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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]

Purpose: The purpose of this review is to discuss the role of toxin inhibition in select infections and to provide recommendations for appropriate antimicrobial selection when toxin inhibition is indicated., Summary: For select organisms, specifically Clostridioides difficile, Staphylococcus aureus, and Streptococcus pyogenes, toxin production plays an integral role in overall disease pathogenesis and progression. Some expert recommendations include utilization of an antimicrobial with toxin inhibition properties as primary or adjunctive therapy for certain infections due to these organisms, but evolving data have made the choice of antitoxin agent less clear. Clindamycin has been the long-standing standard of care agent for toxin inhibition in necrotizing S. aureus and S. pyogenes infections, but linezolid shows promise as an alternative either in the setting of drug shortages or simply when clindamycin is not optimal, while tetracyclines require further study for this indication. The role for adjunctive toxin inhibition in C. difficile infection (CDI) is less defined, as current first-line therapies already have antitoxin properties., Conclusion: Toxin inhibition plays a key role in successful management of patients with infections due to toxin-producing organisms. Adjunctive therapy with a tetracycline could be considered in severe, fulminant CDI, but the associated benefit is variable. The benefit of antitoxin treatment for necrotizing S. aureus and S. pyogenes has been more consistently documented. Recent studies support linezolid as an alternative to clindamycin as an adjunctive S. aureus treatment or as monotherapy when appropriate., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objectives: Bartonella spp., renowned for cat-scratch disease, has limited reports of dissemination. Tissue and blood cultures have limitations in detecting this fastidious pathogen. Molecular testing (polymerase chain reaction, PCR) and cell-free DNA have provided an avenue for diagnoses. This retrospective observational multicenter study describes the incidence of disseminated Bartonella spp. and treatment-related outcomes., Methods: Inclusion criteria were diagnosis of bartonellosis via diagnosis code, serology testing of blood, polymerase chain reaction (PCR) of blood, 16/18S tests of blood or tissue, cultures of blood or tissue, or cell-free DNA of blood or tissue from January 1, 2014, through September 1, 2021. Exclusions were patients who did not receive treatment, insufficient data on treatment course, absence of dissemination, or retinitis as dissemination., Results: Patients were primarily male (n = 25, 61.0%), white (n = 28, 68.3%), with mean age of 50 years (SD 14.4), and mean Charlson comorbidity index of 3.5 (SD 2.1). Diagnosis was primarily by serology (n = 34, 82.9%), with Bartonella henselae (n = 40, 97.6%) as the causative pathogen. Treatment was principally doxycycline with rifampin (n = 17, 41.5%). Treatment failure occurred in 16 (39.0%) patients, due to escalation of therapy during treatment (n = 5, 31.3%) or discontinuation of therapy due to an adverse event or tolerability (n = 5, 31.3%)., Conclusions: In conclusion, this is the largest United States-based cohort of disseminated Bartonella spp. infections to date with a reported 39% treatment failure. This adds to literature supporting obtaining multiple diagnostic tests when Bartonella is suspected and describes treatment options., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Intravenous (IV) antibiotics have historically been considered standard of care for treatment of bloodstream infections (BSIs). Recent literature has shown sequential oral (PO) therapy to be noninferior to IV antibiotics for certain pathogens and disease states. However, a gap exists in the literature for BSI caused by Enterococcus faecalis ., Objective: To compare outcomes of definitive sequential PO therapy to definitive IV therapy in patients with E faecalis BSI., Methods: Multicenter, retrospective, matched cohort study of adult patients with at least one blood culture positive for E faecalis from January 2017 to November 2022. Patients with polymicrobial BSI, concomitant infections requiring prolonged IV antibiotic therapy, those who did not receive antibiotic therapy, and those who died within 72 hours of index culture were excluded. Subjects were matched based on source of infection in a 2:1 (IV:PO) ratio. The primary outcome was a composite of all-cause mortality and treatment failure. Secondary outcomes included hospital length of stay (LOS), antibiotic duration, and 30-day readmission rate., Results: Of the 186 patients who met criteria for inclusion, there was no statistically significant difference in the primary composite outcome for PO compared to IV therapy (14.5% vs 21.8%; OR 0.53 [0.23-1.25]) or 30-day readmission (17.5% vs 29%; OR 0.53 [0.25-1.13]). Hospital LOS was significantly longer in patients receiving IV-only therapy (6 days vs 14 days; P < 0.001)., Conclusion and Relevance: Sequential oral therapy for E faecalis BSI had similar outcomes compared to IV-only treatment and may be considered in eligible patients., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. This material is the result of work supported with resources and the use of facilities at the Charlie Norwood VA Medical Center in Augusta, Georgia. ASN has received funding from the Agency for Healthcare Research and Quality. CMB—Speaker’s bureau (Seres Therapeutics and Shionogi Inc.) The remaining authors have nothing to disclose.

