Evaluating environmental and inhibitory control strategies to improve outcomes in a widely available weight loss program.

BACKGROUND: Although many people try to lose weight, a large proportion of individuals do not achieve clinically significant weight loss. Nonresponse and relapse rates in lifestyle interventions are largely explained by challenges in avoiding or resisting temptation in the context of omnipresent food access. Innovative enhancement strategies are needed to help individuals manage temptation in evidence-based lifestyle interventions. METHODS: This prospective, four-parallel-arm, randomized controlled trial tests the efficacy of two weight management enhancement strategies on weight and dietary outcomes among individuals with overweight or obesity: (1) an environmental control strategy combining modification of the home food environment and grocery delivery (AVOID) and (2) an impulse control strategy involving daily, gamified inhibitory control training (RESIST). Women and men (n = 500) with overweight or obesity (Body Mass Index between 25 and 40.0 kg/m2) will be enrolled in a 12-month commercial weight-loss program (WW, formerly Weight Watchers©) and randomly assigned to one of four conditions: (1) WW alone, (2) WW + AVOID, (3) WW + RESIST, or (4) WW + AVOID + RESIST. Anthropometric, dietary, cognitive, and household food environment assessments will be conducted in English or Spanish at enrollment and at 6- and 12-month follow-up. DISCUSSION: This research addresses the pragmatic question of how to best optimize behavior change: Should we modify the choice environment, strengthen individuals' self-regulation, or both, to maximize behavior change? This work can inform the development of enhancement strategies to promote adherence to lifestyle recommendations and other impulse control challenges.

Statistical methods for validation of predictive models.

Predictive models are widely used in clinical practice. Despite of the increasing number of published AI systems, recent systematic reviews have identified lack of statistical rigor in the development and validation of predictive models. This work reviewed the current literature for predictive performance measures and resampling methods. Furthermore, common pitfalls were discussed.

Are we any WISER yet? Progress and contemporary need for smart trials to include women in coronary artery disease trials.

Despite calls to ensure proportionate representation of both sexes in biomedical research, women continue to be underrepresented in cardiovascular disease (CVD) clinical trials. A comprehensive analysis of seven large suspected ischemic heart disease/coronary artery disease (IHD/CAD) clinical trials (PROMISE, ISCHEMIA, CIAO-ISCHEMIA, ORBITA, FAME, FAME 2 and COURAGE trial) provides understanding of contributions to barriers to enrollment of women and leads to strategies to address these barriers. Specifically, in the seven trials, enrollment of women did not exceed 27%, while numerous barriers are evident. Proposed strategies to improve women´s inclusion in clinical trials, include adding reproductive stage/estrogen status, attention to study design inclusion/exclusion criteria using female thresholds, consideration of diagnostic and intervention study design to be inclusive, increasing women and minorities in leadership positions, including sex as a biological variable (SABV) in study design and statistical analysis, and addressing social and race/ethnicity barriers. Dedicated action to actualizing these steps are needed at this time to developing diagnostic and therapeutic strategies resulting in better care and improved outcomes for CVD in women.

Focal Serous Tubal Intra-Epithelial Carcinoma Lesions Are Associated With Global Changes in the Fallopian Tube Epithelia and Stroma.

Objective: Serous tubal intra-epithelial carcinoma (STIC) lesions are thought to be precursors to high-grade serous ovarian cancer (HGSOC), but HGSOC is not always accompanied by STIC. Our study was designed to determine if there are global visual and subvisual microenvironmental differences between fallopian tubes with and without STIC lesions. Methods: Computational image analyses were used to identify potential morphometric and topologic differences in stromal and epithelial cells in samples from three age-matched groups of fallopian tubes. The Benign group comprised normal fallopian tubes from women with benign conditions while the STIC and NoSTIC groups consisted of fallopian tubes from women with HGSOC, with and without STIC lesions, respectively. For the morphometric feature extraction and analysis of the stromal architecture, the image tiles in the STIC group were further divided into the stroma away from the STIC (AwaySTIC) and the stroma near the STIC (NearSTIC). QuPath software was used to identify and quantitate secretory and ciliated epithelial cells. A secretory cell expansion (SCE) or a ciliated cell expansion (CCE) was defined as a monolayered contiguous run of >10 secretory or ciliated cells uninterrupted by the other cell type. Results: Image analyses of the tubal stroma revealed gradual architectural differences from the Benign to NoSTIC to AwaySTIC to NearSTIC groups. In the epithelial topology analysis, the relative number of SCE and the average number of cells within SCE were higher in the STIC group than in the Benign and NoSTIC groups. In addition, aging was associated with an increased relative number of SCE and a decreased relative number of CCE. ROC analysis determined that an average of 15 cells within SCE was the optimal cutoff value indicating the presence of a STIC lesion in the tubal epithelium. Conclusions: Our findings suggest that global stromal alterations and age-associated reorganization of tubal secretory and ciliated cells are associated with STIC lesions. Further studies will need to determine if these alterations precede STIC lesions and provide permissible conditions for the formation of STIC.

