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BACKGROUND: It has been suggested that hormone therapy may help counter undesirable changes in body composition in older women. OBJECTIVE: This study was designed to test whether estrogen plus progestin (E+P) therapy favorably affects age-related changes in body composition in postmenopausal women. DESIGN: The substudy was composed of 835 women from the estrogen plus progestin trial of the Women's Health Initiative who were randomly assigned to receive either E+P therapy (n = 437) or placebo (n = 398). The women had a mean age of 63.1 y and, on average, were 13.8 y past menopause. More than 17% of the participants were from an ethnic minority. No significant differences in baseline body composition (measured with dual-energy X-ray absorptiometry) by intervention assignment were observed. RESULTS: After 3 y of intervention, the women who received active E+P therapy lost less lean soft tissue mass (-0.04 kg) than did the women who received placebo (-0.44 kg; P = 0.001). Additionally, the women in the E+P group had less upper-body fat distribution than did the women in the placebo group (change in ratio of trunk to leg fat mass: -0.025 for the E+P group and 0.004 for the placebo group; P = 0.003). A sensitivity analysis, which was conducted on the women who took >/=80% of the study medication during the intervention period, corroborated the findings from the intent-to-treat analysis. CONCLUSIONS: A 3-y E+P intervention significantly reduced both the loss of lean soft tissue mass and the ratio of trunk to leg fat mass in postmenopausal women. However, the effect sizes were small, and whether these changes in body composition lead to significant health benefits remains to be confirmed. Copyright © 2005 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Keeping abreast of the antimicrobial stewardship-related articles published each year is challenging. The Southeastern Research Group Endeavor identified antimicrobial stewardship-related, peer-reviewed literature that detailed an actionable intervention during 2022. The top 13 publications were selected using a modified Delphi technique. These manuscripts were reviewed to highlight actionable interventions used by antimicrobial stewardship programs to capture potentially effective strategies for local implementation., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. The views and opinions expressed in this paper represent those of the authors and do not necessarily reflect the position or policy of any previous, current, or potential future employer., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Keeping abreast of the antimicrobial stewardship-related articles published each year is challenging. The Southeastern Research Group Endeavor (SERGE-45) identified antimicrobial stewardship-related, peer-reviewed literature that detailed an "actionable" intervention among hospitalized populations during 2021. The top 13 publications were selected using a modified Delphi technique. These manuscripts were reviewed to highlight "actionable" interventions used by antimicrobial stewardship programs in hospitalized populations to capture potentially effective strategies for local implementation., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The scope of antimicrobial stewardship programs has expanded beyond the acute hospital setting. The need to optimize antimicrobial use in emergency departments, urgent, primary, and specialty care clinics, nursing homes, and long-term care facilities prompted the development of core elements of stewardship programs in these settings. Identifying the most innovative and well-designed stewardship literature in these novel stewardship areas can be challenging. The Southeastern Research Group Endeavor (SERGE-45) network evaluated antimicrobial stewardship-related, peer-reviewed literature published in 2021 that detailed actionable interventions specific to the nonhospital setting. The top 13 publications were summarized following identification using a modified Delphi technique. This article highlights the selected interventions and may serve as a key resource for expansion of antimicrobial stewardship programs beyond the acute hospital setting., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The number of articles related to antimicrobial stewardship published each year has increased significantly over the last decade. Keeping up with the literature, particularly the most innovative, well-designed, or applicable to one's own practice area, can be challenging. The Southeastern Research Group Endeavor (SERGE-45) network reviewed antimicrobial stewardship-related, peer-reviewed literature from 2020 that detailed actionable interventions. The top 13 publications were summarized following identification using a modified Delphi technique. This article highlights the selected interventions and may serve as a key resource for teaching and training, and to identify novel or optimized stewardship opportunities within one's institution., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

