bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of fibrosis changes in chronic hepatitis C patients after virological cure: A systematic review with meta‐analysis
Authors: Liu Zhipeng , Wei Xuewu , Chen Ting , Huang Chuhong , Liu Haiyan , Wang Yan 
Published: August 2016

AbstractBackground and AimVirological cure becomes available for most patients with chronic hepatitis C (CHC), but residual fibrosis can be an independent risk factor for liver‐related complications. We aimed to characterize fibrosis change in CHC patients achieved virological cure.MethodsWe did a systematic literature search for studies that had pre and post‐treatment evaluations of histologic fibrosis in CHC patients with sustained virological response (SVR). We identified the association of SVR with the incidence, extent, and velocity of fibrosis change.ResultsOverall, 3243 patients were included. Interferon‐based regimens were used for all the patients, achieving a median SVR prevalence of 36.2%. Biopsy interval ranged from 1 to 10 years. Mean baseline fibrosis score (METAVIR) was 2.3 points. Compared with non‐SVR patients, SVR patients could have higher incidence of fibrosis regression (35.1% vs 17.0%; OR: 3.3; P < 0.001), regardless of baseline fibrosis severity, way of biopsy evaluation, treatment regimen, or study design, and could have more extent of reduction (−0.31 points vs −0.00 points; P = 0.004). Baseline advanced fibrosis (F > 2) was associated with more rapid regression in both SVR and non‐SVR patients (P < 0.05 for both). SVR patients could have lower incidence of fibrosis progression and maintenance than non‐SVR patients by 4.8% versus 23.1% (OR: 0.20; P = 0.008) and 42.9% versus 55.2% (OR: 0.53; P < 0.001), respectively.ConclusionsThere could be a favorable characteristic of fibrosis regression in SVR patients. However, residential fibrosis may remain an issue because of a non‐ignorable prevalence of fibrosis maintenance among these patients.
Evaluation of transient elastography in assessing liver fibrosis in patients with autoimmune hepatitis
Authors: Xu Qinyu , Sheng Li , Bao Han , Chen Xiaoyu , Guo Canjie , Li Hai , Ma Xiong , Qiu Dekai , Hua Jing 
Published: August 2016

AbstractBackground and AimTransient elastography (TE) can reliably stage liver fibrosis via liver stiffness measurement (LSM) in chronic liver disease. However, the accuracy of TE for assessment of liver fibrosis in patients with autoimmune hepatitis (AIH) is still limited. We evaluate TE in staging liver fibrosis in AIH patients and compare with other noninvasive diagnostic tools.MethodsA total of 100 patients with biopsy‐proven AIH were included. The correlation between LSM and fibrosis stage was analyzed using Spearman correlation test. The optimal cut‐off values of LSM were calculated for predicting individual fibrosis stages using receiver‐operating characteristic curve. The diagnostic accuracy of LSM for severe fibrosis was compared with those of serum biochemical scores.ResultsMedian LSM in AIH patients was higher than that of healthy controls (11.2 ± 8.2 kPa vs 4.3 ± 1.4 kPa, P < 0.01). LSM had significant correlation with fibrosis (r = 0.752, P < 0.01) and increased progressively with increasing fibrosis stages in AIH patients. AUROC values of LSM for stages F ≥ 2, F ≥ 3, and F4 were 0.878 (95%CI: 0.789–0.967), 0.883 (0.820–0.946), and 0.914 (0.852–0.976), respectively. The optimal cut‐off values of LSM for fibrosis stages F ≥ 2, F ≥ 3, and F4 were 6.45, 8.75, and 12.50 kPa, respectively. LSM was superior to APRI score and FIB‐4 score in detecting severe fibrosis (F ≥ 3). Serum ALT levels had minor effect on LSM values.ConclusionsTransient elastography is an accurate and reliable noninvasive tool in assessing liver fibrosis in AIH. Hepatic inflammatory activity had no significant effect on LSM determination.
Randomized clinical trial comparing 10‐ or 14‐day sequential therapy and 10‐ or 14‐day concomitant therapy for the first line empirical treatment of Helicobacter pylori infection
Authors: Park Sung Min , Kim Joon Sung , Kim Byung‐Wook , Ji Jeong‐Seon , Choi Hwang 
Published: August 2016

