bluuebunny/crossref_metadata_2025_split huggingface dataset:
Practical and Robust Identification of Molecular Subtypes in Colorectal Cancer by Immunohistochemistry
Authors: Trinh Anne , Trumpi Kari , De Sousa E Melo Felipe , Wang Xin , de Jong Joan H. , Fessler Evelyn , Kuppen Peter J.K. , Reimers Marlies S. , Swets Marloes , Koopman Miriam , Nagtegaal Iris D. , Jansen Marnix , Hooijer Gerrit K.J. , Offerhaus George J.A. , Kranenburg Onno , Punt Cornelis J. , Medema Jan Paul , Markowetz Florian , Vermeulen Louis 
Published: July 2016

Abstract
Purpose: Recent transcriptomic analyses have identified four distinct molecular subtypes of colorectal cancer with evident clinical relevance. However, the requirement for sufficient quantities of bulk tumor and difficulties in obtaining high-quality genome-wide transcriptome data from formalin-fixed paraffin-embedded tissue are obstacles toward widespread adoption of this taxonomy. Here, we develop an immunohistochemistry-based classifier to validate the prognostic and predictive value of molecular colorectal cancer subtyping in a multicenter study.
Experimental Design: Tissue microarrays from 1,076 patients with colorectal cancer from four different cohorts were stained for five markers (CDX2, FRMD6, HTR2B, ZEB1, and KER) by immunohistochemistry and assessed for microsatellite instability. An automated classification system was trained on one cohort using quantitative image analysis or semiquantitative pathologist scoring of the cores as input and applied to three independent clinical cohorts.
Results: This classifier demonstrated 87% concordance with the gold-standard transcriptome-based classification. Application to three validation datasets confirmed the poor prognosis of the mesenchymal-like molecular colorectal cancer subtype. In addition, retrospective analysis demonstrated the benefit of adding cetuximab to bevacizumab and chemotherapy in patients with RAS wild-type metastatic cancers of the canonical epithelial-like subtypes.
Conclusions: This study shows that a practical and robust immunohistochemical assay can be employed to identify molecular colorectal cancer subtypes and uncover subtype-specific therapeutic benefit. Finally, the described tool is available online for rapid classification of colorectal cancer samples, both in the format of an automated image analysis pipeline to score tumor core staining, and as a classifier based on semiquantitative pathology scoring. Clin Cancer Res; 23(2); 387–98. ©2016 AACR.
ALIAS (Albumin in Acute Ischemic Stroke) Trials
Authors: Martin Renee’ H. , Yeatts Sharon D. , Hill Michael D. , Moy Claudia S. , Ginsberg Myron D. , Palesch Yuko Y. 
Published: July 2016

Background and Purpose—
The ALIAS (Albumin in Acute Ischemic Stroke) part 1 and 2 trials evaluated whether 25% human serum albumin improves clinical outcomes after acute ischemic stroke above and beyond standard of care using similar protocols. The part 1 trial ended prematurely because of safety concerns, and the part 2 trial terminated early because of futility of finding a statistically significant effect of albumin over saline (control) administration. We combine the subject-level data of the part 1 and 2 trials to reevaluate the efficacy and safety outcomes with the larger sample size.

Methods—
The combined data analyses closely follow those conducted in the part 2 trial. The primary outcome is the composite of the modified Rankin Scale and the National Institutes of Health Stroke Scale defined as a composite of modified Rankin Scale score 0 to 1 and National Institutes of Health Stroke Scale score 0 to 1 at 90 days from randomization. The unadjusted analyses use a simple Chi-square test, and those adjusting for baseline covariates use a generalized linear model with log link (to obtain relative risks).

Results—
The participant characteristics at baseline were generally similar between the treatment groups and between the trials; however, thrombolysis use was greater in part 2 (84% versus 75%), and the upper age limit imposed in part 2 resulted in a younger sample (mean age in part 1 was 69 versus 64 in part 2). In the combined sample, the proportions of good outcome in the 2 treatment groups were identical (41%). Similar results were observed in all secondary efficacy outcomes. Pulmonary edema was a consistent safety concern, with a 6-fold increase in the albumin arm (13%) compared with saline (2%; relative risk =7.76, 95% confidence interval 3.87–15.57).