A number of psychometricians have suggested that parallel analysis (PA) tends to yield more accurate results in determining the number of factors in comparison with other statistical methods. Nevertheless, all too often PA can suggest an incorrect number of factors, particularly in statistically unfavorable conditions (e.g., small sample sizes and low factor loadings). Because of this, researchers have recommended using multiple methods to make judgments about the number of factors to extract. Implicit in this recommendation is that, when the number of factors is chosen based on PA, uncertainty nevertheless exists. We propose a Bayesian parallel analysis (B-PA) method to incorporate the uncertainty with decisions about the number of factors. B-PA yields a probability distribution for the various possible numbers of factors. We implement and compare B-PA with a frequentist approach, revised parallel analysis (R-PA), in the contexts of real and simulated data. Results show that B-PA provides relevant information regarding the uncertainty in determining the number of factors, particularly under conditions with small sample sizes, low factor loadings, and less distinguishable factors. Even if the indicated number of factors with the highest probability is incorrect, B-PA can show a sizable probability of retaining the correct number of factors. Interestingly, when the mode of the distribution of the probabilities associated with different numbers of factors was treated as the number of factors to retain, B-PA was somewhat more accurate than R-PA in a majority of the conditions., Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background: Fluoroquinolone (FQ) antibiotics have become a target of many antimicrobial stewardship programmes. Multiple post-marketing warnings from the Food and Drug Administration caution against use of this drug class for certain infections due to risk of harmful adverse effects outweighing benefit. Commonly employed strategies to affect antibiotic prescribing can be restrictive and without improvement in overall antibiotic appropriateness or decrease in collateral damage., Aim: To develop a strategy for sustainable optimization of FQ antibiotics., Setting: Multi-state health-system of 14 hospitals and medical centers., Methods: The health-system antimicrobial stewardship program identified the opportunity to improve FQ utilization. In collaboration with our data and analytics team, specific targets of FQ use in pneumonia and chronic obstructive pulmonary disease were established. Face-to-face provider education and prospective audit and feedback were the mainstays of the campaign. Enhancements to the electronic medical record to support the initiative were also implemented., Findings: There was an overall decrease in FQ utilization by 56.9%. For pneumonia use of FQs decreased from 16.4% to 8.1% and in COPD changed from 29.6% to 9.7% over the same time period., Conclusions: A non-restrictive FQ optimization initiative based on education and feedback decreased both FQ consumption and total antibiotic use across a large multi-hospital health-system., (© 2019 The Authors.)

Past research suggests revised parallel analysis (R-PA) tends to yield relatively accurate results in determining the number of factors in exploratory factor analysis. R-PA can be interpreted as a series of hypothesis tests. At each step in the series, a null hypothesis is tested that an additional factor accounts for zero common variance among measures in the population. Integration of an effect size statistic-the proportion of common variance (PCV)-into this testing process should allow for a more nuanced interpretation of R-PA results. In this article, we initially assessed the psychometric qualities of three PCV statistics that can be used in conjunction with principal axis factor analysis: the standard PCV statistic and two modifications of it. Based on analyses of generated data, the modification that considered only positive eigenvalues ( π ^ SMC : k ' + Λ ^ ) overall yielded the best results. Next, we examined PCV using minimum rank factor analysis, a method that avoids the extraction of negative eigenvalues. PCV with minimum rank factor analysis generally did not perform as well as π ^ SMC : k ' + Λ ^ , even with a relatively large sample size of 5,000. Finally, we investigated the use of π ^ SMC : k ' + Λ ^ in combination with R-PA and concluded that practitioners can gain additional information from π ^ SMC : k ' + Λ ^ and make more nuanced decision about the number of factors when R-PA fails to retain the correct number of factors., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Clinician education and expertise in palliative care varies widely across pediatric oncology programs. The purpose of this evidence-based practice review was to identify interprofessional palliative care education models applicable to pediatric oncology settings as well as methods for evaluating their impact on clinical practice., Results: Based on a literature search in PubMed, CINAHL and Embase, which identified 13 articles meeting inclusion/exclusion criteria, the following three themes emerged: (1) establishment of effective modalities and teaching strategies, (2) development of an interprofessional palliative care curriculum, and (3) program evaluation to assess impact on providers' self-perceived comfort in delivering palliative care and patient/family perceptions of care received. Remarkably, health professionals reported receiving limited palliative care training, with little evidence of systematic evaluation of practice changes following training completion. Improving palliative care delivery was linked to the development and integration of an interprofessional palliative care curriculum. Suggested evaluation strategies included: (1) eliciting patient and family feedback, (2) standardizing care delivery measures, and (3) evaluating outcomes of care.

