bluuebunny/crossref_metadata_2025 huggingface dataset:
Dual-Modality Imaging Probes with High Magnetic Relaxivity and Near-Infrared Fluorescence Based Highly Aminated Mesoporous Silica Nanoparticles
Authors: Fei-Peng Zhu , Guo-Tao Chen , Shou-Ju Wang , Ying Liu , Yu-Xia Tang , Ying Tian , Jian-Dong Wang , Chun-Yan Wang , Xin Wang , Jing Sun , Zhao-Gang Teng , Guang-Ming Lu
Published: May 2016

Dual-modal imaging by combining magnetic resonance (MR) and near-infrared (NIR) fluorescence can integrate the advantages of high-resolution anatomical imaging with high sensitivity in vivo fluorescent imaging, which is expected to play a significant role in biomedical researches. Here we report a dual-modality imaging probe (NIR/MR-MSNs) fabricated by conjugating NIR fluorescent heptamethine dyes (IR-808) and MR contrast agents (Gd-DTPA) within highly aminated mesoporous silica nanoparticles (MSNs-NH2). The dual-modality imaging probes NIR/MR-MSNs possess a size of ca. 120 nm. The NIR/MR-MSNs show not only near-infrared fluorescence imaging property with an emission peak at 794 nm, but also highly MRT1relaxivity of 14.54 mM−1 s−1, which is three times more than Gd-DTPA. In vitro experiment reveals high uptake and retention abilities of the nanoprobes, while cell viability assay demonstrates excellent cytocompatibility of the dual-modality imaging probe. After intratumor injection with the NIR/MR-MSNs, MR imaging shows clear anatomical border of the enhanced tumor region while NIR fluorescence exhibits high sensitive tumor detection ability. These intriguing features suggest that this newly developed dual-modality imaging probes have great potential in biomedical imaging.
Graphite Intended for Green Engineering Developed by Noncontaminant Reverse Abrasion
Authors: Baca Arroyo Roberto
Published: May 2016

Graphite intended for green engineering was synthesized by noncontaminant reverse abrasion, which consists of graphite layers assembled with thickness controlled on SiC sandpaper as insulating substrate. Phase formation of the graphite layers was validated by X-ray diffraction studies and its finished profile by Atomic Force Microscopy (AFM). Transport parameters of only three layers were evaluated from current-voltage curves. Mathematical functions such as derivative and modulation of a signal have been built by graphite circuits using different performance principles, compared to those used with silicon devices. The trends related to electronic engineering should be achieved with design of the graphite-based devices to facilitate their mass production in the near future.
Microblog Sentiment Orientation Detection Using User Interactive Relationship
Authors: Wang Liang , Wang Mei , Guo Xinying , Qin Xuebin
Published: May 2016

The development and popularity of microblog have made sentiment analysis of tweets and Weibo an important research field. However, the characteristics of microblog message pose challenge for the sentiment analysis and mining. The existing approaches mostly focus on the message content and context information. In this paper, we propose a novel microblog sentiment analysis framework by incorporating the social interactive relationship factor in the content-based approach. By exploring the interactive relationship on social network based on posted messages, we build social interactive model to represent the opposition or acceptation behavior. Based on the interactive relationship model, the sentiment of microblog message with sparse emotion terms can be deduced and identified, and the sentiment uncertainty can be alleviated to some extent. Afterwards, we transform the classification problem into an optimization problem. Experimental results on Weibo data set indicate that the proposed method can outperform the baseline methods.
Determination of Cefoperazone Sodium in Presence of Related Impurities by Improved Classical Least Squares Chemometric Methods: A Comparative Study
Authors: Naguib Ibrahim A. , Darwish Hany W.
Published: May 2016

A comparative study is established among 4 chemometric models depending on classical least squares (CLS) approach, namely, spectral residual augmented CLS (SRACLS), net analyte processing CLS (NAP-CLS), orthogonal signal correction CLS (OSC-CLS), and direct orthogonal signal correction CLS (DOSC-CLS). The comparison is expressed through analysis of a case study dataset of UV spectral data of Cefoperazone Sodium (CEF) and its two related impurities: in pure powder form and in pharmaceutical dosage form. Four-level three-factor experimental design was established for optimum analysis. The adopted experimental design gave rise to a training set consisting of 16 mixtures (containing different ratios of interfering species). To test the prediction power of the suggested models, an independent test set consisting of 9 mixtures was used. The presented results show the ability of the proposed models to quantify CEF in presence of two related impurities with high accuracy and selectivity (103.76±1.03,102.07±0.91,101.61±0.72, and101.60±0.72for SRACLS, NAP-CLS, OSC-CLS, and DOSC-CLS, resp.). Dosage form analysis results were compared statistically to a published HPLC methodology showing insignificant difference in terms of precision and accuracy, indicating the suggested models reliability and their suitability for quality control analysis of drug product. Compared to other models, OSC-CLS and DOSC-CLS models gave more accurate results with lower prediction error for test set samples.
The Use of Narrow Diameter Implants in the Molar Area
Authors: Saad M. , Assaf A. , Gerges E.
Published: May 2016

