Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / There is no consensus in the literature about the best tool to assess the oral feeding skills of preterm infants reason why researchers have been trying to figure out what is the most efficient. Objective: To investigate the application of an objective tool to assess the oral feeding skills of preterm infants. Methods: The sample consisted of 44 preterm infants, divided into two strata according gestational age (27 between 30-33 and 17 between 34-36 weeks of gestational age). After medical prescription to begin oral feeding, the objective assessment of the oral feeding skills at first bottlefeeding was made by a speech therapist. Proficiency (percentage of milk taken in the first five minutes in relation to total prescribed) and rate of milk transfer (volume of milk accepted orally in relation to the time required for it) were obtaied. From the combination of these two variables the oral feeding skills were graded in levels as proposed by Lau and Smith (2011). The results were statistically analyzed, considering a significance level of 5% (p <0.05). Results: Significant differences were evidenced between the oral feeding skills levels and feeding duration, proficiency, rate of milk transfer, oral feeding performance and days of hospitalization. Conclusion: We concluded that the tool proposed by Lau and Smith (2011) is a good objective indicator of the oral feeding skills of preterm infants. / Não há um consenso na literatura sobre qual o melhor instrumento para avaliar a habilidade para alimentação por via oral de recém-nascidos pré-termo, o que tem impulsionado pesquisas realizadas no intuito de analisar os instrumentos, buscando descobrir qual o mais eficiente. Objetivo: Analisar a aplicação de um instrumento de avaliação objetiva da habilidade para alimentação oral de recém-nascidos pré-termo. Métodos: Incluiu-se neste estudo 44 recém-nascidos pré-termo, dos quais 27 constituíram o estrato entre 30 e 33 semanas e 17 o estrado de 34 a 36 semanas. Após a prescrição médica para início da alimentação por via oral, a avaliação objetiva da habilidade para alimentação oral na primeira mamada por via oral na mamadeira, foi realizada por uma fonoaudióloga. Foram obtidas a proficiência (percentual do volume ingerido por via oral em relação ao prescrito nos primeiros cinco minutos) e a taxa de transferência (volume de leite aceito por via oral em relação ao tempo necessário para alimentação). A partir da combinação dessas duas variáveis, foram graduados os níveis de habilidade para alimentação oral, conforme proposto por Lau e Smith (2011). Os resultados foram analisados estatisticamente, considerando-se nível de significância de 5% (p<0,05). Resultados: Foram encontradas diferenças significativas entre os níveis de habilidade para alimentação oral e o tempo de alimentação, proficiência, taxa de transferência, desempenho alimentar e dias de internação. Conclusão: A presente pesquisa confirmou a aplicabilidade do protocolo proposto por Lau e Smith (2011) como sendo um indicador objetivo das habilidades de alimentação oral.

INTRODUÇÃO: A recidiva de varizes é frequente após tratamento endoscópico com ligadura elástica para a profilaxia secundária de hemorragia por rotura de varizes esofágicas em pacientes com doença hepática crônica avançada. Alguns estudos relacionaram tanto recidiva quanto ressangramento de varizes com características ecoendoscópicas de vasos paraesofágicos. OBJETIVO: Relacionar avaliações ecoendoscópicas de varizes paraesofágicas, veia ázigos e ducto torácico com recidiva de varizes após erradicação com ligadura elástica em pacientes com doença hepática crônica avançada através de estudo prospectivo e observacional. MÉTODOS: A análise ecoendoscópica foi realizada antes da terapia com ligadura elástica e 1 mês após a erradicação endoscópica das varizes. Os diâmetros máximos das varizes paraesofágicas, da veia ázigos e do ducto torácico foram avaliados em localizações ecoendoscópicas prédeterminadas. Após a erradicação das varizes, os pacientes foram submetidos a endoscopias a cada 3 meses durante o período de 1 ano. Foi verificado se alguma das características ecoendoscópicas analisadas poderia predizer a recidiva das varizes. RESULTADOS: Um total de 30 pacientes completou o protocolo de seguimento por 1 ano. Dezessete (57%) pacientes