bluuebunny/crossref_metadata_2025 huggingface dataset:
Area PEc Neurons Use a Multiphasic Pattern of Activity to Signal the Spatial Properties of Optic Flow
Authors: Raffi Milena , Piras Alessandro , Calzavara Roberta , Squatrito Salvatore
Published: November 2017

The cortical representation of visual perception requires the integration of several-signal processing distributed across many cortical areas, but the neural substrates of such perception are largely unknown. The type of firing pattern exhibited by single neurons is an important indicator of dynamic circuitry within or across cortical areas. Neurons in area PEc are involved in the spatial mapping of the visual field; thus, we sought to analyze the firing pattern of activity of PEc optic flow neurons to shed some light on the cortical processing of visual signals. We quantified the firing activity of 152 optic flow neurons using a spline interpolation function, which allowed determining onset, end, and latency of each neuronal response. We found that many PEc neurons showed multiphasic activity, which is strictly related to the position of the eye and to the position of the focus of expansion (FOE) of the flow field. PEc neurons showed a multiphasic activity comprised of excitatory phases interspersed with inhibitory pauses. This phasic pattern seems to be a very efficient way to signal the spatial location of visual stimuli, given that the same neuron sends different firing patterns according to a specific combination of FOE/eye position.
The Effects of BMP-2, miR-31, miR-106a, and miR-148a on Osteogenic Differentiation of MSCs Derived from Amnion in Comparison with MSCs Derived from the Bone Marrow
Authors: Manochantr Sirikul , Marupanthorn Kulisara , Tantrawatpan Chairat , Kheolamai Pakpoom , Tantikanlayaporn Duangrat , Sanguanjit Prakasit
Published: November 2017

Mesenchymal stromal cells (MSCs) offering valuable anticipations for the treatment of degenerative diseases. They can be found in many tissues including amnion. MSCs from amnion (AM-MSCs) can differentiate into osteoblast similar to that of bone marrow-derived MSCs (BM-MSCs). However, the ability is not much efficient compared to BM-MSCs. This study aimed to examine the effects of BMP-2 and miRNAs on osteogenic differentiation of AM-MSCs compared to those of BM-MSCs. The osteogenic differentiation capacity after miRNA treatment was assessed by ALP expression, ALP activity, and osteogenic marker gene expression. The results showed that the osteogenic differentiation capacity increased after BMP-2 treatment both in AM-MSCs and BM-MSCs. MiR-31, miR-106a, and miR-148a were downregulated during the osteogenic differentiation. After transfection with anti-miRNAs, ALP activity and osteogenic genes were increased over the time of differentiation. The data lead to the potential for using AM-MSCs as an alternative source for bone regeneration. Moreover, the information of miRNA expression and function during osteogenic differentiation may be useful for the development of new therapeutics or enhanced an in vitro culture technique required for stem cell-based therapies in the bone regeneration.
Understanding the Spatial Heterogeneity of CO2 and CH4 Fluxes from an Urban Shallow Lake: Correlations with Environmental Factors
Authors: Zhao Zhenhua , Zhang Dan , Shi Wenmei , Ruan Xiaohong , Sun Jie
Published: November 2017

The spatial variability of carbon dioxide (CO2) and methane (CH4) fluxes across water-air interface in Xuanwu Lake was investigated in two seasons. Due to anthropogenic disturbances, the environmental factors and the fluxes of CO2 and CH4 in lake showed obvious spatial and seasonal variability; their average fluxes in summer are significantly higher than those in autumn. The fluxes in heavy pollution sites with high concentrations of nitrogen and phosphorus nutrient in summer were 3.9 times (142.14 : 36.07 mg·m−2·h−1) for CO2 and 22.3 times for CH4 (6.46 : 0.29) higher than those in little pollution sites. In autumn, they were 12.3 times and 7.1 times higher, respectively. Anthropogenic disturbance and heavy pollution increased their fluxes, but aquatic plants reduced the emission of CO2. Except the sampling site with flourishing lotus, most of sampling sites without aquatic plant are the emission source of CO2 and CH4. The correlation analysis, multiple stepwise regression, and redundancy analysis showed the key environmental factors for CO2 including temperature (T), pH, chemical oxygen demand (CODMn) in water, organic matter (OM), total nitrogen, and ammonia nitrogen in water and sediment. As for CH4, the key environmental factors include turbidity, oxidation-reduction potential, dissolved oxygen, CODMn, and T in water and OM and N-NH4+ in sediment.
Testicular Dysfunction Ameliorative Effect of the Methanolic Roots Extracts of Maytenus procumbens and Ozoroa paniculosa
Authors: Cele Nkosinathi David , Sangweni Nonhlakanipho Felicia , Mosa Rebamang Anthony , Penduka Dambudzo , Lazarus Geraldine Genevive , Singh Moganavelli , Zharare Godfrey Elijah , Opoku Andy Rowland
Published: November 2017

