bluuebunny/crossref_metadata_2025 huggingface dataset:
Innovations for Supporting Communication: Opportunities and Challenges for People with Complex Communication Needs
Authors: Smith Martine M.
Published: April 2019

Individuals with complex communication needs have benefited greatly from technological innovations over the past two decades, as well as from social movements that have shifted focus from disability to functioning and participation in society. Three strands of technological innovation are reviewed in this paper: (1) innovations in the tools that have become available, specifically tablet technologies; (2) innovations in access methods (eye gaze technologies and brain-computer interfaces); and (3) innovations in output, specifically speech technologies. The opportunities these innovations offer are explored, as are some of the challenges that they imply, not only for individuals with complex communication needs, but also for families, professionals, and researchers.
Whole Exome Sequencing Revealed a Novel Nonsense Variant in the GNRHR Gene Causing Normosmic Hypogonadotropic Hypogonadism in a Pakistani Family
Authors: Hussain Hafiz Muhammad Jafar , Murtaza Ghulam , Jiang Xiaohua , Khan Ranjha , Khan Manan , Kakakhel Mian Basit Shah , Khan Teka , Wahab Fazal , Zhang Huan , Zhang Yuanwei , Khan Muhammad Bilal , Ahmed Parvez , Ma Hui , Xu Zhipeng
Published: April 2019

Background: Congenital hypogonadotropic hypogonadism (CHH) is a heterogeneous disorder characterized by delayed or loss of puberty and infertility due to functional deficiency in the hypothalamic gonadotropin-releasing hormone (GnRH). CHH can be classified into 2 subtypes on the basis of olfaction: Kallmann syndrome and normosmic CHH (nCHH). The spectrum of genetic variants causing CHH is continually expanding. Here, we recruited a consanguineous Pakistani family having 2 male and 2 female infertile patients diagnosed with idiopathic nCHH. Aims: The aim of this study was to investigate the genetic cause of nCHH in the family. Methods: Clinical and physical analyses were performed for the patients. Genetic analysis was carried out using whole exome and Sanger sequencing. Results: Clinical and physical investigations confirmed low levels of gonadotropins and failure of secondary sexual development in the patients. Genetic analysis identified a novel nonsense mutation (chr4: g.68619942G>A, c.112C>T, p.Arg38*) in the gonadotropin-releasing hormone receptor gene (GNRHR) recessively co-segregating with nCHH in this family. All the patients are homozygous and their parents are heterozygous carriers, while normal siblings are heterozygous carriers or wild-type for this mutation, indicating that the identified mutation is pathogenic for nCHH in the family. Conclusion: We report the first homozygous nonsense mutation in the GNRHR gene (chr4: g. 68619942G>A, c.112C>T, p. Arg38*) that is associated with familial nCHH. Hence, our study displayed a good correlation of the genotype and phenotype of nCHH patients.
Entrainment of Circadian Rhythms to Temperature Reveals Amplitude Deficits in Fibroblasts from Patients with Bipolar Disorder and Possible Links to Calcium Channels
Authors: Nudell Victoria , Wei Heather , Nievergelt Caroline , Maihofer Adam X. , Shilling Paul , Alda Martin , Berrettini Wade H. , Brennand Kristen J. , Calabrese Joseph R. , Coryell William H. , Covault Jonathan M. , Frye Mark A. , Gage Fred , Gershon Elliot , McInnis Melvin G. , Nurnberger John I. , Oedegaard Ketil J. , Shekhtman Tatyana , Zandi Peter P. , Kelsoe John R. , McCarthy Michael J. ,   The Pharmacogenomics of Bipolar Disorder Study
Published: April 2019

Bipolar disorder (BD) is characterized by recurrent mood episodes, and circadian rhythm disturbances. Past studies have identified calcium channel genes as risk loci for BD. CACNA1C encodes an L-type calcium channel (LTCC) involved in the entrainment of circadian rhythms to light. Another calcium channel, i.e., the ryanodine receptor (RYR), is involved in ­circadian phase delays. It is unknown whether variants in CACNA1C or other calcium channels contribute to the circadian phenotype in BD. We hypothesized that, by using temperature cycles, we could model circadian entrainment in fibroblasts from BD patients and controls to interrogate the circadian functions of LTCCs. Using Per2-luc, a bioluminescent reporter, we verified that cells entrain to temperature rhythms in vitro. Under constant temperature conditions, the LTCC antagonist verapamil shortened the circadian period, and the RYR antagonist dantrolene lengthened the period. However, neither drug affected temperature entrainment. Fibroblasts from BD patients and controls also entrained to temperature. In cells from BD patients, the rhythm amplitude was lower under entrained, but not constant, conditions. Temperature entrainment was otherwise similar between BD and control cells. However, the CACNA1C genotype among BD cells predicted the degree to which cells entrained. We conclude that assessment of rhythms under entrained conditions reveals additional rhythm abnormalities in BD that are not observable under constant temperature conditions.
Development of a Novel Nano­emulsion Formulation to Improve Intestinal Absorption of Cannabidiol
Authors: Nakano Yukako , Tajima Masataka , Sugiyama Erika , Sato Vilasinee Hirunpanich , Sato Hitoshi
Published: April 2019

