bluuebunny/crossref_metadata_2025_split huggingface dataset:
Avoiding verification bias in screening test evaluation in resource poor settings: a case study from Zimbabwe
Authors: Gaffikin Lynne , McGrath John , Arbyn Marc , Blumenthal Paul D 
Published: September 2008

Background Verification bias occurs when the percentage of subjects receiving disease verification differs according to the test result. Statistical adjustment yields unbiased sensitivity and specificity under a missing at random (MAR) assumption. Purpose To use an example from an international study to show how the assumptions needed for unbiased statistical adjustment for verification bias can be undermined by conditions on the ground, and that accuracy of estimates is also compromised by too low a sampling fraction of subjects who test negative. Methods A study in Zimbabwe assessed the accuracy of a screening test for cervical cancer screening, visual inspection with acetic acid (VIA). The study was conducted in two phases, Phase I, where only 10% of subjects with negative tests received verification, and Phase II, in which nearly all subjects were verified. Unadjusted, simple- and covariate-adjusted estimates were compared to investigate factors affecting differences. Bootstrap simulations were used to illustrate the effect of varying test negative sampling fractions. Results Phase I unadjusted sensitivity and specificity were 0.66 (0.61—0.70) and 0.34 (0.31—0.36), respectively. Simple-weighted adjusted estimators accounting only for VIA status were 0.20 (0.17—0.23) and 0.80 (0.78—0.81), respectively, suggesting the test to be useless. It was found that verification (colposcopy) capacity in-country had been exceeded, and that random selection of test negative patients for colposcopy had been compromised. Phase II estimates of sensitivity and specificity were 0.77 and 0.64, respectively. With 9% disease prevalence, a VIA test-negative sampling fraction >50% was necessary for the confidence intervals for sensitivity to have more than a 90% probability of including the true value. Limitations Phase I statistical adjustment was not made for MAR deviations unexplained by the two auxiliary factors, Pap results and STD history. Adjustment was not possible for other unmeasured co-factors. Conclusions While there are standard formulae for correcting for verification bias, these will be biased if the MAR assumption is not met, which can occur through the actions of study personnel or subjects. Design of such studies in low resource environments needs to either require 100% verification, or employ procedures ensuring that the sample of test negatives who receive verification is indeed random. In addition, required test negative sampling fractions need to incorporate information on both disease prevalence and overall sample size. Clinical Trials 2008; 5: 496—503. http://ctj.sagepub.com
Recruitment of a racially and ethnically diverse sample into a physical activity efficacy trial
Authors: Frierson Georita M , Williams David M , Dunsiger Shira , Lewis Beth A , Whiteley Jessica A , Albrecht Anna E , Jakicic John M , Horowitz Santina M , Marcus Bess H 
Published: September 2008

Background Healthy People 2010 underscores the relevance of eliminating health disparities. Thus, it is paramount to create interventions that promote health for all individuals. Purpose This study examined differences in rates of and reasons for ineligibility among non-Hispanic blacks and whites in a randomized controlled physical activity intervention study. Methods Participants (1245 adults) responded to community advertising for the research study. Eligibility at the four pre-randomization assessment sessions was determined by self-reported medical information, resting EKG, 7-Day Physical Activity Recall, fitness test and Stage of Change. We used t-tests to examine the rates of eligibility among participant subgroups. Results Blacks had higher rates of overall ineligibility (86.9%) than whites (75.1%; p < 0.01) and were more likely to be ineligible due to lack of interest or no-show at a pre-randomization appointment (35.4% vs. 24.3%; p < 0.01). Blacks were more likely to be ineligible for medical reasons after the telephone screen (16.3% vs. 7.8%; p = 0.01). Limitations This study did not use a random sampling of potential participants from each of the racial/ethnic groups and thus, there is the potential for selection bias. Conclusions Blacks were more likely to choose not to enroll in the study due to a lack of interest, but had similar rates of overall medical ineligibility to whites. This highlights the importance of strategies that enhance interest among blacks, who initially respond to recruitment advertising. Clinical Trials 2008; 5: 504—516. http://ctj.sagepub.com
Design considerations and rationale of a multi-center trial to sustain weight loss: the weight loss maintenance trial
Authors: Brantley Phillip , Appel Lawrence , Hollis Jack , Stevens Victor , Ard Jamy , Champagne Catherine , Elmer Patricia , Harsha David , Myers Valerie , Proschan Michael , William Vollmer , Svetkey Laura 
Published: September 2008

Background The Weight Loss Maintenance Trial (WLM) is a multi-center, randomized, controlled trial that compares the effects of two 30-month maintenance interventions, i.e., Personal Contact (PC) and Interactive Technology (IT) to a self-directed usual care control group (SD), in overweight or obese individuals who are at high risk for cardiovascular disease. Purpose This paper provides an overview of the design and methods, and design considerations and lessons learned from this trial. Methods All participants received a 6-month behavioral weight loss program consisting of weekly group sessions. Participants who lost 4 kg were randomized to one of three conditions (PC, IT, or SD). The PC condition provided monthly contacts with an interventionist primarily via telephone and quarterly face-to-face visits. The IT condition provided frequent, individualized contact through a tailored, website system. Both the PC and IT maintenance programs encouraged the DASH dietary pattern and employed theory-based behavioral techniques to promote maintenance. Results Design considerations included choice of study population, frequency and type of intervention visits, and choice of primary outcome. Overweight or obese persons with CVD risk factors were studied. The pros and cons of studying this population while excluding others are presented. We studied intervention contact strategies that made fewer demands on participant time and travel, while providing frequent opportunities for interaction. The primary outcome variable for the trial was change in weight from randomization to end of follow-up (30 months). Limitations Limits to generalizability are discussed. Individuals in need of weight loss strategies may have been excluded due to barriers associated with internet use. Other participants may have been excluded secondary to a comorbid condition. Conclusions This paper highlights the design and methods of WLM and informs readers of discussions of critical issues and lessons learned from the trial. Clinical Trials 2008; 5: 546—556. http://ctj.sagepub.com
Molecular biology of bcr-abl1–positive chronic myeloid leukemia
Authors: Quintás-Cardama Alfonso , Cortes Jorge 
Published: September 2008

Abstract
Chronic myeloid leukemia (CML) has been regarded as the paradigmatic example of a malignancy defined by a unique molecular event, the BCR-ABL1 oncogene. Decades of research zeroing in on the role of BCR-ABL1 kinase in the pathogenesis of CML have culminated in the development of highly efficacious therapeutics that, like imatinib mesylate, target the oncogenic kinase activity of BCR-ABL1. In recent years, most research efforts in CML have been devoted to developing novel tyrosine kinase inhibitors (TKIs) as well as to elucidating the mechanisms of resistance to imatinib and other TKIs. Nonetheless, primordial aspects of the pathogenesis of CML, such as the mechanisms responsible for the transition from chronic phase to blast crisis, the causes of genomic instability and faulty DNA repair, the phenomenon of stem cell quiescence, the role of tumor suppressors in TKI resistance and CML progression, or the cross-talk between BCR-ABL1 and other oncogenic signaling pathways, still remain poorly understood. Herein, we synthesize the most relevant and current knowledge on such areas of the pathogenesis of CML.
Elevated growth differentiation factor 15 expression in patients with congenital dyserythropoietic anemia type I
Authors: Tamary Hannah , Shalev Hanna , Perez-Avraham Galit , Zoldan Meira , Levi Itai , Swinkels Dorine W. , Tanno Toshihiko , Miller Jeffery L. 
Published: September 2008

Abstract
Congenital dyserythropoietic anemia (CDA) is a rare group of red blood cell disorders characterized by ineffective erythropoiesis and increased iron absorption. To determine whether growth differentation factor 15 (GDF15) hyper-expression is associated with the ineffective erythropoiesis and iron-loading complications of CDA type I (CDA I), GDF15 levels and other markers of erythropoiesis and iron overload were studied in blood from 17 CDA I patients. Significantly higher levels of GDF15 were detected among the CDA I patients (10 239 ± 3049 pg/mL) compared with healthy volunteers (269 ± 238 pg/mL). In addition, GDF15 correlated significantly with several erythropoietic and iron parameters including Hepcidin-25, Ferritin, and Hepcidin-25/Ferritin ratios. These novel results suggest that CDA I patients express very high levels of serum GDF15, and that GDF15 contributes to the inappropriate suppression of hepcidin with subsequent secondary hemochromatosis.
A dichotomy in bronchiolitis obliterans syndrome after lung transplantation revealed by azithromycin therapy
Authors: Vanaudenaerde B. M. , Meyts I. , Vos R. , Geudens N. , De Wever W. , Verbeken E. K. , Van Raemdonck D. E. , Dupont L. J. , Verleden G. M. 
Published: September 2008

Bronchiolitis obliterans syndrome (BOS) is the most important cause of late mortality following lung transplantation, resulting in major morbidity and a huge burden on healthcare resources. Treatment options are limited, resulting in a mere stabilisation of the lung function decline. Recent introduction of the macrolide antibiotic azithromycin raised new hope after demonstrating lung function improvement in subsets of patients.The present study aimed to provide an overview of the clinical effects on azithromycin in the setting of BOS after lung transplantation, with special emphasis on the anti-inflammatory actions. Moreover, the authors proposed a new frame of thinking centred on a dichotomy in the pathogenesis and clinical phenotype of BOS. Subsets of BOS patients were identified who do or do not respond to azithromycin (regarding forced expiratory volume in one second (FEV1), bronchoalveolar lavage (BAL) neutrophilia/interleukin-8). These observations have shed new light on the current belief that BOS represents a homogenous clinical entity in which the neutrophil is the main culprit.Recent clinical observations, supported by research findings, have revealed a dichotomy in the clinical spectrum of BOS with neutrophilic (partially) reversible allograft dysfunction (responding to azithromycin) and fibroproliferative BOS (not responding to azithromycin). This concept is reinforced by unique data obtained in BOS patients, consisting of histology specimens, physical and radiological examination, FEV1and BAL examination.The acceptance of this dichotomy can improve understanding of the heterogeneous pathological condition that constitutes bronchiolitis obliterans syndrome, thus encouraging a more accurate diagnosis and, ultimately, better tailored treatment for each bronchiolitis obliterans syndrome patient.
Antigen stimulation of peripheral blood mononuclear cells from Mycobacterium bovis infected cattle yields evidence for a novel gene expression program
Authors: Meade Kieran G , Gormley Eamonn , O'Farrelly Cliona , Park Stephen D , Costello Eamon , Keane Joseph , Zhao Yingdong , MacHugh David E 
Published: September 2008

Abstract

Background
Bovine tuberculosis (BTB) caused by Mycobacterium bovis continues to cause substantial losses to global agriculture and has significant repercussions for human health. The advent of high throughput genomics has facilitated large scale gene expression analyses that present a novel opportunity for revealing the molecular mechanisms underlying mycobacterial infection. Using this approach, we have previously shown that innate immune genes in peripheral blood mononuclear cells (PBMC) from BTB-infected animals are repressed in vivo in the absence of exogenous antigen stimulation. In the present study, we hypothesized that the PBMC from BTB-infected cattle would display a distinct gene expression program resulting from exposure to M. bovis. A functional genomics approach was used to examine the immune response of BTB-infected (n = 6) and healthy control (n = 6) cattle to stimulation with bovine tuberculin (purified protein derivative – PPD-b) in vitro. PBMC were harvested before, and at 3 h and 12 h post in vitro stimulation with bovine tuberculin. Gene expression changes were catalogued within each group using a reference hybridization design and a targeted immunospecific cDNA microarray platform (BOTL-5) with 4,800 spot features representing 1,391 genes.

Results
250 gene spot features were significantly differentially expressed in BTB-infected animals at 3 h post-stimulation contrasting with only 88 gene spot features in the non-infected control animals (P ≤ 0.05). At 12 h post-stimulation, 56 and 80 gene spot features were differentially expressed in both groups respectively. The results provided evidence of a proinflammatory gene expression profile in PBMC from BTB-infected animals in response to antigen stimulation. Furthermore, a common panel of eighteen genes, including transcription factors were significantly expressed in opposite directions in both groups. Real-time quantitative reverse transcription PCR (qRT-PCR) demonstrated that many innate immune genes, including components of the TLR pathway and cytokines were differentially expressed in BTB-infected (n = 8) versus control animals (n = 8) after stimulation with bovine tuberculin.

Conclusion
The PBMC from BTB-infected animals exhibit different transcriptional profiles compared with PBMC from healthy control animals in response to M. bovis antigen stimulation, providing evidence of a novel gene expression program due to M. bovis exposure.
CXCR4 expression in papillary thyroid carcinoma: induction by nitric oxide and correlation with lymph node metastasis
Authors: Yasuoka Hironao , Kodama Rieko , Hirokawa Mitsuyoshi , Takamura Yuuki , Miyauchi Akira , Sanke Tokio , Nakamura Yasushi 
Published: September 2008

Abstract

Background
Metastasis to regional lymph nodes is a common step in the progression of cancer. Recent evidence suggests that tumor production of CXCR4 promotes lymph node metastasis. Nitric oxide (NO) may also increase metastatic ability in human cancers.

Methods
Nitrite/nitrate levels and functional CXCR4 expression were assessed in K1 and B-CPAP papillary thyroid carcinoma (PTC) cells after induction and/or inhibition of NO synthesis. CXCR4 expression was also analyzed in primary human PTC. The relationship between nitrotyrosine levels, which are a biomarker for peroxynitrate formation from NO in vivo, CXCR4 expression, and lymph node status was also analyzed.

Results
Production of nitrite/nitrate and functional CXCR4 expression in both cell lines was increased by treatment with the NO donor DETA NONOate. The NOS inhibitor L-NAME eliminated this increase. Positive CXCR4 immunostaining was observed in 60.7% (34/56) of PTCs. CXCR4 expression was significantly correlated with nitrotyrosine levels and lymph node metastasis in human PTC.

Conclusion
Our data indicate that NO stimulates CXCR4 expression in vitro. Formation of the NO biomarker nitrotyrosine was also correlated with CXCR4 expression and lymph node metastasis in human PTC. NO may induce lymph node metastasis via CXCR4 induction in papillary thyroid carcinoma.
The relationship between depressive symptoms, health service consumption, and prognosis after acute myocardial infarction: a prospective cohort study
Authors: Kurdyak Paul A , Gnam William H , Goering Paula , Chong Alice , Alter David A 
Published: September 2008

Abstract

Background
The use of cardiovascular health services is greater among patients with depressive symptoms than among patients without. However, the extent to which such associations between depressive symptoms and health service utilization are attributable to variations in comorbidity and prognostic disease severity is unknown. This paper explores the relationship between depressive symptoms, health service cardiovascular consumption, and prognosis following acute myocardial infarction (AMI).

Methods
The study design was a prospective cohort study with follow-up telephone interviews of 1,941 patients 30 days following AMI discharged from 53 hospitals across Ontario, Canada between December 1999 and February, 2003. Outcome measures were post discharge use of cardiac and non-cardiac health care services. The service utilization outcomes were adjusted for age, sex, income, comorbidity, two validated measures of prognosis (cardiac functional capacity and risk adjustment severity index), cardiac procedures (CABG or PTCA) and drugs prescribed at discharge.

Results
Depressive symptoms were associated with a 24% (Adjusted RR:1.24; 95% CI:1.19–1.30, P < 0.001), 9% (Adjusted RR:1.09; 95% CI:1.02–1.16, P = 0.007) and 43% (Adjusted RR: 1.43; 95% CI:1.34–1.52, P < 0.001) increase in total, cardiac, and non-cardiac hospitalization days post-AMI respectively, after adjusting for baseline patient and hospital characteristics. Depressive-associated increases in cardiac health service consumption were significantly more pronounced among patients of lower than higher cardiac risk severity. Depressive symptoms were not associated with increased mortality after adjusting for baseline patient characteristics.

Conclusion
Depressive symptoms are associated with significantly higher cardiac and non-cardiac health service consumption following AMI despite adjustments for comorbidity and prognostic severity. The disproportionately higher cardiac health service consumption among lower-risk AMI depressive patients may suggest that health seeking behaviors are mediated by psychosocial factors more so than by objective measures of cardiovascular risk or necessity.
A genome-wide association study for late-onset Alzheimer's disease using DNA pooling
Authors: Abraham Richard , Moskvina Valentina , Sims Rebecca , Hollingworth Paul , Morgan Angharad , Georgieva Lyudmila , Dowzell Kimberley , Cichon Sven , Hillmer Axel M , O'Donovan Michael C , Williams Julie , Owen Michael J , Kirov George 
Published: September 2008

Abstract

Background
Late-onset Alzheimer's disease (LOAD) is an age related neurodegenerative disease with a high prevalence that places major demands on healthcare resources in societies with increasingly aged populations. The only extensively replicable genetic risk factor for LOAD is the apolipoprotein E gene. In order to identify additional genetic risk loci we have conducted a genome-wide association (GWA) study in a large LOAD case – control sample, reducing costs through the use of DNA pooling.

Methods
DNA samples were collected from 1,082 individuals with LOAD and 1,239 control subjects. Age at onset ranged from 60 to 95 and Controls were matched for age (mean = 76.53 years, SD = 33), gender and ethnicity. Equimolar amounts of each DNA sample were added to either a case or control pool. The pools were genotyped using Illumina HumanHap300 and Illumina Sentrix HumanHap240S arrays testing 561,494 SNPs. 114 of our best hit SNPs from the pooling data were identified and then individually genotyped in the case – control sample used to construct the pools.

Results
Highly significant association with LOAD was observed at the APOE locus confirming the validity of the pooled genotyping approach.
For 109 SNPs outside the APOE locus, we obtained uncorrected p-values ≤ 0.05 for 74 after individual genotyping. To further test these associations, we added control data from 1400 subjects from the 1958 Birth Cohort with the evidence for association increasing to 3.4 × 10-6 for our strongest finding, rs727153.
rs727153 lies 13 kb from the start of transcription of lecithin retinol acyltransferase (phosphatidylcholine – retinol O-acyltransferase, LRAT). Five of seven tag SNPs chosen to cover LRAT showed significant association with LOAD with a SNP in intron 2 of LRAT, showing greatest evidence of association (rs201825, p-value = 6.1 × 10-7).

Conclusion
We have validated the pooling method for GWA studies by both identifying the APOE locus and by observing a strong enrichment for significantly associated SNPs. We provide evidence for LRAT as a novel candidate gene for LOAD. LRAT plays a prominent role in the Vitamin A cascade, a system that has been previously implicated in LOAD.
Induction- and conditioning-protocol dependent involvement of NR2B-containing NMDA receptors in synaptic potentiation and contextual fear memory in the hippocampal CA1 region of rats
Authors: Zhang Xue-Han , Wu Long-Jun , Gong Bo , Ren Ming , Li Bao-Ming , Zhuo Min 
Published: September 2008

AbstractLong-term potentiation (LTP) in the hippocampal CA1 region requires the activation of N-methyl-D-aspartate receptors (NMDARs). Studies using genetic and pharmacological approaches have reported inconsistent results of the requirement of NR2B-containing NMDARs in LTP in the CA1 region. Pharmacological studies showed that NR2B-containing NMDARs are not required for LTP, while genetic studies reported that over-expression of NR2B-NMDARs enhances LTP and hippocampus-dependent memory. Here, we provide evidence showing that the functional role of NR2B-NMDARs in hippocampal LTP and memory depends on LTP-inducing and behavior-conditioning protocols. Inhibition of NR2B-NMDARs with the NR2B selective antagonist ifenprodil or Ro25-6981 suppressed LTP induced by spike-timing protocol, with no impact on LTP induced by pairing protocol or two-train high-frequency stimulation (HFS) protocol. Inhibition of NR2B-NMDARs did not affect the late phase LTP induced by four-train HFS. Ca2+imaging showed that there was difference in kinetics of intracellular Ca2+signals induced by spiking-timing and pairing protocols. Pre-training intra-CA1 infusion of ifenprodil or Ro25-6981 impaired the contextual fear memory induced by five CS-US pairings, with no effect on the memory induced by one CS-US pairing.