Traditional metronidazole dosing regimens utilize an every 8 h dosing strategy to treat anaerobic and mixed anaerobic infections. However, pharmacokinetic data demonstrate that the half-life of metronidazole is 8-12 h and blood levels at 12 h exceed the in vitro minimum inhibitory concentration (MIC) for most anaerobic infections. The primary objective of this study was to evaluate the frequency of clinical cure among patients who received metronidazole every 12 h compared with those who received an every 8 h frequency. Secondary endpoints included duration of antibiotics, hospital length of stay, escalation of antibiotic therapy, microbiologic cure, and mortality., Methods: This retrospective, single-center, pre-post intervention study of 200 patients between June 2014 to July 2016., Results: No significant differences in clinical cure for every 12 h versus every 8 h metronidazole dosing regimens (85% for both groups, p = 1.00) were found. There were no differences in any of the secondary endpoints, with a mean duration of antibiotic therapy being 5.9 versus 5.8 days and a hospital length of stay averaging 8.1 versus 6.7 days for the 12- and 8-h dosing groups, respectively ( p > 0.05)., Discussion: Findings validate pharmacokinetic data suggesting that an extended metronidazole dosing interval effectively treats anaerobic infections., Competing Interests: Conflict of interest statement: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Parallel analysis (PA) is a useful empirical tool for assessing the number of factors in exploratory factor analysis. On conceptual and empirical grounds, we argue for a revision to PA that makes it more consistent with hypothesis testing. Using Monte Carlo methods, we evaluated the relative accuracy of the revised PA (R-PA) and traditional PA (T-PA) methods for factor analysis of tetrachoric correlations between items with binary responses. We manipulated five data generation factors: number of observations, type of factor model, factor loadings, correlation between factors, and distribution of thresholds. The R-PA method tended to be more accurate than T-PA, although not uniformly across conditions. R-PA tended to perform better relative to T-PA if the underlying model (a) was unidimensional but had some unique items, (b) had highly correlated factors, or (c) had a general factor as well as a group factor. In addition, R-PA tended to outperform T-PA if items had higher factor loadings and sample size was large. A major disadvantage of the T-PA method was that it frequently yielded inflated Type I error rates., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The public and healthcare workers have a high expectation of animal research which they perceive as necessary to predict the safety and efficacy of drugs before testing in clinical trials. However, the expectation is not always realised and there is evidence that the research often fails to stand up to scientific scrutiny and its 'predictive value' is either weak or absent., Discussion: Problems with the use of animals as models of humans arise from a variety of biases and systemic failures including: 1) bias and poor practice in research methodology and data analysis; 2) lack of transparency in scientific assessment and regulation of the research; 3) long-term denial of weaknesses in cross-species translation; 4) profit-driven motives overriding patient interests; 5) lack of accountability of expenditure on animal research; 6) reductionist-materialism in science which tends to dictate scientific inquiry and control the direction of funding in biomedical research. Bias in animal research needs to be addressed before medical research and healthcare decision-making can be more evidence-based. Research funding may be misdirected on studying 'disease mechanisms' in animals that cannot be replicated outside tightly controlled laboratory conditions, and without sufficient critical evaluation animal research may divert attention away from avenues of research that hold promise for human health. The potential for harm to patients and trial volunteers from reliance on biased animal data(1) requires measures to improve its conduct, regulation and analysis. This article draws attention to a few of the many forms of bias in animal research that have come to light in the last decade and offers a strategy incorporating ten recommendations stated at the end of each section on bias. The proposals need development through open debate and subsequent rigorous implementation so that reviewers may determine the value of animal research to human health. The 10Rs + are protected by a Creative Commons Attribution 3.0 Unported License and therefore may be 'shared, remixed or built on, even commercially, so long as attributed by giving appropriate credit with a link to the license, and indicate if changes were made.'