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.)

As the opioid crisis continues to escalate, the management of patients with opioid use disorder has crossed over to the care of patients with chronic infectious diseases, specifically HIV, HBV, and HCV, typically managed in the primary care setting. Consensus guidelines recommend testing for HIV and hepatitis in persons who inject drugs at least annually, but high-risk sexual activity may put other patients at risk as well. Significant barriers to robust care of these patient populations include low rates of HIV and hepatitis testing, limited access to methadone treatment programs, lack of widespread knowledge of how to prescribe office-based opioid treatment, and ongoing stigma surrounding prescribing of HIV treatment and prophylaxis medications. Clinical pharmacists across ambulatory, infectious diseases, and opioid stewardship specialties have the opportunity to play a key role in the implementation and support of harm reduction and medication for opioid use disorder services in the outpatient setting. The goal of this article is to discuss the rationale and evidence for these services and provide a framework for implementation.

The HIV epidemic continues to pose a significant burden on the healthcare system. Although the incidence of annual new infections is decreasing, health disparities persist and most new infections remain concentrated into different racial, ethnic, and minority groups. Pre-exposure prophylaxis (PrEP), which involves those at high risk of acquiring HIV to take chronic medications to prevent acquisition of the virus, is key to preventing new HIV infections. The purpose of this article is to review medication therapies for PrEP and examine their role in personalizing PrEP in different patient populations. Additionally, new medications currently under development for PrEP are reviewed, as well as treatment as prevention (TasP) and post-exposure prophylaxis (PEP). There are currently four medications available for PrEP: the oral options of co-formulated emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or emtricitabine/tenofovir alafenamide (FTC/TAF); injectable long-acting cabotegravir (CAB-LA); and the vaginal ring dapivirine (DPV-VR). FTC/TAF is not currently indicated for persons at risk for HIV through vaginal sex due to lack of studies, but trials are currently ongoing. DPV-VR is available in Zimbabwe and South Africa and has been endorsed by the World Health Organization but is not currently available in the United States. Several agents are also in development for use in PrEP: the novel long-acting injectable lenacapavir, a first-in-class capsid inhibitor, which has no cross-resistance to any existing HIV drug class; the subdermal implant islatravir, a first-in-class translocation inhibitor; and VRC01, a broadly neutralizing antibody (bnAb) which has been evaluated in proof-of-concept studies that may lead to the development of more potent bnAbs. Overall, PrEP is highly effective at preventing HIV infection in high-risk populations. Identifying optimal PrEP regimens in different patient populations is complex and must consider patient-specific factors and medication cost and access considerations. Lastly, providers should consider individual patient preferences with regard to prevention to improve access, retention in care, and adherence., (© 2023 The Authors. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy published by Wiley Periodicals LLC on behalf of Pharmacotherapy Publications, Inc.)

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.)

