bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Genetic Locus Influencing Retinal Venular Tortuosity Is Also Associated With Risk of Coronary Artery Disease
Authors: Veluchamy Abirami , Ballerini Lucia , Vitart Veronique , Schraut Katharina E. , Kirin Mirna , Campbell Harry , Joshi Peter K. , Relan Devanjali , Harris Sarah , Brown Ellie , Vaidya Suraj S. , Dhillon Baljean , Zhou Kaixin , Pearson Ewan R. , Hayward Caroline , Polasek Ozren , Deary Ian J. , MacGillivray Thomas , Wilson James F. , Trucco Emanuele , Palmer Colin N.A. , Doney Alexander S.F. 
Published: October 2019

Objective:
The retina may provide readily accessible imaging biomarkers of global cardiovascular health. Increasing evidence suggests variation in retinal vascular traits is highly heritable. This study aimed to identify the genetic determinants of retinal vascular traits.

Approach and Results:

We conducted a meta-analysis of genome-wide association studies for quantitative retinal vascular traits derived using semi-automatic image analysis of digital retinal photographs from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside; N=1736) and ORCADES (Orkney Complex Disease Study; N=1358) cohorts. We identified a novel genome-wide significant locus at 19q13 (
ACTN4/CAPN12
) for retinal venular tortuosity (
TortV
), and one at 13q34 (
COL4A2
) for retinal arteriolar tortuosity (
TortA
); these 2 loci were subsequently confirmed in 3 independent cohorts (N
total
=1413). In the combined analysis of discovery and replication cohorts, the lead single-nucleotide polymorphism in
ACTN4
/
CAPN12
was rs1808382 (β
s.d.
=-0.109; SE=0.015;
P
=2.39×10-
13
) and in
COL4A2
was rs7991229 (β
s.d.
=0.103; SE=0.015;
P
=4.66×10-
12
). Notably, the
ACTN4
/
CAPN12
locus associated with
TortV
is also associated with coronary artery disease, heart rate, and atrial fibrillation.

Conclusions:
Genetic determinants of retinal vascular tortuosity are also linked to cardiovascular health. These findings provide a molecular pathophysiological foundation for the use of retinal vascular traits as biomarkers for cardiovascular diseases.
Extracellular MicroRNA-92a Mediates Endothelial Cell–Macrophage Communication
Authors: Chang Ya-Ju , Li Yi-Shuan , Wu Chia-Ching , Wang Kuei-Chun , Huang Tzu-Chieh , Chen Zhen , Chien Shu 
Published: October 2019

Objective:
Understanding message delivery among vascular cells is essential for deciphering the intercellular communications in cardiovascular diseases. MicroRNA (miR)-92a is enriched in endothelial cells (ECs) and circulation under atheroprone conditions. Macrophages are the primary immune cells in atherosclerotic lesions that modulate lesion development. Therefore, we hypothesize that, in response to atheroprone stimuli, ECs export miR-92a to macrophages to regulate their functions and enhance atherosclerotic progression.

Approach and Results:

We investigated the macrophage functions that are regulated by EC miR-92a under atheroprone microenvironments. We first determined the distributions of functional extracellular miR-92a by fractionating the intravesicular and extravesicular compartments from endothelial conditioned media and mice serum. The results indicate that extracellular vesicles are the primary vehicles for EC miR-92a transportation. Overexpression of miR-92a in ECs enhanced the proinflammatory responses and low-density lipoprotein uptake, while impaired the migration, of cocultured macrophage. Opposite effects were found in macrophages cocultured with ECs with miR-92a knockdown. Further analyses demonstrated that intravesicular miR-92a suppressed the expression of target gene
KLF4
(Krüppel-like factor 4) in macrophages, suggesting a mechanism by which intravesicular miR-92a regulates recipient cell functions. Indeed, the overexpression of KLF4 rescued the EC miR-92a–induced macrophage atheroprone phenotypes. Furthermore, an inverse correlation of intravesicular miR-92a in blood serum and KLF4 expression in lesions was observed in atherosclerotic animals, indicating the potential function of extracellular miR-92a in regulating vascular diseases.