Implant rehabilitations in the posterior jaw are influenced by many factors such as the condition of the remaining teeth, the force factors related to the patient, the quality of the bone, the maintenance of the hygiene, the limited bone height, the type and extent of edentulism, and the nature of the opposing arch. The gold standard is to place a regular diameter implant (>3.7 mm) or a wide one to replace every missing molar. Unfortunately, due to horizontal bone resorption, this option is not possible without lateral bone augmentation. In this situation, narrow diameter implant (NDI < 3.5 mm) could be the alternative to lateral bone augmentation procedures. This paper presents a clinical study where NDIs were used for the replacement of missing molars. They were followed up to 11 years. Special considerations were observed and many parameters were evaluated. NDI could be used to replace missing molar in case of moderate horizontal bone resorption if strict guidelines are respected. Yet, future controlled prospective clinical trials are required to admit their use as scientific evidence.
Intelligent Prediction of Sieving Efficiency in Vibrating Screens
Authors: Zhang Bin , Gong Jinke , Yuan Wenhua , Fu Jun , Huang Yi
Published: May 2016

In order to effectively predict the sieving efficiency of a vibrating screen, experiments to investigate the sieving efficiency were carried out. Relation between sieving efficiency and other working parameters in a vibrating screen such as mesh aperture size, screen length, inclination angle, vibration amplitude, and vibration frequency was analyzed. Based on the experiments, least square support vector machine (LS-SVM) was established to predict the sieving efficiency, and adaptive genetic algorithm and cross-validation algorithm were used to optimize the parameters in LS-SVM. By the examination of testing points, the prediction performance of least square support vector machine is better than that of the existing formula and neural network, and its average relative error is only 4.2%.
TBCRC-010: Phase I/II Study of Dasatinib in Combination with Zoledronic Acid for the Treatment of Breast Cancer Bone Metastasis
Authors: Mitri Zahi , Nanda Rita , Blackwell Kimberly , Costelloe Colleen M. , Hood Ilona , Wei Caimiao , Brewster Abenaa M. , Ibrahim Nuhad K. , Koenig Kimberly B. , Hortobagyi Gabriel N. , Van Poznak Catherine , Rimawi Mothaffar F. , Moulder-Thompson Stacy
Published: May 2016

Purpose: Osteoclast-mediated bone resorption through src kinase releases growth factors, sustaining bone metastases. This trial determined the recommended phase II dose (RP2D) and clinical efficacy of the src kinase inhibitor dasatinib combined with zoledronic acid in bone predominant, HER2-negative breast cancer metastases.

Experimental Design: A 3+3 lead in phase I design confirmed the RP2D allowing activation of the single-arm, phase II trial. Zoledronic acid was administered intravenously on day 1, and dasatinib was given orally once daily for 28 days each cycle as twice daily administration caused dose-limiting toxicity (DLT). Response was assessed every three cycles. N-telopeptide (NTx) was serially measured.

Results: A total of 25 patients were enrolled. No DLTs were noted at the RP2D of dasatinib = 100 mg/d. Common adverse events were grade 1–2: rash (9/25, 36%), fatigue (9/25, 36%), pain (9/25, 36%), nausea (6/25, 20%). The objective response rate in bone was 5/22 (23%), all partial responses (PR). The clinical benefit rate [PRs + stable disease (SD) ≥ 6 months] in bone was 8/22 (36%). Median time to treatment failure was 2.70 months [95% confidence interval (CI), 1.84–5.72] in the general cohort, 3.65 months (95% CI, 1.97–7.33) in patients with hormone receptor (HR)-positive breast cancer and 0.70 months (95% CI, 0.30–NA) in those with HR-negative disease. Factors associated with response in bone included lower tumor grade, HR-positive status, and pretreatment high NTx levels.

Conclusions: Combination therapy was well tolerated and produced responses in bone in patients with HR-positive tumors. Clin Cancer Res; 22(23); 5706–12. ©2016 AACR.
Density, Distribution, and Composition of Immune Infiltrates Correlate with Survival in Merkel Cell Carcinoma
Authors: Feldmeyer Laurence , Hudgens Courtney W. , Ray-Lyons Genevieve , Nagarajan Priyadharsini , Aung Phyu P. , Curry Jonathan L. , Torres-Cabala Carlos A. , Mino Barbara , Rodriguez-Canales Jaime , Reuben Alexandre , Chen Pei-Ling , Ko Jennifer S. , Billings Steven D. , Bassett Roland L. , Wistuba Ignacio I. , Cooper Zachary A. , Prieto Victor G. , Wargo Jennifer A. , Tetzlaff Michael T.
Published: May 2016

Purpose: Merkel cell carcinoma (MCC) is an aggressive cancer with frequent metastasis and death with few effective therapies. Because programmed death ligand-1 (PD-L1) is frequently expressed in MCC, immune checkpoint blockade has been leveraged as treatment for metastatic disease. There is therefore a critical need to understand the relationships between MCPyV status, immune profiles, and patient outcomes.

Experimental Design: IHC for CD3, CD8, PD-1, PD-L1, and MCPyV T-antigen (to determine MCPyV status) was performed on 62 primary MCCs with annotated clinical outcomes. Automated image analysis quantified immune cell density (positive cells/mm2) at discrete geographic locations (tumor periphery, center, and hotspot). T-cell receptor sequencing (TCRseq) was performed in a subset of MCCs.

Results: No histopathologic variable associated with overall survival (OS) or disease-specific survival (DSS), whereas higher CD3+ (P = 0.004) and CD8+ (P = 0.037) T-cell density at the tumor periphery associated with improved OS. Higher CD8+ T-cell density at the tumor periphery associated with improved DSS (P = 0.049). Stratifying MCCs according to MCPyV status, higher CD3+ (P = 0.026) and CD8+ (P = 0.015) T-cell density at the tumor periphery associated with improved OS for MCPyV+ but not MCPyV− MCC. TCRseq revealed clonal overlap among MCPyV+ samples, suggesting an antigen-specific response against a unifying antigen.