Conclusions—
Treatment with intravenous albumin 25% at 2 g/kg was not associated with improved outcome at 90 days and was associated with increased rates of intracerebral hemorrhage and pulmonary edema.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00235495.
The Draft cdc Circumcision Recommendations: Medical, Ethical, Legal, and Procedural Concerns
Authors: Adler Peter W. 
Published: July 2016

The Centers for Disease Control and Prevention (“cdc”) is poised to recommend that physicians counsel the parents of every newborn boy and heterosexually active adolescent and man in the United States – approximately 36 million boys and men – that the benefits of circumcision outweigh the risks, that parents should take non-medical factors into account in making the “circumcision decision”, and that Medicaid should pay for it.The draftcdcrecommendations are not medically correct, ethically sound, legally permissible or procedurally valid. Accordingly, they should not be implemented and would be legally invalid if they are. They provide erroneous and misleading advice to physicians that exposes them to the threat of lawsuits by men and parents. Thecdcmust revise its draft guidelines to comport with the correct and prevailing view in the Western world that circumcision is on balance deleterious to health; that men have the right to make the “circumcision decision” for themselves; that physicians are not permitted to circumcise healthy boys; and that it is unlawful to use Medicaid to pay for unnecessary surgery.
Paper Orphans: Exploring Child Trafficking for the Purpose of Orphanages
Authors: van Doore Kathryn E. 
Published: July 2016

There are an estimated eight million children residing in orphanages, or residential care facilities, globally and it is estimated that four out of five of these children are not orphans. It is well documented that many of these children are taken from their families by recruiters and sold into orphanages for the purpose of profit. These children are known as “paper orphans”. There is no formal legal academic research available on how international law regards the displacement from family and subsequent construction as an orphan.
This article provides a legal account of the movement of the child from the family to the orphanage, and considers whether this movement can be categorised as child trafficking under international law. The major point of contention as to whether paper orphans are considered trafficked is whether they experience a form of exploitation that is included in the Protocol to Prevent, Suppress and Punish Trafficking in Persons, Especially Women and Children. This article examines the forms of exploitation that have been documented as being experienced by paper orphans and argues that the process of paper orphaning meets the current interpretation of the definition of trafficking.
Acroteriobatus omanensis (Batoidea: Rhinobatidae), a new guitarfish from the Gulf of Oman
Authors: LAST PETER R. , HENDERSON AARON C. , NAYLOR GAVIN J.P. 
Published: July 2016

The recently resurrected genus Acroteriobatus is represented in the western Indian Ocean by eight species, including a new guitarfish Acroteriobatus omanensis sp. nov. This small species (reaching ~60 cm TL) was discovered off Oman in an investigation of the chondrichthyan fauna of the Arabian in 2002 and 2003. Its distinctiveness from other members of the genus Acroteriobatus is strongly supported by molecular data. Acroteriobatus omanensis sp. nov. differs from all other members of the genus by its very narrowly pointed snout and having a dense pattern of small, symmetrically arranged ocelli each consisting of a white spot surrounded by a darker rim. Acroteriobatus annulatus and A. ocellatus have a more-or-less ocellated dorsal colour pattern but the markings are larger and differ in form (ocelli consisting of a small dark central spot surrounded by a dark-edged pale ring in A. annulatus; larger, irregularly shaped ocelli with pale centres surrounded by a dark brown rim in A. ocellatus).
Ensemble Sensitivity Analysis for Mesoscale Forecasts of Dryline Convection Initiation
Authors: Hill Aaron J. , Weiss Christopher C. , Ancell Brian C. 
Published: July 2016