Background: Cannabidiol (CBD) is highly lipophilic, and its oral bioavailability is known to be very low in humans. In this study, we developed a novel nanoemulsion preparation of CBD (CBD-NE) to improve the poor solubility and absorption of CBD. The pharmacokinetic profiles of CBD in rats were evaluated after oral administrations of CBD oil and CBD-NE, and the effect of bile secretion on CBD absorption was also evaluated. Methods: The CBD-NE formulation developed in this study consisted of vitamin E acetate, ethanol, Tween-20, and distilled water (1.7/3.8/70/24.5, w/w%). A CBD oil formulation (CBD oil, control) 100 mg/kg or CBD-NE 50 mg/kg was orally administered to rats, and the blood samples were collected over time. Moreover, the CBD oil or CBD-NE was orally administered to bile-fistulated rats, and the pharmacokinetic profiles of CBD were also evaluated. CBD concentrations in plasma were measured using LC-MS/MS. Results: The particle size of CBD-NE was 35.3 ± 11.8 nm. Mean Tmax of CBD-NE was shortened significantly by the factor of 3 (from 8.00 to 2.40 h, p < 0.001) and AUC0–∞/dose increased by 65% (from 0.272 ± 0.045 to 0.448 ± 0.087 h L/kg) compared with CBD oil. AUC0–∞/dose and Cmax/dose after oral administration of CBD oil were significantly reduced by the factor of 27 and 23 (p < 0.05 and p < 0.01), respectively, in bile-fistulated rats compared with the untreated rats. In contrast, all pharmacokinetic parameters after oral administration of CBD-NE were not significantly different between the untreated and bile-fistulated rats. Therefore, these results demonstrated that conventional CBD oil formulation but not CBD-NE requires bile-mediated micelle formation. Conclusions: The novel NE formulation developed in this study successfully improved the absorption of CBD regardless of bile secretion. The newly developed oral CBD-NE preparation could be useful to achieve a more stable and quicker onset of action by CBD.
Biological Significance of Anti-GH Antibodies in Children Treated with rhGH
Authors: Binder Gerhard , Heidenreich Laura , Schnabel Dirk , Dunstheimer Desirée , Oeverink Rudolf , Kiess Wieland , Körner Antje , Kratzsch Jürgen
Published: April 2019

Background: The occurrence of antidrug antibodies is common in children treated with recombinant human growth hormone (rhGH). However, their clinical significance is unclear. Objective: This study aimed to examine the clinical significance of anti-GH antibodies by analyzing the phenotype of patients who tested positive in relation to the quantity of anti-GH antibodies. Method: In this laboratory-based retrospective study encompassing a time span of 6 years, all positive samples were identified, and senders were contacted. Anti-GH antibodies were measured using a radioprecipitation assay; positive samples underwent a confirmatory assay. Results: Out of a total of 104 samples from 66 patients, positive test results were found in 28 samples from 13 patients. Clinical data were available from all but one. The group with positive test results comprised 6 patients with a normal response to GH provocative tests (group A) and 6 with an insufficient response or with isolated GH deficiency (IGHD) type 1A (group B). Diagnoses in group A were neurosecretory dysfunction, bioinactive GH syndrome and constitutional delay of growth and puberty. Diagnoses in group B were IGHD type 1A, septo-optic dysplasia, and cerebral midline defect with multiple pituitary hormone deficiency. Insufficient growth response to rhGH was absent except in one sibling pair with IGHD type 1A and a patient with cerebral midline defect. These patients had the highest concentrations of anti-GH antibodies. Conclusions: The biological significance of anti-GH antibodies seems to be limited to patients with high concentrations of anti-GH antibodies. For all other patients, we recommend a careful “wait and see” strategy and monitoring antibody titers.
Horner Syndrome as Complication of Acute Sphenoid Sinusitis
Authors: Käcker Christoph , Wagner Franca , Caversaccio Marco , Anschuetz Lukas
Published: April 2019

Horner syndrome is described in this case report as a rare complication of bacterial sphenoid sinusitis. A patient presented with miosis, ptosis, and ophthalmic nerve palsy with acute sphenoid sinusistis and cavernous sinus thrombosis on MRI. The impairment of sympathetic fiberscan can be explained through the direct septic effects of the sphenoid sinusitis and indirectly through thrombosis of the cavernous sinus at the level of the carotid plexus.
Molecular Characterization of a Familial 13.6-Mb 20p11.1p12.1 Duplication without Clinical Consequence
Authors: Masson Julie , Rossi Massimiliano , Labalme Audrey , Till Marianne , Trost Detlef , Morin Isabelle , Schluth-Bolard Caroline , Sanlaville Damien
Published: April 2019

Chromosomal microarray (CMA) is currently considered as a first-tier test in the genetic assessment of patients presenting with intellectual disability and/or multiple congenital abnormalities. The distinction between pathogenic CNVs, polymorphisms, and variants of unknown significance can be a diagnostic dilemma for cytogeneticists. The size of the CNV has been proposed as a useful criterion. We herein report the characterization of a 13.6-Mb interstitial duplication 20p11.1p12.1, found in a child presenting with mild global developmental delay, by standard karyotype and CMA. Unexpectedly, the same CNV was detected in the patient's mother and pregnant sister, who were healthy. On the basis of these results, an implication of this CNV in the neurological problems observed in the proband was considered to be unlikely. This report underlines the complexity of genetic counseling concerning rare chromosomal abnormalities, when little information is available either in the literature or in international cytogenetic databases.
Alcoholic Cirrhosis with Zinc and Copper Co-Deficiency
Authors: Unhapipatpong Chanita , Warodomwichit Daruneewan , Chanprapaph Kumutnart
Published: April 2019

A 54-year-old Thai female with known alcoholic cirrhosis presented with chronic scaly eczematous patches and plaque for over 1 month. Initially, she was treated with oral antibiotics, but the lesions did not improve. The dermatologic examination and history of alcoholic cirrhosis were compatible with zinc deficiency. Moreover, copper deficiency was found together with zinc deficiency. Excessive alcohol consumption can cause zinc and copper co-deficiency. To avoid aggravated copper deficiency after zinc supplementation, copper and zinc were supplemented together in appropriate proportions. On the 2-week follow-up examination, her clinical outcome improved.
Temporary Filtering Bleb Failure Induced by Anterior Chamber Sulfur Hexafluoride Gas: A Complication after Descemet Membrane Endothelial Keratoplasty
Authors: Enders Philip , Avgitidou Georgia , Heindl Ludwig M. , Dietlein Thomas S. , Cursiefen Claus
Published: April 2019