Conclusions:
EC miR-92a can be transported to macrophages through extracellular vesicles to regulate KLF4 levels, thus leading to the atheroprone phenotypes of macrophage and, hence, atherosclerotic lesion formation.
Misdiagnosis Worsens Prognosis in Subarachnoid Hemorrhage With Good Hunt and Hess Score
Authors: Ois Angel , Vivas Elio , Figueras-Aguirre Georgina , Guimaraens Leopoldo , Cuadrado-Godia Elisa , Avellaneda Carla , Bertran-Recasens Bernat , Rodríguez-Campello Ana , Gracia Maria-Pilar , Villalba Gloria , Saldaña Jesus , Capellades Jaume , Fernández-Candil Juan-Luis , Roquer Jaume 
Published: October 2019

Background and Purpose—
Our aim was to describe variables associated with initial misdiagnosis of subarachnoid hemorrhage (SAH). We also analyzed the relationship of misdiagnosis with poor outcome and complications in good Hunt and Hess (HH) cases.

Methods—
In a prospective cohort of 401 patients with SAH, misdiagnosis was defined as failure to correctly identify, at first physician contact, a subsequently documented SAH; this meant no urgent radiological study and lumbar puncture was performed. Poor outcome was defined as modified Rankin Scale score 3 to 6 at 3-month follow-up. We recorded age, sex, hypertension, diabetes mellitus, current smoking, previous antithrombotic treatment, initial HH and radiological severity, presence of aneurysm, first therapeutic procedure, hydrocephalus, delayed cerebral ischemia (DCI), rebleeding, and procedure-related complications.

Results—
Misdiagnosis was confirmed in 104/401 (25.9%) patients, who also had a longer time-to-admission to hospital. Misdiagnosis was associated with less clinical and radiological severity, compared with a correct diagnosis; the 2 groups did not differ in age or cardiovascular risk factor profile. Poor outcome was registered in 167/401 patients (41.6%). Age, misdiagnosis, and greater clinical and radiological initial severity were independent predictors of poor outcome. In the 236 patients (58.8% of cohort) with HH 1–2, misdiagnosis was associated with poor outcome in univariate and multivariate analysis, respectively (odds ratio=3.89; 95% CI, 1.89–8.01). Delayed cerebral ischemia (odds ratio=2.47; 95% CI, 1.2–5.09) and procedure-related complications (odds ratio=2.27; 95% CI, 1.07–4.82) were independently associated with misdiagnosis.

Conclusions—
Misdiagnosis is an unresolved problem in SAH, and it is a missed opportunity for good outcome in patients with HH 1–2. The poor outcome is partially explained by a higher risk of delayed cerebral ischemia and procedure-related complications in misdiagnosed patients. There is a need to improve the diagnostic strategy in patients reporting only a headache (HH 1–2) after SAH.
What Drives Upper-Ocean Temperature Variability in Coupled Climate Models and Observations?
Authors: Small R. Justin , Bryan Frank O. , Bishop Stuart P. , Larson Sarah , Tomas Robert A. 
Published: October 2019

AbstractA key question in climate modeling is to what extent sea surface temperature and upper-ocean heat content are driven passively by air–sea heat fluxes, as opposed to forcing by ocean dynamics. This paper investigates the question using a climate model at different resolutions, and observations, for monthly variability. At the grid scale in a high-resolution climate model with resolved mesoscale ocean eddies, ocean dynamics (i.e., ocean heat flux convergence) dominates upper 50 m heat content variability over most of the globe. For deeper depths of integration to 400 m, the heat content variability at the grid scale is almost totally controlled by ocean heat flux convergence. However, a strong dependence on spatial scale is found—for the upper 50 m of ocean, after smoothing the data to around 7°, air–sea heat fluxes, augmented by Ekman heat transports, dominate. For deeper depths of integration to 400 m, the transition scale becomes larger and is above 10° in western boundary currents. Comparison of climate model results with observations show that the small-scale influence of ocean intrinsic variability is well captured by the high-resolution model but is missing from a comparable model with parameterized ocean-eddy effects. In the deep tropics, ocean dynamics dominates in all cases and all scales. In the subtropical gyres at large scales, air–sea heat fluxes play the biggest role. In the midlatitudes, at large scales >10°, atmosphere-driven air–sea heat fluxes and Ekman heat transport variability are the dominant processes except in the western boundary currents for the 400 m heat content.
Impact of Shrubs on Winter Surface Albedo and Snow Specific Surface Area at a Low Arctic Site: In Situ Measurements and Simulations
Authors: Belke-Brea M. , Domine F. , Barrere M. , Picard G. , Arnaud L. 
Published: October 2019