AbstractBackground and AimWhether concomitant therapy is superior to sequential therapy (ST) as first‐line therapy of Helicobacter pylori in areas with high clarithromycin resistance remains controversial. The aim of this study was to compare the efficacy and tolerability of 10‐ or 14‐day ST with 10‐ or 14‐day concomitant therapy (CT).MethodsThis was a prospective randomized study comparing 10‐ or 14‐day ST with 10‐ or 14‐day CT. The ST‐10 and ST‐14 groups received pantoprazole 40 mg and amoxicillin 1 g twice a day for the first 5 and 7 days followed by pantoprazole 40 mg, clarithromycin 500 mg, and metronidazole 500 mg twice a day for the remaining 5 and 7 days, respectively. The CT‐10 and CT‐14 groups received pantoprazole 40 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg twice daily for 10 and 14 days, respectively.ResultsThree hundred forty‐one patients were randomly allocated to the four groups. The modified intention‐to‐treat eradication rates of ST‐10, ST‐14, CT‐10, and CT‐14 were 91.7%, 91.2%, 94.2%, and 98.5%, respectively. The corresponding per protocol eradication rates were 91.4%, 91.0%, 95.6%, and 98.5%. There was no difference in compliance and adverse events in the four groups. Eradication rates increased sequentially with statistical significance in the following order: ST‐10, ST‐14, CT‐10, and CT‐14 (P = 0.044).ConclusionsAll four regimens achieved eradication rates >90% in per protocol analyses in a country with high clarithromycin resistance. There was no difference in tolerability among the four regimens.
Frontotemporal dementia: from molecular mechanisms to therapy
Authors: Haass Christian , Neumann Manuela 
Published: August 2016

Frontotemporal dementia (FTD) is a heterogeneous clinical syndrome characterized by frontotemporal lobar degeneration (FTLD). Neuropathologically, FTLD is characterized by abnormal protein deposits and almost all cases can now be classified into three major molecular subgroups based on specific accumulating proteins with the most common being FTLD‐tau and FTLD‐TDP (accounting for ~40% and 50%, respectively) and FTLD‐FET (accounting for ~5–10%). In this special issue, the molecular and genetic basics as well as clinical approaches and therapeutics are reviewed in a series of articles.
image
This article is part of the Frontotemporal Dementia special issue.
A Review of Factors Influencing Maturation of Atlantic Salmon, Salmo salar, with Focus on Water Recirculation Aquaculture System Environments
Authors: Good Christopher , Davidson John 
Published: August 2016

AbstractSexual maturation of Atlantic salmon, Salmo salar, is a complex process, with many variables having the capacity to influence the timing and prevalence of maturation and acting as promoters and/or inhibitors of sexual development. Precocious maturation has the capacity to seriously impact production in commercial aquaculture settings, and in response there has been a significant amount of research devoted to understanding this issue in order to develop remedial strategies. Very little research has been conducted specifically examining salmon maturation in land‐based, closed containment water recirculation aquaculture systems, which have recently received attention as an alternative technology for the sustainable production of market‐size Atlantic salmon. Unfortunately, the nascent closed containment salmon industry has thus far experienced high levels of precocious maturation, for reasons that are presently unclear. Given the economic challenges facing the closed containment industry's expansion, it is imperative that best management practices be developed to reduce economic losses from early maturation, in order to assist the sustainable growth of farmed Atlantic salmon production. This review provides a brief summary of published research on factors associated with early salmonid maturation, as well as information from research examining maturation and growout performance of Atlantic salmon in closed containment aquaculture systems.
Initiation time of renal replacement therapy on patients with acute kidney injury: A systematic review and meta‐analysis of 8179 participants
Authors: Wang Caixia , Lv Lin‐Sheng , Huang Hui , Guan Jianqiang , Ye Zengchun , Li Shaomin , Wang Yanni , Lou Tanqi , Liu Xun 
Published: August 2016

AbstractThe early initiation of renal replacement therapy has been recommended for patients with acute renal failure by some studies, but its effects on mortality and renal recovery are unknown. We conducted an updated meta‐analysis to provide quantitative evaluations of the association between the early initiation of renal replacement therapy and mortality for patients with acute kidney injury. After applying inclusion/exclusion criteria, 51 studies, including 10 randomized controlled trials, with a total of 8179 patients were analyzed. Analysis of the included trials showed that patients receiving early renal replacement therapy had a 25% reduction in all‐cause mortality compared to those receiving late renal replacement therapy (risk ratio [RR] 0.75, 95% CI [0.69, 0.82]). We also noted a 30% increase in renal recovery (RR 1.30, 95% CI [1.07, 1.56]), a reduction in hospitalization of 5.84 days (mean difference [MD], 95% CI [–10.27, –1.41]) and a reduction in the duration of mechanical ventilation of 2.33 days (MD, 95% CI [–3.40, –1.26]) in patients assigned to early renal replacement therapy. The early initiation of renal replacement therapy was associated with a decreased risk of all‐cause mortality compared with the late initiation of RRT in patients with acute kidney injury. These findings should be interpreted with caution given the heterogeneity between studies. Further studies are needed to identify the causes of mortality and to assess whether mortality differs by dialysis dose.
Technical Note: Development of a 3D printed subresolution sandwich phantom for validation of brain SPECT analysis
Authors: Negus Ian S. , Holmes Robin B. , Jordan Kirsty C. , Nash David A. , Thorne Gareth C. , Saunders Margaret 
Published: August 2016

