bluuebunny/crossref_metadata_2025_split huggingface dataset:
Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials
Authors: Cleland John G F , Bunting Karina V , Flather Marcus D , Altman Douglas G , Holmes Jane , Coats Andrew J S , Manzano Luis , McMurray John J V , Ruschitzka Frank , van Veldhuisen Dirk J , von Lueder Thomas G , Böhm Michael , Andersson Bert , Kjekshus John , Packer Milton , Rigby Alan S , Rosano Giuseppe , Wedel Hans , Hjalmarson Åke , Wikstrand John , Kotecha Dipak ,   Beta-blockers in Heart Failure Collaborative Group
Published: September 2017

Abstract

Aims
Recent guidelines recommend that patients with heart failure and left ventricular ejection fraction (LVEF) 40–49% should be managed similar to LVEF ≥ 50%. We investigated the effect of beta-blockers according to LVEF in double-blind, randomized, placebo-controlled trials.

Methods and results
Individual patient data meta-analysis of 11 trials, stratified by baseline LVEF and heart rhythm (Clinicaltrials.gov: NCT0083244; PROSPERO: CRD42014010012). Primary outcomes were all-cause mortality and cardiovascular death over 1.3 years median follow-up, with an intention-to-treat analysis. For 14 262 patients in sinus rhythm, median LVEF was 27% (interquartile range 21–33%), including 575 patients with LVEF 40–49% and 244 ≥ 50%. Beta-blockers reduced all-cause and cardiovascular mortality compared to placebo in sinus rhythm, an effect that was consistent across LVEF strata, except for those in the small subgroup with LVEF ≥ 50%. For LVEF 40–49%, death occurred in 21/292 [7.2%] randomized to beta-blockers compared to 35/283 [12.4%] with placebo; adjusted hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.34–1.03]. Cardiovascular death occurred in 13/292 [4.5%] with beta-blockers and 26/283 [9.2%] with placebo; adjusted HR 0.48 (95% CI 0.24–0.97). Over a median of 1.0 years following randomization (n = 4601), LVEF increased with beta-blockers in all groups in sinus rhythm except LVEF ≥50%. For patients in atrial fibrillation at baseline (n = 3050), beta-blockers increased LVEF when &lt; 50% at baseline, but did not improve prognosis.

Conclusion
Beta-blockers improve LVEF and prognosis for patients with heart failure in sinus rhythm with a reduced LVEF. The data are most robust for LVEF &lt; 40%, but similar benefit was observed in the subgroup of patients with LVEF 40–49%.
Improvement of Foxp3 stability through CNS2 demethylation by TET enzyme induction and activation
Authors: Someya Kazue , Nakatsukasa Hiroko , Ito Minako , Kondo Taisuke , Tateda Kenn-ichi , Akanuma Takashi , Koya Ikuko , Sanosaka Tsukasa , Kohyama Jun , Tsukada Yu-ichi , Takamura-Enya Takeji , Yoshimura Akihiko 
Published: September 2017

Abstract
Since induced regulatory T cells (iTregs) can be produced in a large quantity in vitro, these cells are expected to be clinically useful to induce immunological tolerance in various immunological diseases. Foxp3 (Forkhead box P3) expression in iTregs is, however, unstable due to the lack of demethylation of the CpG island in the conserved non-coding sequence 2 (CNS2) of the Foxp3 locus. To facilitate the demethylation of CNS2, we over-expressed the catalytic domain (CD) of the ten-eleven translocation (TET) protein, which catalyzes the steps of the iterative demethylation of 5-methylcytosine. TET-CD over-expression in iTregs resulted in partial demethylation of CNS2 and stable Foxp3 expression. We also discovered that TET expression was enhanced under low oxygen (5%) culture conditions, which facilitated CNS2 DNA demethylation and stabilization of Foxp3 expression in a TET2- and TET3-dependent manner. In combination with vitamin C treatment, which has been reported to enhance TET catalytic activity, iTregs generated under low oxygen conditions retained more stable Foxp3 expression in vitro and in vivo and exhibited stronger suppression activity in a colitis model compared with untreated iTregs. Our data indicate that the induction and activation of TET enzymes in iTregs would be an effective method for Treg-mediated adoptive immunotherapy.
Necessary Ornaments
Authors: Glixon Jonathan E. 
Published: September 2017