Conclusions: These findings establish the tumor-associated immune infiltrate at the tumor periphery as a robust prognostic indicator in MCC and provide a mechanistic rationale to further examine whether the immune infiltrate at the tumor periphery is relevant as a biomarker for response in ongoing and future checkpoint inhibitor trials in MCC. Clin Cancer Res; 22(22); 5553–63. ©2016 AACR.
Chronic Hepatitis D; at a Standstill?
Authors: Rizzetto Mario
Published: May 2016

Chronic hepatitis D (CHD) is a severe liver disease with worldwide distribution caused by the hepatitis D virus (HDV). Therapy of CHD is at a standstill. It still relies on interferon (IFN), introduced empirically in the 1980s; results are limited. With the peghilated IFNs that are now in use, only 25% of CHD reach a sustained viral response, that is, clear the HDV-RNA 6 months after stopping therapy. However, HDV remains infectious and ready to reactivate at very low titers undetectable by current assays, if the HBsAg persists in serum; relapses of hepatitis D post-therapy are frequent and further diminish the therapeutic response. The major obstacle to CHD therapy is the minimalist nature of the HDV. It does not encode for any enzymatic function but is replicated by host RNA polymerases deceived to recognize the viral RNA as it were a cellular DNA; therefore, it has no replicative machinery of its own to be targeted by antivirals. The only help required from hepatitis B virus (HBV) is the HBsAg coat to attach to hepatocytes and assembly in the virion; HBV antivirals that decrease HBV-DNA but leave HBsAg unaffected are of no avail in CHD. Novel therapeutic strategies are under evaluation. Myrcludex B, a peptidic inhibitor of HBV entry, was used with some success in vitro in the mouse to block the Na+-tauro chocolate cotransporting polypeptide and prevent entry of the HD virion into hepatocytes. The nuclei acid polymer REP-2139 was shown to distinctly diminish serum HBsAg and HDV-RNA by blocking HBsAg entry and inhibiting its intracellular synthesis. Prenylation of the large HD-antigen is critical for its interaction with the HBsAg in the assembly of the virion. A proof of concept study in humans has shown that the prenylation inhibitor lonafarnib reduced HDV-viremia.
The Pathogenesis of Autoimmune Liver Disease
Authors: Arndtz Katherine , Hirschfield Gideon M.
Published: May 2016

Background: Autoimmune liver disease (AILD) encompasses 3 main distinct clinical diseases: autoimmune hepatitis, primary biliary cholangitis (formally known as cirrhosis, PBC) and primary sclerosing cholangitis (PSC). These conditions are an important, yet under-appreciated cause of patient morbidity and mortality with ongoing unmet needs for further research and clinical advances. Key Messages: There is observational evidence for genetic predisposition, with all 3 conditions being more common in first degree relatives. AILD is associated with the presence of auto-antibodies and higher risks of other non-hepatic auto-immune conditions. Genetic risk association studies have identified HLA and non-HLA risk loci for the development of disease, with some HLA loci providing prognostic information. This re-enforces the concept that genetic predisposition to autoimmunity is important, likely in the context of environmental exposures. Such environmental triggers are unclear but relevant risks include smoking, drug and xenobiotic exposure as well as the complexities of the microbiome. There is evidence for a loss of immune tolerance to self-antigens playing a part in the development of these conditions. In particular the IL-2 and IL-12 regulatory pathways have been implicated in pre-disposing to an unopposed inflammatory response within the liver. Main immunological themes revolve around loss of immune tolerance leading to T-cell mediated injury, imbalance in the regulation of immune cells and defective immune response to foreign antigens. For PBC and PSC, there is then the added complexity of the consequences of cholestasis on hepato-biliary injury, immune regulation and liver fibrosis. Conclusions: Whilst specific disease causes and triggers are still lacking, AILD arises on the background of collective genetic and environmental risk, leading to chronic and abnormal hepato-biliary immune responses. Effective and more rational therapy will ultimately be developed when the multiple pathways to liver injury are better understood.
Endovascular Management of Sigmoid Sinus Diverticulum
Authors: Paramasivam Srinivasan , Furtado Sunil , Shigamatsu Tomoyoshi , Smouha Eric
Published: May 2016

Sigmoid sinus diverticulum (SSD) is a rare vascular disorder due to dehiscence of the sigmoid plate. It may be associated with prediverticular venous sinus stenosis (SS) and usually presents as pulsatile tinnitus. The mechanism of development of the SSD and tinnitus from a sinus diverticulum and associated SS is unclear. Previous case reports have suggested that remodeling of the venous system targeting the stenosis, elimination of the diverticulum, or both, have resulted in symptom relief. We present a case of SSD with SS, treated by stenting of the stenosis along with coil embolization of the diverticulum, resulting in complete relief of symptoms. We have also reviewed the literature and discussed the evolution of management from open surgical treatment to endovascular treatment.
Pathogenesis and Management of Alcoholic Liver Disease
Authors: Farooq M. Omar , Bataller Ramon
Published: May 2016