Purpose:To make an adaptable, head shaped radionuclide phantom to simulate molecular imaging of the brain using clinical acquisition and reconstruction protocols. This will allow the characterization and correction of scanner characteristics, and improve the accuracy of clinical image analysis, including the application of databases of normal subjects.Methods:A fused deposition modeling 3D printer was used to create a head shaped phantom made up of transaxial slabs, derived from a simulated MRI dataset. The attenuation of the printed polylactide (PLA), measured by means of the Hounsfield unit on CT scanning, was set to match that of the brain by adjusting the proportion of plastic filament and air (fill ratio). Transmission measurements were made to verify the attenuation of the printed slabs. The radionuclide distribution within the phantom was created by adding 99mTc pertechnetate to the ink cartridge of a paper printer and printing images of gray and white matter anatomy, segmented from the same MRI data. The complete subresolution sandwich phantom was assembled from alternate 3D printed slabs and radioactive paper sheets, and then imaged on a dual headed gamma camera to simulate an HMPAO SPECT scan.Results:Reconstructions of phantom scans successfully used automated ellipse fitting to apply attenuation correction. This removed the variability inherent in manual application of attenuation correction and registration inherent in existing cylindrical phantom designs. The resulting images were assessed visually and by count profiles and found to be similar to those from an existing elliptical PMMA phantom.Conclusions:The authors have demonstrated the ability to create physically realistic HMPAO SPECT simulations using a novel head‐shaped 3D printed subresolution sandwich method phantom. The phantom can be used to validate all neurological SPECT imaging applications. A simple modification of the phantom design to use thinner slabs would make it suitable for use in PET.
Preclinical Profile and Clinical Efficacy of a Novel Hepatitis C Virus NS5A Inhibitor, EDP-239
Authors: Owens Christopher M. , Brasher Bradley B. , Polemeropoulos Alex , Rhodin Michael H. J. , McAllister Nicole , Peng Xiaowen , Wang Ce , Ying Lu , Cao Hui , Lawitz Eric , Poordad Fred , Rondon Juan , Box Terry D. , Zeuzem Stefan , Buggisch Peter , Lin Kai , Qiu Yao-Ling , Jiang Lijuan , Colvin Richard , Or Yat Sun 
Published: August 2016

ABSTRACT

EDP-239, a novel hepatitis C virus (HCV) inhibitor targeting nonstructural protein 5A (NS5A), has been investigated
in vitro
and
in vivo
. EDP-239 is a potent, selective inhibitor with potency at picomolar to nanomolar concentrations against HCV genotypes 1 through 6. In the presence of human serum, the potency of EDP-239 was reduced by less than 4-fold. EDP-239 is additive to synergistic with other direct-acting antivirals (DAAs) or host-targeted antivirals (HTAs) in blocking HCV replication and suppresses the selection of resistance
in vitro
. Furthermore, EDP-239 retains potency against known DAA- or HTA-resistant variants, with half-maximal effective concentrations (EC
50
s) equivalent to those for the wild type. In a phase I, single-ascending-dose, placebo-controlled clinical trial, EDP-239 demonstrated excellent pharmacokinetic properties that supported once daily dosing. A single 100-mg dose of EDP-239 resulted in reductions in HCV genotype 1a viral RNA of >3 log
10
IU/ml within the first 48 h after dosing and reductions in genotype 1b viral RNA of >4-log
10
IU/ml within 96 h. (This study has been registered at ClinicalTrials.gov under identifier NCT01856426.)
The interglacial of the Nar Valley, Norfolk
Authors: Stevens Leonora Ann 
Published: August 2016