Abstract
This chapter is concerned first of all with the organs installed in the exterior churches of Venetian nunneries, to be played by male professionals (not in the interior churches as common in many other cities, where the nuns played). The financing, construction, and decoration of the organs, and such important makers as Colombo, Piaggia, Nacchini, Dacii, and Callido are considered, along with the varying approaches to maintaining and restoring the organs. The employment of organists varied considerably depending on the availability of funds, with the wealthy nunneries hiring prestigious players. Every nunnery also had a set of church bells in a bell tower, almost always three in number. As with organs, there were standard approaches to financing and construction. Evidence about how the bells were used in nunnery churches is scanty, but what remains is analysed here.
Non-Standard Parametric Statistical Inference
Authors: Cheng Russell 
Published: September 2017

AbstractThis book discusses the fitting of parametric statistical models to data samples. Emphasis is placed on (i) how to recognize situations where the problem is non-standard, when parameter estimates behave unusually, and (ii) the use of parametric bootstrap resampling methods in analysing such problems. Simple and practical model building is an underlying theme. A frequentist viewpoint based on likelihood is adopted, for which there is a well-established and very practical theory. The standard situation is where certain widely applicable regularity conditions hold. However, there are many apparently innocuous situations where standard theory breaks down, sometimes spectacularly. Most of the departures from regularity are described geometrically in the book, with mathematical detail only sufficient to clarify the non-standard nature of a problem and to allow formulation of practical solutions. The book is intended for anyone with a basic knowledge of statistical methods typically covered in a university statistical inference course who wishes to understand or study how standard methodology might fail. Simple, easy-to-understand statistical methods are presented which overcome these difficulties, and illustrated by detailed examples drawn from real applications. Parametric bootstrap resampling is used throughout for analysing the properties of fitted models, illustrating its ease of implementation even in non-standard situations. Distributional properties are obtained numerically for estimators or statistics not previously considered in the literature because their theoretical distributional properties are too hard to obtain theoretically. Bootstrap results are presented mainly graphically in the book, providing easy-to-understand demonstration of the sampling behaviour of estimators.
The Skew Normal Distribution
Authors: Cheng Russell 
Published: September 2017

AbstractThis chapter considers the univariate skew-normal distribution, a generalization of the normal that includes the normal as a special case. The most natural parametrization is non-standard. This is because the Fisher information matrix is then singular at the true parameter value when the true model is the normal special case. The log-likelihood is then particularly flat in a certain coordinate direction. Standard theory cannot then be used to calculate the asymptotic distribution of all the parameter estimates. This problem can be handled using an alternative parametrization. There is another special case: the half/folded normal distribution. This occurs in the usual parametrization when the shape parameter is infinite. This is not a problem computationally and is easily handled. There are many generalizations to skew-t distributions and to tractable multivariate forms and regression versions. A very brief review is included of these.
Finite Mixture Models
Authors: Cheng Russell 
Published: September 2017

AbstractFitting a finite mixture model when the number of components, k, is unknown can be carried out using the maximum likelihood (ML) method though it is non-standard. Two well-known Bayesian Markov chain Monte Carlo (MCMC) methods are reviewed and compared with ML: the reversible jump method and one using an approximating Dirichlet process. Another Bayesian method, to be called MAPIS, is examined that first obtains point estimates for the component parameters by the maximum a posteriori method for different k and then estimates posterior distributions, including that for k, using importance sampling. MAPIS is compared with ML and the MCMC methods. The MCMC methods produce multimodal posterior parameter distributions in overfitted models. This results in the posterior distribution of k being biased towards high k. It is shown that MAPIS does not suffer from this problem. A simple numerical example is discussed.
Are there populations suffering genetic erosion that would benefit from augmented gene flow?
Authors: Frankham Richard , Ballou Jonathan D. , Ralls Katherine , Eldridge Mark D. B. , Dudash Michele R. , Fenster Charles B. , Lacy Robert C. , Sunnucks Paul 
Published: September 2017

AbstractHaving identified small geographically and genetically isolated populations, we need to determine whether they are suffering genetic erosion, and if so, whether there are any other populations to which they could be crossed. We should next ask whether crossing is expected to be harmful or beneficial, and if beneficial, whether the benefits would be large enough to justify a genetic rescue attempt. Here, we address these questions based on the principles established in the preceding chapters.
Observation of Dog-Ear Regression by Anatomical Location
Authors: Jennings Thomas A. , Keane James C. , Varma Rajat , Walsh Stephanie B. , Huang Conway C. 
Published: September 2017

BACKGROUND
When an excision is performed by a method other than elliptical excision, direct primary wound closure can result in standing cones or “dog-ears.” In 2008, Lee and colleagues noted that dog-ears of <8 mm in height have a statistically greater tendency to resolve without further surgical correction than larger dog-ears.