Alcoholic liver disease (ALD) is a leading cause of liver-related morbidity and mortality. ALD encompasses a spectrum of disorders ranging from asymptomatic steatosis, alcoholic steatohepatitis, fibrosis, cirrhosis and its related complications. Moreover, patients can develop an acute-on-chronic form of liver failure called alcoholic hepatitis (AH). Most patients are diagnosed at advanced stages of the disease with higher rates of complications and mortality. The mainstream of therapy of ALD patients, regardless of the disease stage, is prolonged alcohol abstinence. The current therapeutic regimens for AH (i.e. prednisolone) have limited efficacy and targeted therapies are urgently needed. The development of such therapies requires translational studies in human samples and suitable animal models that reproduce clinical and histological features of AH. In recent years, new animal models that simulate some of the features of human AH have been developed, and translational studies using human samples have identified potential pathogenic factors and histological parameters that predict survival. In this review, we discuss the pathogenesis and management of ALD, focusing on AH, its current therapies and potential treatment targets.
Genetics in Common Liver Diseases: From Pathophysiology to Precise Treatment
Authors: Lammert Frank
Published: May 2016

In the past 2 decades, advances in genetics have improved our understanding of liver disease and physiology. Firstly, developments in genomic technologies drove the identification of genes responsible for monogenic (Mendelian) liver diseases. Over the last decade, genome-wide association studies allowed for the dissection of the genetic susceptibility to complex liver diseases such as fatty liver disease and drug-induced liver injury, in which environmental co-factors play critical roles. The findings have allowed the identification and elaboration of pathophysiological processes, have indicated the need for reclassification of liver diseases and risk factors and have already pointed to new disease treatments. This is illustrated by the interaction of alcohol, overnutrition and the PNPLA3 gene, which represents an ‘infernal triangle' for the liver. In the future, genetics will allow further stratification of liver diseases and contribute to personalized (precision) medicine, offering novel opportunities for translational research and clinical care of our patients.
Acute Liver Failure - It's Just a Matter of Cell Death
Authors: Sowa Jan-Peter , Gerken Guido , Canbay Ali
Published: May 2016

Background: Acute liver failure (ALF) is characterized by a sudden loss of hepatic function due to hepatocyte cell death and dysfunction in previously healthy individuals. The clinical presentation of ALF is associated with coagulopathy (international normalized ratio ≥1.5) and hepatic encephalopathy, although the latter may be less pronounced. Without appropriate and timely intensive care or liver transplantation (LTx), ALF will result in multi-organ failure and death. Various causes may induce ALF, with acetaminophen (APAP) intoxication and acute hepatitis B infection as most common causes in industrialized countries. While conventional terminology discerns acute, acute-on-chronic and acute-on cirrhosis liver failure, some chronic liver diseases (i.e. autoimmune hepatitis (AIH), Wilson's disease) can remain undiagnosed until an initial presentation as ALF. Key Messages: Upon definite diagnosis of ALF, the underlying cause must be identified, since etiology affects prognosis and clinical management. Individual prognosis should be evaluated with one of various available scoring systems. Most widely used are Model for End-Stage Liver Disease, the King's College Criteria and the Clichy criteria. Other markers, that is, cell death markers, lactate or thyroid status, may improve diagnostic accuracy of classic scores, though routine use of these is not yet established. Etiology-specific treatment under intensive care should be performed, if possible (APAP and amanita intoxication, acute viral hepatitides and AIH). LTx is the only curative option for other causes, unknown reasons of ALF or when etiology-specific therapy fails. In ambiguous cases, that is, suspected drug induced ALF or AIH, co-infection with hepatitis E virus should be tested, as this might be more common than it is currently supposed to be. Conclusions: Despite major improvements in clinical management of ALF patients, a significant proportion of ALF cases remains without clear identification of the underlying cause or unrecognized multiple causes. In depth analyzes of ambiguous ALF cases is warranted to further improve clinical management.
Extended Abstract: Management of Liver Cancer
Authors: Galle Peter Robert
Published: May 2016

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. HCC represents more than 90% of primary liver cancers. There is a growing incidence of HCC worldwide. In the Western world, HCC arises in a cirrhotic background in up to 90% of cases, and cirrhosis itself is a progressive disease that affects patient survival. Thus, outcome in patients with HCC and the chances for anti-tumor treatment and its results are dependent not only on tumor-associated factors but also on liver function.
Molecular Pathogenesis and Current Therapy in Intrahepatic Cholangiocarcinoma
Authors: Høgdall Dan , O'Rourke Colm J. , Taranta Andrzej , Oliveira Douglas V.N.P. , Andersen Jesper B.
Published: May 2016

Intrahepatic cholangiocarcinoma (iCCA) comprises one of the most rapidly evolving cancer types. An underlying chronic inflammatory liver disease that precedes liver cancer development for several decades and creates a pro-oncogenic microenvironment frequently impairs progress in therapeutic approaches. Depending on the cellular target of malignant transformation, a large spectrum of molecular and morphological patterns is observed. As such, it is crucial to advance our existing understanding of the molecular pathogenesis of iCCA, particularly its genomic heterogeneity, to improve current clinical strategies and patient outcome. This was achieved for other cancers, such as breast carcinoma, facilitated by the delineation of patient subsets and of precision therapies. In iCCA, many questions persevere as to the evolutionary process and cellular origin of the initial transforming event, the context of tumor plasticity and the causative features driving the disease. Molecular profiling and pathological techniques have begun to underline persistent alterations that may trigger inherited drug resistance (a hallmark of hepatobiliary and pancreatic cancers), metastasis and disease recurrence. In this review, we will focus on the key molecular achievements that are currently advancing the characterization and stratification of iCCA. We will discuss current clinical practice and how genomic achievements may advance diagnosis and therapy as well as ultimately improve patient outcome.
Validation of the Oral Survey-B System for Electronic Data Capture in National Oral Health Surveys
Authors: Carvalho J.C. , Declerck D. , De Vos E. , Kellen J. , Van Nieuwenhuysen J.P. , Vanobbergen J. , Bottenberg P. , Declerck C.
Published: May 2016