AbstractTwo cases of dryline convection initiation (CI) over north Texas have been simulated (3 April 2012 and 15 May 2013) from a 50-member WRF-DART ensemble adjustment Kalman filter (EAKF) ensemble. In this study, ensemble sensitivity analysis (ESA) is applied to a convective forecast metric, maximum composite reflectivity (referred to as the response function), as a simple proxy for CI to analyze dynamic mesoscale sensitivities at the surface and aloft. Analysis reveals positional and magnitude sensitivities related to the strength and placement of important dynamic features. Convection initiation is sensitive to the evolving temperature and dewpoint fields upstream of the forecast response region in the near-CI time frame (0–12 h), prior to initiation. The sensitivity to thermodynamics is also manifest in the magnitude of dewpoint gradients along the dryline that triggers the convection. ESA additionally highlights the importance of antecedent precipitation and cold pool generation that modifies the pre-CI environment. Aloft, sensitivity of CI to a weak short-wave trough and capping inversion-level temperature is coherent, consistent, and traceable through the entire forecast period. Notwithstanding the (often) non-Gaussian distribution of ensemble member forecasts of convection, which violate the underpinnings of ESA theory, ESA is demonstrated to sufficiently identify regions that influence dryline CI. These results indicate an application of ESA for severe storm forecasting at operational centers and forecast offices as well as other mesoscale forecasting applications.
Repetitive Stresses Generate Osteochondral Lesions in Skeletally Immature Rabbits
Authors: Stone Austin V. , Little Kevin J. , Glos David L. , Stringer Keith F. , Wall Eric J. 
Published: July 2016

Background: The origin of juvenile osteochondritis dissecans (OCD) is unknown. Existing experimental animal models of OCD most frequently involve surgically created lesions but do not examine repetitive stress as a possible cause of OCD. Hypothesis: Repetitive stresses can cause OCD-like lesions in immature animals. Study Design: Controlled laboratory study. Methods: Six juvenile rabbits were subjected to repetitive loading forces of approximately 160% body weight to the right hindlimb during five 45-minute sessions per week for 5 weeks. The contralateral limb was the unloaded control. After 5 weeks, rabbits were euthanized and examined with radiographs, micro–computed tomography, and gross and histopathologic analysis. Results: All 6 rabbits developed osteochondral lesions in loaded limbs on the medial and lateral femoral condyles, while contralateral unloaded limbs did not demonstrate lesions. Loaded limbs developed relative osteopenia in the femoral epiphysis and tibial metaphysis with associated decreased trabecular density. Loaded limbs also demonstrated increased femoral subchondral bone thickness near the lesions. Lesions did not have grossly apparent extensive articular cartilage damage; however, cartilage thickness increased on histology with reduced ossification. Loaded knees demonstrated abundant chondrocyte cloning, limited cartilage fissuring, and a focal loss of cellularity at the articular surface. Conclusion: Low-grade lesions in human OCD have little gross articular cartilage involvement despite substantial changes to the subchondral bone as shown on magnetic resonance imaging and radiographs. Histopathology findings in this study included cartilage thickening and chondrocyte cloning resembling those of recently published human OCD biopsy studies. Our animal model supports the hypothesis that repetitive stress to immature knees may contribute to the development of human OCD. This model may be useful in understanding the pathophysiology and healing of human OCD. Clinical Relevance: Repetitive physiologic stress generated changes to the subchondral bone in immature animals without causing extensive articular damage. The similarities of these lesions in gross and histologic appearance with human OCD support repetitive stress as the likely the cause for human OCD.
Meta-analysis of the Interval between the Onset and Management of Bipolar Disorder
Authors: Dagani Jessica , Signorini Giulia , Nielssen Olav , Bani Moira , Pastore Adriana , Girolamo Giovanni de , Large Matthew 
Published: July 2016