OBJECTIVE
To stratify dog-ears by anatomic location and inform on the need for correction at the time of surgery.

MATERIALS AND METHODS
After tumor extirpation, patients were counseled that primary closure of the surgical wound would result in dog-ears at the wound apices. Dog-ears were left uncorrected in participating patients. At 6 months, patients were assessed for resolution of the dog-ears and asked to rate the appearance of the scar.

RESULTS
A total of 140 dog-ears were observed in the study period. Anatomical locations included the hand/foot, trunk, limb, and head/neck. Among these dog-ears, 114/140 (81%) showed complete resolution. Patient satisfaction with the scar appearance correlated well with the dog-ear resolution, with most patients rating the appearance of the scar as good to excellent.

CONCLUSION
This study suggests that dog-ears on the hand and dog-ears ≤4 mm on the trunk may be observed without any final cosmetic penalty.
Clinical and Confocal Microscopy Study of Plasma Exeresis for Nonsurgical Blepharoplasty of the Upper Eyelid: A Pilot Study
Authors: Rossi Elena , Farnetani Francesca , Trakatelli Myrto , Ciardo Silvana , Pellacani Giovanni 
Published: September 2017

BACKGROUND
Plasma exeresis is an evolving technique for nonsurgical treatment of several skin conditions. Reflectance confocal microscopy (RCM) is a noninvasive tool that allows the “in vivo” imaging of the skin.

OBJECTIVE
To evaluate the clinical improvement and collagen remodeling of the upper eyelid dermatochalasis after plasma exeresis.

METHODS
Ten patients were subjected to 3 interventions of plasma exeresis. Photographic and RCM images were acquired at T0 (baseline) and T1 (4–6 weeks after final plasma exeresis). Eyelid dermatochalasis was rated as absent, mild, moderate, and severe according to the facial laxity rating scale, at clinical images at T0 and T1. An expert RCM evaluator classified collagen according to the predominant pattern of reticulated, coarse, huddled, or curled at T0 and T1.

RESULTS
Clinical improvement of 2.6 ratings was observed at clinical evaluation. Collagen was classified as long straight fibers in all cases, according to RCM images.

CONCLUSION
Plasma exeresis in this pilot study shows promising remodeling effects on the collagen of the upper eyelid, as viewed by RCM, and clinically improved appearance for the patient cohort, without any serious adverse events. This study suggests that plasma exeresis could be a valid solution for eyelid dermatochalasis, but further studies are required.
Childhood Visceral Leishmaniasis: Distinctive Features and Diagnosis of a Re-emerging Disease. An 11-year Experience From a Tertiary Referral Center in Athens, Greece
Authors: Krepis Panagiotis , Krepi Adamantia , Argyri Ioanna , Aggelis Anastasios , Soldatou Alexandra , Papaevangelou Vasiliki , Tsolia Maria 
Published: September 2017

Background:
Visceral leishmaniasis (VL) remains a public health issue in Greece. The aim of this study was to describe the clinical and epidemiologic characteristics of pediatric VL in our region as well as to evaluate the laboratory findings and the diagnostic techniques that are applied.

Methods:
We retrospectively reviewed the medical records of all children diagnosed with VL in an 11-year period at a tertiary public hospital in the region of Athens. Demographic features, clinical information and laboratory findings were accessed.

Results:
A total of 43 cases were recorded during 2005–2015. Median age of the patients was 3.7 years. Pallor (100%), fever (98%), hepatosplenomegaly (55.8%) and appetite loss (32.6%) were the most common presentations of the disease. The predominant laboratory abnormalities were anemia (100%), thrombocytopenia (90.7%), elevated inflammatory markers (86.1%) and decreased albumin/globulin (A/G) ratio (72.1%). Four patients developed secondary hemophagocytic lymphohistiocytosis syndrome, whereas in 3 others abdominal ultrasound showed splenic nodules. Bone marrow aspiration detected Leishmania parasites in 92.7% of cases and the rapid rK39 strip test indicated anti-Leishmania antibodies in 97.1% of children. In addition, all patients in whom indirect immunofluorescent antibody test was implemented had positive results.