Eighteen amino sugar analogues were screened against Trypanosoma cruzi glucokinase (TcGlcK), a potential drug-target of the protozoan parasite in order to assess for viable enzyme inhibition. The analogues were divided into three amino sugar scaffolds that included d-glucosamine (d-GlcN), d-mannosamine (d-ManN), and d-galactosamine (d-GalN); moreover, all but one of these compounds were novel. TcGlcK is an important metabolic enzyme that has a role in producing G6P for glycolysis and the pentose phosphate pathway (PPP). The inhibition of these pathways via glucose kinases (i.e., glucokinase and hexokinase) appears to be a strategic approach for drug discovery. Glucose kinases phosphorylate d-glucose with co-substrate ATP to yield G6P and the formed G6P enters both pathways for catabolism. The compound screen revealed five on-target confirmed inhibitors that were all from the d-GlcN series, such as compounds 1, 2, 4, 5, and 6. Four of these compounds were strong TcGlcK inhibitors (1, 2, 4, and 6) since they were found to have micromolar inhibitory constant (K i ) values around 20 μM. Three of the on-target confirmed inhibitors (1, 5, and 6) revealed notable in vitro anti-T. cruzi activity with IC 50 values being less than 50 μM. Compound 1 was benzoyl glucosamine (BENZ-GlcN), a known TcGlcK inhibitor that was the starting point for the design of the compounds in this study; in addition, TcGlcK - compound 1 inhibition properties were previously determined [D'Antonio, E. L. et al. (2015) Mol. Biochem. Parasitol. 204, 64-76]. As such, compounds 5 and 6 were further evaluated biochemically, where formal K i values were determined as well as their mode of TcGlcK inhibition. The K i values determined for compounds 5 and 6 were 107 ± 4 μM and 15.2 ± 3.3 μM, respectively, and both of these compounds exhibited the competitive inhibition mode., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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.)

The Home Observation for Measurement of the Environment (HOME) Inventory is designed to assess the quality and quantity of support, stimulation, and structure provided to children in the home environment. HOME has been widely used for research and applied purposes. We focused on an abbreviated version of the Early Adolescent HOME (EA-HOME-A) that was administered to 15-year-old adolescents and their parents ( N = 958) as part of the NICHD (National Institute of Child Health and Human Development) Study of Early Child Care and Youth Development. Our study had two objectives. First, we hypothesized and tested a bifactor model that specified a general factor in support of the use of the HOME total score and group factors for subsets of items in support of the content domain scores. Second, we applied structural equation modeling to relate the EA-HOME-A factors to outcome factors assessing maladaptive behaviors, autonomy, self-control, and cognitive-academic performance. The results supported the construct validity of the EA-HOME-A with respect to its internal structure as well as its correlates.

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.

Reliabilities of scores for experimental tasks are likely to differ from one study to another to the extent that the task stimuli change, the number of trials varies, the type of individuals taking the task changes, the administration conditions are altered, or the focal task variable differs. Given that reliabilities vary as a function of the design of these tasks and the characteristics of the individuals taking them, making inferences about the reliability of scores in an ongoing study based on reliability estimates from prior studies is precarious. Thus, it would be advantageous to estimate reliability based on data from the ongoing study. We argue that internal consistency estimates of reliability are underutilized for experimental task data and in many applications could provide this information using a single administration of a task. We discuss different methods for computing internal consistency estimates with a generalized coefficient alpha and the conditions under which these estimates are accurate. We illustrate use of these coefficients using data for three different tasks.

The root mean square error of approximation (RMSEA) and the comparative fit index (CFI) are two widely applied indices to assess fit of structural equation models. Because these two indices are viewed positively by researchers, one might presume that their values would yield comparable qualitative assessments of model fit for any data set. When RMSEA and CFI offer different evaluations of model fit, we argue that researchers are likely to be confused and potentially make incorrect research conclusions. We derive the necessary as well as the sufficient conditions for inconsistent interpretations of these indices. We also study inconsistency in results for RMSEA and CFI at the sample level. Rather than indicating that the model is misspecified in a particular manner or that there are any flaws in the data, the two indices can disagree because (a) they evaluate, by design, the magnitude of the model's fit function value from different perspectives; (b) the cutoff values for these indices are arbitrary; and (c) the meaning of "good" fit and its relationship with fit indices are not well understood. In the context of inconsistent judgments of fit using RMSEA and CFI, we discuss the implications of using cutoff values to evaluate model fit in practice and to design SEM studies.

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.'