Objective: To evaluate the length of the interval between the onset and the initial management of bipolar disorder (BD). Method: We conducted a meta-analysis using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Systematic searches located studies reporting estimates of the age of onset (AOO) and indicators of the age at initial management of BD. We calculated a pooled estimate of the interval between AOO and age at management. Factors influencing between-study heterogeneity were investigated using sensitivity analyses, meta-regression, and multiple meta-regression. Results: Twenty-seven studies, reporting 51 samples and a total of 9415 patients, met the inclusion criteria. The pooled estimate for the interval between the onset of BD and its management was 5.8 years (standardized difference, .53; 95% confidence interval, .45 to .62). There was very high between-sample heterogeneity ( I2 = 92.6; Q = 672). A longer interval was found in studies that defined the onset according to the first episode (compared to onset of symptoms or illness) and defined management as age at diagnosis (rather than first treatment or first hospitalization). A longer interval was reported among more recently published studies, among studies that used a systematic method to establish the chronology of illness, among studies with a smaller proportion of bipolar I patients, and among studies with an earlier mean AOO. Conclusions: There is currently little consistency in the way researchers report the AOO and initial management of BD. However, the large interval between onset and management of BD presents an opportunity for earlier intervention.
Serum paraoxonase activity and oxidative stress levels in patients with cutaneous anthrax
Authors: Karadas S , Aslan M , Ceylan MR , Sunnetcioglu M , Bozan N , Kara H , Demir H 
Published: July 2016

Introduction: Anthrax is a bacterial disease caused by the aerobic sporeforming bacterium Bacillus anthracis. It has been suggested that oxidative stress plays an important role in the pathogenesis of B. anthracis. The aim of this study was to investigate serum paraoxonase 1 (PON1) activity, catalase activity, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) levels in patients with cutaneous anthrax. Materials and methods: Fifteen patients with cutaneous anthrax and 15 healthy controls were enrolled in this study. The serum MDA levels, SOD levels, paraoxonase, arylesterase, and catalase activities were measured using a spectrophotometer. Results: The serum SOD levels, paraoxonase, arylesterase, and catalase activities were significantly lower in patients with cutaneous anthrax than in controls (for all, p < 0.001), whereas MDA levels were significantly higher ( p < 0.001). No significant correlation was found between serum paraoxonase activity, arylesterase activity, SOD levels, and MDA levels (all, p > 0.05) in patients with cutaneous anthrax. Conclusions: The current study was the first to show decreased antioxidant levels and increased oxidant levels in patients with cutaneous anthrax. Therefore, decreased PON1 activity may play a role in the pathogenesis of cutaneous anthrax.
Accurate Measurement of First Metatarsophalangeal Range of Motion in Patients With Hallux Rigidus
Authors: Vulcano Ettore , Tracey Joseph A. , Myerson Mark S. 
Published: July 2016

Background: The reliability of range of motion (ROM) measurements has not been established for the hallux metatarsophalangeal (MTP) joint in patients with hallux rigidus. The aim of the present study was to prospectively assess the clinical versus radiographic difference in ROM of the arthritic hallux MTP joint. Method: One hundred consecutive patients who presented with any grade of hallux rigidus were included in this prospective study to determine the hallux MTP range of motion. Clinical range of motion using a goniometer and radiographic range of motion on dynamic x-rays was recorded. Results: The mean difference between clinical and radiographic dorsiflexion was 13 degrees ( P < .001). For all measurements, clinical dorsiflexion was equal to or less than radiographically measured dorsiflexion. The difference was significantly greater in patients with a clinical dorsiflexion of less than 30 degrees than in patients with 30 degrees or more. Radiographic measurement of hallux dorsiflexion had an excellent intra- and interobserver reliability. Conclusion: We describe a reliable, reproducible, and straightforward method of measuring hallux MTP ROM that improved upon measuring clinical ROM. Level of Evidence: Level II, prospective comparative study.
Muscle and Joint Factors Associated With Forefoot Deformity in the Diabetic Neuropathic Foot
Authors: Cheuy Victor A. , Hastings Mary K. , Commean Paul K. , Mueller Michael J. 
Published: July 2016