apresentaram recidiva de varizes. Não houve relação entre os diâmetros máximos da veia ázigos e do ducto torácico com a recidiva de varizes. O diâmetro máximo de varizes paraesofágicas foi fator preditivo para recidiva de varizes em ambos os períodos avaliados. Os diâmetros das varizes paraesofágicas que melhor se relacionaram com recidiva de varizes foram 6,3 mm antes da ligadura elástica (sensibilidade de 52,9%, especificidade de 92,3% e área sob a curva ROC de 0,749) e 4 mm após a ligadura elástica (70,6% de sensibilidade, 84,6% de especificidade e área sob a curva ROC de 0,801). CONCLUSÃO: A medida ecoendoscópica do diâmetro das varizes paraesofágicas pode predizer a recidiva das varizes esofágicas no primeiro ano após a erradicação com ligadura elástica. O diâmetro de varizes paraesofágicas após a ligadura elástica é o melhor fator preditivo, pois apresenta menor valor de corte, maior sensibilidade e maior área sob a curva ROC / INTRODUCTION: Variceal recurrence after endoscopic band ligation for secondary prophylaxis is a frequent event. Some studies have reported a correlation between variceal recurrence and variceal re-bleeding with the endoscopic ultrasound (EUS) features of para-esophageal vessels. OBJECTIVE: A prospective observational study was conducted to correlate EUS evaluation of para-esophageal varices, azygos vein and thoracic duct with variceal recurrence after endoscopic band ligation variceal eradication in patients with in advanced chronic hepatic disease. METHODS: EUS was performed before and 1 month after endoscopic band ligation variceal eradication. Para-esophageal varices, azygos vein and thoracic duct maximum diameters were evaluated in pre-determined anatomic stations. After endoscopic band ligation variceal eradication, patients were submitted to endoscopic examinations every 3 months for 1 year. We looked for EUS features that could predict variceal recurrence. RESULTS: A total of 30 patients completed 1-year endoscopic follow-up. Seventeen (57%) patients presented variceal recurrence. There was no correlation between azygos vein and thoracic duct diameters with variceal recurrence. The maximum diameter of para-esophageal varices predicted variceal recurrence in both evaluation periods. Para-esophageal varices diameters that best correlated with variceal recurrence were 6.3 mm before endoscopic band ligation (52.9% sensitivity, 92.3% specificity, and 0.749 area under ROC curve); and 4 mm after endoscopic band ligation (70.6% sensitivity, 84.6% specificity, and 0.801 area under ROC curve). CONCLUSION: We conclude that paraesophageal varices diameter measured by EUS predicts variceal recurrence within one year after endoscopic band ligation variceal eradication. Paraesophageal diameter after variceal eradication is a better recurrence predictor, because it has lower cut-off parameter, higher sensitivity and higher area under the ROC curve

Introdução: o uso da videolaparoscopia na doença de Crohn (DC) teve seu início nos anos 90, com ressalvas à possível dificuldade técnica que a DC complexa ou recorrente poderia impor à sua realização. Diversos estudos ao longo das décadas de 90 e 2000 mostraram ser a mesma factível, quando comparada à laparoscopia para DC primária, além de demonstrarem maior benefício da laparoscopia comparada à cirurgia aberta/convencional nos casos de DC recorrente. Entretanto, não houve estudos sobre resultados cirúrgicos após repetidas ressecções laparoscópicas. Objetivo: avaliar resultados pós-operatórios em curto prazo no tratamento da DC, comparando pacientes submetidos a uma segunda ressecção intestinal laparoscópica e pacientes sem cirurgia prévia. Além disso, comparar os mesmos resultados pós-operatórios entre pacientes submetidos a uma segunda ressecção intestinal laparoscópica e pacientes sendo submetidos a laparoscopia para DC e história prévia de ressecção intestinal prévia por laparotomia. Materiais e métodos: foi realizado análise retrospectiva a partir de base de dados mantida prospectivamente de pacientes submetidos a laparoscopia para tratamento da DC no Hospital Beaujon, França, entre 2005 e 2010. Os desfechos analisados foram: conversão para cirurgia aberta, tempo operatório, taxa de enterotomias inadvertidas no intra-operatório, morbidade, necessidade de reintervenção (cirúrgica ou radiológica) e tempo total de