Purpose: Several novel techniques have been developed recently to assess the breadth of a speaker's vocabulary exhibited in a language sample. The specific aim of this study was to increase our understanding of the validity of the scores generated by different lexical diversity (LD) estimation techniques. Four techniques were explored: D, Maas, measure of textual lexical diversity, and moving-average type-token ratio., Method: Four LD indices were estimated for language samples on 4 discourse tasks (procedures, eventcasts, story retell, and recounts) from 442 adults who are neurologically intact. The resulting data were analyzed using structural equation modeling., Results: The scores for measure of textual lexical diversity and moving-average type-token ratio were stronger indicators of the LD of the language samples. The results for the other 2 techniques were consistent with the presence of method factors representing construct-irrelevant sources., Conclusion: These findings offer a deeper understanding of the relative validity of the 4 estimation techniques and should assist clinicians and researchers in the selection of LD measures of language samples that minimize construct-irrelevant sources.

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.

Sijtsma and van der Ark (2015) focused in their lead article on three frameworks for reliability estimation in nursing research: classical test theory (CTT), factor analysis (FA), and generalizability theory. We extend their presentation with particular attention to CTT and FA methods. We first consider the potential of yielding an overly negative or an overly positive assessment of reliability based on coefficient alpha. Next, we discuss other CTT methods for estimating reliability and how the choice of methods affects the interpretation of the reliability coefficient. Finally, we describe FA methods, which not only permit an understanding of a measure's underlying structure but also yield a variety of reliability coefficients with different interpretations. On a more general note, we discourage reporting reliability as a two-choice outcome--unsatisfactory or satisfactory; rather, we recommend that nursing researchers make a conceptual and empirical argument about when a measure might be more or less reliable, depending on its use.

Purpose: A review of case reports and other published data on fetal and neonatal outcomes associated with maternal use of bisphosphonate medications is presented., Summary: Bisphosphonates can persist in the bone matrix for years, even after therapy is discontinued, potentially resulting in fetal bisphosphonate exposure during pregnancy. Adverse effects of bisphosphonates on fetal outcomes have been observed in animal studies, but the bisphosphonate doses administered were much higher than those typically used in clinical practice. A literature search of PubMed (1946-May 2014) and ToxNet identified 15 articles describing the use of bisphosphonate medications by women before and/or during pregnancy (in total, the articles described 65 mother-child pairs); the agents used included alendronate, ibandronate, risedronate, etidronate, pamidronate, tiludronate, and zoledronic acid, with the reported durations of use ranging from one-time treatments to periods of months or years. Adverse outcomes possibly attributable to bisphosphonate use included marginal decreases in gestational age and birth weight and transient neonatal electrolyte abnormalities (e.g., hypocalcemia, hypercalcemia, hyperphosphatemia); however, no long-term health consequences were reported in any infant. Overall, the available published data appear to indicate that maternal bisphosphonate use does not pose a high risk of fetal or neonatal harm. Nonetheless, in cases of known or suspected fetal bisphosphonate exposure, monitoring for neonatal hypocalcemia and associated neuromuscular and cardiac symptoms is advised., Conclusion: A limited body of published data suggests that maternal use of bisphosphonates before or during pregnancy does not have serious fetal or neonatal adverse effects., (Copyright © 2014 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

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: Although it is recommended that smokers undergoing surgery for lung cancer quit smoking to reduce post-operative complications, few studies have examined patterns of smoking in the peri-operative period. The goals of this study were to determine: (1) patterns of smoking during post-operative recovery, (2) types of cessation strategies used to quit smoking, and (3) factors related to smoking after lung cancer surgery., Methods: Data were collected from 94 patients through chart review, tobacco, health status, and symptom questionnaires at 1, 2, and 4 months after surgery. Smoking status was assessed through self-report and urinary cotinine measurement., Results: Eighty-four patients (89%) were ever-smokers and 35 (37%) reported smoking at diagnosis. Thirty-nine (46%) ever-smokers remained abstinent, 13 (16%) continued smoking at all time-points, and 32 (38%) relapsed. Ten (46%) of those who relapsed were former-smokers and had not smoked for at least 1 year. Sixteen (46%) of those who were smoking at diagnosis received cessation assistance with pharmacotherapy being the most common strategy. Factors associated with smoking during recovery were younger age and quitting smoking < or =6 months before the diagnosis of lung cancer. Factors that were marginally significant were lower educational level, male gender, lower number of comorbidities, and the presence of pain., Conclusion: Only half of those who were smoking received assistance to quit prior to surgery. Some patients were unable to quit and relapse rates post-surgery were high even among those who quit more than 1 year prior. Innovative programs incorporating symptom management and relapse prevention may enhance smoking abstinence during post-operative care.