Conclusions:
VL still affects children in our area. Fever, splenomegaly, anemia and appetite loss are the typical findings in children. Noninvasive techniques (immunofluorescent antibody test, rK39) in combination with bone marrow microscopy are useful in the diagnosis of pediatric VL.
Vocal tremor: where are we at?
Authors: Richards Amanda L. 
Published: September 2017

Purpose of review
Vocal tremor in movement disorders is often overlooked, although it has a significant impact on quality of life. Careful observation of tremor phenomenology allows for accurate diagnosis and tailored treatment.

Recent findings
The central pathways associated with various vocal tremor-associated diseases have been further elucidated.

Summary
Patients are likely to benefit from a combination of medical and interventional treatments delivered within a multidisciplinary setting
Proteus Syndrome With a Cranial Intraosseous Lipoma
Authors: Wolfswinkel Erik M. , Imahiyerobo Thomas A. , McComb J. Gordon , Sanchez-Lara Pedro A. , Urata Mark. M. 
Published: September 2017

Abstract
Intraosseous lipomas are almost exclusively seen in the long bones. Presence in the craniofacial skeleton is extremely rare. A 7-year-old male is presented with a marked craniofacial deformation from a bony tumor containing an intraosseous lipoma. This finding established a clinical diagnosis of Proteus syndrome. Given the size of the tumor, producing an extensive deformity, three-dimensional modeling was used to generate a three-dimensional printed implant. The process to achieve a successful outcome is herein described.
Septic Shock Nonsurvivors Have Persistently Elevated Acylcarnitines Following Carnitine Supplementation
Authors: Puskarich Michael A. , Evans Charles R. , Karnovsky Alla , Das Arun K. , Jones Alan E. , Stringer Kathleen A. 
Published: September 2017

ABSTRACT

Introduction:
Sepsis-induced metabolic disturbances include hyperlactatemia, disruption of glycolysis, protein catabolism, and altered fatty acid metabolism. It may also lower serum l-carnitine that supports the use of l-carnitine supplementation as a treatment to ameliorate several of these metabolic consequences.

Methods:
To further understand the association between l-carnitine-induced changes in serum acylcarnitines, fatty acid metabolism and survival, serum samples from (T0), 12 hfollowing completion (T24) of l-carnitine (n = 16) or placebo (n = 15) administration, and 48 h (T48) after enrollment from patients with septic shock enrolled in a randomized control trial were assayed for acylcarnitines, free fatty acids, and insulin. Data were analyzed comparing 1-year survivors and nonsurvivors within treatment groups.

Results:
Mortality was 8 of 16 (50%) and 12 of 15 (80%) at 1 year for l-carnitine and placebo-treated patients, respectively. Free carnitine, C2, C3, and C8 acylcarnitines were higher among nonsurvivors at enrollment. l-Carnitine treatment increased levels of all measured acylcarnitines; an effect that was sustained for at least 36 h following completion of the infusion and was more prominent among nonsurvivors. Several fatty acids followed a similar, though less consistent pattern. Glucose, lactate, and insulin levels did not differ based on survival or treatment arm.

Conclusions:
In human patients with septic shock, l-Carnitine supplementation increases a broad range of acylcarnitine concentrations that persist after cessation of infusion, demonstrating both immediate and sustained effects on the serum metabolome. Nonsurvivors demonstrate a distinct metabolic response to l-carnitine compared with survivors, which may indicate preexisting or more profound metabolic derangement that constrains any beneficial response to treatment.
Pretreatment With Argon Protects Human Cardiac Myocyte-Like Progenitor Cells from Oxygen Glucose Deprivation-Induced Cell Death by Activation of AKT and Differential Regulation of Mapkinases
Authors: Qi Hong , Soto-Gonzalez Lourdes , Krychtiuk Konstantin A. , Ruhittel Sarah , Kaun Christoph , Speidl Walter S. , Kiss Attila , Podesser Bruno K. , Yao Shanglong , Markstaller Klaus , Klein Klaus U. , Tretter Verena 
Published: September 2017