Traditional parallel analysis (T-PA) estimates the number of factors by sequentially comparing sample eigenvalues with eigenvalues for randomly generated data. Revised parallel analysis (R-PA) sequentially compares the k th eigenvalue for sample data to the k th eigenvalue for generated data sets, conditioned on k - 1 underlying factors. T-PA and R-PA are conceptualized as stepwise hypothesis-testing procedures and, thus, are alternatives to sequential likelihood ratio test (LRT) methods. We assessed the accuracy of T-PA, R-PA, and LRT methods using a Monte Carlo approach. Although no method was uniformly more accurate across all 180 conditions, the PA approaches outperformed LRT methods overall. Relative to T-PA, R-PA tended to perform better within the framework of hypothesis testing and to evidence greater accuracy in conditions with higher factor loadings., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Cytomegalovirus (CMV) infection is an important cause of neurologic disease in the context of advanced human immunodeficiency virus (HIV) infection and is recognized as a cause of immune reconstitution inflammatory syndrome (IRIS) after initiation of highly active antiretroviral therapy (HAART). Central nervous system vasculitis secondary to CMV has only rarely been described in the context of HIV, despite the established ability of CMV to infect microvascular endothelial cells in the brain. However, we report a case that demonstrates the association between CMV and multiple small vessel cerebral infarct lesions after initiation of HAART.

Background: Vitamin D deficiency or insufficiency has been observed among populations in the northern United States. However, data on the prevalence of vitamin D deficiency in areas of high sun exposure, such as Arizona, are limited., Objective: The purpose of this study was to analyze serum 25-hydroxyvitamin D [25(OH)D] concentrations in residents of southern Arizona and to evaluate predictors of 25(OH)D in this population., Design: Cross-sectional analyses of serum from participants in a colorectal adenoma prevention study were conducted to determine rates of vitamin D deficiency. Participants were categorized into 4 groups on the basis of serum 25(OH)D concentrations: <10.0 ng/mL, > or =10.0 ng/mL and <20.0 ng/mL, > or =20.0 ng/mL and <30.0 ng/mL, and > or =30.0 ng/mL., Results: The mean serum 25(OH)D concentration for the total population was 26.1 +/- 9.1 ng/mL. Of 637 participants, 22.3% had 25(OH)D concentrations >30 ng/mL, 25.4% had concentrations <20 ng/mL, and 2.0% had concentrations <10 ng/mL. Blacks (55.5%) and Hispanics (37.6%) were more likely to have deficient 25(OH)D concentrations (<20 ng/mL) than were non-Hispanic whites (22.7%). Sun exposure had a greater effect on 25(OH)D in whites than in blacks and Hispanics, whereas BMI appeared to be more important in the latter groups., Conclusion: Despite residing in a region with high chronic sun exposure, adults in southern Arizona are commonly deficient in vitamin D deficiency, particularly blacks and Hispanics.

Objectives: The molecular factors contributing to the development of Barrett's esophagus (BE) are unclear. Our previous studies showed that BE tissues secrete interleukin-6 (IL-6) and express proteins associated with IL-6 signaling, including IL-6 receptor, activated signal transducer and activators of transcription 3 (STAT3), and antiapoptotic proteins Bcl-x(L) and Mcl-1. Here, we test the hypothesis that bile acids and gastric acids, two components of refluxate associated with gastresophageal reflux disease, activate the IL-6/STAT3 pathway., Materials and Methods: Immunohistochemistry was used to assess levels of phosphorylated STAT3 in esophageal tissue samples from BE patients with different grades of dysplasia. Seg-1 esophageal adenocarcinoma cells were evaluated for STAT3 activation and IL-6 and Bcl-x(L) expression by molecular biology techniques, including Western blot, reverse transcription-PCR, and ELISA after exposure to control media (pH 7.4), media supplemented with a 0.1 mmol/L bile acid cocktail with media at pH 4 or media at pH 4 with bile acid cocktail., Results: Immunohistochemical analysis showed that activated, phosphorylated STAT3 is expressed in nuclei of dysplastic BE and cancer tissues. Treatment of Seg-1 cells with media containing bile acid cocktail and acidified to pH 4 resulted in increased activation of STAT3, IL-6 secretion, and increased expression of Bcl-x(L). Inhibition of the STAT3 pathway using STAT3 small interfering RNA or Janus-activated kinase inhibitor resulted in increased apoptosis., Conclusions: The IL-6/STAT3 antiapoptotic pathway is induced by short exposure to bile acid cocktail and low pH. This alteration, if persistent in vivo, may underlie the development of dysplastic BE and tumor progression.