Summary
The geology and palaeobotany of the Pleistocene deposits in the Nar Valley, Norfolk, have been investigated. A low till is overlain by interglacial sediments consisting of lacustrine beds underlying an estuarine clay. These are covered by an upper till and glacial gravel.
The pollen analysis of the lacustrine sediments shows an early phase of park-tundra and then, due to an amelioration in the climate, the expansion of the mixed oak forest suggesting that the climate was at least as warm as at the present day. The pollen in the estuarine clay traces the decline of this forest and the increase in coniferous trees, indicating that the marine transgression took place after the climatic optimum.
The tills are defined and correlated with others in East Anglia by a comparison of the texture, erratics and the preferred orientation of the stones. The Jurassic erratics and the westerly preferred orientation of the stones indicate that the lower till was deposited during the Lowestoft Advance, while the upper till has a N.-S. preferred orientation comparable to the Gipping Advance.
This correlation of the tills indicates that the Nar Valley interglacial sediments are in a stratigraphical position similar to that of the Hoxne interglacial beds. The similarities between the vegetational successions of these two deposits is further evidence that the Nar Valley interglacial beds are of Great (Hoxnian, Elster/Saale) Interglacial age.
Both the pollen diagrams and the marine faunas of the Nar Valley and Clacton estuarine clays are very similar. These deposits, however, occur at different heights above sea level, and this is attributed to some relative vertical movement since their deposition.
Inhibiting Mitochondrial DNA Ligase IIIα Activates Caspase 1–Dependent Apoptosis in Cancer Cells
Authors: Sallmyr Annahita , Matsumoto Yoshihiro , Roginskaya Vera , Van Houten Bennett , Tomkinson Alan E. 
Published: August 2016

Abstract
Elevated levels of DNA ligase IIIα (LigIIIα) have been identified as a biomarker of an alteration in DNA repair in cancer cells that confers hypersensitivity to a LigIIIα inhibitor, L67, in combination with a poly (ADP-ribose) polymerase inhibitor. Because LigIIIα functions in the nucleus and mitochondria, we examined the effect of L67 on these organelles. Here, we show that, although the DNA ligase inhibitor selectively targets mitochondria, cancer and nonmalignant cells respond differently to disruption of mitochondrial DNA metabolism. Inhibition of mitochondrial LigIIIα in cancer cells resulted in abnormal mitochondrial morphology, reduced levels of mitochondrial DNA, and increased levels of mitochondrially generated reactive oxygen species that caused nuclear DNA damage. In contrast, these effects did not occur in nonmalignant cells. Furthermore, inhibition of mitochondrial LigIIIα activated a caspase 1–dependent apoptotic pathway, which is known to be part of inflammatory responses induced by pathogenic microorganisms in cancer, but not nonmalignant cells. These results demonstrate that the disruption of mitochondrial DNA metabolism elicits different responses in nonmalignant and cancer cells and suggests that the abnormal response in cancer cells may be exploited in the development of novel therapeutic strategies that selectively target cancer cells. Cancer Res; 76(18); 5431–41. ©2016 AACR.
Assessing Immune-Related Adverse Events of Efficacious Combination Immunotherapies in Preclinical Models of Cancer
Authors: Liu Jing , Blake Stephen J. , Harjunpää Heidi , Fairfax Kirsten A. , Yong Michelle C.R. , Allen Stacey , Kohrt Holbrook E. , Takeda Kazuyoshi , Smyth Mark J. , Teng Michele W.L. 
Published: August 2016

Abstract
New combination immunotherapies are displaying both efficacy and immune-related adverse events (irAE) in humans. However, grade 3/4 irAEs occur in a high proportion, which can lead to discontinuation of treatment and can result in fatalities if not promptly treated. Prolonged T regulatory cell (Treg) depletion in tumor-bearing Foxp3-DTR mice using diphtheria toxin (DT) mirrored the spectrum of antitumor responses and severity of irAEs that can occur in ipilimumab/nivolumab-treated patients. In contrast, transient Treg depletion or anti-CTLA-4/PD-1 therapy had equivalent effects in mice, lowering the immune tolerance threshold and allowing irAEs to be more easily induced following treatment with additional immunomodulatory antibodies. Transient Treg depletion of DT in combination with anti-PD-1 or anti-TIM-3 monoclonal antibodies had a high therapeutic window compared with DT plus anti-CD137. In contrast, DT plus anti-CD137–treated mice developed severe irAEs similar to grade 3/4 clinical symptoms. These irAEs appeared because of an infiltration of activated proliferating effector T cells in the tissues producing IFNγ and TNF; however, TNF blockade decreased irAEs severity without impacting on tumor growth. Cancer Res; 76(18); 5288–301. ©2016 AACR.
Tissue Stiffness and Hypoxia Modulate the Integrin-Linked Kinase ILK to Control Breast Cancer Stem-like Cells
Authors: Pang Mei-Fong , Siedlik Michael J. , Han Siyang , Stallings-Mann Melody , Radisky Derek C. , Nelson Celeste M. 
Published: August 2016