The aims of the present study were to incorporate and to validate the electronic capture of participant-related outcomes into the Oral Survey-B System, which was originally developed for the electronic capture of clinical data. The validation process compared the performances of electronic and handwritten data captures. The hypothesis of noninferiority would be established if participants performed electronic data capture of the questionnaire survey with an effectiveness of at least 95% of that of handwritten data capture. In this multicenter, randomized, one-period crossover study design, participants (n = 261) were allocated to start with either electronic or handwritten data capture. The incorporation of the electronic self-completed questionnaire into the Oral Survey-B System was successful. The validation of the electronic questionnaire was performed by participants aged from 18 to 75 years. The interrater reliability of participants performing electronic and handwritten data capture of nonclinical assessments per questionnaire and per entry showed a kappa value of 0.72 (95% CI: 0.53-0.94). The noninferiority of electronic data capture in relation to that of the handwritten data capture and transfer was shown (p < 0.0001; 95% CI: 1.47-2.99). In conclusion, the electronic capture of participant-related outcomes with the Oral Survey-B System, originally designed for capture of clinical data, was validated. The electronic data capture was accurate and limited the number of errors. The participants were able to perform electronic data capture effectively, supporting its implementation in further National Oral Health Surveys. With the consideration of participant preference and time savings, this could lead to the implementation of electronic data capture worldwide in National Oral Health Surveys.
Consistent Occurrence of Hydrocarbonoclastic Marinobacter Strains in Various Cultures of Picocyanobacteria from the Arabian Gulf: Promising Associations for Biodegradation of Marine Oil Pollution
Authors: Al-Wahaib Dhuha , Al-Bader Dhia , Al-Shaikh Abdou Dana K. , Eliyas Mohamed , Radwan Samir S.
Published: May 2016

Fifteen nonaxenic cultures of picocyanobacteria were isolated from the Arabian Gulf, from which 122 heterotrophic bacterial strains were obtained. Based on their 16S rRNA gene sequences, those strains were affiliated with 22 different species, 82.8% of which belonged to the genus Marinobacter, known to comprise hydrocarbonoclastic strains. The remaining species belonged to the genera Alcanivorax, Bacillus, Halomonas, Mesorhizobium, and Paenibacillus, and a Bacteriodetes bacterium also known to comprise hydrocarbonoclastic strains. All the picocyanobacterial cultures harbored one or more strains of Marinobacter. Marinobacter in addition to Alcanivorax and other genera isolated from those picocyanobacteria grew on Tween 80, crude oil, and pure hydrocarbons as sole sources of carbon and energy, i.e. they are related to the obligate hydrocarbonoclastic bacteria group. They consumed crude oil, n-octadecane, and phenanthrene in batch cultures. The results indicated that Marinobacter isolates seemed to grow better and consume more oil in the presence of their host picocyanobacteria than in their absence. Such natural microbial associations assumingly play a role in bioremediation of spilled hydrocarbons in the Arabian Gulf. Similar associations probably occur in other marine environments as well and are active in oil spill removal.
Estimated GFR and Mortality in Older Men: Are All eGFR Formulae Equal?
Authors: Canales Muna T. , Blackwell Terri , Ishani Areef , Taylor Brent C. , Hart Allyson , Barrett-Connor Elizabeth , Lewis Cora , Beyth Rebecca J. , Stone Katie , Ensrud Kristine E. ,   for the Outcomes of Sleep Disorders in Older Men (MrOS Sleep) Study
Published: May 2016

Background: Recently, the first estimated glomerular filtration rate (eGFR) formula specifically developed for community-dwelling older adults, the Berlin Initiative Study Equation 2 (BIS2), was reported. To date, however, no study has examined the performance of the BIS2 to predict death in older adults as compared to equations used clinically and in research. Methods: We prospectively followed 2,994 community-dwelling men (age 76.4 ± 5.6) enrolled in the MrOS Sleep Study. We calculated baseline eGFR from serum creatinine and cystatin-C using the BIS2, Chronic Kidney Disease Epidemiology (CKD-EPIcr,cysc), CKD-EPIcysc and CKD-EPIcr equations. Analyses included Cox-proportional hazards regression and net reclassification improvement (NRI) for the outcomes of all-cause and cardiovascular death. Results: Follow-up time was 7.3 ± 1.9 years. By BIS2, 42 and 11% had eGFR <60 and <45, respectively, compared to CKD-EPIcr (23 and 6%), CKD-EPIcysc (36 and 13%) and CKD-EPIcr,cysc (28 and 8%). BIS2 eGFR <45 was associated with twofold higher rate of all-cause mortality when compared to eGFR ≥75 after multivariate adjustment (HR 2.1, 95% CI 1.5-2.8). Results were similar for CKD-EPIcr,cysc <45 (HR 2.1, 95% CI 1.6-2.7) and CKD-EPIcysc <45 (HR 2.1, 95% CI 1.7-2.7) and weaker for CKD-EPIcr <45 (HR 1.5, 95% CI 1.2-2.0). In NRI analyses, when compared to CKD-EPIcr,cysc, both BIS2 and CKD-EPIcr equations more often misclassified participants with respect to mortality. We found similar results for cardiovascular death. Conclusion: The BIS2 did not outperform and the CKD-EPIcr was inferior to the cystatin C-based CKD-EPI equations to predict death in this cohort of older men. Thus, the cystatin C-based CKD-EPI equations are the formulae of choice to predict death in community-dwelling older men.
Within-Home Blood Pressure Variability on a Single Occasion Has Clinical Significance
Authors: Shibasaki Seiichi , Hoshide Satoshi , Kario Kazuomi
Published: May 2016

