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TLRs initiate innate immune signaling pathways via Toll/IL-1R (TIR) domains on their cytoplasmic tails. Various bacterial species also express TIR domain-containing proteins that contribute to bacterial evasion of the innate immune system. Bacterial TIR domains, along with the mammalian sterile α and TIR motif-containing protein 1 and TIRs from plants, also have been found to exhibit NADase activity. Initial X-ray crystallographic studies of the bacterial TIR from Acinetobacter baumannii provided insight into bacterial TIR structure but were unsuccessful in cocrystallization with the NAD+ ligand, leading to further questions about the TIR NAD binding site. In this study, we designed a Course-Based Undergraduate Research Experience (CURE) involving 16-20 students per year to identify amino acids crucial for NADase activity of A. baumannii TIR domain protein and the TIR from Escherichia coli (TIR domain-containing protein C). Students used structural data to identify amino acids that they hypothesized would play a role in TIR NADase activity, and created plasmids to express mutated TIRs through site-directed mutagenesis. Mutant TIRs were expressed, purified, and tested for NADase activity. The results from these studies provide evidence for a conformational change upon NAD binding, as was predicted by recent cryogenic electron microscopy and hydrogen-deuterium exchange mass spectrometry studies. Along with corroborating recent characterization of TIR NADases that could contribute to drug development for diseases associated with dysregulated TIR activity, this work also highlights the value of CURE-based projects for inclusion of a diverse group of students in authentic research experiences.
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Acinetobacter baumannii , NAD+ Nucleosidase , Acinetobacter baumannii/genética , NAD+ Nucleosidase/metabolismo , NAD+ Nucleosidase/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Humanos , NAD/metabolismo , Sítios de Ligação , Domínios Proteicos , Mutagênese Sítio-Dirigida , Cristalografia por Raios X , Imunidade InataRESUMO
There remains a large need for a greater understanding of the metastatic process within the prostate cancer field. Our research aims to understand the adaptive - ergo potentially metastatic - responses of cancer to changing microenvironments. Emerging evidence has implicated a role of the Polyaneuploid Cancer Cell (PACC) state in metastasis, positing the PACC state as capable of conferring metastatic competency. Mounting in vitro evidence supports increased metastatic potential of cells in the PACC state. Additionally, our recent retrospective study of prostate cancer patients revealed that PACC presence in the prostate at the time of radical prostatectomy was predictive of future metastatic progression. To test for a causative relationship between PACC state biology and metastasis, we leveraged a novel method designed for flow-cytometric detection of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) in subcutaneous, caudal artery, and intracardiac mouse models of metastasis. This approach provides both quantitative and qualitative information about the number and PACC-status of recovered CTCs and DTCs. Collating data from all models, we found that 74% of recovered CTCs and DTCs were in the PACC state. In vivo colonization assays proved PACC populations can regain proliferative capacity at metastatic sites following dormancy. Additional direct and indirect mechanistic in vitro analyses revealed a PACC-specific partial Epithelial-to-Mesenchymal-Transition phenotype and a pro-metastatic secretory profile, together providing preliminary evidence that PACCs are mechanistically linked to metastasis.
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Rapid and reliable circulating tumor cell (CTC) and disseminated tumor cell (DTC) detection are critical for rigorous evaluation of in vivo metastasis models. Clinical data show that each step of the metastatic cascade presents increasing barriers to success, limiting the number of successful metastatic cells to fewer than 1 in 1,500,000,000. As such, it is critical for scientists to employ approaches that allow for the evaluation of metastatic competency at each step of the cascade. Here, we present a flow cytometry-based method that enables swift and simultaneous comparison of both CTCs and DTCs from single animals, enabling evaluation of multiple metastatic steps within a single model system. We present the necessary gating strategy and optimized sample preparation conditions necessary to capture CTCs and DTCs using this approach. We also provide proof-of-concept experiments emphasizing the appropriate limits of detection of these conditions. Most importantly, we successfully recover CTCs and DTCs from murine blood and bone marrow. In Supplemental materials, we expand the applicability of our method to lung tissue and exemplify a potential multi-plexing strategy to further characterize recovered CTCs and DTCs. This approach to multiparameter flow cytometric detection and analysis of rare cells in in vivo models of metastasis is reproducible, high throughput, broadly applicable, and highly adaptable to a wide range of scientific inquiries. Most notably, it simplifies the recovery and analysis of CTCs and DTCs from the same animal, allowing for a rapid first look at the comparative metastatic competency of various model systems throughout multiple steps of the metastatic cascade.
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BACKGROUND: Behavioural weight loss programs are effective first-line treatments for obesity and are recommended by the US Preventive Services Task Force. Gaining an understanding of intervention components that are found helpful by different demographic groups can improve tailoring of weight loss programs. This paper examined the perceived helpfulness of different weight loss program components. METHODS: Participants (n = 236) from the active intervention conditions of the Practice-based Opportunities for Weight Reduction (POWER) Hopkins Trial rated the helpfulness of 15 different components of a multicomponent behavioural weight loss program at 24-month follow-up. These ratings were examined in relation to demographic variables, treatment arm and weight loss success. RESULTS: The components most frequently identified as helpful were individual telephone sessions (88%), tracking weight online (81%) and coach review of tracking (81%). The component least frequently rated as helpful was the primary care providers' general involvement (50%). Groups such as older adults, Blacks and those with lower education levels more frequently reported intervention components as helpful compared with their counterparts. DISCUSSION: Weight loss coaching delivered telephonically with web support was well received. Findings support the use of remote behavioural interventions for a wide variety of individuals.
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PURPOSE: To evaluate effects of two behavioral weight-loss interventions (in-person, remote) on health-related quality of life (HRQOL) compared to a control intervention. METHODS: Four hundred and fifty-one obese US adults with at least one cardiovascular risk factor completed five measures of HRQOL and depression: MOS SF-12 physical component summary (PCS) and mental component summary; EuroQoL-5 dimensions single index and visual analog scale; PHQ-8 depression symptoms; and PSQI sleep quality scores at baseline and 6 and 24 months after randomization. Change in each outcome was analyzed using outcome-specific mixed-effects models controlling for participant demographic characteristics. RESULTS: PCS-12 scores over 24 months improved more among participants in the in-person active intervention arm than among control arm participants (P < 0.05, ES = 0.21); there were no other statistically significant treatment arm differences in HRQOL change. Greater weight loss was associated with improvements in most outcomes (P < 0.05 to < 0.0001). CONCLUSIONS: Participants in the in-person active intervention improved more in physical function HRQOL than participants in the control arm did. Greater weight loss during the study was associated with greater improvement in all PRO except for sleep quality, suggesting that weight loss is a key factor in improving HRQOL.
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Terapia Comportamental , Obesidade/terapia , Qualidade de Vida , Redução de Peso , Adulto , Depressão , Feminino , Nível de Saúde , Humanos , Internet , Masculino , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Obesidade/psicologia , Medição da Dor , Transtornos do Sono-Vigília , Resultado do TratamentoRESUMO
Birth cohort has been shown to be related to morbidity and mortality from other diseases and conditions, yet little is known about the potential for birth cohort in its relation to pneumonia and influenza (P&I) outcomes. This issue is particularly important in older adults, who experience the highest disease burden and most severe complications from these largely preventable diseases. The objective of this analysis is to assess P&I patterns in US seniors with respect to age, time, and birth cohort. All Medicare hospitalizations due to P&I (ICD-9CM codes 480-487) were abstracted and categorized by single-year of age and influenza year. These counts were then divided by intercensal estimates of age-specific population levels extracted from the US Census Bureau to obtain age- and season-specific rates. Rates were log-transformed and linear models were used to assess the relationships in P&I rates and age, influenza year, and cohort. The increase in disease rates with age accounted for most of the variability by age and influenza season. Consistent relationships between disease rates and birth cohorts remained, even after controlling for age. Seasonal associations were stronger for influenza than for pneumonia. These findings suggest that there may be a set of unmeasured characteristics or events people of certain ages experienced contemporaneously that may account for the observed differences in P&I rates in birth cohorts. Further understanding of these circumstances and those resulting age and cohort groups most vulnerable to P&I may help to target health services towards those most at risk of disease.
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Influenza Humana/epidemiologia , Pneumonia/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Efeito de Coortes , Estudos de Coortes , Feminino , Hospitalização/tendências , Humanos , Estudos Longitudinais , Masculino , Análise de RegressãoRESUMO
Herpes simplex virus type 2 (HSV-2) is one of the most prevalent sexually transmitted infections, and it increases the risk of transmission of human immunodeficiency virus type 1 at least twofold. Individual-level factors are insufficient to explain geographic and population variation in HSV-2, suggesting the need to identify ecologic factors. The authors sought to determine the geographic prevalence and community-level factors associated with HSV-2 after controlling for individual-level factors among slums in Chennai, India. From March to June 2001, participants aged 18-40 years voluntarily completed a survey and were tested for HSV-2. Community characteristics were assessed through interviews with key informants and other secondary data sources. Multilevel nonlinear analysis was conducted. Eighty-five percent of eligible persons completed the survey; of these, 98% underwent HSV-2 testing, producing a final sample of 1,275. Participants were of Tamil ethnicity, were predominantly female and married, and were on average 30 years old. Fifteen percent were infected with HSV-2, and there was significant variation in HSV-2 prevalence among communities. After controlling for individual-level factors, the authors identified community-level factors, including socioeconomic status and the presence of injection drug users, that were independently associated with HSV-2 and explained 11% of the variance in prevalence. Future studies are needed to test mechanisms through which these community-level factors may be operating.
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Herpes Genital/epidemiologia , Herpes Genital/etiologia , Herpesvirus Humano 2 , Adolescente , Adulto , Feminino , Herpes Genital/transmissão , Herpes Genital/virologia , Humanos , Índia/epidemiologia , Masculino , Projetos Piloto , Prevalência , Características de Residência , Fatores de Risco , Comportamento Sexual , Classe Social , Inquéritos e QuestionáriosRESUMO
Because of differences in case-mix across states, state-level case-mix-adjusted end-stage renal disease (ESRD) incident rates are reported in each United States Renal Data System Annual Data Report to make the across-state comparisons valid. The adjusted rates were estimated by the direct adjustment method, a widely used method for adjusted event rate calculation, based on observed category-specific ESRD incident rates in each state (called the observation-based method). However, when some adjusting categories in a state are small, the adjusted rate and the standard error for this state as estimated by this method may be inaccurate. This report proposes a model-based method that can overcome the disadvantages of the observation-based method and can be extended to continuous adjusting variables. National ESRD incident data and national population data from 1990 to 1999 were used. State-level adjusted ESRD incident rates were estimated by both the observation- and the model-based methods. For the model-based method, a Poisson regression model was used to estimate category-specific ESRD incident rates. For large-population states, both observation- and model-based methods produced similar estimates for adjusted ESRD incident rates. For small-population states, however, the observation-based method produced year-to-year estimates of adjusted ESRD incident rates that varied considerably and also had very large standard errors. In contrast, the model-based method produced stable estimates. The model-based method can overcome the disadvantages of the observation-based method for estimating state-level adjusted ESRD incident rates, especially for small states.
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Falência Renal Crônica/epidemiologia , Modelos Estatísticos , Distribuição por Idade , Povo Asiático , População Negra , Censos , Bases de Dados Factuais , Métodos Epidemiológicos , Feminino , Inquéritos Epidemiológicos , Humanos , Incidência , Indígenas Norte-Americanos , Masculino , Análise de Regressão , Estudos Retrospectivos , Estados Unidos/epidemiologia , População BrancaRESUMO
OBJECTIVE: Our goal was to provide health-care providers, patients, and the general public with an assessment of currently available data regarding the use of adjuvant therapy for breast cancer. PARTICIPANTS: The participants included a non-Federal, non-advocate, 14-member panel representing the fields of oncology, radiology, surgery, pathology, statistics, public health, and health policy as well as patient representatives. In addition, 30 experts in medical oncology, radiation oncology, biostatistics, epidemiology, surgical oncology, and clinical trials presented data to the panel and to a conference audience of 1000. EVIDENCE: The literature was searched with the use of MEDLINE(TM) for January 1995 through July 2000, and an extensive bibliography of 2230 references was provided to the panel. Experts prepared abstracts for their conference presentations with relevant citations from the literature. Evidence from randomized clinical trials and evidence from prospective studies were given precedence over clinical anecdotal experience. CONSENSUS PROCESS: The panel, answering predefined questions, developed its conclusions based on the evidence presented in open forum and the scientific literature. The panel composed a draft statement, which was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after the conference. The draft statement was made available on the World Wide Web immediately after its release at the conference and was updated with the panel's final revisions. The statement is available at http://consensus.nih.gov. CONCLUSIONS: The panel concludes that decisions regarding adjuvant hormonal therapy should be based on the presence of hormone receptor protein in tumor tissues. Adjuvant hormonal therapy should be offered only to women whose tumors express hormone receptor protein. Because adjuvant polychemotherapy improves survival, it should be recommended to the majority of women with localized breast cancer regardless of lymph node, menopausal, or hormone receptor status. The inclusion of anthracyclines in adjuvant chemotherapy regimens produces a small but statistically significant improvement in survival over non-anthracycline-containing regimens. Available data are currently inconclusive regarding the use of taxanes in adjuvant treatment of lymph node-positive breast cancer. The use of adjuvant dose-intensive chemotherapy regimens in high-risk breast cancer and of taxanes in lymph node-negative breast cancer should be restricted to randomized trials. Ongoing studies evaluating these treatment strategies should be supported to determine if such strategies have a role in adjuvant treatment. Studies to date have included few patients older than 70 years. There is a critical need for trials to evaluate the role of adjuvant chemotherapy in these women. There is evidence that women with a high risk of locoregional tumor recurrence after mastectomy benefit from postoperative radiotherapy. This high-risk group includes women with four or more positive lymph nodes or an advanced primary cancer. Currently, the role of postmastectomy radiotherapy for patients with one to three positive lymph nodes remains uncertain and should be tested in a randomized controlled trial. Individual patients differ in the importance they place on the risks and benefits of adjuvant treatments. Quality of life needs to be evaluated in selected randomized clinical trials to examine the impact of the major acute and long-term side effects of adjuvant treatments, particularly premature menopause, weight gain, mild memory loss, and fatigue. Methods to support shared decision-making between patients and their physicians have been successful in trials; they need to be tailored for diverse populations and should be tested for broader dissemination.
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Adjuvantes Farmacêuticos/administração & dosagem , Adjuvantes Farmacêuticos/uso terapêutico , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/terapia , Adjuvantes Farmacêuticos/efeitos adversos , Idoso , Antineoplásicos Hormonais/efeitos adversos , Ensaios Clínicos como Assunto , Feminino , Humanos , MEDLINE , Pessoa de Meia-IdadeRESUMO
Maps of regional morbidity and mortality rates play an important role in assessing environmental equity. They provide effective tools for identifying areas with potentially elevated risk, determining spatial trend, and formulating and validating aetiological hypotheses about disease. Bayes and empirical Bayes methods produce stable small-area rate estimates that retain geographic and demographic resolution. The beauty of the Bayesian approach lies in its ability to structure complicated models, inferential goals and analyses. Three inferential goals are relevant to disease mapping and risk assessment: (i) computing accurate estimates of disease rates in small geographic areas; (ii) estimating the distribution of disease rates over the region; (iii) ranking the disease rates so that environmental investigation can be prioritized. No single set of estimates can simultaneously optimize these three goals, and Shen and Louis propose a set of estimates that perform well on all three goals. These are optimal for estimating the distribution of rates and for ranking, and maintain a high accuracy in estimating area-specific rates. However, the Shen/Louis method is sensitive to choice of priors. To address this issue we introduce a robustified version of the method based on a smoothed non-parametric estimate of the prior. We evaluate the performance of this method through a simulation study, and illustrate it using a data set of county-specific lung cancer rates in Ohio.
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Teorema de Bayes , Métodos Epidemiológicos , Neoplasias Pulmonares/mortalidade , Algoritmos , Humanos , Incidência , Mapas como Assunto , Ohio/epidemiologia , Distribuição de Poisson , Medição de RiscoRESUMO
We apply a linear mixed-effects model to multivariate failure time data. Computation of the regression parameters involves the Buckley-James method in an iterated Monte Carlo expectation-maximization algorithm, wherein the Monte Carlo E-step is implemented using the Metropolis-Hastings algorithm. From simulation studies, this approach compares favorably with the marginal independence approach, especially when there is a strong within-cluster correlation.