Abstract
Breast tumors are stiffer and more hypoxic than nonmalignant breast tissue. Here we report that stiff and hypoxic microenvironments promote the development of breast cancer stem-like cells (CSC) through modulation of the integrin-linked kinase ILK. Depleting ILK blocked stiffness and hypoxia-dependent acquisition of CSC marker expression and behavior, whereas ectopic expression of ILK stimulated CSC development under softer or normoxic conditions. Stiff microenvironments also promoted tumor formation and metastasis in ovo, where depleting ILK significantly abrogated the tumorigenic and metastatic potential of invasive breast cancer cells. We further found that the ILK-mediated phenotypes induced by stiff and hypoxic microenvironments are regulated by PI3K/Akt. Analysis of human breast cancer specimens revealed an association between substratum stiffness, ILK, and CSC markers, insofar as ILK and CD44 were expressed in cancer cells located in tumor regions predicted to be stiff. Our results define ILK as a key mechanotransducer in modulating breast CSC development in response to tissue mechanics and oxygen tension. Cancer Res; 76(18); 5277–87. ©2016 AACR.
Prognostic Value of the Change in Heart Rate From the Supine to the Upright Position in Patients With Chronic Heart Failure
Authors: Maeder Micha T. , Zurek Marzena , Rickli Hans , Tobler Daniel , Kiencke Stephanie , Suter Thomas , Yoon Se‐Il , Julius Barbara , Pfisterer Matthias E. , Brunner‐La Rocca Hans‐Peter ,   for the TIME‐CHF Investigators
Published: August 2016

Background

The prognostic value of the change in heart rate from the supine to upright position (∆
HR
) in patients with chronic heart failure (
HF
) is unknown.

Methods and Results

∆
HR
was measured in patients enrolled in the Trial of Intensified Medical Therapy in Elderly Patients with Congestive Heart Failure (
TIME
‐
CHF
) who were in sinus rhythm and had no pacemaker throughout the trial (n=321). The impact of ∆
HR
on 18‐month outcome (
HF
hospitalization‐free survival) was assessed. In addition, the prognostic effect of changes in ∆
HR
between baseline and month 6 on outcomes in the following 12 months was determined. A lower ∆
HR
was associated with a higher risk of death or
HF
hospitalization (hazard ratio 1.79 [95% confidence interval {95%
CI
} 1.19‐2.75] if ∆
HR
≤3 beats/min [bpm],
P
=0.004). In the multivariate analysis, lower ∆
HR
remained an independent predictor of death or
HF
hospitalization (hazard ratio 1.75 [95%
CI
, 1.18‐2.61] if ∆
HR
≤3 bpm,
P
=0.004) along with ischemic
HF
etiology, lower estimated glomerular filtration rate, presence and extent of rales, and no baseline β‐blocker use. In patients without event during the first 6 months, the change in ∆
HR
from baseline to month 6 predicted death or
HF
hospitalization during the following 12 months (hazard ratio=2.13 [95%
CI
1.12–5.00] if rise in ∆
HR
<2 bpm;
P
=0.027).

Conclusions

∆
HR
as a simple bedside test is an independent prognostic predictor in patients with chronic
HF
. ∆
HR
is modifiable, and changes in ∆
HR
also provide prognostic information, which raises the possibility that ∆
HR
may help to guide treatment.

Clinical Trial Registration Information

URL
:
www.isrctn.org
. Unique identifier:
ISRCTN
43596477.
Should the United States Reject MAD? Damage Limitation and U.S. Nuclear Strategy toward China
Authors: Glaser Charles L. , Fetter Steve 
Published: August 2016

Abstract
As China invests in its nuclear forces and U.S.-China relations become increasingly strained, questions of U.S. nuclear doctrine require greater attention. The key strategic nuclear question facing the United States is whether to attempt to maintain and enhance its damage-limitation capability against China. The answer is less straightforward than it was during the Cold War, because China's nuclear force is orders of magnitude smaller than the Soviet force was. Part of the answer depends on the military-technical feasibility of the United States achieving a significant damage-limitation capability: What would be the outcome of military competition over the survivability of China's intercontinental ballistic missiles, submarine-launched ballistic missiles, and command and control, and over the effectiveness of U.S. ballistic missile defenses? The answer also depends on the benefits that a damage-limitation capability would provide; these could include contributions to homeland deterrence, extended deterrence, and reassurance of U.S. regional allies. The final piece of the analysis concerns the potential costs of a damage-limitation capability, which could include increased escalatory pressures during crises and growing political tension between the United States and China. A thorough analysis demonstrates that the United States should forgo such a capability because the prospects for preserving a significant damage-limitation capability are poor; the deterrent benefits would be small; and the escalatory and political costs would be relatively large.