The traditional use of medicinal plants in the management of sexual dysfunctions has a long history. This study investigated testicular dysfunction ameliorative effect of the methanolic roots extracts of Maytenus procumbens and Ozoroa paniculosa in a butanol‐induced testicular dysfunction rat model. The rats in respective experimental groups were orally administered with the extract at 50 and 250 mg/kg bw, daily for 28 days. The cytotoxicity of the extracts was evaluated against HEK293, MCF‐7, and HT29 cell lines. The extracts exhibited moderate (LC50 30.3–330.2 μg/mL) to weak (LC50 200.8–438.4 μg/mL) cytotoxicity level on the cancer and normal cells, respectively. While relatively lower serum testosterone levels and total sperm count along with decreased numbers of spermatogonia were noted in the untreated group, all these parameters were improved in the groups treated with the extracts at 250 mg/kg. Improved histomorphological changes of the testes were also observed when compared to the untreated group. While the extracts (at 250 mg/kg) increased serum reduced glutathione content and decreased malondialdehyde content, a relatively higher serum creatinine level was also observed in the treated animals group. The results indicate that the two plant extracts have potential to ameliorate testicular dysfunction.
Inventory Control System for a Healthcare Apparel Service Centre with Stockout Risk: A Case Analysis
Authors: Pan An , Hui Chi-Leung
Published: November 2017

Based on the real-world inventory control problem of a capacitated healthcare apparel service centre in Hong Kong which provides tailor-made apparel-making services for the elderly and disabled people, this paper studies a partial backordered continuous review inventory control problem in which the product demand follows a Poisson process with a constant lead time. The system is controlled by an (Q,r) inventory policy which incorporate the stockout risk, storage capacity, and partial backlog. The healthcare apparel service centre, under the capacity constraint, aims to minimize the inventory cost and achieving a low stockout risk. To address this challenge, an optimization problem is constructed. A real case-based data analysis is conducted, and the result shows that the expected total cost on an order cycle is reduced substantially at around 20% with our proposed optimal inventory control policy. An extensive sensitivity analysis is conducted to generate additional insights.
A Language as a Self-Organized Critical System
Authors: Gromov Vasilii A. , Migrina Anastasia M.
Published: November 2017

A natural language (represented by texts generated by native speakers) is considered as a complex system, and the type thereof to which natural languages belong is ascertained. Namely, the authors hypothesize that a language is a self-organized critical system and that the texts of a language are “avalanches” flowing down its word cooccurrence graph. The respective statistical characteristics for distributions of the number of words in the texts of English and Russian languages are calculated; the samples were constructed on the basis of corpora of literary texts and of a set of social media messages (as a substitution to the oral speech). The analysis found that the number of words in the texts obeys power-law distribution.
Solid Lipid Curcumin Particles Induce More DNA Fragmentation and Cell Death in Cultured Human Glioblastoma Cells than Does Natural Curcumin
Authors: Maiti Panchanan , Al-Gharaibeh Abeer , Kolli Nivya , Dunbar Gary L.
Published: November 2017