AbstractErect shrubs in the Arctic reduce surface albedo when branches protrude above the snow and modify snow properties, in particular specific surface area (SSA). Important consequences are changes in the land surface–atmosphere energy exchange and the increase of snow melting in autumn, possibly inducing reduced soil thermal insulation and in turn permafrost cooling. Near Umiujaq (56.5°N, 76.5°W) in the Canadian low Arctic where dwarf birches (Betula glandulosa) are expanding, spectral albedo (400–1080 nm) under diffuse light and vertical profiles of SSA were measured in November and December 2015 at four sites: three with protruding branches and one with only snow. At the beginning of the snow season (8 November), shrub-induced albedo reductions were found to be wavelength dependent and as high as 55% at 500 nm and 18% at 1000 nm, which, integrated over the measurement range (400–1080 nm), corresponds to 70 W m−2 of additional absorbed energy. The impact of shrubs is not just snow darkening. They also affect snow SSA in multiple ways, by accumulating snow with high SSA during cold windy precipitation and favoring SSA decrease by inducing melting during warm spells. However, the impact on the radiation budget of direct darkening from shrubs likely dominates over the indirect change in SSA. Spectral albedo was simulated with a linear mixing equation (LME), which fitted well with observed spectra. The average root-mean-square error was 0.009. We conclude that LMEs are a suitable tool to parameterize mixed surface albedo in snow and climate models.
Imaging of Bone Perfusion and Metabolism in Subjects Undergoing Total Ankle Arthroplasty Using 18F-Fluoride Positron Emission Tomography
Authors: Dyke Jonathan P. , Garfinkel Jonathan H. , Volpert Lauren , Sanders Austin , Newcomer Meghan , Dutruel Silvina P. , Sofka Carolyn M. , Ellis Scott J. , Demetracopoulos Constantine A. 
Published: October 2019

Background: Total ankle arthroplasty (TAA) continues to exhibit a relatively high incidence of complications and need for revision surgery compared to knee and hip arthroplasty. One common mode of failure in TAA is talar component subsidence. This may be caused by disruption in the talar blood supply related to the operative technique. The purpose of this study was to quantify changes in talar bone perfusion and turnover before and after TAA with the INBONE II system using 18F-fluoride positron emission tomography / computed tomography (PET/CT). Methods: Nine subjects (5 M/4 F) aged 68.9 ± 8.2 years were enrolled for 18F-fluoride PET/CT imaging before and 3 months after TAA. Regions of interest (ROI) were placed on the postoperative CT images in the body of the talus beneath the talar component and overlaid on the fused static PET images. Standard uptake values (SUVs) along with dynamic K1 (bone blood flow) and ki (bone metabolism or osteoblastic turnover) were calculated. Results: The SUV underneath the talar component compared to that measured at baseline before surgery was 1.93 ± 0.29 preoperatively vs 2.47 ± 0.37 postoperatively ( P > .05). K1 was 0.84 ± 0.16 mL/min/mL preoperatively vs 1.51 ± 0.23 mL/min/mL postoperatively ( P = .026). ki was constant at 0.09 ± 0.03 mL/min/mL preoperatively vs 0.12 ± 0.03 mL/min/mL postoperatively ( P > .05). Conclusion: Our study was the first to link 18F-fluoride PET/CT with pre-post evaluation of total ankle replacements. The study quantified perfusion within the talus beneath the TAA implant supporting the hypothesis that perfusion of the talus remained intact after surgery. Level of Evidence: Level II, prospective cohort study with development of diagnostic criteria.
Influence of Maternal Prepregnancy Obesity and Excessive Gestational Weight Gain on Maternal and Child Gastrointestinal Microbiome Composition: A Systematic Review
Authors: Dreisbach Caitlin , Prescott Stephanie , Alhusen Jeanne 
Published: October 2019