Antineutrophil cytoplasmic antibody profiles differ according to type of primary sclerosing cholangitis and autoimmune hepatitis.

OBJECTIVES: To determine the frequency of the antineutrophil cytoplasmic antibodies (ANCA), antiproteinase-3 and antimyeloperoxidase, in primary sclerosing cholangitis (PSC) with or without inflammatory bowel disease (IBD+ or IBD-) and in different types of autoimmune hepatitis (AIH). Additionally, to verify the agreement between ANCA patterns by indirect immunofluorescence and their antigenic specificities by ELISA. METHODS: For this study, 249 patients were enrolled (42 PSC/IBD+; 33 PSC/IBD-; 31 AIH type-1; 30 AIH type-2; 31 AIH type-3; 52 primary biliary cirrhosis; 30 healthy controls) whose serum samples were tested for ANCA autoantibodies. RESULTS: There were fewer female subjects in the PSC/IBD- group (p=0.034). Atypical perinuclear-ANCA was detected more frequently in PSC/IBD+ patients than in PSC/IBD- patients (p=0.005), and was significantly more frequent in type-1 (p<0.001) and type-3 AIH (p=0.012) than in type-2 AIH. Proteinase-3-ANCA was detected in 25 samples (only one with cytoplasmic-ANCA pattern), and more frequently in PSC/IBD+ than in PSC/IBD- patients (p=0.025). Myeloperoxidase-ANCA was identified in eight samples (none with the perinuclear-ANCA pattern). Among the 62 reactive samples for atypical perinuclear-ANCA, 13 had antigenic specific reactions for proteinase-3 and myeloperoxidase. CONCLUSIONS: PSC/IBD+ differed from PSC/IBD- in terms of sex and proteinase 3-ANCA and atypical perinuclear-ANCA reactivity, the latter of which was more frequently detected in type-1 and type-3 AIH than in type-2 AIH. There was no agreement between ANCA patterns and antigenic specificities in IBD and autoimmune liver diseases, which reinforces the need for proteinase-3 and myeloperoxidase antibody testing.

Antineutrophil cytoplasmic antibody profiles differ according to type of primary sclerosing cholangitis and autoimmune hepatitis

OBJECTIVES: To determine the frequency of the antineutrophil cytoplasmic antibodies (ANCA), antiproteinase-3 and antimyeloperoxidase, in primary sclerosing cholangitis (PSC) with or without inflammatory bowel disease (IBD+ or IBD-) and in different types of autoimmune hepatitis (AIH). Additionally, to verify the agreement between ANCA patterns by indirect immunofluorescence and their antigenic specificities by ELISA. METHODS: For this study, 249 patients were enrolled (42 PSC/IBD+; 33 PSC/IBD-; 31 AIH type-1; 30 AIH type-2; 31 AIH type-3; 52 primary biliary cirrhosis; 30 healthy controls) whose serum samples were tested for ANCA autoantibodies. RESULTS: There were fewer female subjects in the PSC/IBD- group (p=0.034). Atypical perinuclear-ANCA was detected more frequently in PSC/IBD+ patients than in PSC/IBD- patients (p=0.005), and was significantly more frequent in type-1 (p<0.001) and type-3 AIH (p=0.012) than in type-2 AIH. Proteinase-3-ANCA was detected in 25 samples (only one with cytoplasmic-ANCA pattern), and more frequently in PSC/IBD+ than in PSC/IBD- patients (p=0.025). Myeloperoxidase-ANCA was identified in eight samples (none with the perinuclear-ANCA pattern). Among the 62 reactive samples for atypical perinuclear-ANCA, 13 had antigenic specific reactions for proteinase-3 and myeloperoxidase. CONCLUSIONS: PSC/IBD+ differed from PSC/IBD- in terms of sex and proteinase 3-ANCA and atypical perinuclear-ANCA reactivity, the latter of which was more frequently detected in type-1 and type-3 AIH than in type-2 AIH. There was no agreement between ANCA patterns and antigenic specificities in IBD and autoimmune liver diseases, which reinforces the need for proteinase-3 and myeloperoxidase antibody testing.