hospitalização. Resultados: foram analisados 18 pacientes com laparoscopia prévia (grupo A), 90 pacientes sem cirurgia prévia (grupo B) e 26 pacientes com laparotomia prévia (grupo C). Em nossa análise principal, comparando os grupos A e B, vemos grupos semelhantes em relação a dados demográficos, exceto maior número de casos complexos no grupo A (83,3 vs 46,7%; p=0,005) e tipo de operação realizada (p < 0,001). Quanto aos resultados, apenas o tempo operatório foi significativamente mais longo no grupo A (180 minutos vs. 150 minutos; p=0,013). A taxa de conversão, enterotomia inadvertida, morbidade, necessidade de reintervenção e tempo de hospitalização foram similares entre os grupos. Em nossa segunda análise, entre os grupos A e C, não houve diferença significativa quanto aos mesmos resultados analisados. Conclusão: apesar de um maior tempo operatório, uma segunda ressecção laparoscópica mantém os mesmos benefícios vistos em uma ressecção intestinal laparoscópica primária. Os mesmos benefícios são vistos quando os resultados são comparados com pacientes submetidos previamente a uma ressecção intestinal por laparotomia, em especial quando nas mãos de equipe experiente / Introduction: the use of laparoscopy in Crohn\'s disease (CD) had its beginning in the 90s, despite the possible challenge of technical difficulty that the complex or recurrent CD could impose to its realization. Numerous studies over the decades of 90 and 2000 showed laparoscopy in recurrent CD to be feasible compared to laparoscopy for primary CD, and have also shown the benefits of laparoscopic compared to open conventional surgery in patients with recurrent CD. However, there were no studies on surgical outcomes after repeated laparoscopic resections. Objective: 1. to evaluate postoperative short-term results regarding surgical treatment of CD, comparing patients who underwent a second laparoscopic bowel resection and patients without prior surgery. 2. to compare the same postoperative results among patients who underwent a second laparoscopic bowel resection patients and patients undergoing laparoscopic resection with history of prior intestinal resection by laparotomy. Materials and methods: a retrospective analysis from prospectively maintained database of patients undergoing laparoscopy for treatment of CD in Hospital Beaujon, France, between 2005 and 2010, was performed. The outcomes analyzed were: conversion to open surgery, operative time, intraoperative inadvertent enterotomy, morbidity, need for re-intervention (surgical or radiological) and length of hospitalization. Results: 18 patients with previous laparoscopy (group A), 90 patients without previous surgery (group B) and 26 patients with previous laparotomy (group C) were included. In our main analysis, comparing the groups A and B, groups were similar in respect to demographic data, except number of complex cases in group A (83.3 vs 46.7%; p = 0.005) and type of surgery performed (p < 0.001). As for the results, operative time was significantly longer in group A (180 minutes vs. 150 minutes; p = 0.013). Conversion rate, inadvertent enterotomy, morbidity, need for re-intervention and hospital stay were similar between groups. In our second analysis, between groups A and C, there was no significant difference between groups regarding the same variables. Conclusion. In spite of a longer operative time, a second laparoscopic resection guarantees the same benefits seen in a primary laparoscopic bowel resection. The same benefits are kept compared to patients who underwent prior bowel resection by laparotomy, especially when in the hands of experienced staff

Objetivo: Avaliar o prognóstico clínico do transplante multivisceral (TMV) na vigência de trombose difusa do sistema porto-mesentérico. Introdução. O transplante hepático (TH) na vigência de cirrose e trombose difusa do sistema porto-mesentérico é controverso e muitas vezes contraindicado em muitos centros de transplante hepático. O transplante hepático utilizando técnicas alternativas como a hemitransposição portocava falha na eliminação de complicações provenientes da hipertensão portal. O TMV substitui o fígado e todo o sistema venoso porto-mesentérico. Métodos: Uma base de dados de pacientes submetidos a transplante intestinal foi mantida com análise prospectiva de resultados. O diagnóstico de trombose difusa do sistema porto-mesentérico foi estabelecido através de tomografia abdominal em fases arterial e venosa, ou por ressonância magnética com reconstrução venosa. Resultados: Vinte e cinco pacientes com trombose de porta, estádio IV, foram submetidos ao TMV. Onze pacientes receberam transplante renal concomitante. Rejeição aguda confirmada por biópsia foi notada em cinco pacientes, que foram tratados com sucesso. Com um seguimento médio de 2,8 anos, a sobrevida de enxertos e pacientes foi de 80%, 72% e 72%, respectivamente. Até a presente data, todos os sobreviventes estão com boa função de enxerto e sem nenhum sintoma ou evidência de hipertensão portal. Conclusão: O TMV deve ser considerado como opção para o tratamento de pacientes com trombose portomesentérica difusa. O transplante multivisceral é o único procedimento que reverte completamente a hipertensão portal e a doença de base com uma sobrevida superior ao TH com reconstruções vasculares alternativas / Objective: To evaluate the clinical outcomes of multivisceral transplantation (MVT) in the setting of diffuse thrombosis of the portomesenteric venous system. Background: Liver transplantation (LT) in the face of cirrhosis and diffuse portomesenteric thrombosis (DPMT) is controversial and contraindicated in many transplant centers. LT using alternative techniques such as portocaval hemitransposition fails to eliminate complications of portal hypertension. MVT replaces the liver and the thrombosed portomesenteric system. Methods: A database of intestinal transplant patients was maintained with prospective analysis of outcomes. The diagnosis of diffuse PMT was established with dual-phase abdominal computed tomography or magnetic resonance imaging with venous reconstruction. Results: Twentyfive patients with grade IV DPMT received 25 MVT. Eleven patients underwent simultaneous cadaveric kidney transplantation. Biopsy proven acute cellular rejection was noted in 5 recipients, which was treated successfully. With a median follow-up of 2.8 years, patient and graft survival were 80%, 72%, and 72% at 1, 3, and 5 years, respectively. To date, all survivors have good graft function without any signs of residual/recurrent features of portal hypertension. Conclusions: MVT can be considered as an option for the treatment of patients with diffuse DPMT. MVT is the only procedure that completely reverses portal hypertension and addresses the primary disease, while achieving superior survival results in comparison to the alternative vascular reconstructions

Objetivo: Investigar a deglutição em indivíduos com a Síndrome Richieri Costa-Pereira (SRCP), com o propósito de verificar a presença sintomas de disfagia por parte dos cuidadores e paciente, bem como sinais de disfagia. Casuística e Método: Estudo retrospectivo e prospectivo, no qual foram avaliados 19 indivíduos com a SRCP, entre 26 dias e 30 anos de idade, de ambos os sexos. Foram levantados sintomas de disfagia por meio de entrevista, bem como análise de prontuários, seguida de avaliação clínica e instrumental da deglutição (videoendoscopia da deglutição - VED) para investigar os sinais de disfagia. A deglutição foi classificada de acordo com a Functional Oral Intake Scale - FOIS e a Escala de Comprometimento Funcional da Deglutição - ECFD. Resultados: Todos os indivíduos maiores de 4 anos (n=12) se alimentavam por via oral exclusiva (VO), sem restrições (FOIS nível 7), assim realizaram única avaliação, apesar de constatada a presença de sinais de comprometimento da deglutição em 8 casos na ECFD. Os indivíduos menores de 3 meses de idade (n=7), com alimentação exclusiva por sonda alimentadora na primeira avaliação (FOIS nível 1), foram acompanhados por apresentarem sintomas e sinais de disfagia detectados nas avaliações clínica e instrumental. Ao longo do estudo, foi verificado o desenvolvimento de mecanismo de proteção das vias aéreas com melhora da deglutição, sendo que 4 casos passaram a se alimentar exclusivamente por VO na última avaliação. Conclusão: Sintomas de disfagia, principalmente na população infantil, estão presentes, assim como sinais de disfagia, em diferentes graus, durante toda a evolução do tratamento, mesmo na ausência de sintomas; os indivíduos com a SRCP desenvolveram mecanismo de proteção das vias aéreas realizando a deglutição de maneira adaptada e estabelecendo assim condições para a alimentação por via oral exclusiva. / Objective: To investigate swallowing in individuals with Richieri Costa-Pereira syndrome (RCPS), in order to verify the presence of dysphagia symptoms by caregivers and patients, as well as dysphagia signs. Methods: A retrospective and prospective study in which 19 subjects with RCPS, aged 26 days - 30 years, both genders, were evaluated. Data from dysphagia symptoms were collected through interviews and records analysis, followed by clinical and instrumental swallowing evaluation (Flexible Endoscopic Evaluation of Swallowing FEES) to investigate dysphagia signs. Swallowing was classified according to the Functional Oral Intake Scale - FOIS and Swallowing Functional Impairment Scale - SFIS. Results: A single assessment was performed in all subjects older than 4 years (n=12). They were exclusively oral fed without restrictions (FOIS level 7) although impaired swallowing signs were observed in 8 cases on the ECFD. Individuals younger than 3 months (n=7), were exclusively tube fed in the first evaluation (FOIS level 1), and were followed up for presenting dysphagia symptoms and signs detected in clinical and instrumental evaluation. The development of airway protection mechanism with swallowing improvement was verified during the study, and 4 cases (n=7) were exclusively oral fed in the last assessment. Conclusion: Dysphagia symptoms are present especially in children as well as dysphagia signs, which may vary in degrees, even when no symptoms are reported throughout treatment evolution. Individuals with RCPS developed protective airways mechanism performing adapted swallowing and thereby establishing conditions for exclusively oral feeding.

Orientador: Maria Beatriz Duarte Gavião / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-24T16:58:30Z (GMT). No. of bitstreams: 1 Strini_PolyanneJunqueiraSilvaAndresen_D.pdf: 1536403 bytes, checksum: 660235bf6e3720dfc8efe64a5a11f203 (MD5) Previous issue date: 2014 / Resumo: O número de idosos está aumentando mundialmente, fato que sugere a necessidade de melhor entendimento de fatores individuais e ambientais relacionados ao envelhecimento. O objetivo deste estudo foi analisar a qualidade de vida geral, a avaliação subjetiva das condições bucais, os níveis de depressão e estresse percebido, presença de disfunções orofaciais e níveis salivares de cortisol e alfa-amilase em idosos institucionalizados. A amostra foi composta por 76 indivíduos de ambos os gêneros, com idade mínima de 60 anos, submetidos a exame clínico intraoral para a verificação da presença de próteses. Foram aplicados os questionários "Medical Outcomes Study 36-Item Short-Form Health Survey" (SF-36) para a avaliação da qualidade de vida geral; "Oral Health Assessment Index" (GOHAI) para a avaliação subjetiva das condições bucais; "Perceived Stress Scale" (PSS), para avaliação da percepção de situações estressantes; "Geriatric Depression Scale" (GDS-15) para a avaliação da presença de depressão e "Nordic Orofacial Test ¿ Screening" (NOT-S) para a avaliação da presença de disfunções orofaciais. As amostras de saliva foram coletadas durante dois dias, ao acordar e 30 minutos após, obtendo a Resposta do Cortisol ao Acordar - ACR e a Resposta da Alfa-amilase ao Acordar - AAAR. Os dados foram submetidos à análise estatística por meio do coeficiente de correlação de Spearman, regressão linear múltipla (?=0.05), teste Chi-square ou Exato de Fisher e teste Kruskal-Wallis. Os resultados mostraram correlação positiva entre o valor total de GOHAI e SF-36, correlação negativa entre o domínio função física de GOHAI e PSS e escores de GDS-15. A regressão linear múltipla mostrou uma interrelação entre os escores de PSS e domínio físico do GOHAI porém não houve associação com ACR e AAAR. Correlação positiva foi observada entre o domínio Função Psicossocial de GOHAI e NOT-S para os indíviduos com próteses em ambas arcadas dentárias e entre GOHAI total e NOT-S para os indivíduos com pelo menos uma prótese. Pode-se concluir que os indivíduos avaliaram a condição bucal como desfavorável e da mesma forma consideraram a saúde geral como inapropriada. Da mesma forma, os indivíduos portadores de próteses ou não podem apresentar dificuldades relacionadas com aspectos físicos e psicológicos, que podem causar dor e desconforto ocasionando impactos na qualidade de vida / Abstract: The number of elderly is increasing worldwide, which suggests the need for better understanding of individual and environmental factors related to aging. The aim of this study was to assess overall quality of life and subjective assessment of oral conditions, levels of depression and perceived stress, presence of orofacial dysfunctions and levels of salivary cortisol and alpha-amylase in institutionalized elderly. The sample comprised 76 subjects of both genders, with minimum age 60 years, submitted to intraoral clinical examination to verify the presence of prostheses. Questionnaire "Medical Outcomes Study 36-Item Short-Form Health Survey" (SF-36) was applied to assess overall quality of life; "Oral Health Assessment Index" (GOHAI) for the subjective assessment of oral conditions; "Perceived Stress Scale" (PSS), to evaluate the perception of stressful situations; "Geriatric Depression Scale" (GDS-15) for evaluating the presence of depression and "Nordic Orofacial Test - Screening" (NOT-S) to assess the presence of orofacial dysfunctions. Multiple linear regression showed an interrelationship between PSS scores and physical domain of GOHAI but there was no association with ACR and AAAR. Positive correlation was observed between Psychosocial Function GOHAI domain and NOT-S for individuals with prostheses in both dental arches and between total NOT-S and GOHAI for individuals with at least one prostheses. Similarly, individuals with prostheses or not may present difficulties related to physical and psychological aspects, which may cause pain and discomfort impacting on quality of life / Doutorado / Anatomia / Doutora em Biologia Buco-Dental

In mammals, newly synthesized proteins destined for secretion are translocated cotranslationally into the lumen of the Endoplasmic Reticulum (ER). Once inside, these nascent polypeptide chains are bound by a lumenal ER protein called BiP (Immunoglobulin Binding Protein) or Grp 78 (Glucose Regulated Protein 78). It is hypothesized that this binding is necessary to protect the nascent chains until they are properly folded or assembled with other subunits. When the proteins are folded and assembled, they are released from BiP by a process that is dependent on ATP hydrolysis. Since ATP is synthesized mainly in the mitochondria, we hypothesized that there must be an ATP transporter in the ER which would allow the protein mediated transport of ATP from the cytosol into the ER lumen. We studied the transport of ATP in vitro and found that ATP enters the lumen of the ER in a saturable manner with a Kmapp~3μM. ATP transport is dependent on time, protein, and vesicle integrity, it is also inhibited by the general anion transport inhibitor, 4,4' diisothiocyano-2,2'-disulfonic acid stilbene (DIDS). We also found that the transport was inhibited by membrane impermeable protein modifying agents such as N-ethlymaleamide (NEM) and Pronase when added to intact ER vesicles. These results suggest that the transport is mediated by a protein with an active cytoplasmic face. Using monoclonal and polyclonal antibodies to BiP and Grp94 (another resident ER protein) and U.V. crosslinking, we demonstrated that after transport of ATPα32P into intact vesicles, radiolabeled BiP and Grp94 could be immunoprecipitated. We also found that labeling of lumenal proteins with ATP is dependent on the transport of ATP. Finally using ATP labeled with 35S, we concluded that BiP was able to bind intact ATP and we confirmed earlier work that BiP was thiophosphorylated while Grp94 is not. The second area of study involves processes that occur further along the secretory pathway in the Golgi apparatus. It was known from previous work that the nucleotide sugar substrates necessary for the synthesis of the linkage region, UDP-xylose (UDP-Xyl), UDP-galactose (UDP-Gal) and UDP-glucuronic acid (UDP-GlcA) were transported into the Golgi apparatus from the cytosol via protein mediated transporters. In order to eventually purify one of these transporter proteins, we wanted to reconstitute their activities. We were able to reconstitute the activities that exhibited kinetic parameters and inhibitor sensitivities very similar to those seen in intact Golgi vesicles. In the case of UDP-xylose it was necessary to prepare the liposomes using endogenous Golgi lipids in order to get transport activity similar to