroxide, so it would have the potential of false-positive result. Immunochemical tests, which use antibodies detect against human hemoglobin with great sensitivity, but the tests are limited by loss of hemoglobin antigenicity at room temperature and require processing in a laboratory. In order to decrease the false-positive of detecting heme and decreasing the cost of the detection against hemoglobin in stools, in the study, we ues the distill water to extract the heme (m/z 616) and hemoglobin in stools and analysis with the reflectron and linear mode of MALDI-TOF/MS. In this study, at first, we used the stimulated stomach acid decomposing the hemoglobin to release the heme, to stimulate the gastrointestinal bleeding. Second, we used the distill water to extract the hemoglobin in stools, and detected by the linear mode of MALDI-TOF/MS, and the detection limit of MALDI-TOF/MS against hemoglobin in stool was better than the immunochemical tests. Third, the same strategy was applied to fifty-nine patients (including nineteen esophageal cancer patients, twenty gastric cancer patients and colorectal cancer patients) stools to detect heme and hemoglobin by MALDI-TOF/MS and the results were compared with the fecal occult blood test. In the detection of heme, MALDI-TOF/MS had not detect heme, but the Guaiac-based fecal occult-blood test had detected, it would be that the stools had the oxidants (not heme) to react the reagent. In addition, MALDI-TOF/MS had detected heme, but the Guaiac-based fecal occult-blood test had no results, those cases would be catched up in the future. In the detection of hemoglobin, using immunochemical tests to be the reference index, MALDI-TOF/MS had the false-negative result might come from the complicated matrix effect of stools, so that the hemoglobin could not form the good crystalline with matrix CHCA. The false-positive results of MALDI-TOF/MS might come from the criteria of hemoglobin signal.

Lange Zeit galt der Dünndarm als „Blackbox“ des Gastrointestinaltraktes. Seit Einführung der Videokapselendoskopie im Jahr 2001 eröffnete sich eine Methode, den Dünndarm zu visualisieren. An einem Kollektiv von 203 Patienten habe ich Indikationen, Ergebnisse und klinischen Nutzen von Dünndarmkapselendoskopien in einem Zeitraum von 4 Jahren untersucht. Der Dünndarm ist in der Gastroduodeno- und Koloskopie nicht komplett zugänglich, so dass bei entsprechender Indikation die nicht-invasive Videokapselendoskopie vorgenommen werden kann. Sie ist in der Lage 2-4 Bilder pro Sekunde in einem Zeitraum von 8-9 Stunden aufzunehmen, die als Film von ca. 50.000 Bildern zusammengestellt und interpretiert werden kann. Die Daten zur diagnostischen Ausbeute dieser Untersuchung variieren und sind abhängig von der entsprechenden Indikation. Zur Überprüfung des klinischen Nutzens habe ich daher in meiner Arbeit speziell die Passagezeiten und die erhobenen Befunde, wie Erosionen, Ulzerationen, Angiodysplasien, Petechien, Venektasien, Lymphangiektasien, Erytheme, Ödeme, Zottenreliefveränderungen, extrinsische Engen und Erhabenheiten im Hinblick für ihre diagnostische Bedeutung ausgewertet. Berücksichtigt wurden die Auswertbarkeit, Komplikationsrate sowie Vor- und Nachuntersuchungen. Das Aufklärungsgespräch erfolgte mindestens einen Tag vor der Videokapselendoskopie. Die Abführmaßnahmen entsprachen einer Koloskopievorbereitung. Das Studienkollektiv (203 Patienten) bestand aus 58% männlichen und 42% weiblichen Patienten. Der Altersdurchschnitt betrug 58 Jahre, die Altersspanne reichte von 8-90 Jahren. Über 93% nahmen die Videokapsel selbstständig ein, eine Applikation erfolgte bei 7% der Patienten in den Bulbus duodeni. Folgende Indikationen führten bei unserer Patientenklientel zu der Videokapselendoskopie: unklare gastrointestinale Blutung (45,3%), unklare abdominelle Schmerzen (24,1%), unklare Anämie (11,3%), Verdacht auf/ oder Komplikation bei Morbus Crohn (6,5%), unklare Diarrhoe (6,4%), Polyp- und Tumorsuche (5,4%), rezidivierendes unklares Erbrechen und Eiweißverlustsyndrom (jeweils 0,5%). Eine komplette Dünndarmpassage konnte innerhalb der Aufzeichnungszeit von 8-9 Stunden bei 84% der Patienten erreicht werden. Der Mittelwert der Magenpassagezeit lag bei 21 Minuten und der Dünndarmpassagezeit bei 6 Stunden. Die Komplikation Kapselretention trat bei 2% auf. Pathologische Befunde im Dünndarm wurden bei 85% detektiert. Die höchste diagnostische Ausbeute ergab sich bei der Abklärung der unklaren gastrointestinalen Blutung (80%) und bei der unklaren Anämie (78%), als häufigste Ursache wurden Schleimhautläsionen (43%) gefunden. Unklare abdominelle Schmerzen wiesen eine niedrigere diagnostische Ausbeute (41%) auf. Therapeutische Maßnahmen resultierten bei 73% der untersuchten Patienten aus den Kapselergebnissen. Eine medikamentöse Therapie wurde bei 66% eingeleitet oder verändert, Endoskopien wurden bei 4% und eine operative Therapie bei 4,4% durchgeführt. Damit ist die Dünndarmkapselendoskopie bei klarer Fragestellung und guter Darmvorbereitung eine sichere und sinnvolle Untersuchungsmethode, insbesondere zur Klärung unklarer gastrointestinaler Blutungen. Spezifische Dünndarmerkrankungen, wie der M. Crohn oder Tumore können relativ sicher ausgeschlossen werden.