Palliative care consultation team: symptom relief in first 48 hours of hospitalization.

OBJECTIVE: To compare the relief of symptoms provided by palliative care consultation team (PCCT) compared to the traditional care team (TC), in patients with advanced cancer in the first 48 hours of hospitalization. METHOD: Allocated to PCCT Group and TC Group, this study assessed 290 patients according to the Edmonton Symptom Assessment System (ESAS) within the first 48 hours of hospitalization. The main outcome was a minimum 2-point reduction in symptom intensity. RESULTS: At 48 hours, the PCCT Group had a 2-point reduction in the mean differences (p <0.001) in pain, nausea, dyspnea, and depression; and TC Group, on nausea and sleep impairment (p <0.001). Multiple Logistic Regression found for the PCCT Group a greater chance of pain relief (OR 2.34; CI 1.01-5.43; p = 0.049). CONCLUSION: There was superiority of the PCCT Group for pain relief, dyspnea and depression. There is a need for more studies that broaden the understanding of team modalities.

Palliative care consultation team: symptom relief in first 48 hours of hospitalization / Equipo interconsultor en cuidados paliativos: alivio de síntomas en las primeras 48 horas de hospitalización / Equipe interconsultora em cuidados paliativos: alívio de sintomas nas primeiras 48 horas de hospitalização

ABSTRACT Objective: To compare the relief of symptoms provided by palliative care consultation team (PCCT) compared to the traditional care team (TC), in patients with advanced cancer in the first 48 hours of hospitalization. Method: Allocated to PCCT Group and TC Group, this study assessed 290 patients according to the Edmonton Symptom Assessment System (ESAS) within the first 48 hours of hospitalization. The main outcome was a minimum 2-point reduction in symptom intensity. Results: At 48 hours, the PCCT Group had a 2-point reduction in the mean differences (p <0.001) in pain, nausea, dyspnea, and depression; and TC Group, on nausea and sleep impairment (p <0.001). Multiple Logistic Regression found for the PCCT Group a greater chance of pain relief (OR 2.34; CI 1.01-5.43; p = 0.049). Conclusion: There was superiority of the PCCT Group for pain relief, dyspnea and depression. There is a need for more studies that broaden the understanding of team modalities.

RESUMEN Objetivo: Comparar el alivio de síntomas obtenido por equipo interconsultor en cuidados paliativos (ICP) al obtenido por equipo de cuidado tradicional (CT), en enfermos con cáncer avanzado en las primeras 48 horas de hospitalización. Método: Alocados en los Equipos ICP y Equipo CT, 290 pacientes han sido evaluados por la Escala de Síntomas de Edmonton (ESAS) en las primeras 48 horas de la hospitalización. El desenlace principal ha sido la reducción mínima de 2 puntos en la intensidad de síntomas. Resultados: En 48 horas, el Equipo ICP tuvo reducción de 2 puntos en las medias de las diferencias (p < 0,001) del dolor, náusea, disnea y depresión; y el Equipo CT, en la náusea y perjuicio del sueño (p < 0,001). Regresión Logística Múltiple mostró para el Equipo ICP mayor oportunidad de alivio del dolor (RC 2,34; CI 1,01-5,43; p = 0,049). Conclusión: Hubo superioridad del Equipo ICP para alivio del dolor, disnea y depresión. Estudios que amplíen la comprensión acerca de las modalidades de equipo son necesarios.