Background: Maternal obesity is a well-known risk factor for significant obstetric and neonatal complications. The influence of the gastrointestinal microbiome in the setting of maternal obesity during pregnancy is less understood. The purpose of this systematic review is to synthesize the literature on the relationships between maternal obesity and excessive gestational weight gain (EGWG) and the composition of maternal and child gastrointestinal microbiomes. Method: We searched CINHAL, OVID Medline, Web of Science, and PubMed for relevant literature using medical subject heading terms related to obesity, pregnancy, and the gastrointestinal microbiome. We assessed 249 articles for potential inclusion using the preferred reporting items for systematic review and meta-analyses framework and deemed 11 articles as relevant for this review. Results: Maternal obesity was associated with significant microbial changes in both maternal and infant fecal microbiome biospecimens including increases in Bacteroidetes, Firmicutes, and the Actinobacteria phyla and decreases in Bifidobacteria. However, inconsistencies in uniform taxonomic results across all studies mean that evidence of specific microbial associations with obesity and EGWG is inconclusive. Conclusion: Our findings suggest that both maternal and child gastrointestinal microbiome composition is altered in the setting of maternal obesity and EGWG during pregnancy. Future microbiome studies should concentrate on the investigation of metagenomic sequencing to elucidate microbial function rather than solely taxonomic composition. More diverse populations of mothers should be sampled to address health disparities and adverse outcomes of underrepresented populations. Finally, analytic pipelines should be standardized across studies to aid in reproducibility.
Multiple Myeloma: New Insights and Therapeutic Approaches
Authors: Anderson Kenneth C. , Kyle Robert A. , Dalton William S. , Landowski Terry , Shain Kenneth , Jove Richard , Hazlehurst Lori , Berenson James 
Published: October 2019

AbstractThis review discusses the evolution of novel diagnostic and treatment strategies for multiple myeloma based upon increased understanding of basic disease pathogenesis. Although myeloma has remained an incurable illness to date, these new developments will derive treatments to improve outcome and achieve eventual cure.In Section I, Dr. Kyle reviews the results of current therapy for multiple myeloma, including high dose therapy and stem cell transplantation which have proven to achieve improved response rates, event-free, and overall survival. Supportive therapy, such as erythropoietin to treat disease-related anemia, and methods of prophylaxis against infection, which both lessen toxicities of treatment and improve quality of life for patients, are also addressed.In Section II, Dr. Dalton with Drs. Landowski, Shain, Jove and Hazlehurst discusses mechanisms of drug resistance in myeloma, with emphasis on novel treatment approaches to prevent development of drug resistance and to overcome drug resistance. Laboratory studies delineating mechanisms whereby myeloma cells resist drug-induced apoptosis provide the framework for related treatment protocols for patients with refractory disease.In Section III, Dr. Berenson reviews the management of complications in bone, which occur in the majority of patients with myeloma and are the major cause of decreased quality of life. New insights into the mediators of bone resorption and new bone formation in the marrow milieu have already derived effective bisphosphonate therapy. These drugs not only reduce bone complications and related pain, thereby improving quality of life, but also may have intrinsic anti-tumor activity by virtue of inducing tumor cell adherence to marrow, reducing interleukin-6 secretion, inducing tumor cell apoptosis, or inhibiting angiogenesis.In the last section, Dr. Anderson explores the potential for future therapies which offer great promise to improve patient outcomes. First, drugs which alter the marrow microenvironment include thalidomide and its derivative immunomodulatory drugs, which act directly on tumor cells to induce apoptosis or G1 growth arrest, alter tumor cell adhesion to marrow stroma, inhibit angiogenesis, and trigger a cellular anti-tumor response. The proteasome inhibitors both act directly on tumor cells and also inhibit the transcription factor NFκB-dependent upregulation of IL-6 secretion triggered by tumor cell adhesion. Second, delineation of both growth and apoptotic pathways has derived novel treatment strategies. Third, the preclinical basis and early clinical trial results using vaccination and adoptive immunotherapy to harness autoimmune and alloimmune anti-myeloma responses are presented. This review sets the stage for an evolving new biologically based treatment paradigm in myeloma targeting both the tumor and its microenvironment to improve outcome and achieve eventual cure.
Congenital Hemorrhagic Disorders: New Insights into the Pathophysiology and Treatment of Hemophilia
Authors: Hedner Ulla , Ginsburg David , Lusher Jeanne M. , High Katherine A. 
Published: October 2019