Background: Barrett's oesophagus is a premalignant condition associated with an increased risk for the development of oesophageal adenocarcinoma (ADCA). Previous studies indicated that oxidative damage contributes to the development of ADCA., Objective: To test the hypothesis that bile acids and gastric acid, two components of refluxate, can induce oxidative stress and oxidative DNA damage., Methods: Oxidative stress was evaluated by staining Barrett's oesophagus tissues with different degrees of dysplasia with 8-hydroxy-deoxyguanosine (8-OH-dG) antibody. The levels of 8-OH-dG were also evaluated ex vivo in Barrett's oesophagus tissues incubated for 10 min with control medium and medium acidified to pH 4 and supplemented with 0.5 mM bile acid cocktail. Furthermore, three oesophageal cell lines (Seg-1 cells, Barrett's oesophagus cells and HET-1A cells) were exposed to control media, media containing 0.1 mM bile acid cocktail, media acidified to pH 4, and media at pH 4 supplemented with 0.1 mM bile acid cocktail, and evaluated for induction of reactive oxygen species (ROS)., Results: Immunohistochemical analysis showed that 8-OH-dG is formed mainly in the epithelial cells in dysplastic Barrett's oesophagus. Importantly, incubation of Barrett's oesophagus tissues with the combination of bile acid cocktail and acid leads to increased formation of 8-OH-dG. An increase in ROS in oesophageal cells was detected after exposure to pH 4 and bile acid cocktail., Conclusions: Oxidative stress and oxidative DNA damage can be induced in oesophageal tissues and cells by short exposures to bile acids and low pH. These alterations may underlie the development of Barrett's oesophagus and tumour progression.

Purpose: Thioredoxin-1 (Trx-1) is a cellular redox protein that promotes tumor growth, inhibits apoptosis, and up-regulates hypoxia-inducible factor-1alpha and vascular endothelial growth factor. Objectives of this study were to determine safety, tolerability, pharmacodynamics, and pharmacokinetics of PX-12, a small-molecule inhibitor of Trx-1., Experimental Design: Thirty-eight patients with advanced solid tumors received PX-12 at doses of 9 to 300 mg/m(2), as a 1- or 3-h i.v. infusion on days 1 to 5, repeated every 3 weeks., Results: At the 300 mg/m(2) dose level, one patient experienced a reversible episode of pneumonitis during the first cycle, and a second patient developed pneumonitis after the second cycle. Doses up to 226 mg/m(2) were well tolerated, and grade 3/4 events were uncommon (<3% of patients). The limiting factor on this dosing schedule was pungent odor caused by expired drug metabolite, 2-butanethiol. The best response was stable disease in seven patients (126-332 days). Whereas PX-12 was not detectable following the infusion, the C(max) of its inactive metabolite, 2-mercaptoimidazole, increased linearly with dose. PX-12 treatment lowered plasma Trx-1 concentrations in a dose-dependent manner., Conclusions: PX-12, the first Trx-1 inhibitor to enter clinical trials, was tolerated up to a dose of 226 mg/m(2) by a 3-h infusion. Based on pharmacodynamic and pharmacokinetic data, a trial of prolonged infusion schedule of PX-12 has been initiated.

There is an increasing demand for the development of intermediate biomarkers to assess colon cancer risk. We previously determined that a live cell bioassay, which assesses apoptosis resistance in the nonneoplastic colonic mucosa, detects approximately 50% of patients with colon cancer. A hypothesis-driven biomarker that reflects apoptosis resistance in routine formalin-fixed, paraffin-embedded tissue would be easier to use. Cytochrome c oxidase is a critical enzyme that controls mitochondrial respiration and is central to apoptosis. We did an immunohistochemical study of cytochrome c oxidase subunit I expression in 46 colonic mucosal samples from 16 patients who had undergone a colonic resection. These included five patients without evidence of colonic neoplasia (three normal and two diverticulitis), three patients with tubulovillous adenomas, and eight patients with colonic adenocarcinomas. Analysis of aberrancies in expression of cytochrome c oxidase subunit I showed that, compared with nonneoplasia, the patients with neoplasia had a higher mean incidence of crypts having decreased expression (1.7 versus 22.8, P = 0.03) and a higher mean incidence having crypt-restricted loss (0.6 versus 3.2, P = 0.06). The percentage with segmented loss was low and was similar in the two groups. Combining these results, the mean % normal (i.e., with none of the three types of abnormality) was 96.7 in nonneoplasia versus only 73.2 in patients with neoplasia (P = 0.02). It should be noted that a defect in cytochrome c oxidase subunit I immunostaining was not detected in all biopsy samples from each patient for whom some abnormality was found, indicating a "patchiness" in the cytochrome c oxidase subunit I field defect. As a result of this "patchiness," the increased variability in the incidence of crypt-restricted loss of cytochrome c oxidase subunit I expression was a statistically significant feature of the neoplasia group. Crypt-restricted loss of cytochrome c oxidase subunit I has not been previously reported in colonic mucosa and is presumably the result of a crypt-restricted stem cell mutation. Decreased cytochrome c oxidase subunit I expression also significantly correlated with apoptosis resistance, a factor known to contribute to carcinogenesis. The results suggest, however, that aberrant cytochrome c oxidase subunit I expression may be a better biomarker than loss of apoptosis competence for increased colon cancer risk.

Background: Ursodeoxycholic acid (UDCA) treatment is associated with a reduced incidence of colonic neoplasia in preclinical models and in patients with conditions associated with an increased risk for colon cancer. We conducted a phase III, double-blind placebo-controlled trial of UDCA to evaluate its ability to prevent colorectal adenoma recurrence., Methods: We randomly assigned 1285 individuals who had undergone removal of a colorectal adenoma within the past 6 months to daily treatment with UDCA (8-10 mg/kg of body weight; 661 participants) or with placebo (624 participants) for 3 years or until follow-up colonoscopy. Recurrence rates (number of recurrent adenomas per unit time) were compared by use of a Huber-White variance estimator. Proportions of participants with one or more recurrent adenomas were compared with a Pearson chi-square statistic; adjusted odds ratios (ORs) were obtained by logistic regression. All statistical tests were two-sided., Results: We observed a non-statistically significant 12% reduction in the adenoma recurrence rate associated with UDCA treatment, compared with placebo treatment. However, UDCA treatment was associated with a statistically significant reduction (P = .03) in the recurrence of adenomas with high-grade dysplasia (adjusted OR = 0.61, 95% confidence interval = 0.39 to 0.96). We observed no statistically significant differences between UDCA and placebo groups in recurrence with regard to adenoma size, villous histology, or location., Conclusions: UDCA treatment was associated with a non-statistically significant reduction in total colorectal adenoma recurrence but with a statistically significant 39% reduction in recurrence of adenomas with high-grade dysplasia. Because severely dysplastic lesions have a high risk of progression to invasive colorectal carcinoma, this finding indicates that future chemoprevention trials of UDCA in individuals with such lesions should be considered.

Objective: To examine baseline predictors of T-cell receptor rearrangement excision circle (TREC) levels and their changes during treatment with combined antiretroviral therapy., Methods: Peripheral blood and lymph node lymphocytes were examined for the presence of TREC by real-time polymerase chain reaction and circulating lymphocyte phenotypes were examined by flow cytometry. Correlates for CD4 and CD8 cell TREC levels at baseline were identified among CD4 and CD8 immunophenotypes, viral load and patient demographics; the significance of TREC changes after initiation of antiretroviral therapy was assessed., Results: Circulating TREC levels correlated inversely with age, with HIV RNA levels, with activation markers on circulating T cells and with naive CD4 but not CD8 cell frequencies. With initiation of antiretroviral therapy, TREC and naive T cell frequencies increased in peripheral blood during the first 2 weeks of treatment and these changes correlated negatively with TREC frequencies in lymph node aspirates, particularly among CD8 T cells., Conclusions: These findings suggest that recent thymic emigrants are sequestered in lymphoid tissue during uncontrolled HIV replication and are selectively released into circulation rapidly after initiation of antiretroviral therapies.