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: To report on a retrospective analysis of the cumulative experience from eight institutions using the GliaSite Radiotherapy System as a brachytherapy boost in the initial management of glioblastoma multiforme., Methods and Materials: Eight institutions provided data on 20 patients with histologically proven glioblastoma multiforme with a median age of 59 years (range, 39-76) and median Karnofsky performance scale of 80 (range, 50-100). After maximal surgical debulking, patients were treated with GliaSite brachytherapy to a median dose of 50 Gy, followed by external beam radiotherapy to a median dose of 60 Gy (range, 46-60 Gy), for a cumulative dose escalation of 110 Gy (range, 84-130 Gy)., Results: The average survival for this study population was 11.4 months (range, 4-29). When the patients' survival was compared with that of historical controls according to their Radiation Therapy Oncology Group recursive partitioning analysis class, the average survival was increased by 3 months (95% confidence interval, 0.23-4.9) corresponding to a 43% increase (p = 0.033). Three patients (14%) experienced Radiation Therapy Oncology Group Grade 3 central nervous system toxicity. Of the treatment failures, 50% were >2 cm from the edge of the balloon., Conclusion: The results of this analysis have demonstrated that dose escalation (>100 Gy) with GliaSite is well tolerated and associated with minimal toxicity. Local control improved with the use of GliaSite brachytherapy. The putative survival advantage seen in this study needs to be interpreted with caution; nevertheless, the data provide sufficient justification to investigate the potential role of radiation dose escalation in conjunction with GliaSite in the initial treatment of glioblastoma multiforme.

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.

In a colorectal polyp prevention trial, some participants might have their follow-up colonoscopy conducted before the scheduled time (i.e. at the end of the trial). This results in variable follow-up lengths for participants and the data of recurrence status at the end of the trial can be considered as current status data. In this paper, we use a weighted logistic regression model to estimate recurrence rate of adenoma data at the end of the trial. The weights are used to adjust for variable follow-up. We show that logistic regression tends to underestimate recurrence rate. In a simulation study, we show that Kaplan-Meier estimator derived from the right endpoint of the current status data tends to overestimate recurrence rate in contrast to logistic regression and the weighted logistic regression method can produce reasonable estimates of recurrence rate even under a high non-compliance rate compared to conventional logistic regression and Kaplan-Meier estimator. The method described here is illustrated with an example from a colon cancer study., (Copyright (c) 2006 John Wiley & Sons, Ltd.)

Stability in simulated gastric fluid has been suggested as a parameter for consideration in the allergenicity assessment of transgenic proteins. However, the relationship between the stability of proteins in simulated gastric fluid and allergenicity has been inconsistent among studies conducted with reference allergens and non-allergens. Differences in laboratory methods and data interpretation have been implicated as possible causes for conflicting study results. We attempted to mitigate some of the methodological inconsistencies among laboratory methods by applying a kinetic interpretation to results of digestion experiments conducted with a set of known allergens and putative non-allergens. We found that pepsinolysis in simulated gastric fluid generally followed an exponential (pseudo-first-order) pattern of decay, at least during the terminal (slower) phase of digestion, allowing the calculation of digestion half-lives. While digestibility estimates were reproducible and robust, results for the proteins evaluated in this study did not support a significant association between stability in simulated gastric fluid and allergenicity.

Multivariate methods for analyzing group differences in means on dependent variables include multivariate analysis of variance, discriminant analysis, and multivariate analysis of factor means. To make appropriate choices among these methods, researchers should understand the statistical models underlying them. We present these models using path diagrams within a structural equation modeling framework. Results for the different methods are presented for an example concerning coping with asthma.