Background: Diabetic forefoot joint deformities are a known risk factor for skin breakdown and amputation, but the causes of deformity are not well understood. The purposes of this study were to determine the effects of intrinsic foot muscle deterioration and limited ankle joint mobility on the severity of metatarsophalangeal joint (MTPJ) deformity, and determine the relationships between these potential contributing factors and indicators of diabetic complications (peripheral neuropathy and advanced glycation end products). Methods: A total of 34 participants with diabetic neuropathy (average age, 59 years; range 41-73) were studied. MTPJ angle and intrinsic foot muscle deterioration were measured with computed tomography and magnetic resonance imaging, respectively. Maximum ankle dorsiflexion was measured using kinematics. Skin intrinsic fluorescence served as a proxy measure for advanced glycation end product accumulation. Results: Total forefoot lean muscle volume ( r = −0.52, P < .01) and maximum ankle dorsiflexion ( r = −0.42, P < .05) were correlated with severity of MTPJ deformity. Together they explained 35% of the variance of MTPJ angle. Neuropathy was correlated with forefoot muscle deterioration ( ρ = 0.53, P < .01). Skin intrinsic fluorescence was correlated to severity of neuropathy ( r = 0.50, P < .01) but not maximum ankle dorsiflexion, or forefoot deterioration when controlling for neuropathy. Conclusion: These results suggest that the interplay of intrinsic foot muscle deterioration and limited ankle mobility may be the primary contributor to the development of MTPJ deformity. Identifying these muscle and ankle motion impairments as risk factors for MTPJ deformity supports the need for targeted interventions early in the disease process to slow, or possibly stop the progression of deformity over time and reduce the risk of amputation. Level of Evidence: Level IV, case series.
The patient’s perspective: How to create awareness for improving access to care and treatment of MS patients?
Authors: Vermersch Patrick , Faller Andreas , Czarnota-Szałkowska Dominika , Meesen Bianca , Thalheim Christoph 
Published: July 2016

Background: There is currently no known cure for multiple sclerosis (MS). Four stakeholders play a major role in MS: healthcare professionals, regulators, payers and patients. Objective: In Europe, patients are represented by the European Multiple Sclerosis Platform (EMSP), which aims to improve MS management and patients’ quality of life. Results: The EMSP has recently shown that there are major disparities in Europe in terms of access to care and treatment. Implementing the Code of Good Practice and a standardised MS nurse training may be useful in harmonising MS management across Europe. Additionally, the burden for novel therapeutic options to be approved by regulatory agencies has to decrease in order to provide faster access of treatment to patients. Data collection (e.g. national registers) also appears crucial to help research and shape the most effective policy in each country. Finally, people with MS should get appropriate (financial) support in order to complete their studies and find a job, as their active participation in society requires proper access to education and employment. Moreover, as they are the ones affected by MS, they seem to be best placed to represent themselves and their needs and should be consulted more often during decision-making processes by policy makers, regulators and payers.
The payer’s perspective: What is the burden of MS and how should the patient’s perspective be integrated in health technology assessment conducted for taking decisions on access to care and treatment?
Authors: Gold Ralf , Toumi Mondher , Meesen Bianca , Fogarty Emer 
Published: July 2016

Background: In Europe, there exists considerable variability in access to care and treatment for multiple sclerosis (MS). Objectives: To improve this situation, we identified key issues payers should take into account when making decisions on access to care and treatment for MS. We also give an overview of the different dimensions determining total MS burden and discuss why it is key to integrate the patient’s perspective in estimating this burden. Results: The total burden of MS relates to three dimensions: clinical, humanistic and economic. Although the clinical burden is extensively studied, crucial information is still missing about MS pathophysiology, how MS-related symptoms will develop during the disease course and which patients will progress more rapidly. With regard to the humanistic burden, information on patient-reported quality of life systematically collected in clinical trials for registration purposes is still scarce. Early engagement between pharmaceutical companies, the European Medicines Agency and health technology agencies to prospectively identify key evidence needs for the regulatory and reimbursement processes is required as a first step towards more equal access to care and treatment in MS in Europe. Patients’ expectations regarding treatment outcomes should be better researched and integrated into decision-making and patients should be counselled in this process.