Chromatin remodeling enzymes are increasingly implicated in a variety of important cellular functions. Various components of chromatin remodeling complexes, including several members of the SWI/SNF family, have been shown to be disrupted in cancer. In this study we identified as a target for gene inactivation in colon cancer the gene for helicase-like transcription factor (HLTF), a SWI/SNF family protein. Loss of HLTF expression accompanied by HLTF promoter methylation was noted in nine of 34 colon cancer cell lines. In these cell lines HLTF expression was restored by treatment with the demethylating agent 5-azacytidine. In further studies of primary colon cancer tissues, HLTF methylation was detected in 27 of 63 cases (43%). No methylation of HLTF was detected in breast or lung cancers, suggesting selection for HLTF methylation in colonic malignancies. Transfection of HLTF suppressed 75% of colony growth in each of three different HLTF-deficient cell lines, but showed no suppressive effect in any of three HLTF-proficient cell lines. These findings show that HLTF is a common target for methylation and epigenetic gene silencing in colon cancer and suggest HLTF is a candidate colon cancer suppressor gene.

Pyrimidine bases are rapidly catabolized in growing plant tissues. The final enzyme of the catabolic pathway, beta-ureidopropionase (beta-UP; EC 3.5.1.6), was partially purified from the shoots of etiolated maize (Zea mays) seedlings. The enzyme had a K(m) for beta-ureidopropionate (the substrate derived from uracil) of 11 microM. Only one enantiomer of racemic beta-ureidoisobutyrate (derived from thymine) was processed with a K(m) of 6 microM. The enzyme was inactivated by dialysis against 1,10-phenanthroline and activity could be partially restored by addition of Zn(2+). Maize beta-UP was very sensitive to inactivation by iodoacetamide. This could be prevented by addition of substrate, indicating the presence of an active site Cys. The enzyme was strongly inhibited by short chain aliphatic acids and aryl propionates, the most potent inhibitor of which was 2-(2, 6-dinitrophenoxy)-propionate (I(50) = 0.5 microM). A gene for Arabidopsis beta-UP encodes a polypeptide of 405 amino acids and has about 55% homology with the enzymes from other eukaryotic organisms. Several highly conserved residues link the plant beta-UP with a larger class of prokaryotic and eukaryotic amidohydrolases. An Arabidopsis cDNA truncated at the N terminus by 14 residues was cloned and overexpressed in Escherichia coli. The recombinant enzyme (43.7 kD) was soluble, functional, and purified to homogeneity with yields of 15 to 20 mg per 30 g fresh weight of E. coli cells. The recombinant enzyme from Arabidopsis and the native enzyme from maize had molecular masses of approximately 440 kD, indicating the enzyme is a decamer at pH 7.

Objective: To develop and implement a rating system evaluating the extensiveness of state laws restricting youth access to tobacco., Design: State laws on youth access to tobacco were analysed and assigned ratings on nine items. Six items addressed specific tobacco-control provisions, and three related to enforcement provisions. For each item, a target was specified reflecting public health objectives. Achieving the target resulted in a rating of +4 points; for three items, a rating of +5 was possible if the target was exceeded. Criteria for lower ratings were established for situations when the target was not met., Setting: United States., Results: State scores (sum of the ratings across all nine items) ranged from 0-18 in 1993, 2-21 in 1994, and 1-21 in 1995 and 1996, out of a possible total of 39. The average score across states was 7.2 in 1993, 7.9 in 1994, 8.2 in 1995, and 9.0 in 1996. The overall mean rating (per item) was 0.80 in 1993, 0.88 in 1994, 0.91 in 1995, and 1.00 in 1996, on a scale where 4.0 indicates that the target goals (per item) were met. From 1993 to 1996, scores increased for 20 states, decreased for one state, and remained unchanged for the others. The number of states for which state preemption of local tobacco regulation was a factor doubled from 10 states in 1993 to 20 states in 1996., Conclusions: Although all states have laws addressing youth access to tobacco, this analysis reveals that, as of the end of 1996, the progress towards meeting health policy targets is slow, and state legislation that preempts local tobacco regulation is becoming more common.