that seen in the intact Golgi vesicles. This suggested a specific lipid requirement for the UDP-xylose transporter. These transporters seem to be antiporters, whereby the nucleotide sugar enters the lumen of the Golgi coupled to the equimolar exit of the corresponding nucleoside monophosphate (Hirschberg, C.B. and Snider, M.D. 1987). We also showed that we could reproduce the hypothesized antiporter system in the reconstituted proteoliposomes by preloading the proteoliposomes with the putative antiporter molecule UMP. The rationale for developing the reconstituted system is eventually to use this system to purify one of these nucleotide sugar translocators. In the last set of studies, I have shown that this reconstituted system can be used to monitor the purification of the UDP-galactose translocator. Using column chromatography we were able to purify this membrane translocator protein 45,000 fold from a rat liver homogenate.

Background: Recent national trends and distribution of ileal pouch-anal anastomosis (IPAA) procedures for patients with ulcerative colitis (UC) are unknown. We examined the frequency of use of elective IPAA procedures among patients with UC and the distribution of IPAA procedures across more than 140 U.S. academic medical centers and their affiliates. Methods: Data were obtained from the University HealthSystem Consortium for patients with a primary diagnosis of UC admitted electively between 2012 and 2015. Results: The mean age of the study population (n=6,875) was 43 years and 57% were men. Among these, one-third (n=2,307) underwent an IPAA, while two-thirds (n=4,568) underwent colectomy, proctectomy, proctocolectomy or other procedures. The proportion of IPAA cases among all elective admissions was relatively stable at 33-35% during the years under study. A total of 131 hospitals, out of 279 hospitals participating in the UHC, performed IPAA. The median number of IPAA cases performed annually was 1.9 [IQR 0.8 – 4.3]. Nearly one half (48%) of these cases were performed by the top ten hospitals. Overall, only a total of 30 centers performed ³ five elective IPAA cases annually. Conclusions: Although the frequency of elective IPAA surgery in recent years has been stable, nearly one half of all IPAA cases was performed at ten hospitals. The concentration of IPAA cases at high-volume centers, and the steady number of cases performed annually, have potential implications for fellowship training, patient clinical outcomes and access to care.

Background: Treatment decisions for elderly patients with gallbladder pathology are complex. Little is known about what factors go into treatment decisions in this population. We used Medicare data to examine gender-based differences in the use of cholecystectomy vs. cholecystostomy tube placement in elderly patients with acute cholecystitis. Methods: We queried a 5% random sample of Medicare data (2009-2011) for patients >65 admitted for acute cholecystitis (by ICD-9 code) who subsequently underwent a cholecystectomy and/or cholecystostomy tube placement. Demographic information (age, race), clinical characteristics (Elixhauser index, presence of biliary pathology), and hospital outcomes (case fatality rate, length of stay, need for ICU care) were compared by gender. A multivariable model was used to examine predictors of cholecystectomy vs. cholecystostomy tube placement. Results: Of 4063 patients admitted with cholecystitis undergoing the procedures of interest just over half (58%) were women. The majority of patients (93%) underwent cholecystectomy. Compared to women, men were younger (average age 76 vs. 78, p value < 0.01) and had few comorbidities (average Elixhauser 1.2 vs. 1.4 p value < 0.01). Case fatality rate was similar between men (2.5%) and women (2.4% p value 0.48). A higher percentage of men spent time in the ICU (36%) compared to women (31% p value < 0.01). On multivariable analysis men were 30% less likely to undergo cholecystectomy (OR 0.69, 95% CI 0.53-0.91). Conclusion: Elderly men are less likely than elderly women to undergo cholecystectomy for acute cholecystitis despite being younger with less co morbidity and are more likely to spend time in the ICU. More research is needed to determine whether a difference in treatment is contributing to the higher rate of ICU utilization in elderly men with acute cholecystitis.