Herein, we report two clinical cases with acute temporary filtering bleb obstruction by gas tamponade after Descemet membrane endothelial keratoplasty (DMEK) surgery and postoperative intraocular pressure (IOP) peaks. Both patients underwent uncomplicated DMEK surgery with 20% sulfur hexafluoride (SF6) anterior chamber tamponade and had previous trabeculectomy for glaucoma. Prior to surgery, both patients showed patent bleb function with low to normal IOP without antiglaucomatous medication. After uneventful DMEK surgery, both patients showed postoperative IOP peaks of up to 50 mm Hg despite patent inferior iridotomy and no sign of a pupillary block. In both cases, SF6 gas bubbles could be visualized obstructing the bleb. Both patients were treated with IOP-lowering agents topically as well as systemically. In addition, anterior chamber paracenteses were performed to reduce the SF6 volume within the anterior chamber. Under this treatment, IOP normalized within the first 18 h after surgery. We hypothesize that the SF6 gas tamponade from the anterior chamber migrates into the ostium and below the bleb, leading to an acute temporary insufficiency of bleb function and to a consecutive IOP peak after surgery. In contrast to a pupillary block, this mechanism cannot be antagonized by preoperative iridotomy and needs to be taken into account for every glaucoma patient with functional bleb undergoing DMEK surgery.
Immunoglobulin Heavy Chain Gene Rearrangement Studies in the Diagnosis of a Paediatric Conjunctival Lesion
Authors: Lim Benjamin Cheuk Hung , Sandercoe Trent M.
Published: April 2019

We present a case whereby standard immunohistochemistry and flow cytometry studies for a conjunctival biopsy were unable to reliably differentiate between the two distinct pathological processes of benign reactive lymphoid hyperplasia from conjunctival lymphoma. A tissue diagnosis was only able to be conclusively attained after the application of immunoglobulin heavy chain rearrangement studies to the specimen. This is unusual and to our knowledge has not been previously expressed in the literature. Hence, the use of these further molecular studies may have great potential clinical implications in helping resolve such diagnostic dilemmas.
Counteracting the Metabolic Effects of Glucose Load in Peritoneal Dialysis Patients; an Exercise-Based Approach
Authors: Khan Sana F. , Ronco Claudio , Rosner Mitchell H.
Published: April 2019

Glucose-based peritoneal dialysis (PD) solutions are the predominantly used dialysate in PD patients. Glucose absorption has been shown to be associated with several unfavorable metabolic complications. Several studies have shown positive effects of exercise in end-stage renal disease patients. This paper provides an overview of glucose-associated metabolic complications, and proposed exercise regimens to counteract the caloric load associated with glucose absorption.
Consequences of Glomerular Hyperfiltration: The Role of Physical Forces in the Pathogenesis of Chronic Kidney Disease in Diabetes and Obesity
Authors: Chagnac Avry , Zingerman Boris , Rozen-Zvi Benaya , Herman-Edelstein Michal
Published: April 2019

Background: Glomerular hyperfiltration (GH) is a hallmark of renal dysfunction in diabetes and obesity. Recent clinical trials demonstrated that SGLT2 inhibitors are renoprotective, possibly by abating hyperfiltration. The present review considers the current evidence for a cause-to-effect relationship between hyperfiltration-related physical forces and the development of chronic kidney disease (CKD). Summary: Glomerular hyperfiltration is associated with glomerular and tubular hypertrophy. Hyperfiltration is mainly due to an increase in glomerular capillary pressure, which increases tensile stress applied to the capillary wall structures. In addition, the increased ultrafiltrate flow into Bowman’s space heightens shear stress on the podocyte foot processes and body surface. These mechanical stresses lead to an increase in glomerular basement membrane (GBM) length and to podocyte hypertrophy. The ability of the podocyte to grow being limited, a mismatch develops between the GBM area and the GBM area covered by foot processes, leading to podocyte injury, detachment of viable podocytes, adherence of capillaries to parietal epithelium, synechia formation and segmental sclerosis. Mechanical stress is also applied to post-filtration structures, resulting in dilation of glomerular and tubular urinary spaces, increased proximal tubular sodium reabsorption by hypertrophied epithelial cells and activation of mediators leading to tubulointerstitial inflammation, hypoxia and fibrosis Key Messages: GH-related mechanical stress leads to both adaptive and maladaptive glomerular and tubular changes. These flow-related effects play a central role in the pathogenesis of glomerular disease. Attenuation of hyperfiltration is thus an important therapeutic target in diabetes and obesity-induced CKD.
Surgery in Chronic Pancreatitis: Indication, Timing and Procedures
Authors: Bouwense Stefan A.W. , Kempeneers Marinus A. , van Santvoort Hjalmar C. , Boermeester Marja A. , van Goor Harry , Besselink Marc G. ,   Dutch Pancreatitis Study Group
Published: April 2019

Chronic pancreatitis is a chronic inflammation of the pancreas with pain as its severest symptom and often an impaired quality of life. Surgical intervention plays an important role in the management of pain but is generally kept as a last resort when conservative measures and endoscopy have failed. However, in the last few years multiple studies suggested the superiority of (early) surgical treatment in chronic pancreatitis for multiple end points, including pain relief. In this paper we highlight the most recent high-quality evidence on surgical therapy in chronic pancreatitis and the rationale for early (surgical) intervention.
The influence of mode of delivery on neonatal and maternal short and longterm outcomes
Authors: Prado Daniela Siqueira , Mendes Rosemar Barbosa , Gurgel Rosana Queiroz , Barreto Ikaro Daniel de Carvalho , Cipolotti Rosana , Gurgel Ricardo Queiroz
Published: April 2019