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Modelos Lineares , Algoritmos , Animais , Biometria , Método de Monte Carlo , Análise Multivariada , Neoplasias Experimentais/induzido quimicamente , Ratos , Análise de RegressãoRESUMO
OBJECTIVE: To test the effect of daily supplemental calcium on serum total and high-density lipoprotein cholesterol (HDL-C) levels and blood pressure in adults. DESIGN: Randomized, double-blind, placebo-controlled clinical trial; adjunct study to a trial of calcium and colon cell proliferation in patients with sporadic adenoma. SETTING: Outpatient clinic. PATIENTS: A total of 193 men and women, aged 30 to 74 years. INTERVENTION: Treatment with 1.0 and 2.0 g/d of elemental calcium vs placebo over a 4-month period for cholesterol determinations and 6 months for blood pressure. MAIN OUTCOME MEASURES: Serum total cholesterol and HDL-C levels, systolic and diastolic blood pressure. RESULTS: Because there were no apparent differences in responses between the 1.0-g and 2.0-g calcium groups, their data were combined and compared with those of the placebo group. Among all participants, the mean total cholesterol level dropped 0.07 mmol/L (2.9 mg/dL) (1.3%) (P = .43) more, and the mean HDL-C level dropped 0.01 mmol/L (0.4 mg/dL) (1.1%) (P = .71) less in the calcium group than in the placebo group. Among participants without a history of hypercholesterolemia, the mean total cholesterol level dropped 0.18 mmol/L (6.8 mg/dL) (3.3%) (P = .10) and the HDL-C level dropped 0.02 mmol/L (0.6 mg/dL) (1.5%) (P = .61) more in the calcium group than in the placebo group. Among all participants, there was no apparent change in blood pressure until 6 months, when the mean systolic blood pressure dropped 0.8 mm Hg (0.6%) (P = .85) and the mean diastolic blood pressure dropped 0.4 mm Hg (0.5%) (P = .80) more in the calcium group than in the placebo group. CONCLUSIONS: There were no substantial or statistically significant effects of calcium supplementation on total cholesterol or HDL-C levels or on blood pressure. There was a suggestion (not statistically significant) of a 0.07 to 0.18 mmol/L (3-7 mg/dL) or 2% to 4% drop in the total cholesterol level, a finding similar to that reported in other studies, which indicates the need for further study.
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Pressão Sanguínea/efeitos dos fármacos , Cálcio/uso terapêutico , HDL-Colesterol/sangue , Suplementos Nutricionais , Pólipos Adenomatosos , Cálcio/administração & dosagem , Pólipos do Colo/terapia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
Quality adjusted survival has been increasingly advocated in clinical trials to be assessed as a synthesis of survival and quality of life. We investigate nonparametric estimation of its expectation for a general multistate process with incomplete follow-up data. Upon establishing a representation of expected quality adjusted survival through marginal distributions of a set of defined events, we propose two estimators for expected quality adjusted survival. Expressed as functions of Nelson-Aalen estimators, the two estimators are strongly consistent and asymptotically normal. We derive their asymptotic variances and propose sample-based variance estimates, along with evaluation of asymptotic relative efficiency. Monte Carlo studies show that these estimation procedures perform well for practical sample sizes. We illustrate the methods using data from a national, multicenter AIDS clinical trial.
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Modelos Estatísticos , Anos de Vida Ajustados por Qualidade de Vida , Análise de Sobrevida , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Humanos , Análise Multivariada , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Estatísticas não ParamétricasRESUMO
By formalizing the relation among components and 'borrowing information' among them, Bayes and empirical Bayes methods can produce more valid, efficient and informative statistical evaluations than those based on traditional methods. In addition, Bayesian structuring of complicated models and goals guides development of appropriate statistical approaches and generates summaries which properly account for sampling and modelling uncertainty. Computing innovations enable implementation of complex and relevant models, thereby substantially increasing the role of Bayes/empirical Bayes methods in important statistical assessments. Policy-relevant statistical assessments involve synthesis of information from a set of related components such as medical clinics, geographic regions or research studies. Typical assessments include inference for individual parameters, synthesis over the collection of components (for example, the parameter histogram) and comparisons among parameters (for example, ranks). The relative importance of these goals depends on the context. Bayesian structuring provides a guide to valid inference. For example, while posterior means are the 'obvious' and optimal estimates for individual components under squared error loss, their empirical distribution function (EDF) is underdispersed and never valid for estimating the EDF of the true, underlying parameters. Effective histogram estimates result from optimizing a loss function based in a distance between the histogram and its estimate. Similarly, ranking observed data usually produces poor estimates and ranking posterior means can be inappropriate. Effective estimates should be based on a loss function that caters directly to ranks. Using examples of 'borrowing information', shrinkage and the variance/bias trade-off we motivate Bayes and empirical Bayes analysis. Then, we outline the formal approach and discuss 'triple-goal' estimates with values that when ranked produce optimal ranks, for which the EDF is an optimal estimate of the parameter EDF and such that the values themselves are effective estimates of co-ordinate-specific parameters. We use basic models and data analysis examples to highlight the conceptual and structural issues.