Background: The National Cancer Institute (NCI)-sponsored clinical trials cooperative groups place more than 25 000 American patients in treatment trials every year. Equal access and proportional representation of all races/ethnicities is desired., Purpose: Our objectives were to evaluate the inclusion of African-Americans, Hispanics, and non-Hispanic whites in NCI-sponsored treatment trials and to determine if there is proportional racial/ethnic representation., Methods: During the period of January 1, 1991, through June 30, 1994, 99 495 cancer patients were enrolled in clinical trials and declared themselves as non-Hispanic black, non-Hispanic white, or Hispanic (of any race). In the analysis, participants in NCI treatment trials were subdivided into three age groups: birth to 19 years, 20-49 years, and 50 or more years. The racial/ethnic composition of each of these age groups was compared with the racial/ethnic makeup of the American population with cancer. Estimates of the number of incident cancer cases per year were made for each racial/ethnic group within each age group using data from the Surveillance, Epidemiology, and End Results (SEER) Program and the 1990 Census. The percentage of all cancer patients who were in each racial/ethnic group were compared with the population that entered clinical trials. Comparisons are also made separately for patients with leukemia and breast, colorectal, lung, and prostate cancers., Results: Among patients 0-19 years old, 20-49 years old, and 50 years old or older there is relatively proportional representation of non-Hispanic blacks, Hispanics, and non-Hispanic whites in trials. It is noted that more than 70% of cancer patients aged 0-19 years are estimated to enter cooperative group clinical trials compared with 4.0% of cancer patients aged 20-49 years and 1.5% of patients aged 50 years or older., Conclusions: Accrual of American cancer patients to NCI-sponsored treatment trials generally parallels the incident burden of disease among non-Hispanic African-Americans, Hispanics, and non-Hispanic whites., Implications: This study shows that the NCI clinical trials are, as a whole, racially/ethnically representative of the American population and suggests that there is equal access to NCI clinical trials.

The small-sample performance of some recently proposed nonparametric methods of constructing confidence intervals for the median survival time, based on randomly right-censored data, is compared with that of two new methods. Most of these methods are equivalent for large samples. All proposed intervals are either 'test-based' or 'reflected' intervals, in the sense defined in the paper. Coverage probabilities for the interval estimates were obtained by exact calculation for uncensored data, and by stimulation for three life distributions and four censoring patterns. In the range of situations studied, 'test-based' methods often have less than nominal coverage, while the coverage of the new 'reflected' confidence intervals is closer to nominal (although somewhat conservative), and these intervals are easy to compute.

We conducted reproducibility studies on an in vivo objective method of documenting cataracts: Scheimpflug photography using the Topcon SL 45 camera. Normal and cataractous lenses were photographed and the photographs digitized and analyzed using a Perkin Elmer microdensitometer attached to a PDP 11 and Vax 11/780 computer. Linear densitometry was performed through the center of the lens. We found very good reproducibility. The intraclass correlation for the mean densities in the nucleus was 0.95: that is, intra- and interobserver variability accounted for only 5% of the overall variability. For the anterior cortex, intraclass correlation was 0.88 and for posterior cortex it was 0.84. This method may be useful, within limits, in future clinical trials of anticataract medications.

In comparing two survival distributions, a Mantel-Haenszel statistic can be computed after each death as a non-linear two-sample rank statistic. The distributions of both the maximum and terminal statistics in such a sequence are studied numerically, in the absence of censoring, and appropriate critical values are determined. The maximum statistic is applied to simultaneous inference, and both the maximum and terminal statistics are used as the basis for early stopping procedures (especially in the pseudo-sequential context). Procedures based on the two statistics are compared for power and for early decision properties such as stopping index and (for exponential distributions) stopping time.

Suppose a continuous diagnostic measurement is used to classify patients, and suppose E1 false negative errors and E2 false positive errors result. The quantities E1 and E2, and the total number of misclassifications, L = E1 + E2, depend on the choice of cut-off value. We have determined the null distribution of min L, where minimization is over all possible cut-off values. The statistic, min L, can be used as a quick one-sided two-sample test, and min L is also useful for evaluating publications which present only a 2 X 2 table of false positives, false negatives, true positives and true negatives. In such cases, one can use min L to assess the usefulness of the diagnostic measurement, even if one suspects that the authors chose that particular cut-off value which minimized L after looking at the data. We extend these results to a more general weighted loss L = vE1 + MUE2 where v and mu are positive integers, and we show that min L is a generalization of the one-sided two-sample Kolmogorov-Smirnov statistic, and, indeed, exactly equivalent to that statistic for appropriate choices of v and mu.