Introducción: La hemorragia digestiva alta (HDA) es una de las emergencias más frecuentes en medicina. Parte de su abordaje incluye la realización de una segunda endoscopia de control programada llamada “second look” (SL) con el propósito de reducir la incidencia de resangrado. No obstante, existe controversia en cuando su indicación y utilidad. Objetivo: Evaluar la efectividad del SL en la prevención del resangrado intrahospitalario en pacientes adultos con HDA no variceal. Métodos: Se llevó a cabo un estudio de cohorte retrospectivo sobre 1 144 pacientes con diagnóstico de HDA admitidos en la Unidad de Hemorragia Digestiva de un centro de referencia de la Seguridad Social en Lima, Perú; durante los años 2012 y 2014. La variable de respuesta fue el resangrado y la variable de exposición fue la programación a SL. Además se midió la hemoglobina al ingreso, comorbilidades, trasfusión de paquetes globulares y variables endoscópicas. Se calculó la incidencia acumulada (IA), riesgo relativo (RR), efectividad y mediante un modelo lineal generalizado de familia Poisson link log con errores estándar robustos se estimaron razones de tasas de incidencia (RTI). Resultados: La IA global de resangrado fue de 24,48% (n=280). Se encontró diferencia significativa entre las incidencias acumuladas (IA) entre el grupo de SL y el grupo de control (11,7 % vs 29,0 %, respectivamente, p<0,01). El RR fue 0,40 (IC95%:0,29-0,56) y la efectividad fue de 59,81% (IC95%: 44,17-71,08). En los modelos de regresión también se encontró una disminución de las tasas de incidencia tanto en el modelo crudo (RTI: 0,34 IC95%: 0,24-0,49), como en el modelo ajustado con diferencia estadística significativa entre los sometidos y no sometidos a SL (RTI: 0,12 IC95%: 0,08-0,18), por las variables asociadas con el resangrado (RTI: 0,21 IC95%: 0,15-0,30) y por las variables que cumplían los criterios clásicos de confusión (RTI: 0,12 IC95%: 0,08-0,18). Conclusiones: El SL es efectivo en la prevención de resangrado intrahospitalario en pacientes adultos con HDA en un hospital de referencia nacional. / Background: Upper gastrointestinal bleeding (UGIB) is one of the most common medical emergencies. Part of its approach includes performing a second endoscopy, known as second look (SL). However, its indications and usefulness are controversial. Objectives: To evaluate the effectiveness of SL in preventing nosocomial rebleeding in adult patients with non-variceal upper gastrointestinal bleeding. Methods: A retrospective cohort of 1144 patients diagnosed with UGIB admitted at a Digestive Bleeding Unit of a reference center for Social Security in Lima, Peru was performed; during the years 2012 and 2014. The response variable was rebleeding and the exposure variable was programmed SL. Besides hemoglobin on admission, comorbidities, blood transfusion and endoscopic variables were measured. The cumulative incidence, relative risk (RR) and effectiveness were calculated, and using a generalized linear model of the Poisson family link log with robust standard errors, incidence rate ratios (IRR) were estimated. Results: The cumulative incidence rebleeding overall was 24.48% (n = 280). Significant difference between the cumulative incidences (IA) between the SL group and the control group (11.7% vs 29.0%, respectively, p <0.01) was found. The RR was 0.40 (95% CI 0.29 - 0.56) .The calculated effectiveness was 59.81% (95% CI: 44.17 - 71.08). The regression models also found a decrease in incidence in both crude model (IRR: 0.34 95% CI 0.24 to 0.49) and in the adjusted models. The first model was adjusted for variables with statistically significant differences between exposed and unexposed (IRR: 0.12 95% CI 1.8 to 0.18), the second was adjusted for variables that were significantly associated with rebleeding (IRR 0.21 95% CI 0.15-0.30). The third model was adjusted for variables that met classical criteria of confusion (IRR: 0.12 95% CI 0.08 to 0.18). / Tesis

京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第19277号 / 社医博第68号 / 新制||社医||9(附属図書館) / 32279 / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 松原 和夫, 教授 今中 雄一, 教授 髙橋 良輔 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM