bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exercise during school hours when added to patient education improves outcome for 2 years in adolescent patellofemoral pain: a cluster randomised trial
Authors: Rathleff M S , Roos E M , Olesen J L , Rasmussen S 
Published: November 2014

BackgroundPatellofemoral pain (PFP) is common among adolescents and associated with long-lasting pain and disability. Patient education and exercise therapy are commonly used treatments in primary and secondary care but the effect of these treatments in adolescents is unknown. We aimed to determine the effect of exercise therapy as an add-on therapy to patient education compared with education alone.Methods121 adolescents from 15–19 years of age were cluster randomised to patient education or patient education combined with exercise therapy. Patient education covered self-management of pain and information on PFP. Exercise therapy consisted of supervised exercises on school premises (3/week for 3 months) and instructions on home-based exercises. Adherence to exercises was assessed as attendance and weekly text messages. Primary outcome measure was self-reported recovery (seven-point Likert scale) at 12 months with additional follow-ups at 3, 6 and 24 months.ResultsAdolescents randomised to patient education and exercise therapy were more likely to have recovered at 12 months (OR, 1.73, 95% CI 1.02 to 2.93, number needed to treat (NNT) of 11). Similar results were observed at 3 and 6 months (OR 1.88 and 1.43) while the effect was further increased at 24 months (OR of 2.52, NNT of 5). A higher total number of weekly exercise sessions increased the odds of recovery.ConclusionsIn adolescent PFP, the addition of exercise therapy for 3 months was more effective than patient education alone. The effect was apparent at 3 months and increased up to 2 years. Adherence to exercises was important and improved the odds of recovery.Trial registration numberclinicaltrials.gov reference:NCT01438762.
Validation of a Coding Algorithm to Identify Bladder Cancer and Distinguish Stage in an Electronic Medical Records Database
Authors: Mamtani Ronac , Haynes Kevin , Boursi Ben , Scott Frank I. , Goldberg David S. , Keefe Stephen M. , Vaughn David J. , Malkowicz S. Bruce , Lewis James D. 
Published: November 2014

Abstract
Studies on outcomes in bladder cancer rely on accurate methods to identify patients with bladder cancer and differentiate bladder cancer stage. Medical record and administrative databases are increasingly used to study cancer incidence, but few have distinguished cancer stage, and none have focused on bladder cancer. In this study, we used data from The UK Health Improvement Network (THIN) to identify patients with bladder cancer using at least one diagnostic code for bladder cancer, and distinguish muscle-invasive from non-invasive disease using a subsequent code for cystectomy. Algorithms were validated against a gold standard of physician-completed questionnaires, pathology reports, and consultant letters. Algorithm performance was evaluated by measuring positive predictive value (PPV) and corresponding 95% confidence interval (CI). Among all patients coded with bladder cancer (n = 194), PPV for any bladder cancer was 99.5% (95% CI, 97.2–99.9). PPV for incident bladder cancer was 93.8% (95% CI, 89.4–96.7). PPV for muscle-invasive bladder cancer was 70.1% (95% CI, 59.4–79.5) in patients with cystectomy (n = 95) and 83.9% (95% CI, 66.3–94.5) in those with cystectomy plus additional codes for metastases and death (n = 31). Using our codes for bladder cancer, the age- and sex-standardized incidence rate (SIR) of bladder cancer in THIN approximated that measured by cancer registries (SIR within 20%), suggesting that sensitivity was high as well. THIN is a valid and novel database for the study of bladder cancer. Our algorithm can be used to examine the epidemiology of muscle-invasive bladder cancer or outcomes following cystectomy for patients with muscle invasion. Cancer Epidemiol Biomarkers Prev; 24(1); 303–7. ©2014 AACR.
A Phase I Study of PF-04449913, an Oral Hedgehog Inhibitor, in Patients with Advanced Solid Tumors
Authors: Wagner Andrew J. , Messersmith Wells A. , Shaik M. Naveed , Li Sherry , Zheng Xianxian , McLachlan Karen R. , Cesari Rossano , Courtney Rachel , Levin Wendy J. , El-Khoueiry Anthony B. 
Published: November 2014

Abstract
Purpose: To estimate the maximum tolerated dose (MTD) of single-agent PF-04449913, and to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity in patients with advanced tumors.
Experimental Design: A 3+3 design was used in this open-label, multicenter, phase I study and dose escalation/de-escalation applied until identification of the MTD. PF-04449913 was orally administered once daily in continuous 28-day treatment cycles. The starting dose was 80 mg.
Results: A total of 23 patients were enrolled; 19 were evaluable for first-cycle dose-limiting toxicity (DLT). The first-cycle DLT rate at the 640 mg dose level was 33.3%, and the MTD was estimated to be 320 mg once daily. The recommended phase II dose was not determined. PF-04449913 was generally well tolerated at doses of 80 to 320 mg once daily. The most common treatment-related adverse events (AE) were grade 1–2 dysgeusia, fatigue, decreased appetite, nausea, dizziness, dehydration, and diarrhea. Treatment-related grade 3 AEs only occurred in patients receiving PF-04449913 640 mg once daily. No treatment-related grade 4–5 AEs were reported. Pharmacokinetic analysis indicated a generally dose-proportional kinetics with biphasic elimination, supporting once-daily dosing. PF-04449913 modulated hedgehog signaling at the dose levels tested, as demonstrated by &gt;80% downregulation of GLI1 expression in the skin of treated patients. Eight patients (34.8%) achieved stable disease; none had complete or partial response. Three patients with disease progression at enrollment had prolonged disease stabilization (≥6 months).
Conclusions: The results obtained in this study support further evaluation of PF-04449913 in patients with advanced solid tumors. Clin Cancer Res; 21(5); 1044–51. ©2014 AACR.
Plasma Metabolomic Profiles of Breast Cancer Patients after Short-term Limonene Intervention
Authors: Miller Jessica A. , Pappan Kirk , Thompson Patricia A. , Want Elizabeth J. , Siskos Alexandros P. , Keun Hector C. , Wulff Jacob , Hu Chengcheng , Lang Julie E. , Chow H.-H. Sherry 
Published: November 2014

Abstract
Limonene is a lipophilic monoterpene found in high levels in citrus peel. Limonene demonstrates anticancer properties in preclinical models with effects on multiple cellular targets at varying potency. While of interest as a cancer chemopreventive, the biologic activity of limonene in humans is poorly understood. We conducted metabolite profiling in 39 paired (pre/postintervention) plasma samples from early-stage breast cancer patients receiving limonene treatment (2 g QD) before surgical resection of their tumor. Metabolite profiling was conducted using ultra-performance liquid chromatography coupled to a linear trap quadrupole system and gas chromatography-mass spectrometry. Metabolites were identified by comparison of ion features in samples to a standard reference library. Pathway-based interpretation was conducted using the human metabolome database and the MetaCyc database. Of the 397 named metabolites identified, 72 changed significantly with limonene intervention. Class-based changes included significant decreases in adrenal steroids (P &lt; 0.01), and significant increases in bile acids (P ≤ 0.05) and multiple collagen breakdown products (P &lt; 0.001). The pattern of changes also suggested alterations in glucose metabolism. There were 47 metabolites whose change with intervention was significantly correlated to a decrease in cyclin D1, a cell-cycle regulatory protein, in patient tumor tissues (P ≤ 0.05). Here, oral administration of limonene resulted in significant changes in several metabolic pathways. Furthermore, pathway-based changes were related to the change in tissue level cyclin D1 expression. Future controlled clinical trials with limonene are necessary to determine the potential role and mechanisms of limonene in the breast cancer prevention setting. Cancer Prev Res; 8(1); 86–93. ©2014 AACR.
Severe Adverse Immunologic Reaction in a Patient with Glioblastoma Receiving Autologous Dendritic Cell Vaccines Combined with GM-CSF and Dose-Intensified Temozolomide
Authors: Mitchell Duane A. , Sayour Elias J. , Reap Elizabeth , Schmittling Robert , DeLeon Gabriel , Norberg Pamela , Desjardins Annick , Friedman Allan H. , Friedman Henry S. , Archer Gary , Sampson John H. 
Published: November 2014