Objective: To review the cumulative experience of 10 institutions in treating recurrent malignant gliomas with the brachytherapy device, GliaSite Radiation Therapy System., Methods: The patient population consisted of 95 patients with recurrent grade 3 or 4 gliomas, a median age of 51 years, and a median Karnofsky performance status score of 80. All patients had previously undergone resection and had received external beam radiotherapy as part of their initial treatment. After recurrence, each patient underwent maximal surgical debulking of their recurrent lesion and placement of an expandable balloon catheter (GliaSite) in the tumor cavity. The balloon was afterloaded with liquid I (Iotrex) to deliver a median dose of 60 Gy to an average depth of 1 cm with a median dose rate of 52.3 Gy/hr. Patients were carefully followed with serial magnetic resonance imaging and monthly examinations for tumor progression, side effects, and survival., Results: The median survival for all patients, measured from date of GliaSite placement, was 36.3 weeks with an estimated 1 year survival of 31.1%. The median survival was 35.9 weeks for patients with an initial diagnosis of glioblastoma multiforme and 43.6 weeks for those with non- glioblastoma multiforme malignant gliomas. Analysis of the influence of various individual prognostic factors on patient survival demonstrated that only Karnofsky performance status significantly predicted for improved survival. There were three cases of pathologically documented radiation necrosis., Conclusion: Reirradiation of malignant gliomas with the GliaSite Radiation Therapy System after reresection seems to provide a modest survival benefit above what would be expected from surgery alone. This report not only confirms the initial results of the feasibility study but provides evidence that similar outcomes can be obtained outside of a clinical trial.

Thus far, there has been a paucity of studies that have assessed the value of the different gastroesophageal reflux disease (GERD) symptom characteristics in identifying patients with long-segment Barrett's esophagus versus those with short-segment Barrett's esophagus. To determine if any of the symptom characteristics of GERD correlates with long-segment Barrett's esophagus versus short-segment Barrett's esophagus. Patients seen in our Barrett's clinic were prospectively approached and recruited into the study. All patients underwent an endoscopy, validated GERD symptoms questionnaire and a personal interview. Of the 88 Barrett's esophagus patients enrolled into the study, 47 had short-segment Barrett's esophagus and 41 long-segment Barrett's esophagus. Patients with short-segment Barrett's esophagus reported significantly more daily heartburn symptoms (84.1%) than patients with long-segment Barrett's esophagus (63.2%, P = 0.02). There was a significant difference in reports of severe to very severe dysphagia in patients with long-segment Barrett's esophagus versus those with short-segment Barrett's esophagus (76.9%vs. 38.1%, P = 0.02). Longer duration in years of chest pain was the only symptom characteristic of gastroesophageal reflux disease associated with longer lengths of Barrett's mucosa. Reports of severe or very severe dysphagia were more common in long-segment Barrett's esophagus patients. Only longer duration of chest pain was correlated with longer lengths of Barrett's esophagus.

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.

Transient errors are caused by variations in feelings, moods, and mental states over time. If these errors are present, coefficient alpha is an inflated estimate of reliability. A true-score model is presented that incorporates transient errors for test-retest data, and a reliability estimate is derived. This estimate, referred to as the test-retest alpha, is less than coefficient alpha if transient error is present and is less susceptible to effects due to item recall than a test-retest correlation. An assumption underlying the test-retest alpha is essential tau equivalency of items. A test-retest split-half coefficient is presented as an alternative to the test-retest alpha when this assumption is violated. The test-retest alpha is the mean of all possible test-retest split-half coefficients.

We designed a pharmacokinetic and pharmacodynamic phase I study of sequential topotecan (2.55-6.3mg/m2) by 72h infusion followed by five daily doses of etoposide for patients with refractory acute leukemia based upon synergistic anti-tumor activity of topoisomerase I and II inhibitors in vitro. Eight of the 29 patients achieved bone marrow aplasia and two patients achieved clinical remission. Common grade 3-4 toxicities included hepatic and gastrointestinal dysfunction, and correlated with increased steady-state plasma topotecan concentration. The predicted up-regulation of topoisomerase II activity by topoisomerase I inhibition was not observed at this dose and schedule and may provide insight into the modest anti-leukemia activity of the regimen.

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.