There is growing evidence that diversely defined blood pressure variability (BPV) is an independent predictor of hypertensive target organ damage (TOD) and cardiovascular events. Several mechanisms have been speculated to underlie episodes of increased BPV, including the impairment of autonomic or hormonal regulation, renal dysfunction, and increased arterial stiffness. Within-home BPV, defined as differences in BP values obtained on a single occasion at home, could have prognostic significance for hypertensive TOD. It is typically thought that BP values are decreased with repeated measurements on a single occasion at home, but in the present subanalysis of 4,149 J-HOP (Japan Morning Surge-Home Blood Pressure) study patients, approximately 20% of the patients' home BP values were increased or unchanged by repeated measurements on a single occasion. In addition, those patients were likely to have hypertensive TOD. Thus, home BP measurement should be taken twice or more to detect the increase trend in home BP, which has been defined as within-home BPV.
Parallel Universes for Models of X Chromosome Dosage Compensation in Drosophila: A Review
Authors: Birchler James A.
Published: May 2016

Dosage compensation in Drosophila involves an approximately 2-fold increase in expression of the single X chromosome in males compared to the per gene expression in females with 2 X chromosomes. Two models have been considered for an explanation. One proposes that the male-specific lethal (MSL) complex that is associated with the male X chromosome brings histone modifiers to the sex chromosome to increase its expression. The other proposes that the inverse effect which results from genomic imbalance would tend to upregulate the genome approximately 2-fold, but the MSL complex sequesters histone modifiers from the autosomes to the X to mute this autosomal male-biased expression. On the X, the MSL complex must override the high level of resulting histone modifications to prevent overcompensation of the X chromosome. Each model is evaluated in terms of fitting classical genetic and recent molecular data. Potential paths toward resolving the models are suggested.
Acetylic Salicylic Acid for the Treatment of Chronic Obstructive Pulmonary Disease: A Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Schwameis Richard , Pils Sophie , Weber Maria , Hagmann Michael , Zeitlinger Markus , Sauermann Robert
Published: May 2016

Purpose: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the world. Current treatment options provide relief from symptoms rather than stop disease progress. Results from various preclinical experiments suggest a causal benefit of acetylic salicylic acid (ASA) in the treatment of COPD. Hence, this study set out to examine the clinical benefit of ASA in the treatment of COPD. COPD patients (Global Initiative for Chronic Obstructive Lung Disease II-III) received either once daily 500 mg of ASA or a matching placebo for 12 weeks in addition to their preexisting medication. Clinical response in terms of pulmonary function testing, symptomatic response and adverse events were assessed. After 40 subjects were included, the study was stopped and an interim analysis was performed. The addition of ASA to the treatment of subjects with COPD had no effect on clinical features or spirometry (forced expiratory volume in 1 s: F = 0.49, d.f.1 = 1, d.f.2 = 74, p = 0.486) and non-pulmonary markers. COPD represents a complex of different diseases, although currently classified mainly by markers of lung function. If future trials test the effects of anti-inflammatory therapies, COPD subpopulations should be predefined based on inflammatory features.
Spread Direction and Prognostic Factors in Limb-Onset Sporadic Amyotrophic Lateral Sclerosis
Authors: Hu Fangfang , Jin Jiaoting , Jia Rui , Xiang Li , Qi Huaguang , Chen Xin , Dang Jingxia
Published: May 2016

Objective: To investigate the spread direction and prognostic factors in limb-onset sporadic amyotrophic lateral sclerosis (sALS). Methods: Medical records of 128 patients with sALS were reviewed. Variables studied were age at symptom onset, gender, region and lateralization of onset, onset to diagnosis interval (ODI), progression direction, bulbar-involved, time from onset to bulbar-involved, ALSFRS-r, upper motor neuron (UMN) signs and progression rate. Results: First, the horizontal and vertical directions are major spreading directions in limb-onset sALS. Second, in crossed and interposed groups, while ODI is shorter, the progression rate is faster and UMN signs are more pronounced (p < 0.05). Third, ALSFRS-r, UMN signs and progression rate have significant differences between with-bulbar-involved and without-bulbar-involved (p < 0.05). The progression rate is related to the time from onset symptoms to bulbar-involved (correlation coefficient -0.535, p = 0.00). Fourth, in multivariate regression analysis, progression rate could respectively increase by about 1.14 and 3.89 times with shorter ODI and bulbar-involved in limb-onset sALS patients. Conclusions: The horizontal and vertical directions are the major spread directions in limb-onset sALS. Except for ALSFRS-r and ODI, bulbar-involved is an adverse factor for ALS progression, and progression rate is related to the time from onset symptoms to bulbar-involved.
Galectin-3 in Renal Pathology: More Than Just an Innocent Bystander?
Authors: Desmedt Valérie , Desmedt Stéphanie , Delanghe Joris R. , Speeckaert Reinhart , Speeckaert Marijn M.
Published: May 2016