Two decades after the discovery of the Hepatitis C Virus (HCV), Hepatitis C infection still persists to be a global health problem. With the recent approval of the first set of directly acting antivirals (DAAs), the rate of sustained viral response for HCV-infected patients increased significantly. However, a complete cure has not been found yet. Drug development efforts primarily target NS3/4A protease, bifunctional serine protease-RNA helicase of HCV. HCV NS3/4A is critical in viral function; protease domain processes the viral polyprotein and helicase domain aids replication of HCV genome by unwinding double stranded RNA transcripts produced by NS5B, RNA-dependent RNA polymerase of HCV. Protease and helicase domains can be isolated, expressed and purified separately while retaining function. Isolated domains of HCV NS3/4A have been extensively used in biochemical and biophysical studies for scientific and therapeutic purposes to evaluate functional capability and mechanism. However, these domains are highly interdependent and modulate the activities of each other bidirectionally. Interdomain dependence was demonstrated in comparative studies where activities of isolated domains versus the full length protein were evaluated. Nevertheless, specific factors affecting interdependence have not been thoroughly studied. Chapter II investigates the domain-domain interface formed between protease and helicase domains as a determinant in interdependence. Molecular dynamics simulations performed on single chain NS3/4A constructs demonstrated the importance of interface in the coupled dynamics of the two domains. The role of the interface in interdomain communication was experimentally probed by disrupting the domain-domain interface through Ala-scanning mutations in selected residues in the interface with significant buried surface areas. These interface mutants were assayed for both helicase and protease related activities. Instead of downregulating the activities of either domain, interface mutants caused enhancement of protease and helicase activities. In addition, the interface had minimal effect in RNA unwinding activity of the helicase domain, the mere presence of the protease domain was the main protagonist in elevated RNA unwinding activity. In conclusion, I suspect that the interface formed between the domains is transient in nature and plays a regulatory role more than a functional role. In addition, I found results supporting the suggestion that an alternate domain-domain arrangement other than what is observed in crystal structures is the active, biologically relevant conformation for both the helicase and the protease. Chapter III investigates structural features of HCV NS3/4A protease inhibitors in relation to effects on inhibitor potency, susceptibility to drug resistance and modulation of potency by the helicase domain. Nearly all NS3/4A protease inhibitors share common features, with major differences only in bulky P2 extension groups and macrocyclization statuses. Enzymatic inhibition profiles of different drugs were analyzed for wildtype isolated protease domain and single chain NS3/4A helicase-protease construct, their multi drug resistant variants, and additional helicase mutants. Inhibitor potency was mainly influenced by macrocyclization, where macrocyclic drugs were significantly more potent compared to acyclic variants. Potency loss with respect to resistance mutations primarily depended on the P2 extension, while macrocyclization had minimal effect except for P2-P4 macrocyclic compounds which were up to an order of magnitude more susceptible to mutations A156T and, in lesser extent, D168A. Modulation by helicase domain was also dependent on P2 extension, although opposite trends were observed for danoprevir analogs versus others. In conclusion, this study provides a basis for future inhibitor development in both avoiding drug resistance and exploitation of the helicase domain for additional efficacy. In this thesis, I have provided evidence further supporting and revealing the details of domain-domain dependency in HCV NS3/4A. Lessons learned here will aid future research for dissecting the interdependency to gain a better understanding of HCV NS3/4A function, which can possibly be extended to all Flaviviridae NS3 protease-helicase complexes. In addition, interdomain dependence can be exploited in future drug development efforts to create better drugs that will pave the way to an effective cure.