OBJECTIVE: To evaluate the impact of mode of delivery on breastfeeding incentive practices and on neonatal and maternal short and long-term complications. METHODS: A cohort study was conducted between June 2015 and April 2016 with 768 puerperal women from 11 maternities in Sergipe, interviewed in the first 24 hours, 45–60 days and 6–8 months after delivery. Associations between breastfeeding incentive practices, neonatal and maternal, both short-term and late complications, and the exposure variables were evaluated by the relative risk (95%CI) and the Fisher exact test. RESULTS: The C-section newborns had less skin-to-skin contact immediately after delivery (intrapartum C-section: 0.18, 95%CI 0.1–0.31 and elective C-section: 0.36, 95%CI 0.27–0.47) and less breastfeeding within one hour of birth (intrapartum C-section: 0.43, 95%CI 0.29–0.63 and elective C-section: 0.44, 95%CI 0.33–0.59). Newborns from elective C-section were less frequently breastfed in the delivery room 0.42 (95%CI 0.2–0.88) and roomed-in less 0.85 (95%CI 0.77–0.95). Women submitted to intrapartum C-section had greater risk of early complications 1.3 (95%CI 1.04–1.64, p = 0.037) and sexual dysfunction 1.68 (95%CI 1.14–2.48, p = 0.027). The frequency of neonatal complications, urinary incontinence and depression according to the mode of delivery was similar. CONCLUSIONS: The C-section was negatively associated with breastfeeding incentive practices; in addition, C-section after labor increased the risk of early maternal complications and sexual dysfunction.
Injury-Induced Shedding of Extracellular Vesicles Depletes Endothelial Cells of Cav-1 (Caveolin-1) and Enables TGF-β (Transforming Growth Factor-β)–Dependent Pulmonary Arterial Hypertension
Authors: Oliveira Suellen D.S. , Chen Jiwang , Castellon Maricela , Mao Mao , Raj J. Usha , Comhair Suzy , Erzurum Serpil , Silva Claudia L.M. , Machado Roberto F. , Bonini Marcelo G. , Minshall Richard D.
Published: April 2019

Objective—

To determine whether pulmonary arterial hypertension is associated with endothelial cell (EC)–Cav-1 (caveolin-1) depletion, EC-derived extracellular vesicle cross talk with macrophages, and proliferation of Cav-1 depleted ECs via TGF-β (transforming growth factor-β) signaling.

Approach and Results—

Pulmonary vascular disease was induced in Sprague-Dawley rats by exposure to a single injection of VEGFRII (vascular endothelial growth factor receptor II) antagonist SU5416 (Su) followed by hypoxia (Hx) plus normoxia (4 weeks each–HxSu model) and in WT (wild type;
Tie2.Cre
−
;
Cav1

lox/lox

) and EC-
Cav1
−/−
(Tie2.Cre
+
;
Cav1

fl/fl

) mice (Hx: 4 weeks). We observed reduced lung Cav-1 expression in the HxSu rat model in association with increased Cav-1+ extracellular vesicle shedding into the circulation. Whereas WT mice exposed to hypoxia exhibited increased right ventricular systolic pressure and pulmonary microvascular thickening compared with the group maintained in normoxia, the remodeling was further increased in EC-
Cav1
−/−
mice indicating EC Cav-1 expression protects against hypoxia-induced pulmonary hypertension. Depletion of EC Cav-1 was associated with reduced BMPRII (bone morphogenetic protein receptor II) expression, increased macrophage-dependent TGF-β production, and activation of pSMAD2/3 signaling in the lung. In vitro, in the absence of Cav-1, eNOS (endothelial NO synthase) dysfunction was implicated in the mechanism of EC phenotype switching. Finally, reduced expression of EC Cav-1 in lung histological sections from human pulmonary arterial hypertension donors was associated with increased plasma concentration of Cav-1, extracellular vesicles, and TGF-β, indicating Cav-1 may be a plasma biomarker of vascular injury and key determinant of TGF-β–induced pulmonary vascular remodeling.

Conclusions—

EC Cav-1 depletion occurs, in part, via Cav-1+ extracellular vesicle shedding into the circulation, which contributes to increased TGF-β signaling, EC proliferation, vascular remodeling, and pulmonary arterial hypertension.
Circulating TNFSF14 (Tumor Necrosis Factor Superfamily 14) Predicts Clinical Outcome in Patients With Stable Coronary Artery Disease
Authors: Hsu Chien-Yi , Tseng Wei-Kung , Wu Yen-Wen , Lin Tsung-Hsien , Yeh Hung-I. , Chang Kuan-Cheng , Wang Ji-Hung , Chou Ruey-Hsing , Huang Chun-Yao , Huang Po-Hsun , Leu Hsin-Bang , Yin Wei-Hsian , Wu Chau-Chung , Lin Shing-Jong , Chen Jaw-Wen
Published: April 2019

Objective—

Basic research indicates that TNFSF14 (tumor necrosis factor superfamily 14) may be involved in the pathogenesis of atherosclerosis. Given the requirements of new biomarkers for risk classification in coronary artery disease (CAD), we conducted a longitudinal analysis to investigate if TNFSF14 levels are associated with the risk of cardiovascular events among patients with stable CAD.

Approach and Results—

In total, 894 patients with CAD were enrolled in a multicenter prospective study. The primary outcome was the occurrence of cardiovascular death, nonfatal myocardial infarction, and stroke. The secondary outcome was the occurrence of all-cause death, nonfatal myocardial infarction, stroke, revascularization, and hospitalization because of angina or heart failure. During the mean follow-up period of 22±9 months, 32 patients reached the primary outcome and 166 patients reached the secondary outcome. Kaplan-Meier analysis showed that the event-free survival was significantly different in the first and fourth quartile groups in subjects categorized by TNFSF14 levels. In multivariate Cox proportional hazard regression analysis, TNFSF14 was independently associated with the risk of cardiovascular events after adjustment for various relevant factors (adjusted hazard ratio, 1.14; 95% CI, 1.04–1.25). In the validation cohort of 126 multivessel patients with CAD, TNFSF14 was confirmed to provide good prognostic predictive value for composite cardiovascular events (adjusted hazard ratio, 1.11; 95% CI, 1.04–1.19).

Conclusions—

This is the first study to demonstrate that increased TNFSF14 levels were independently associated with the occurrence of cardiovascular events in patients with stable CAD. Future studies are worthy to validate if TNFSF14 could be a novel prognostic biomarker for CAD outcomes over different populations.
Cell-Specific Effects of GATA (GATA Zinc Finger Transcription Factor Family)-6 in Vascular Smooth Muscle and Endothelial Cells on Vascular Injury Neointimal Formation
Authors: Zhuang Tao , Liu Jie , Chen Xiaoli , Pi Jingjiang , Kuang Yashu , Wang Yanfang , Tomlinson Brain , Chan Paul , Zhang Qi , Li Ying , Yu Zuoren , Zheng Xiangjian , Reilly Muredach , Morrisey Edward , Zhang Lin , Liu Zhongmin , Zhang Yuzhen
Published: April 2019

Objective—

Transcription factor GATA (GATA zinc finger transcription factor family)-6 is highly expressed in vessels and rapidly downregulated in balloon-injured carotid arteries and viral delivery of GATA-6 to the vessels limited the neointimal formation, however, little is known about its cell-specific regulation of in vivo vascular smooth muscle cell (VSMC) phenotypic state contributing to neointimal formation. This study aims to determine the role of vascular cell-specific GATA-6 in ligation- or injury-induced neointimal hyperplasia in vivo.

Approach and Results—

Endothelial cell and VSMC-specific GATA-6 deletion mice are generated, and the results indicate that endothelial cell-specific GATA-6 deletion mice exhibit significant decrease of VSMC proliferation and attenuation of neointimal formation after artery ligation and injury compared with the wild-type littermate control mice. PDGF (platelet-derived growth factor)-B is identified as a direct target gene, and endothelial cell-GATA-6-PDGF-B pathway regulates VSMC proliferation and migration in a paracrine manner which controls the neointimal formation. In contrast, VSMC-specific GATA-6 deletion promotes injury-induced VSMC transformation from contractile to proliferative synthetic phenotype leading to increased neointimal formation. CCN (cysteine-rich 61/connective tissue growth factor/nephroblastoma overexpressed family)-5 is identified as a novel target gene, and VSMC-specific CCN-5 overexpression in mice reverses the VSMC-GATA-6 deletion-mediated increased cell proliferation and migration and finally attenuates the neointimal formation.

Conclusions—

This study gives us a direct in vivo evidence of GATA-6 cell lineage-specific regulation of PDGF-B and CCN-5 on VSMC phenotypic state, proliferation and migration contributing to neointimal formation, which advances our understanding of in vivo neointimal hyperplasia, meanwhile also provides opportunities for future therapeutic interventions.
Abstract 104: The Use of Nitrated apolipoprotein A1 (NT-ApoA1) to Predict Mortality in Patients with Known or Suspected Coronary Artery Disease
Authors: Al-Sadawi Mohammed , Parpas Alexander , Ullah Abid , Avadhani Sriya , Javaid Kiran , Cavusoglu Samantha , Woo Lena , Kamran Haroon , Marmur Jonathan D , Cavusoglu Erdal
Published: April 2019

Background:
Studies have suggested that nitrated apolipoprotein A1 (NT-apoA1) levels may be associated with coronary artery disease (CAD). We therefore hypothesized that NT-apoA1 might be associated with the prediction of all-cause mortality in CAD patients.

Methods:
Using an ELISA, we measured plasma NT-apoA1 levels in 236 patients with known or suspected coronary artery disease (CAD) undergoing coronary angiography. The patients were then followed prospectively for the development of all-cause mortality for up to 7 years.

Results:
Lower NT-apoA1 levels were associated with worse renal function, lower HDL levels, higher triglyceride levels and lower ejection fraction. There was positive correlation between NT-apoA1 and HDL cholesterol levels (correlation coefficient 0.366; p <0.0001). After adjustment for a variety of baseline clinical, angiographic and laboratory parameters, log plasma NT-ApoA1 levels were an independent predictor of all-cause mortality [HR, 0.279; 95% CI, 0.084-0.922; p=0.036]. Furthermore, all-cause mortality was lower in patients whose plasma NT-ApoA1 levels were greater than or equal to the median value of the cohort compared to those whose levels were lower than median value (25.88% vs 8.82%; p = 0.001 by log-rank test).

Conclusions:
Higher NT-apoA1 levels are significantly associated with lower all-cause mortality in CAD patients, which may relate to HDL cholesterol function. Further studies are warranted to investigate this paradoxical finding.
Abstract 115: Gender Based Disparity in Transcatheter Aortic Valve Replacement Utilization: Insights from Nationwide Inpatient Sample 2012-2016
Authors: Dahiya Garima , Nestasie Michael , Power Juliette E , Bobby Kendra J , Qing Yin , Liu Anran , Joshi Aditya A , Buchanich Jeanine M , Poornima Indu G
Published: April 2019

Background:
Transcatheter aortic valve replacement (TAVR) has increasingly become the treatment of choice for symptomatic, severe aortic stenosis in patients at high surgical risk. While women have better morbidity & mortality outcomes following TAVR, it is unclear if there is gender disparity in utilization. We investigated gender-based utilization trends of TAVR and assessed associations with income quartiles & comorbidities.

Methods:
The Nationwide Inpatient Sample (NIS) data was queried from January 2012 to December 2016 to identify patients undergoing TAVR using International Classification of Diseases (ICD) procedural codes. Statistical analyses included baseline comparisons by gender, analyzing associations between gender, TAVR utilization, income & co-morbidities, with use of Chi-square test for categorical variables and Wilcoxon rank sum test for age. The associations were also analyzed using a propensity score matched subset & a logistic regression model.

Results:
We identified 21,859 TAVR patients (46.9% women, n=10,259). Women were older than men (median, IQR: 83, 77-87 vs 82, 76-87) and had higher prevalence of hypertension, diastolic heart failure, and pulmonary hypertension (p<0.001). Conversely diabetes, renal disease, atrial fibrillation, prior coronary angioplasty, and systolic heart failure were more prevalent in men (Table 1). TAVR utilization trend from 2012 to 2016 demonstrated a widening gap between the genders (p= 0.006) (Figure A). Median household income was associated with TAVR utilization in women in the entire cohort (p=0.028). However, in the propensity score matched subset, though heterogeniety was noted, the association was not significant per income quartile per year (Figure B). Combining data from all years, a multivariable logistic regression model confirmed that gender-based utilization did not associate with socio-economic factors such as income after adjustment for comorbidities.

Conclusion:
These findings showed widening utilization gap of TAVR between men and women, despite knowledge of better long-term outcomes in women. Economic factors were not associated with the gender disparity in TAVR utilization. Therefore, further research into TAVR registries is needed to analyze factors impacting this disparity and measures to correct it.
Abstract 121: An Investigation of Plant-based, Mediterranean, Paleolithic, and Dash Diets Study (the VA Beach Diet Study)
Authors: Edwards Joshua , Talreja Deepak , Buchanan Holly , Talreja Roshan , Thomas Brant , Hyeon Choi Hyeon , Clair Jesse S , Joyner Sarah , Dodani Sunita
Published: April 2019

Background and Study Objectives:
The rising incidence of cardiovascular disease (CVD) over the last 25 years has become a public health priority, especially its prevention through lifestyle interventions. Many studies have reported that higher adherence to Mediterranean, vegan or whole-food, plant based (WFPB) diets may decrease CVD incidence and mortality. However evidence on the health effects of various diets on CVD health is equivocal. The objective of this study is to compare and assess the relative impact of four different types of diets; i.e. a) WFPB; b) Mediterranean; c) Paleolithic; and d) Dietary Approaches to Stop Hypertension (DASH) diets on CVD health.

Methods:
This is a 6-month prospective clinical trial examining 280 participants stratified into four nonrandomized groups over a two month intervention with a follow up at six months of encouraged diet compliance. Clinical and behavioral measures related to CVD were collected; including, HDL, LDL, Total Cholesterol and Triglycerides. 60-day difference in CVD factors were analyzed using Repeated Measures ANOVA between all diets and two-tailed t-test to compare the WFPB diet vs. all other diets.

Results:
Significant 60-day differences between all diets were seen for HDL (p<0.0001), LDL (p<0.0002), Triglycerides (p<0.0001) and total cholesterol (p<0.0001). Between group analysis further revealed that participants on the WFPB diet had greater significant differences in LDL (14% decrease), triglycerides (18% decrease) and total cholesterol (13% decrease) compared to all other diets. Conversely, after 60 days, the Mediterranean diet (5% increase) followed by the DASH diet (3% increase) had significant greater increases in HDL when compared to the WFPB diet (10% decrease). After 6 months, significant decreases in HDL remained in the WFPB diet (20% decrease) compared to DASH and Paleo diets (both 8% decrease).

Conclusion:
Participants in the WFPB diet group demonstrated significant improvements in modifiable CVD risk factors compared to other diet categories over 60 days. Future research exploring the impact of quality of WFPB diets on long-term health outcomes is necessary
Abstract 133: Early Impact of Systematizing the Evaluation of Patients with Heart Failure Presenting to the Emergency Department
Authors: Hejjaji Vittal , Scholes Alison M , Khariton Yevgeniy , Kennedy Kevin , Dean Evelyn , Barrios Joseph , Spertus John A
Published: April 2019

Introduction:
It can be difficult in patients with heart failure (HF) who present to the emergency department (ED) with shortness of breath to decide who warrants admission and who can be safely sent home. At our institution, there was great variability across ED physicians’ admission rates (66%-100%). To address this, we developed an evidence-based protocol to support more consistent HF evaluation in the ED and implemented the program with the help of a multi-disciplinary team.

Methods:
HF patients presenting to the ED with shortness of breath were eligible for the CODE HF protocol, which was hinged on the use of the prospectively-validated Emergency Heart Failure Mortality Risk Grade (EHMRG) score. Patients with a <1% 7-day mortality were eligible for discharge, if their symptoms improved and the patient and ED physician were comfortable with discharge. The protocol also included HF education in the ED and follow-up. Outcomes included a comparison of patients on and off the CODE HF pathway (1/18-10/18) for ED length of stay, ED discharge, time to outpatient visits among those discharged from the ED and short-stay (potentially unnecessary) hospitalizations. Pearson Chi-square and one-way ANOVA tests were used for comparison. Given our experience that non-patient factors were responsible for not using the protocol, patient-level adjustment was not done.

Results:
A total of 112 patients out of 933 HF patients seen in the ED between 1/18 and 10/18 were managed through the CODE HF protocol. The EHMRG was calculated in 82 (73%) patients (45 high risk, 37 low risk). When used, the CODE HF protocol was associated with 46% greater rates of ED discharges (14.1% vs 25.9%), a 7-day faster cardiology follow-up visit (25 vs 16 days) and 36% fewer hospital short-stays of <48 hours (12.6% vs 8%) among admitted patients (p<0.05 for all). Importantly, the protocol reduced time in the ED by 42 minutes (288 vs 246 minutes).

Conclusions:
In this quality improvement pilot study, early implementation of the CODE HF protocol showed more effective care being delivered. A more robust study with wider implementation and evaluation of its impact on return visits is underway.
Abstract 141: Using Geographic Information Systems (GIS) to Analyze Statewide Regional Data - A Feasibility Project from the Kentucky Stroke Encounter Quality Improvement Project (SEQIP)
Authors: Moore Kari , Merritt Allison , Bobo Bonita , Graham Amy , Kuhn Alexander ,   Kentucky Stroke Encounter Quality Improvement Project (SEQIP)
Published: April 2019

Background:
The Stroke Encounter Quality Improvement Project (SEQIP) is a collaboration between certified stroke centers, the AHA/ASA and the Kentucky Department for Public Health (KDPH) to implement statewide QI initiatives to improve the care of stroke patients. From 2009 to 2018, 23 hospital in Kentucky participating in SEQIP have entered 76,222 stroke patient records into Get With The Guidelines® (GWTG) / Patient Management Tool™ (PMT).

Purpose:
Geographic information systems (GIS) tools can expand our understanding of care and outcomes based on patient location. The purpose of this project was to demonstrate the methods of linking a disease management registry with GIS mapping and analysis program,) to understand challenges when performing this link, and to derive meaningful insight on stroke care and outcomes by zip code.

Methods:
Stroke data from GWTG and PMT was compiled and downloaded by KDPH. The information was converted to a database file for use in ArcGIS. After excluding those who had missing or incomplete zip codes, records were Geocoded annually from 2009 to 2018. The data were then matched to one of 945 zip codes in Kentucky. Data were summarized by zip code, calendar year by the number of ischemic strokes; number IV alteplase administration; rate ischemic stroke receiving IV alteplase; number and rate of ischemic stroke patients arriving to hospital by EMS, privately owned vehicle or transfer; and median time from last known well to hospital arrival; and medical history of hypertension. Additional data including hospitals, certified stroke centers, drive time analysis, etc. were added to maps.

Results:
Mapping GWTG and PMT stroke data is feasible and may allow for additional analysis by location.

Conclusion:
Using GIS mapping and methodology can assist hospital stroke coordinators and public health officials in developing and implementing interventions to improvement stroke care and outcomes. Further analysis including socioeconomic, demographic and marketing/consumer preference data is planned to better understand variations by zip codes. This feasibility project provides an example of a useful application of GIS analyses applied to data registry including GWTG and PMT.
Abstract 146: Evolving Clinical Benefits and Social Value of Lipid Lowering Therapies
Authors: MacEwan Joanna P , Zhao Lauren M , Everson Katie , Liu Larry , Fang Sun , Lakdawalla Darius N
Published: April 2019

Background and Objectives:
In 2013-14, approximately 30% of adults (20 years of age or older) in the United States (US) had high low-density lipoprotein cholesterol (LDL-C, LDL-C≥ 200 mg/dL). Elevated LDL-C is associated with an increased risk of cardiovascular disease (CVD) related events and death, and a key target for therapy. The lipid lowering treatment (LLT) landscape has evolved significantly over the course of the last 40 years with the introduction of statins, fibrates, ezetimibe, CETP inhibitors, and PCSK9 inhibitors (PCSK9i). Currently, statins are first-line therapy for LDL-C reduction. This study quantified the effect of LLT use since 1987 on CVD-related mortality and morbidity.

Methods:
Descriptive analyses of the rates of LLT use and LLT spending over time were conducted using both NHANES (1999-2014) and MEPS data (1996-2016), and the association between LDL-C levels and mortality and hospitalizations were identified in the literature. By using hazard ratios from published clinical trials, and NHANES data on the number of LLT users and frequency of non-fatal CVD events among these users, the total number of non-fatal CVD events prevented over time was calculated. Events avoided were calculated as the difference between CVD events observed among LLT users and events that would have occurred in the absence of LLT use. The latter was calculated using the difference in events between treated and untreated patients in LLT trials. The value associated with the prevention of non-fatal CVD events due to LLT use was calculated as the product of the costs associated with treating CVD events and the total number of CVD events prevented. The value of mortality reduction was calculated as the product of the value of a statistical life year ($150,000) and the life expectancy gain from the WOSCOPS and ODYSSEY clinical trials. This value was compared with LLT spending.

Results:
The uptake of statins and ezetimibe between 1999 and 2014 prevented an estimated total of 2.8M myocardial infarctions (MIs) and 1.7M strokes in the US. The cumulative value derived from MI and stroke events prevented through statin and ezetimibe use, though largely driven by statin use, from 1999–2012 amounted to approximately $258B (2018 USD) and $37B, respectively. The use of statins from 1999–2012 resulted in an additional 12.6 million life-years at a value of $1.9T, and we estimate that statin use could generate an additional $953.1B in value to society from 2018–2025 through reductions in CVD mortality, with patients retaining 94% of the value.

Conclusions:
Innovation in the LLT landscape, particularly through the introduction and uptake of statins, ezetimibe and PCSK9is, yields significant value to society through the reduction of costs associated with both fatal and non-fatal CVD events. Of the value that accrues to society from the utilization of statins, patients retain approximately 95%.
Abstract 159: Did the Hospital Readmission Reduction Program Result in Delayed Readmissions Just After 30 days?
Authors: Nathan Ashwin S , Martinez Joseph , Giri Jay , Navathe Amol
Published: April 2019

Background:
The Hospital Readmission Reduction Program (HRRP) was enacted in March 2010 and imposed financial penalties beginning in October 2012 for hospitals with higher-than-expected 30-day readmissions for acute myocardial infarction (AMI), congestive heart failure (CHF) and pneumonia. The HRRP has been associated with reduced readmissions for these conditions, however, evidence has suggested an increase in mortality for heart failure and pneumonia as an unintended consequence of this program. Because of strong hospital responses to the HRRP, we examined whether hospitals postponed readmissions around the 30-day threshold, resulting in a spike in “delayed” readmission just after 30 days.

Methods:
Hospital admissions for AMI, CHF, and pneumonia were identified between January 2007 and October 2015 using the Medicare Provider Analysis and Review database, containing admissions for all fee-for-service Medicare enrollees. Stroke was studied as a control condition because it was not included in HRRP. Following prior literature, we divided the overall study period into three phases: January 2007 to March 2009 represented the pre-HRRP phase, April 2009 to September 2012 represented the implementation phase, and October 2012 to October 2015 represented the penalty phase. We used an interrupted time-series analysis to examine whether there was an increased probability of readmissions between days 31 to 35 as compared to days 25 to 30. This was implemented using Poisson and Quasi-Poisson models to generate a slope and intercept change model with adjustments for seasonality by condition. We then compared the changes in slopes for AMI, CHF, pneumonia and stroke in the separate phases.

Results:
A total of 68,020,501 admissions were included in this analysis. For AMI, the slopes for readmissions between days 31 to 35 as compared to days 25 to 30 over time were -0.003, 0.001 and -0.0003 for the three phases, respectively. The change in slope between the pre-HRRP and penalty phase was 0.003 (p=0.31). For pneumonia, the slopes for readmissions between days 31 to 35 as compared to days 25 to 30 over time were 0.002, -0.0004 and 0.001 for the three phases, respectively. The change in slope between the pre-HRRP and penalty phase was -0.001 (p=0.74). For CHF, the slopes for readmissions between days 31 to 35 as compared to days 25 to 30 over time were 0.001, -0.0002 and -0.001 for the three phases, respectively. The change in slope between the pre-HRRP and penalty phase was -0.001 (p=0.29). For stroke, the changes in slope between days 31 to 35 as compared to days 25 to 30 were 0.002, 0.0004 and -0.002 for the three phases, respectively. The change in slope between the pre-HRRP and penalty phase was -0.004 (p=0.11).

Conclusions:
Using a national sample of Medicare enrollees, we found no association between the start of HRRP and higher likelihood of readmissions for AMI, CHF, or pneumonia just after 30 days.
Abstract 174: Healthcare Provider Compliance with the 2013 ACC/AHA Blood Cholesterol Guidelines for Statin Therapy for Diabetic Patients of Ages 40 to 75
Authors: Saleh Ahmed , Ganatra Sarju , Labib Sherif
Published: April 2019

Introduction:
On the basis of documented outcome benefit in randomized clinical trials, 2013 ACC/AHA blood cholesterol guidelines advocate use of moderate to high intensity statin therapy in all diabetic patients ages 40 -75. Recent published observations suggest variable provider compliance with this recommendation. This study investigates provider adherence to this recommendation and the predictors of such decision-making at a single academic tertiary care center.

Methods:
We retrospectively reviewed all diabetic patients, ages of 40-75, who were evaluated at our institution in the outpatient setting in 2015. Patient characteristics including demographics, cardiovascular co-morbidities and statin use were obtained from the electronic medical records. Statin prescribing frequency was analyzed by age group, gender and indication, whether primary or secondary prevention. Correlation and regression analyses were done to determine the effect of patient characteristics on statin prescription and the predictors of prescribing statins, respectively.

Results:
Of the 18,389 patients with diabetes, 10,338 (56.2%) were on statin therapy of any dose. Of those treated, 94.9% were on appropriate statin intensity. In the multivariate model, independent predictors of failure to prescribe statins were: Absence of diagnosis of hyperlipidemia (OR 3.60, 95% CI 3.31-3.92, p<0.0005), absence of hypertension (OR 1.42, 95% CI 1.30-1.56, p<0.0005), absence of atherosclerotic cardiovascular disease (coronary, cerebral or peripheral arterial disease) (OR1.41, 95% CI 1.16-1.70, p=0.001), age less than 60 (OR 1.35, 95% CI 1.24-1.46, p<0.0005), and female gender (OR 1.27, 95% CI 1.17-1.38, p=0.037). Absence of coronary artery disease (46.7% vs 29.9%, p<0.0005), absence of stroke history (44.0% vs 36.9%, p=0.003), BMI less than 30 (45.3% vs 43.3%, p=0.027) and lack of a cardiologist provider (44.3% vs 41.9%, p=0.009) were associated with failure to prescribe statins, but were not independent predictors.

Conclusions:
Only 56.2% of patients in an outpatient setting in our study who have an indication for statin use on the basis of diabetes received a prescription for statin therapy. Independent predictors of failure to prescribe statins were: absence of hyperlipidemia, absence of hypertension, absence of ischemic vascular disease, age less than 60, and female gender. Future educational interventions should focus on these predictors in order to improve provider compliance with initiation of statin therapy in eligible diabetic patients.