ABSTRACTBackground:The noble gas argon induces cardioprotection in a rabbit model of myocardial ischemia and reperfusion. However, no studies in human primary cells or subjects have been performed so far. We used human cardiac myocyte-like progenitor cells (HCMs) to investigate the protective effect on the cellular level.Methods:HCMs were pretreated with 30% or 50% argon before oxygen–glucose deprivation (OGD) and reperfusion. We evaluated apoptotic states by flow cytometry and the activation of mitogen-activated protein kinase (MAPKs) members extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), p38 MAPkinase, and protein kinase B (Akt) by Westernblot analysis and by activity assays of downstream transcription factors. Specific inhibitors were used to proof a significant participation of these pathways in the protection by argon. Beneficial effects were further assessed by TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay, lactate dehydrogenase (LDH), mitochondrial deoxyribonucleic acid (mtDNA), and cytokine release.Results:Pretreatment with 30% or 50% argon for 90 min before OGD resulted in a significant protection of HCMs against apoptosis. This effect was reversed by the application of MAPK and Akt inhibitors during argon exposure. Argon 30% reduced the release of LDH by 33% and mtDNA by 45%. The release of interleukin 1β was reduced by 44% after OGD and more than 90% during reperfusion.Conclusions:Pretreatment with argon protects HCMs from apoptosis under ischemic conditions via activation of Akt, Erk, and biphasic regulation of JNK. Argon gas is cheap and easily administrable, and might be a novel therapy to reduce myocardial ischemia–reperfusion injury.
Neurological toxicities associated with immune-checkpoint inhibitors
Authors: Touat Mehdi , Talmasov Daniel , Ricard Damien , Psimaras Dimitri 
Published: September 2017

Purpose of review
Immune-checkpoint inhibitors (ICIs) constitute a novel class of agents recently approved to treat a number of human malignancies. Due to their immunomodulatory mechanism of action, ICIs can generate a wide range of immune-related adverse events (irAEs) of which neurological toxicities are of special interest because of their potential severity. The objective of this review is to examine the recent literature describing neurological irAEs and discuss their optimal management.

Recent findings
As opposed to irAEs involving other organs, neurological complications of ICIs are uncommon. These complications encompass various toxicities of the central and peripheral nervous systems, including myositis, myasthenia gravis, demyelinating polyradiculoneuropathy, meningitis and encephalitis. Neurologic irAEs are often responsive to corticosteroids and other immune-modulating treatments (e.g. plasmapheresis, intravenous immunoglobulin), which have been used in patients presenting with severe neurologic irAEs or irAEs unresponsive to corticosteroids. Data from literature indicate that early treatment is critical for reducing the morbidity associated with neurologic irAEs.

Summary
ICI-associated irAEs constitute a new group of neurologic complications of systemic anticancer therapies. Although potentially severe, these rare neurologic toxicities are often responsive to immune-modulating therapies. Early recognition and treatment is crucial for timely improvement of functional outcome and requires a multidisciplinary approach.
LRP1 Regulates Peroxisome Biogenesis and Cholesterol Homeostasis in Oligodendrocytes and is Required in CNS Myelin Development and Repair
Authors: Lin林靚蘋 Jing-Ping , Mironova Yevgeniya A. , Shrager Peter , Giger Roman J. 
Published: September 2017

AbstractThe low-density lipoprotein related-receptor-1 (LRP1) is a large endocytic and signaling receptor. We show thatLrp1is required for proper CNS myelinogensisin vivo. Either global inducible or oligodendrocyte (OL)-lineage specific ablation ofLrp1impairs myelin development and adult white matter repair. In primary oligodendrocyte progenitor cells (OPCs),Lrp1deficiency reduces cholesterol levels and attenuates differentiation into mature OLs. Despite a strong increase in the sterol-regulatory element-binding protein-2,Lrp1-/-OPCs are not able to maintain normal cholesterol levels, suggesting more global metabolic deficits. Mechanistic studies identified a decrease in peroxisomal biogenesis factor-2 and a reduction in peroxisomes localized to OL processes. Treatment ofLrp1-/-OPCs with cholesterol or pharmacological activation of peroxisome proliferator-activated receptor-γ with pioglitazone is not sufficient to promote differentiation; however when combined, cholesterol and pioglitazone treatment enhance OL production. Collectively, our studies identify a novel link between LRP1, peroxisomes, and OPC differentiation during white matter development and repair.