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Teorema de Bayes , Interpretação Estatística de Dados , Animais , Bioensaio , Carcinógenos/toxicidade , Ponte de Artéria Coronária/mortalidade , Guatemala/epidemiologia , Honduras/epidemiologia , Humanos , Funções Verossimilhança , Distribuição Normal , Roedores , Toxoplasmose/epidemiologiaRESUMO
Recent regulatory action requires the assessment of environmental justice (equitable protection from the burdens of environmental hazards across sociodemographic subpopulations) in the siting of hazardous waste sites, and prioritization of environmental remediation efforts. Assessments of environmental justice require linking exposure, demographic, and health data. The geographic nature of the data makes the use of geographic information systems attractive for environmental justice assessments. Typical geographic assessments compare the composition of 'exposed' populations, while typical statistical assessments focus on differences in health outcomes between population subgroups, possibly adjusted for exposure. We outline an alternate approach based on summarized differences between exposure distributions within each population subgroup. We illustrate how such summaries provide a tool for site evaluation (e.g., defining exposure inequities resulting from locating a new potential hazard at any of a number of possible sites). In addition, we describe summaries, based on dose-response relationships, to describe risk differences imposed by the observed exposure differences. Reported toxic emissions from Allegheny County, Pennsylvania illustrate the approach.
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Exposição Ambiental/análise , Saúde Ambiental/legislação & jurisprudência , Geografia , Política Pública , Teorema de Bayes , Humanos , Formulação de Políticas , Medição de Risco , Classe SocialRESUMO
Arylamine N-acetyltransferase 2 (NAT2) is involved in both the detoxification and bioactivation of carcinogenic arylamines and other mutagens. This enzyme is polymorphic, and the fast and slow phenotypes are thought to be risk factors for colon and bladder cancer, respectively. Here, we report on a case-control study of adenomatous and hyperplastic polyps, with particular attention to tobacco smoking, a known risk factor for adenomas, and polymorphisms of NAT2. All participants underwent complete colonoscopy and were subsequently divided into case and control groups on the basis of pathology. Cases were diagnosed with confirmed adenomas (n = 527) or hyperplastic polyps (n = 200); controls (n = 633) had no history of colonic neoplasia and no polyps at colonoscopy. NAT2 genotype was determined using an oligonucleotide ligation assay and fast, intermediate, or slow phenotype imputed. Multivariate-adjusted odds ratios (ORs) and 95% confidence intervals were computed using logistic regression adjusting for age, sex, nonsteroidal anti-inflammatory drug use, and hormone replacement therapy use. Smoking was associated with an increased risk of adenomas [current versus never smoking OR = 2.0 (95% confidence interval, 1.4-2.9)] and hyperplastic polyps [current versus never smoking OR = 4.1 (2.6-6.5)]. NAT2 status among adenomatous polyp patients and hyperplastic polyp patients, respectively, showed ORs of 1.1 (0.8-1.4) and 1.2 (0.8-1.6; intermediate versus slow) and 1.1 (0.6-1.9) and 0.9 (0.4-1.9; fast versus slow). There were no differences in risk when adenoma patients were stratified on multiplicity, size, or histopathological subtype of polyps. Never-smokers showed no variation in risk across acetylator status for either species of polyp, whereas current smokers showed ORs of 2.0 (1.2-3.2) and 2.3 (1.4-3.9) for adenomas and 3.9 (2.1-7.1) and 4.9 (2.6-9.4) for hyperplastic polyps for slow and intermediate/fast NAT2, respectively, compared with slow-NAT2 never-smokers. Risks of both multiple [OR = 4.3 (2.1-8.8)] and large [OR = 3.8 (1.9-7.5)] adenomas were somewhat elevated in current smokers with an intermediate/fast phenotype compared with smokers with a slow NAT2 phenotype, but the interaction was not statistically significant. Risk of hyperplastic polyps and adenomatous polyps is strongly related to smoking. There is little suggestion of interaction between NAT2 status and smoking and no relationship with NAT2 genotype alone.