Abstract
Therapeutic vaccination of patients with cancer-targeting tumor-associated antigens is a promising strategy for the specific eradication of invasive malignancies with minimal toxicity to normal tissues. However, as increasingly potent modalities for stimulating immunologic responses are developed for clinical evaluation, the risk of inflammatory and autoimmune toxicities also may be exacerbated. In this report, we describe the induction of a severe (grade 3) immunologic reaction in a patient with newly diagnosed glioblastoma (GBM) receiving autologous RNA-pulsed dendritic cell (DC) vaccines admixed with GM-CSF and administered coordinately with cycles of dose-intensified temozolomide. Shortly after the eighth administration of the admixed intradermal vaccine, the patient experienced dizziness, flushing, conjunctivitis, headache, and the outbreak of a disseminated macular/papular rash and bilateral indurated injection sites. Immunologic workup of patient reactivity revealed sensitization to the GM-CSF component of the vaccine and the production of high levels of anti–GM-CSF autoantibodies during vaccination. Removal of GM-CSF from the DC vaccine allowed continued vaccination without incident. Despite the known lymphodepletive and immunosuppressive effects of temozolomide, these observations demonstrate the capacity for the generation of severe immunologic reactivity in patients with GBM receiving DC-based therapy during adjuvant dose-intensified temozolomide. Cancer Immunol Res; 3(4); 320–5. ©2014 AACR.
Immunity to the Vacuolar ATPase Complex Accessory Unit ATP6S1 in Patients with Malignant Melanoma
Authors: Zhou Jun , Gupta Meghna , Wu Xinqi , Yoon Charles , Giobbie-Hurder Anita , Hodi F. Stephen 
Published: November 2014

Abstract
The augmentation of high-titer antibodies to ATP6S1 is associated with favorable clinical outcomes in patients who received vaccination with autologous, irradiated tumor cells engineered to secrete GM-CSF and allogeneic bone marrow transplantation. Cellular immune responses to ATP6S1 are unknown. To define its role as an immune target, examination of cellular responses to ATP6S1 and immunity related to current therapies such as checkpoint blockade is needed. We used an overlapping peptide library representing the full-length ATP6S1 protein to screen for cellular responses from the peripheral blood of patients with stage III and IV melanoma. Reactive peptide pools were used to determine the individual peptide activity and epitopes. Recombinant ATP6S1 protein was used in an ELISA to assess potential correlation with humoral immune responses and changes in immunity related to CTLA-4 blockade with ipilimumab in these patients. We observed a broad array of CD4+ and CD8+ cellular responses against ATP6S1, including the identification of several MHC class I and II ATP6S1 epitopes. The generation of specific CD4+ and cytotoxic T cells revealed potent functional capability elicited by ipilimumab treatment in patients with metastatic melanoma, which revealed potent functional capability, including cytokine production, proliferation responsiveness to melanoma cell lines, and tumor-cell killing. Furthermore, the augmented humoral immune responses to ATP6S1 as a function of ipilimumab treatment were associated with beneficial clinical outcomes. These results support the continued development of ATP6S1 as a biomarker and therapeutic target. Cancer Immunol Res; 3(1); 59–67. ©2014 AACR.
Loss of MicroRNA-106b-25 Cluster Promotes Atrial Fibrillation by Enhancing Ryanodine Receptor Type-2 Expression and Calcium Release
Authors: Chiang David Y. , Kongchan Natee , Beavers David L. , Alsina Katherina M. , Voigt Niels , Neilson Joel R. , Jakob Heinz , Martin James F. , Dobrev Dobromir , Wehrens Xander H.T. , Li Na 
Published: November 2014

Background—

Enhanced sarcoplasmic reticulum Ca
2+
-leak via ryanodine receptor type-2 (RyR2) contributes to the pathogenesis of atrial fibrillation (AF). Recent studies have shown that the level of RyR2 protein is elevated in atria of patients with paroxysmal AF, suggesting that microRNA-mediated post-transcriptional regulation of RyR2 might be an underlying mechanism. Bioinformatic analysis suggests that miR-106b and miR-93, members of the miR-106b-25 cluster, could bind to RyR2-3′-untranslated region and suppress its translation. Thus, we tested the hypothesis that loss of the miR-106b-25 cluster promotes AF via enhanced RyR2-mediated sarcoplasmic reticulum Ca
2+
-leak.

Methods and Results—

Quantitative real-time polymerase chain reaction showed that the levels of mature miR-106b, miR-93, and miR-25 were lower in atria of patients with paroxysmal AF when compared with patients in sinus rhythm. In vitro assay showed that miR-93 reduced RyR2-3′-untranslated region luciferase activity. Total RyR2 protein in atrial tissue of miR-106b-25
−/−
mice was increased by 42% when compared with wild-type littermates but still maintained a normal subcellular distribution. Ca
2+
-spark frequency and total sarcoplasmic reticulum Ca
2+
-leak were increased in atrial myocytes of miR-106b-25
−/−
mice. Telemetry ECG recordings revealed that miR-106b-25
−/−
mice exhibited more frequent atrial ectopy and were also more susceptible to pacing-induced AF than wild-type littermates. Increased sarcoplasmic reticulum Ca
2+
-release and AF susceptibility in miR-106b-25
−/−
mice were abolished by the RyR2 blocker K201.

Conclusions—
These results suggest that miR-106b-25 cluster–mediated post-transcriptional regulation of RyR2 is a potential molecular mechanism involved in paroxysmal AF pathogenesis. As such, the miR-106b-25 cluster could be a novel gene-therapy target in AF associated with enhanced RyR2 expression.
Cost‐Effectiveness of Supervised Exercise, Stenting, and Optimal Medical Care for Claudication: Results From the Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) Trial
Authors: Reynolds Matthew R. , Apruzzese Patricia , Galper Benjamin Z. , Murphy Timothy P. , Hirsch Alan T. , Cutlip Donald E. , Mohler Emile R. , Regensteiner Judith G. , Cohen David J. 
Published: November 2014

Background

Both supervised exercise (
SE
) and stenting (
ST
) improve functional status, symptoms, and quality of life compared with optimal medical care (
OMC
) in patients with claudication. The relative cost‐effectiveness of these strategies is not well defined.

Methods and Results

The Claudication: Exercise Versus Endoluminal Revascularization (
CLEVER
) study randomized patients with claudication due to aortoiliac stenosis to a 6‐month
SE
program, to
ST
, or to
OMC
. Participants who completed 6‐month follow‐up (n=98) were included in a health economic analysis through 18 months. Costs were assessed using resource‐based methods and hospital billing data. Quality‐adjusted life‐years were estimated using the
EQ
‐5D. Markov modeling based on the in‐trial results was used to explore the impact of assumptions about the longer term durability of observed differences in quality of life. Through 18 months, mean healthcare costs were $5178, $9804, and $14 590 per patient for
OMC
,
SE
, and
ST
, respectively. Measured quality‐adjusted life‐years through 18 months were 1.04, 1.16, and 1.20. In our base case analysis, which assumed that observed differences in quality of life would dissipate after 5 years, the incremental cost‐effectiveness ratios were $24 070 per quality‐adjusted life‐year gained for
SE
versus
OMC
, $41 376 for
ST
versus
OMC
, and $122 600 for
ST
versus
SE
. If the treatment effect of
ST
was assumed to be more durable than that of
SE
, the incremental cost‐effectiveness ratio for
ST
versus
SE
became more favorable.

Conclusions

Both
SE
and
ST
are economically attractive by
US
standards relative to
OMC
for the treatment of claudication in patients with aortoiliac disease.
ST
is more expensive than
SE
, with uncertain incremental benefit.

Clinical Trial Registration

URL:
www.clinicaltrials.gov
, Unique identifier: NCT00132743.
Pupillometry as a Glimpse into the Neurochemical Basis of Human Memory Encoding
Authors: Cohen Hoffing Russell , Seitz Aaron R. 
Published: November 2014

Abstract
Neurochemical systems are well studied in animal learning; however, ethical issues limit methodologies to explore these systems in humans. Pupillometry provides a glimpse into the brain's neurochemical systems, where pupil dynamics in monkeys have been linked with locus coeruleus (LC) activity, which releases norepinephrine (NE) throughout the brain. Here, we use pupil dynamics as a surrogate measure of neurochemical activity to explore the hypothesis that NE is involved in modulating memory encoding. We examine this using a task-irrelevant learning paradigm in which learning is boosted for stimuli temporally paired with task targets. We show that participants better recognize images that are paired with task targets than distractors and, in correspondence, that pupil size changes more for target-paired than distractor-paired images. To further investigate the hypothesis that NE nonspecifically guides learning for stimuli that are present with its release, a second procedure was used that employed an unexpected sound to activate the LC–NE system and induce pupil-size changes; results indicated a corresponding increase in memorization of images paired with the unexpected sounds. Together, these results suggest a relationship between the LC–NE system, pupil-size changes, and human memory encoding.
The Attentional Blink Impairs Detection and Delays Encoding of Visual Information: Evidence from Human Electrophysiology
Authors: Dell'Acqua Roberto , Dux Paul E. , Wyble Brad , Doro Mattia , Sessa Paola , Meconi Federica , Jolicœur Pierre 
Published: November 2014