The diagnostic and treatment strategies related to hemophilia are rapidly evolving. This article focuses on some of the issues of importance. Diagnostic advances in molecular genetics are reviewed by Dr. Ginsburg in Section I, including the current state of knowledge regarding the mutations responsible for hemophilia, with reference to the potential clinical applications of DNA diagnosis and prenatal testing.Within the area of new therapeutic approaches in hemophilia, recombinant factor VIII and factor IX concentrates, their use and availability are addressed by Dr. Lusher in Section II as well as the use of so-called “primary prophylaxis” with the aim of decreasing long-term hemophilia athropathy. The use of radionuclide synovectomy as replacement for more invasive methods is also reviewed.Various approaches to the ongoing challenge of the management of hemophilia patients with inhibitors against factor VIII and factor IX are reviewed by Dr. Hedner in Section III, including the principles for immune tolerance induction and the use of recombinant factor VIIa to induce hemostasis in bleeding patients with inhibitors.In Section IV, gene therapy in hemophilia is reviewed by Dr. High, who focuses on recent developments in the rapidly moving field of gene therapy for hemophilia. Three phase I trials of gene therapy for hemophilia were initiated in 1999, and additional proposed trials are currently in the regulatory review process. Certain aspects of the pathophysiology of hemophilia make it an attractive model for a gene-based approach to treatment. These include latitude in choice of target tissue, a wide therapeutic window, the availability of small and large animal models of the disease, and the ease of determining therapeutic efficacy. Since there is very little published information regarding the ongoing trials, this section reviews the approaches being used, the published pre-clinical data, and considerations affecting clinical trial design in hemophilia gene therapy.
Advances in Therapy and the Management of Antithrombotic Drugs for Venous Thromboembolism
Authors: Ansell Jack E. , Weitz Jeffrey I. , Comerota Anthony J. 
Published: October 2019

AbstractThis review focuses on antithrombotic therapy for venous thromboembolism and covers a diverse range of topics including a discussion of emerging anticoagulant drugs, a renewed focus on thrombolytic agents for selected patients, and an analysis of the factors leading to adverse events in patients on warfarin, and how to optimize therapy. In Section I Dr. Weitz discusses new anticoagulant drugs focusing on those that are in the advanced stages of development. These will include drugs that (a) target factor VIIa/tissue factor, including tissue factor pathway inhibitor and NAPc2; (b) block factor Xa, including the synthetic pentasaccharide and DX9065a; (c) inhibit factors Va and VIIIa, i.e., activated protein C; and (d) block thrombin, including hirudin, argatroban, bivalirudin and H376/95. Oral formulations of heparin will also be reviewed.In Section II, Dr. Comerota will discuss the use of thrombolysis for selected patients with venous thromboembolism. Fibrinolytic therapy, which has suffered from a high risk/benefit ratio for routine deep venous thrombosis, may have an important role to play in patients with iliofemoral venous thrombosis. Dr. Comerota presents his own results with catheter-directed thrombolytic therapy and the results from a large national registry showing long-term outcomes and the impact on quality of life.In Section III, Dr. Ansell presents a critical analysis of the factors responsible for adverse events with oral anticoagulants and the optimum means of improving outcomes. The poor status of present day anticoagulant management is reviewed and the importance of achieving a high rate of “time in therapeutic range,” is emphasized. Models of care to optimize outcomes are described, with an emphasis on models that utilize patient self-testing and patient self-management of oral anticoagulation which are considered to be the ultimate in anticoagulation care. The treatment of venous and arterial thromboembolism is undergoing rapid change with respect to the development of new antithrombotic agents, an expanding list of new indications, and new methods of drug delivery and management. In spite of these changes, many of the traditional therapeutics are still with us and continue to play a vital role in the treatment of thromboembolic disease. The following discussion touches on a wide range of therapeutic interventions, from old to new, exploring the status of anticoagulant drug development, describing a new intervention for iliofemoral venous thrombosis, and analyzing the critical factors for safe and effective therapy with oral anticoagulants.