RESUMO Objetivo: Comparar o alívio de sintomas obtido por equipe interconsultora em cuidados paliativos (ICP) ao obtido por equipe de cuidado tradicional (CT), em doentes com câncer avançado nas primeiras 48 horas de hospitalização. Método: Alocados nos Grupos ICP e Grupo CT, 290 pacientes foram avaliados pela Escala de Sintomas de Edmonton (ESAS) nas primeiras 48 horas da hospitalização. O desfecho principal foi a redução mínima de 2 pontos na intensidade de sintomas. Resultados: Em 48 horas, o Grupo ICP teve redução de 2 pontos nas médias das diferenças (p < 0,001) da dor, náusea, dispneia e depressão; e o Grupo CT, na náusea e prejuízo do sono (p < 0,001). Regressão Logística Múltipla mostrou para o Grupo ICP maior chance de alívio da dor (RC 2,34; CI 1,01-5,43; p = 0,049). Conclusão: Houve superioridade do Grupo ICP para alívio da dor, dispneia e depressão. Estudos que ampliem a compreensão sobre modalidades de equipe são necessários.

Comparison between continuous and discrete doses for model based designs in cancer dose finding.

Despite of an extensive statistical literature showing that discretizing continuous variables results in substantial loss of information, categorization of continuous variables has been a common practice in clinical research and in cancer dose finding (phase I) clinical trials. The objective of this study is to quantify the loss of information incurred by using a discrete set of doses to estimate the maximum tolerated dose (MTD) in phase I trials, instead of a continuous dose support. Escalation With Overdose Control and Continuous Reassessment Method were used because they are model-based designs where dose can be specified either as continuous or as a set of discrete levels. Five equally spaced sets of doses with different interval lengths and three sample sizes with sixteen scenarios were evaluated to compare the operating characteristics between continuous and discrete dose designs by Monte Carlo simulation. Loss of information was quantified by safety and efficiency measures. We conclude that if there is insufficient knowledge about the true MTD value, as commonly happens in phase I clinical trials, a continuous dose scheme minimizes information loss. If one is required to implement a design using discrete doses, then a scheme with 9 to 11 doses may yield similar results to the continuous dose scheme.

Small-Volume, Fast-Emptying Gastric Pouch Leads to Better Long-Term Weight Loss and Food Tolerance After Roux-en-Y Gastric Bypass.

INTRODUCTION: Anatomical and functional influences on gastric bypass (GBP) results are often poorly evaluated and not yet fully understood. PURPOSE: The purpose of this study is to evaluate the influence of the gastric pouch volume and its emptying rate on long-term weight loss and food tolerance after GBP. MATERIALS AND METHODS: Weight loss, food tolerance, pouch volumetry (V) by three-dimensional reconstruction, and pouch emptying rate by 4 h scintigraphy were evaluated in 67 patients. Cutoffs were identified for V and retention percentage (%Ret) at 1 h (%Ret1). From these parameters, the sample was categorized, looking for associations between V, %Ret, weight loss, and food tolerance, assessed by a questionnaire for quick assessment of food tolerance (SS). RESULTS: PO median follow-up time was 47 months; median V was 28 mL; %Ret at 1, 2, and 4 h were 8, 2, and 1%, respectively. There were associations between V ≤ 40 mL and higher emptying rates up to 2 h (V ≤ 40 mL: %Ret1 = 6, %Ret2 = 2, p = 0.009; V > 40 mL: %Ret1 = 44, %Ret2 = 13.5, p = 0.045). An association was found between higher emptying speed in 1 h and higher late weight loss (WL), represented by lower percentage of excess weight loss (%EWL) regain (p = 0.036) and higher %EWL (p = 0.033) in the group with %Ret1 ≤ 12%, compared to the group %Ret1 ≥ 25%. Better food tolerance (SS > 24), was associated with lower %Ret1 (p = 0.003). CONCLUSION: Smaller pouch size is associated with a faster gastric emptying, greater WL maintenance, and better food tolerance. These data suggest that a small pouch with rapid emptying rate is an important technical parameter for good outcomes in GBP.

A Bayesian Adaptive Design in Cancer Phase I Trials using Dose Combinations in the Presence of a Baseline Covariate.

A Bayesian adaptive design for dose finding of a combination of two drugs in cancer phase I clinical trials that takes into account patients heterogeneity thought to be related to treatment susceptibility is described. The estimation of the maximum tolerated dose (MTD) curves is a function of a baseline covariate using two cytotoxic agents. A logistic model is used to describe the relationship between the doses, baseline covariate, and the probability of dose limiting toxicity (DLT). Trial design proceeds by treating cohorts of two patients simultaneously using escalation with overdose control (EWOC), where at each stage of the trial, the next dose combination corresponds to the α quantile of the current posterior distribution of the MTD of one of two agents at the current dose of the other agent and the next patient's baseline covariate value. The MTD curves are estimated as function of Bayes estimates of the model parameters at the end of trial. Average DLT, pointwise average bias, and percent of dose recommendation at dose combination neighborhoods around the true MTD are compared to the design that uses the covariate to the one that ignores the baseline characteristic. We also examine the performance of the approach under model misspecifications for the true dose-toxicity relationship. The methodology is further illustrated by the case of a pre-specified discrete set of dose combinations.

Cyclooxygenase-2 gene polymorphisms and susceptibility to colorectal cancer in a Brazilian population.

BACKGROUND: Multi-ethnicity of Brazilian population displays high levels of genomic diversity. Polymorphism may detect people at higher risk of developing cancer, distinctive response to treatment, and prognosis. Cyclooxygenase-2 (COX-2) is induced in response to growth factors and cytokines, and is expressed in inflammatory diseases, precancerous lesions and colorectal cancer (CRC). The aim of this study was to evaluate the influence of COX-2 -1195A > G and 8473T > C polymorphisms as a risk factor of developing CRC. METHODS: We evaluated COX-2 Single Nucleotide Polymorphism (SNP) of 230 CRC patients and 196 healthy controls by Real-Time Polymerase Chain Reaction. RESULTS: Populations were in Hardy-Weinberg equilibrium (HWE), except for control group of 8473T > C SNP. The frequencies were similar in both groups for genotypes and haplotypes. There was no association between studied polymorphisms and risk of CRC. CONCLUSIONS: The gene polymorphisms studied do not participate in the genetic susceptibility to CRC in a Brazilian population.

Higher MELD score increases the overall cost on the waiting list for liver transplantation: a micro-costing analysis based study.

BACKGROUND:: The pre-transplant period is complex and includes lots of procedures. The severity of liver disease predisposes to a high number of hospitalizations and high costs procedures. Economic evaluation studies are important tools to handle costs on the waiting list for liver transplantation. OBJECTIVE:: The objective of the present study was to evaluate the total cost of the patient on the waiting list for liver transplantation and the main resources related to higher costs. METHODS:: A cost study in a cohort of 482 patients registered on waiting list for liver transplantation was carried out. In 24 months follow-up, we evaluated all costs of materials, medicines, consultations, procedures, hospital admissions, laboratorial tests and image exams, hemocomponents replacements, and nutrition. The total amount of each resource or component used was aggregated and multiplied by the unitary cost, and thus individual cost for each patient was obtained. RESULTS:: The total expenditure of the 482 patients was US$ 6,064,986.51. Outpatient and impatient costs correspond to 32.4% of total cost (US$ 1,965,045.52) and 67.6% (US$ 4,099,940.99) respectively. Main cost drivers in outpatient were: medicines (44.31%), laboratorial tests and image exams (31.68%). Main cost drivers regarding hospitalizations were: medicines (35.20%), bed use in ward and ICU (26.38%) and laboratorial tests (13.72%). Patients with MELD score between 25-30 were the most expensive on the waiting list (US$ 16,686.74 ± 16,105.02) and the less expensive were those with MELD below 17 (US$ 5,703.22 ± 9,318.68). CONCLUSION:: Total costs on the waiting list for liver transplantation increased according to the patient's severity. Individually, hospitalizations, hemocomponents reposition and hepatocellular carcinoma treatment were the main cost drivers to the patient on the waiting list. The longer the waiting time, the higher the total cost on list, causing greater impact on health systems.

Higher MELD score increases the overall cost on the waiting list for liver transplantation: a micro-costing analysis based study / Altos valores de MELD aumentam o custo total em lista de espera para o transplante hepático. Um estudo de microcusteio

ABSTRACT BACKGROUND: The pre-transplant period is complex and includes lots of procedures. The severity of liver disease predisposes to a high number of hospitalizations and high costs procedures. Economic evaluation studies are important tools to handle costs on the waiting list for liver transplantation. OBJECTIVE: The objective of the present study was to evaluate the total cost of the patient on the waiting list for liver transplantation and the main resources related to higher costs. METHODS: A cost study in a cohort of 482 patients registered on waiting list for liver transplantation was carried out. In 24 months follow-up, we evaluated all costs of materials, medicines, consultations, procedures, hospital admissions, laboratorial tests and image exams, hemocomponents replacements, and nutrition. The total amount of each resource or component used was aggregated and multiplied by the unitary cost, and thus individual cost for each patient was obtained. RESULTS: The total expenditure of the 482 patients was US$ 6,064,986.51. Outpatient and impatient costs correspond to 32.4% of total cost (US$ 1,965,045.52) and 67.6% (US$ 4,099,940.99) respectively. Main cost drivers in outpatient were: medicines (44.31%), laboratorial tests and image exams (31.68%). Main cost drivers regarding hospitalizations were: medicines (35.20%), bed use in ward and ICU (26.38%) and laboratorial tests (13.72%). Patients with MELD score between 25-30 were the most expensive on the waiting list (US$ 16,686.74 ± 16,105.02) and the less expensive were those with MELD below 17 (US$ 5,703.22 ± 9,318.68). CONCLUSION: Total costs on the waiting list for liver transplantation increased according to the patient's severity. Individually, hospitalizations, hemocomponents reposition and hepatocellular carcinoma treatment were the main cost drivers to the patient on the waiting list. The longer the waiting time, the higher the total cost on list, causing greater impact on health systems.

RESUMO CONTEXTO: O período pré-transplante é complexo e inclui grande quantidade de procedimentos. A gravidade da doença hepática predispõe a um alto número de internações e procedimentos de alto custo. Estudos em avaliação econômica são uma importante ferramenta para o manejo dos custos em lista de espera para o transplante hepático. OBJETIVO: O objetivo do presente estudo foi avaliar o custo total do paciente em lista de espera para o transplante hepático e os principais recursos relacionados ao alto custo. MÉTODOS: Foi realizado um estudo de coorte em 482 pacientes registrados em lista de espera para o transplante hepático. Os pacientes foram acompanhados por um período de 24 meses, no qual foram avaliados todos os custos de materiais, medicamentos, consultas, procedimentos internações, exames laboratoriais e de imagem, reposição de hemocomponentes e nutrição recebida. A quantidade total de cada recurso e componente utilizado foi obtida e multiplicada pelo seu valor unitário e, desta maneira, o custo individual de cada paciente foi obtido. RESULTADOS: O total gasto pelos 482 pacientes foi de US$ 6.064.986,51. Os custos ambulatoriais corresponderam a 32,4% do total (US$ 1.965.045,52) e os custos em internação corresponderam a 67,6% do total (US$ 4.099.940,99). Os principais determinantes do custo em ambulatório foram: medicamentos (44,31%) e exames laboratoriais e de imagem (31,68%). Os principais determinantes de custo em internações foram: medicamentos (35,20%), utilização do leito em enfermaria e em UTI (26,38%) e exames laboratoriais (13,72%) Pacientes com valores de MELD entre 25-30 foram os de maiores custos em lista de espera (US$ 16.686,74 ± 16,105.02) e os de menor custo foram os pacientes com MELD abaixo de 17 (US$ 5.703,22 ± 9.318,68). CONCLUSÃO: O custo total em lista de espera para o transplante hepático aumenta de acordo com a gravidade do paciente. Individualmente, internações, reposição de hemocomponentes e o tratamento do paciente com carcinoma hepatocelular são os principais determinantes de custo para os pacientes em lista de espera para o transplante hepático. Quanto maior o tempo de espera, maiores serão os custos em lista, causando maior impacto nos sistemas de saúde.

Dose Finding for Drug Combination in Early Cancer Phase I Trials using Conditional Continual Reassessment Method.

We describe a dose escalation algorithm for drug combinations in cancer phase I clinical trials. Parametric models for describing the association between the doses and the probability of dose limiting toxicity are used assuming univariate monotonicity of the dose-toxicity relationship. Trial design proceeds using the continual reassessment method, where at each stage of the trial, we seek the dose of one agent with estimated probability of toxicity closest to a target probability of toxicity given the current dose of the other agent. A Bayes estimate of the maximum tolerated dose (MTD) curve is proposed at the conclusion of the trial for continuous doses or a set of MTDs is determined in the case of discrete dose levels. We evaluate design operating characteristics in terms of safety of the trial and percent of dose recommendation at dose combination neighborhoods around the true MTD under various model generated scenarios and misspecification. The method is further assessed for varying algorithms enrolling cohorts of two and three patients receiving different doses and compared to previous approaches such as escalation with overdose control and two-dimensional design.

Hypolactasia is associated with insulin resistance in nonalcoholic steatohepatitis.

AIM: To assess lactase gene (LCT)-13910C>T polymorphisms in Brazilian non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) patients in comparison with healthy controls. METHODS: This was a transverse observational clinical study with NAFLD patients who were followed at the Hepatology Outpatient Unit of the Hospital das Clínicas, São Paulo, Brazil. The polymorphism of lactase non-persistence/lactase persistence (LCT-13910C>T) was examined by PCR-restriction fragment length polymorphism technique in 102 liver biopsy-proven NAFLD patients (steatosis in 9 and NASH in 93) and compared to those of 501 unrelated healthy volunteers. Anthropometric, clinical, biochemical and liver histology data were analyzed. Continuous variables were compared using the t or Mann-Whitney tests, and categorical data were compared with the Fisher's exact test. Univariate logistic regression and multivariate logistic regression adjusted for gender and age were performed. RESULTS: No differences in the LCT-13910 genotype frequencies were noted between the NAFLD patients (66.67% of the patients with steatosis were CC, 33.33% were CT, and none were TT; 55.91% of the patients with NASH were CC, 39.78% were CT, and 4.3% were TT; P = 0.941) and the healthy controls (59.12% were CC, 35.67% were CT, and 5.21% were TT) or between the steatosis and NASH patients. That is, the distribution of the lactase non-persistence/lactase persistence polymorphism (LCT-13910C>T) in the patients with NAFLD was equal to that in the general population. In the NASH patients, the univariate analysis revealed that the lactase non-persistence (low lactase activity or hypolactasia) phenotype was associated with higher insulin levels (23.47 ± 15.94 µU/mL vs 15.8 ± 8.33 µU/mL, P = 0.027) and a higher frequency of insulin resistance (91.84% vs 72.22%, P = 0.02) compared with the lactase persistence phenotype. There were no associations between the LCT genotypes and diabetes (P = 0.651), dyslipidaemia (P = 0.328), hypertension (P = 0.507) or liver histology in these patients. Moreover, in the NASH patients, hypolactasia was an independent risk factor for insulin resistance even after adjusting for gender and age [OR = 5.0 (95%CI: 1.35-20; P = 0.017)]. CONCLUSION: The LCT-13910 genotype distribution in Brazilian NAFLD patients was the same as that of the general population, but hypolactasia increased the risk of insulin resistance in the NASH patients.

The Lowest Prevalence of Cholelithiasis in the Americas - An Autopsy-based Study.

OBJECTIVES: This study used autopsy to evaluate the prevalence of cholelithiasis and its associated risk factors in a population of healthy, young subjects who suffered a violent or natural death. METHODS: This study is a prospective evaluation of autopsies of 446 individuals from 2011 to 2013 in Brazil. Of that sample, 330 (74%) subjects died from violent deaths and 116 (26%) died naturally. The presence of biliary calculi, previous cholecystectomy, gender, age, ethnicity, body mass index (BMI) and alcohol use were evaluated. RESULTS: In the natural death group, 6.9% (95% CI 3.39 to 13.28) (3.08% of the male subjects and 11.76% of the female subjects) exhibited evidence of gallbladder disease. In the violent death group, only 2.12% (95% CI 0.96 to 4.43) (2.17% of the male subjects and 1.85% of the female subjects) of the subjects exhibited evidence of gallbladder disease. Age was correlated with the prevalence of gallbladder disease, but BMI was correlated with only gallbladder disease in the natural death group. CONCLUSIONS: This population has the lowest prevalence of cholelithiasis in the Americas. Dietary habits, physical activity, ethnicity, alcohol consumption and genetic factors may be responsible for this low prevalence.

The Lowest Prevalence of Cholelithiasis in the Americas - An Autopsy-based Study

OBJECTIVES: This study used autopsy to evaluate the prevalence of cholelithiasis and its associated risk factors in a population of healthy, young subjects who suffered a violent or natural death. METHODS: This study is a prospective evaluation of autopsies of 446 individuals from 2011 to 2013 in Brazil. Of that sample, 330 (74%) subjects died from violent deaths and 116 (26%) died naturally. The presence of biliary calculi, previous cholecystectomy, gender, age, ethnicity, body mass index (BMI) and alcohol use were evaluated. RESULTS: In the natural death group, 6.9% (95% CI 3.39 to 13.28) (3.08% of the male subjects and 11.76% of the female subjects) exhibited evidence of gallbladder disease. In the violent death group, only 2.12% (95% CI 0.96 to 4.43) (2.17% of the male subjects and 1.85% of the female subjects) of the subjects exhibited evidence of gallbladder disease. Age was correlated with the prevalence of gallbladder disease, but BMI was correlated with only gallbladder disease in the natural death group. CONCLUSIONS: This population has the lowest prevalence of cholelithiasis in the Americas. Dietary habits, physical activity, ethnicity, alcohol consumption and genetic factors may be responsible for this low prevalence.

Interferon lambda and hepatitis C virus core protein polymorphisms associated with liver cancer.

BACKGROUND: Hepatitis C virus (HCV) infection is often persistent and gradually advances from chronic hepatitis to liver cirrhosis and hepatocellular carcinoma (HCC). Worldwide, hepatocellular carcinoma is the fifth most common neoplasm. METHOD OF STUDY: the Interferon lambda (IFNL) polymorphisms genotypes (rs8099917, rs12979860 and rs12980275) and the presence of mutations in HCV core protein were analyzed in 59 patients with HCC, and also in 50 cirrhotic patients (without HCC). RESULTS: the rs12980275-AG genotype was associated with HCC on age-adjusted analysis (OR 2.42, 95% CI 1.03-5.69, P=0.043). Core substitutions R70Q and L91M were mainly found in genotype 1b isolates. Furthermore, a borderline level of statistical significance association was found among the presence of amino acid Glutamine (Q) in the position 70 and IFNL3 genotype AG (P=0.054). CONCLUSIONS: the screening of these polymorphisms and functional studies would be useful in clinical practice for identifying groups at high risk of HCC development.

Association of IFNL3 and IFNL4 polymorphisms with hepatitis C virus infection in a population from southeastern Brazil.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and associated complications such as liver cirrhosis and hepatocellular carcinoma (HCC). Viral and host factors are known to be predictors for antiviral therapy. Host factors that are predictors of sustained viral response (SVR) were discovered by genome-wide association studies (GWAS), including single-nucleotide polymorphisms (SNPs) in or near the interferon lambda gene (rs8099917, rs12979860 and rs368234815). The aim of the present study was to verify the genotype frequencies of SNPs rs8099917, rs12979860 and rs368234815 and to evaluate the association between SNPs and the outcome of HCV infection, taking into account the population ancestry. In this study, there was an association of the three polymorphisms with both clinical outcome and response to treatment with PEG-IFN and RBV. The polymorphisms rs12979860 and rs368234815 were associated with increased sensitivity (97.7 %, 95 % CI 87.2-100, and 93.3 %, 95 % CI 81.3-98.3; respectively) and with a greater predictive value of a positive response to treatment. In multivariable analysis adjusted by gender, age and ancestry, the haplotype G/T/ΔG was related to non-response to treatment (OR = 21.09, 95 % CI 5.33-83.51; p < 0.001) and to a higher chance of developing chronic infection (OR = 5.46, 95 % CI 2.06-14.46; p = 0.001) when compared to the haplotype T/C/TT. These findings may help to adjust our treatment policies for HCV infection based on greater certainty in studies with populations with such genetic characteristics, as well as allowing us to get to know the genetic profile of our population for these polymorphisms.