Background: Galectin-3 is a member of a closely related lectin family, which is detected in several vertebrate epithelial and myeloid cell types. This beta-galactoside-binding soluble protein plays an important role in multiple biological processes. Depending on its location, type of injury or site of damage, the effects by galectin-3 can be various and sometimes contrasting. Summary: In this review, we discuss the general characteristics and functions of galectin-3. More specifically, we focus on the role of galectin-3 in the onset and development of diabetic and non-diabetic nephropathies. Finally, the therapeutic potential of anti-galectin-3 inhibitors is discussed. Key Messages: Due to its multifunctional character, galectin-3 plays a pivotal role in interstitial fibrosis and progression of chronic kidney disease. Inhibition of galectin-3 may be a promising therapeutic strategy to prevent end-stage renal disease.
Early Stent Thrombosis and Mortality After Primary Percutaneous Coronary Intervention in ST-Segment–Elevation Myocardial Infarction
Authors: Dangas George D. , Schoos Mikkel M. , Steg Philippe Gabriel , Mehran Roxana , Clemmensen Peter , van ‘t Hof Arnoud , Prats Jayne , Bernstein Debra , Deliargyris Efthymios N. , Stone Gregg W.
Published: May 2016

Background—

Early stent thrombosis (ST) within 30 days after primary percutaneous coronary intervention in ST-segment–elevation myocardial infarction is a serious event. We sought to determine the predictors of and risk of mortality after early ST according to procedural antithrombotic therapy.

Methods and Results—

In a patient-level pooled analysis from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) and European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) trials, we examined 30-day outcomes in 4935 patients undergoing primary percutaneous coronary intervention with stent implantation at 188 international sites, randomized to either bivalirudin or heparin±a glycoprotein IIb/IIIa inhibitor (GPI). Early ST occurred in 100 patients (2.0%), 20 of whom (20.0%) died. Bivalirudin was associated with higher rates of early ST compared with heparin±GPI (2.5% versus 1.6%,
P
=0.04), because of more acute (≤24 h) ST (1.5% versus 0.2%,
P
<0.0001), with the risk limited to the first 4 hours after percutaneous coronary intervention. The rates of subacute (1–30 days) ST were similar with bivalirudin and heparin±GPI (1.0% versus 1.4%,
P
=0.24). Among patients with early ST, mortality within 30 days occurred in 4 of 60 (6.7%) bivalirudin-treated patients compared with 16 of 40 (40.0%) heparin±GPI–treated patients (adjusted hazard ratio, 0.12; 95% CI, 0.04–0.39;
P
=0.0004 and adjusted hazard ratio, 0.122; 95% CI, 0.04–0.39;
P
=0. 0004). Thus, 30-day mortality attributable to early ST occurred in 4 of 2479 (0.2%) bivalirudin-treated patients versus 16 of 2456 (0.7%) heparin±GPI–treated patients (
P
=0.007).

Conclusions—

In the present large-scale pooled analysis from 2 multicenter randomized trials, early ST was more frequent in patients treated with bivalirudin compared with heparin±GPI because of increased ST within 4 hours after primary percutaneous coronary intervention. However, the mortality attributable to early ST was significantly lower after bivalirudin than after heparin±GPI.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifiers: NCT00433966 (HORIZONS-AMI) and NCT01087723 (EUROMAX).
Gender-Related Differential Effects of Obesity on Health-Related Quality of Life via Obesity-Related Comorbidities
Authors: Audureau Etienne , Pouchot Jacques , Coste Joël
Published: May 2016

Background—

Negative effects of obesity on health-related quality of life (HRQoL) have been reported, especially in women, but the relative contribution of cardiometabolic and other obesity-related comorbidities to such effects remains unclear. Our objective was to model the association by sex between body mass index and HRQoL and to precisely quantify the indirect effects mediated by obesity-related comorbidities.

Methods and Results—

Data were drawn from the latest French Decennial Health Survey, a nationwide cross-sectional study conducted in 2003 (21 239 adults aged 25–64 years analyzed). HRQoL was measured by the 36-item short-form health survey questionnaire. A mediation analysis based on the counterfactual framework was performed to quantify the proportion of obesity effects on HRQoL mediated by related comorbidities, including cardiometabolic risk factors (diabetes mellitus, hypertension, dyslipidemia) and diseases (ischemic heart disease, cerebrovascular, and peripheral vascular disease), musculoskeletal disorders, and asthma. After multiple linear regression, inverse associations were found between increasing body mass index category and physically oriented and most mentally oriented 36-item short-form health survey dimensions, with evidence of greater effects in women. Mediation analysis revealed that obesity effects were significantly mediated by several comorbidities, more apparently in men (eg, proportion of obesity class II total effect mediated via cardiometabolic factors: general health 27.0% [men] versus 13.6% [women]; proportion of obesity class II total effect mediated via total count of comorbidities: physical functioning 17.8% [men] versus 7.7% [women] and general health 37.1% [men] versus 20.3% [women]).