AbstractThis article explores the time course of the functional interplay between detection and encoding stages of information processing in the brain and the role they play in conscious visual perception. We employed a multitarget rapid serial visual presentation (RSVP) approach and examined the electrophysiological P3 component elicited by a target terminating an RSVP sequence. Target-locked P3 activity was detected both at frontal and parietal recording sites and an independent component analysis confirmed the presence of two distinct P3 components. The posterior P3b varied with intertarget lag, with diminished amplitude and postponed latency at short relative to long lags—an electroencephalographic signature of the attentional blink (AB). Under analogous conditions, the anterior P3a was also reduced in amplitude but did not vary in latency. Collectively, the results provide an electrophysiological record of the interaction between frontal and posterior components linked to detection (P3a) and encoding (P3b) of visual information. Our findings suggest that, although the AB delays target encoding into working memory, it does not slow down detection of a target but instead reduces the efficacy of this process. A functional characterization of P3a in attentive tasks is discussed with reference to current models of the AB phenomenon.
Theta Oscillations Modulate Attentional Search Performance Periodically
Authors: Dugué Laura , Marque Philippe , VanRullen Rufin 
Published: November 2014

Abstract
Visual search—finding a target element among similar-looking distractors—is one of the prevailing experimental methods to study attention. Current theories of visual search postulate an early stage of feature extraction interacting with an attentional process that selects candidate targets for further analysis; in difficult search situations, this selection is iterated until the target is found. Although such theories predict an intrinsic periodicity in the neuronal substrates of attentional search, this prediction has not been extensively tested in human electrophysiology. Here, using EEG and TMS, we study attentional periodicities in visual search. EEG measurements indicated that successful and unsuccessful search trials were associated with different amounts of poststimulus oscillatory amplitude and phase-locking at ∼6 Hz and opposite prestimulus oscillatory phase at ∼6 Hz. A trial-by-trial comparison of pre- and poststimulus ∼6 Hz EEG phases revealed that the functional interplay between prestimulus brain states, poststimulus oscillations, and successful search performance was mediated by a partial phase reset of ongoing oscillations. Independently, TMS applied over occipital cortex at various intervals after search onset demonstrated a periodic pattern of interference at ∼6 Hz. The converging evidence from independent TMS and EEG measurements demonstrates that attentional search is modulated periodically by brain oscillations. This periodicity is naturally compatible with a sequential exploration by attention, although a parallel but rhythmically modulated attention spotlight cannot be entirely ruled out.
Lower limb amputation in England: prevalence, regional variation and relationship with revascularisation, deprivation and risk factors. A retrospective review of hospital data
Authors: Ahmad Naseer , Thomas G Neil , Gill Paramjit , Chan Colin , Torella Francesco 
Published: November 2014

Objective We describe the prevalence of major lower limb amputation across England and its relationship with revascularisation, patient demography and disease risk factors. Design Retrospective cohort study. Setting England 1 April 2003 to 31 March 2009. Participants Patients aged 50–84 years. Main outcome measures Age standardised prevalence rates were calculated using Hospital Episode Statistics as the numerator with census data as the denominator. The outcome measure ‘amputation with revascularisation’ was created if an amputation could be linked with a revascularisation. Logistic regression determined the odds of having an amputation with a revascularisation across England. Regression was performed unadjusted and repeated after controlling for demographic (age, sex, social deprivation) and disease risk factors (diabetes, hypertension, coronary heart disease, cerebrovascular disease, smoking). Results There were 25,312 amputations and 136,215 revascularisations, and 7543 cases were linked. The prevalence rate per 100,000 (95% confidence intervals) for amputation was 26.3 (26.0–26.6) with rates significantly higher in Northern England (North: 31.7; 31.0–32.3, Midlands: 26.0; 25.3–26.7, South: 23.1; 22.6–23.5). The revascularisation rate was 141.6 (140.8–142.3) with significantly higher rates again in Northern England (North: 182.1; 180.5–183.7, Midlands: 121.3; 119.8–122.9, South 124.9; 123.9–125.8). The odds of having an amputation with a revascularisation remained significantly higher in the North (OR 1.22; 1.13–1.33) even after controlling demographic and disease risk factors. Conclusions There is a North–South divide in England for both major lower limb amputation and revascularisation. The higher odds of having an amputation with a revascularisation in the North were not fully explained by greater levels of deprivation or disease risk factors.