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Pólipos Adenomatosos/etiologia , Arilamina N-Acetiltransferase/genética , Neoplasias do Colo/etiologia , Pólipos do Colo/etiologia , Polimorfismo Genético/genética , Neoplasias Retais/etiologia , Fumar/efeitos adversos , Pólipos Adenomatosos/enzimologia , Adulto , Fatores Etários , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Carcinógenos/metabolismo , Estudos de Casos e Controles , Neoplasias do Colo/enzimologia , Pólipos do Colo/enzimologia , Colonoscopia , Intervalos de Confiança , Terapia de Reposição de Estrogênios , Feminino , Humanos , Hiperplasia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutagênicos/metabolismo , Razão de Chances , Fenótipo , Neoplasias Retais/enzimologia , Fatores SexuaisRESUMO
Dietary protein restriction has been reported to delay the need for renal replacement therapy in clinical trials and meta-analyses. However, less clear is what effect dietary protein has on the rate of decline in renal function. We pooled the results of 13 randomized controlled trials (n = 1,919 patients) and found that dietary protein restriction reduced the rate of decline in estimated glomerular filtration rate by only 0.53 mL/min/yr (95% confidence interval [CI], 0.08 to 0.98 mL/min/yr). We also used weighted regression analysis to determine the reasons for the differences in the results of these 13 randomized trials along with 11 other nonrandomized controlled trials (n = 2,248 patients). The effect of dietary protein restriction (glomerular filtration rate decline in treatment minus control) was substantially less in randomized versus nonrandomized trials (regression coefficient, -5.2 mL/min/yr; 95% CI, -7.8 to -2.5 mL/min/yr; P < 0.05) and relatively greater among diabetic versus nondiabetic patients (5.4 mL/min/yr; 95% CI, 0.3 to 10.5 mL/min/yr; P < 0.05), while there was a trend toward a greater effect with each additional year of follow-up (2.1 mL/min/yr; 95% CI, -0.05 to 4.2 mL/min/yr; P = NS). However, the number of diabetic patients studied was small and the duration of follow-up was short in most trials. No other patient or study characteristics altered the effect of dietary protein restriction on the rate of decline in renal function. Thus, although dietary protein restriction retards the rate of renal function decline, the relatively weak magnitude of this effect suggests that better therapies are needed to slow the rate of renal disease progression.
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Proteínas Alimentares/administração & dosagem , Taxa de Filtração Glomerular , Falência Renal Crônica/dietoterapia , Nefropatias Diabéticas/dietoterapia , Nefropatias Diabéticas/fisiopatologia , Progressão da Doença , Humanos , Falência Renal Crônica/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
OBJECTIVE: Evaluate safety and efficacy of oral ganciclovir (GCV) for preventing cytomegalovirus (CMV) disease in HIV-infected persons at high risk for CMV disease. DESIGN: Double-blind, placebo-controlled, randomized clinical trial in primary care clinics and private practice offices specializing in the care of people with HIV. Interventions were oral GCV (1000 mg three times/day) or placebo. Protocol amendment allowed switch to open-label oral GCV. Main outcome measures were confirmed CMV retinal or gastrointestinal mucosal disease, and death. The study enrolled 994 people co-infected with CMV and HIV, with at least one CD4 count recorded < 100 x 10(6) cells/l. RESULTS: At study completion (15 months median follow-up), CMV event rates in the oral GCV and control groups were 13.1 and 14.6 per 100 person years, respectively, a hazard ratio (HR) of 0.92 [95% confidence interval (CI), 0.65-1.27; P = 0.6]. At protocol amendment event rates were 12.7 and 15.0, respectively (HR, 0.85; 95% CI, 0.56-1.30; P = 0.45). At study completion, event rates for death were 26.6 and 32.0 (HR, 0.84; P = 0.09), and at protocol amendment were 18.9 and 19.6 (HR, 0.95; P = 0.78), respectively. At protocol amendment for the CMV endpoint, the oral GCV treatment effect was associated with baseline use of didanosine (ddI). For patients taking ddI at randomization, HR was 7.48 (P = 0.02). For patients not taking ddI, HR was 0.62 (P = 0.04). These HR were statistically different (P = 0.0006). CONCLUSIONS: In our study, 3 g/day oral GCV did not significantly reduce CMV disease incidence, but there was a suggestion of a death-rate reduction. Furthermore, results suggest that oral GVC decreased risk of CMV disease in patients not prescribed ddI, and increased risk in those prescribed ddI. For the CMV endpoint, our study differs markedly from the only similar study, although for the death endpoint, a combined analysis of studies indicated significant reduction in death rate.