Conclusions—

Women have a greater overall impact of obesity on HRQoL, but with proportionally lower effects mediated by cardiometabolic and other obesity-related conditions, suggesting the possible role of other specific psychosocial processes.
Ideal Cardiovascular Health and Risk of Frailty in Older Adults
Authors: Graciani Auxiliadora , García-Esquinas Esther , López-García Esther , Banegas José R. , Rodríguez-Artalejo Fernando
Published: May 2016

Background—

The major cardiovascular risk factors and existing cardiovascular disease have been linked to increased risk of the frailty syndrome. However, the association between ideal cardiovascular health and the risk of frailty in older adults is uncertain.

Methods and Results—

Prospective cohort study of 1745 individuals (≥60 years and free of cardiovascular disease) recruited during 2008 to 2010. Cardiovascular health was defined as having 7 ideal metrics: never smoking, physically active, healthy diet, body mass index <25 kg/m
2
, untreated serum cholesterol <200 mg/dL, untreated blood pressure <140/90 mm Hg, and untreated fasting serum glucose <100 mg/dL. Participants were followed-up through 2012 to assess incident frailty, defined as ≥3 of the 5 Fried criteria. Statistical analyses were performed with Cox regression and adjusted for main confounders. During a mean follow-up of 3.5 years, 117 cases of incident frailty were identified. Compared with meeting 0 to 1 ideal metrics, the hazard ratio (95% confidence interval) of frailty was 0.51 (0.30–0.84) for 2 metrics and 0.630 (0.39–0.99) for ≥3 metrics. Results were similar after excluding incident cases of cardiovascular disease. The number of ideal metrics showed a tendency to a reduced risk of all frailty criteria. The cardiovascular metrics associated with the greatest reduction of frailty risk were being physically active and ideal body mass index.

Conclusions—

Reaching old age in ideal cardiovascular health is associated with a reduced risk of frailty. This highlights the importance of a life-course approach for frailty prevention.
Quantifying Selection Bias in National Institute of Health Stroke Scale Data Documented in an Acute Stroke Registry
Authors: Thompson Michael P. , Luo Zhehui , Gardiner Joseph , Burke James F. , Nickles Adrienne , Reeves Mathew J.
Published: May 2016

Background—

As a measure of stroke severity, the National Institutes of Health Stroke Scale (NIHSS) is an important predictor of patient- and hospital-level outcomes, yet is often undocumented. The purpose of this study is to quantify and correct for potential selection bias in observed NIHSS data.

Methods and Results—

Data were obtained from the Michigan Stroke Registry and included 10 262 patients with ischemic stroke aged ≥65 years discharged from 23 hospitals from 2009 to 2012, of which 74.6% of patients had documented NIHSS. We estimated models predicting NIHSS documentation and NIHSS score and used the Heckman selection model to estimate a correlation coefficient (ρ) between the 2 model error terms, which quantifies the degree of selection bias in the documentation of NIHSS. The Heckman model found modest, but significant, selection bias (ρ=0.19; 95% confidence interval: 0.09, 0.29;
P
<0.001), indicating that because NIHSS score increased (ie, strokes were more severe), the probability of documentation also increased. We also estimated a selection bias–corrected population mean NIHSS score of 4.8, which was substantially lower than the observed mean NIHSS score of 7.4. Evidence of selection bias was also identified using hospital-level analysis, where increased NIHSS documentation was correlated with lower mean NIHSS scores (
r
=–0.39;
P
<0.001).

Conclusions—

We demonstrate modest, but important, selection bias in documented NIHSS data, which are missing more often in patients with less severe stroke. The population mean NIHSS score was overestimated by >2 points, which could significantly alter the risk profile of hospitals treating patients with ischemic stroke and subsequent hospital risk–adjusted outcomes.
Is Isolated Low High-Density Lipoprotein Cholesterol a Cardiovascular Disease Risk Factor?
Authors: Bartlett Jacquelaine , Predazzi Irene M. , Williams Scott M. , Bush William S. , Kim Yeunjung , Havas Stephen , Toth Peter P. , Fazio Sergio , Miller Michael
Published: May 2016

Background—

Although the inverse association between high-density lipoprotein cholesterol (HDL-C) and risk of cardiovascular disease (CVD) has been long established, it remains unclear whether low HDL-C remains a CVD risk factor when levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) are not elevated. This is a timely issue because recent studies have questioned whether HDL-C is truly an independent predictor of CVD.

Methods and Results—

3590 men and women from the Framingham Heart Study offspring cohort without known CVD were followed between 1987 and 2011. Low HDL-C (<40 mg/dL in men and <50 mg/dL in women) was defined as isolated if TG and LDL-C were both low (<100 mg/dL). We also examined higher thresholds for TG (150 mg/dL) and LDL-C (130 mg/dL) and compared low versus high HDL-C phenotypes using logistic regression analysis to assess association with CVD. Compared with isolated low HDL-C, CVD risks were higher when low HDL-C was accompanied by LDL-C ≥100 mg/dL and TG <100 mg/dL (odds ratio 1.3 [1.0, 1.6]), TG ≥100 mg/dL and LDL-C <100 mg/dL (odds ratio 1.3 [1.1, 1.5]), or TG and LDL-C ≥100 mg/dL (odds ratio 1.6, [1.2, 2.2]), after adjustment for covariates. When low HDL-C was analyzed with higher thresholds for TG (≥150 mg/dL) and LDL-C (≥130 mg/dL), results were essentially the same. In contrast, compared with isolated low HDL-C, high HDL-C was associated with 20% to 40% lower CVD risk except when TG and LDL-C were elevated.

Conclusions—

CVD risk as a function of HDL-C phenotypes is modulated by other components of the lipid panel.