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Antivirais/administração & dosagem , Infecções por Citomegalovirus/prevenção & controle , Citomegalovirus , Ganciclovir/administração & dosagem , Administração Oral , Adolescente , Adulto , Antivirais/efeitos adversos , Método Duplo-Cego , Feminino , Ganciclovir/efeitos adversos , Humanos , Masculino , Resultado do TratamentoRESUMO
Colorectal epithelial cell proliferative kinetics are altered in patients at increased risk for colon cancer: proliferation rates [labeling index (LI)] are higher and there is a shift of the proliferative zone from one confined to the lower 60% of the colonic crypt to one that includes the entire crypt (higher phi(h)). To assess factors associated with LI and phi(h), we performed a cross-sectional analysis using baseline rectal mucosal biopsies from sporadic adenoma patients participating in a chemoprevention trial. Biopsies (taken without preparatory cleansing) were taken 10 cm above the level of the anus, and proliferation was assessed by detection of endogenous S-phase-associated proliferating cell nuclear antigen by immunohistochemical methods. High-quality, scorable biopsies were obtained for 115 patients, and using analysis of covariance and multiple linear regression, the LI and phi(h) were evaluated in relation to diet and other lifestyle factors, demographics, anthropometrics, family history of colon cancer, and polyp history. Statistically significant findings included the following: (a) The LI for those in the upper versus the lowest tertile of vegetable and fruit consumption was, proportionately, 35% lower (3.4% versus 5.3%; P < 0.001); for vitamin supplement users versus nonusers, it was 36% lower (3.3 versus 5.2%; P < 0.001); for recurrent versus incident polyp patients, it was 36% higher (6.2 versus 4.0%; P < 0.001); and for those with rectal polyps only versus those with colon polyps only, it was 28% higher (6.0 versus 4.3%; P = 0.05); and (b) the phi(h) for those in the upper versus the lowest tertile of sucrose consumption was, proportionately, 48% higher (7.1% versus 3.7%; P = 0.01). These results indicate that (a) colorectal epithelial cell proliferation rates are higher in recurrent adenoma patients than in incident adenoma patients and in patients with rectal adenomas only versus those with colon adenomas only, but they are lower in patients with higher intakes of vegetables and fruit and in those who take vitamin/mineral supplements, and (b) the distribution of proliferating cells is shifted toward more inclusion of the upper 40% of the crypt in patients with higher intakes of sucrose. The pattern of positive, negative, and null associations of potential risk factors with cell proliferation is similar to that commonly found with colonic neoplasms.
Assuntos
Adenoma/etiologia , Neoplasias do Colo/etiologia , Adenoma/patologia , Adulto , Idoso , Divisão Celular/fisiologia , Neoplasias do Colo/patologia , Estudos Transversais , Dieta , Células Epiteliais/citologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Retais/etiologia , Neoplasias Retais/patologia , Fatores de RiscoRESUMO
We propose two test statistics based on the covariance process of the martingale residuals for testing independence of bivariate survival data. The first test statistic takes the supremum over time of the absolute value of the covariance process, and the second test statistic is a time-weighted summary of the process. We derive asymptotic properties of the two test statistics under the null hypothesis of independence. In addition, we derive the asymptotic distribution of the weighted test and construct optimal weights for contiguous alternatives to independence. Through simulations, we compare the performance of the proposed tests and the inner product of the Savage scores statistics of Clayton and Cuzick (1985, Journal of the Royal Statistical Society, Series A 148, 82-108). These demonstrate that the supremum test is generally more powerful with comparatively little power loss relative to their test when Clayton's family alternative holds, and the weighted test is more powerful when the weight is appropriately chosen.