Despite recent advancements in cancer therapies, glioblastoma multiforme (GBM) remains largely incurable. Curcumin (Cur), a natural polyphenol, has potent anticancer effects against several malignancies, including metastatic brain tumors. However, its limited bioavailability reduces its efficiency for treating GBM. Recently, we have shown that solid lipid Cur particles (SLCPs) have greater bioavailability and brain tissue penetration. The present study compares the efficiency of cell death by Cur and/or SLCPs in cultured GBM cells derived from human (U‐87MG) and mouse (GL261) tissues. Several cell viability and cell death assays and marker proteins (MTT assay, annexin‐V staining, TUNEL staining, comet assay, DNA gel electrophoresis, and Western blot) were investigated following the treatment of Cur and/or SLCP (25 μM) for 24–72 h. Relative to Cur, the use of SLCP increased cell death and DNA fragmentation, produced longer DNA tails, and induced more fragmented nuclear lobes. In addition, cultured GBM cells had increased levels of caspase‐3, Bax, and p53, with decreases in Bcl2, c‐Myc, and both total Akt, as well as phosphorylated Akt, when SLCP, rather Cur, was used. Our in vitro work suggests that the use of SLCP may be a promising strategy for reversing or preventing GBM growth, as compared to using Cur.
Advances and Current Concepts in the Medical Management of Gastroenteropancreatic Neuroendocrine Neoplasms
Authors: Alexandraki Krystallenia I. , Karapanagioti Aggeliki , Karoumpalis Ioannis , Boutzios Georgios , Kaltsas Gregory A.
Published: November 2017

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare and heterogeneous group of tumors presenting as localised or metastatic disease and in a subset with distinct clinical syndromes. Treatment is aimed at controlling the functional syndrome, eradicating the tumor, and/or preventing further tumor growth. Surgery is the treatment of choice in removing the primary tumor and/or reducing tumor burden but cannot be applied to all patients. Somatostatin analogs (SS-analogs) obtain control of functional syndromes in the majority of GEP-neuroendocrine tumors (NETs); phase III trials have shown that SS-analogs can be used as first-line antiproliferative treatment in patients with slow-growing GEP-NETs. The role of the recently approved serotonin inhibitor, telotristat ethyl, and gastrin receptor antagonist, netazepide, is evolving. Streptozotocin-based chemotherapy has been used for inoperable or progressing pancreatic NENs but the orally administered combination of capecitabine/temozolomide is becoming more popular due to its better tolerability and potential effect in other GEP-NENs. Phase III trials have shown efficacy of molecular targeted therapies in GEP-NETs and of radionuclide treatment in patients with midgut carcinoid tumors expressing somatostatin receptors. Most patients will develop disease progression necessitating further therapeutic options. A combination of currently available treatments along with the molecular signature of each tumor will guide future treatment.
Disparity Between Indications for and Utilization of Implantable Cardioverter Defibrillators in Asian Patients With Heart Failure
Authors: Chia Yvonne May Fen , Teng Tiew-Hwa Katherine , Tan Eugene S.J. , Tay Wan Ting , Richards A. Mark , Chin Calvin Woon Loong , Shimizu Wataru , Park Sang Weon , Hung Chung-Lieh , Ling Lieng H. , Ngarmukos Tachapong , Omar Razali , Siswanto Bambang B. , Narasimhan Calambur , Reyes Eugene B. , Yu Cheuk-Man , Anand Inder , MacDonald Michael R. , Yap Jonathan , Zhang Shu , Finkelstein Eric A. , Lam Carolyn S.P.
Published: November 2017

Background—

Implantable cardioverter defibrillators (ICDs) are lifesaving devices for patients with heart failure (HF) and reduced ejection fraction. However, utilization and determinants of ICD insertion in Asia are poorly defined. We determined the utilization, associations of ICD uptake, patient-perceived barriers to device therapy and, impact of ICDs on mortality in Asian patients with HF.

Methods and Results—

Using the prospective ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) registry, 5276 patients with symptomatic HF and reduced ejection fraction (HFrEF) from 11 Asian regions and across 3 income regions (high: Hong Kong, Japan, Korea, Singapore, and Taiwan; middle: China, Malaysia, and Thailand; and low: India, Indonesia, and Philippines) were studied. ICD utilization, clinical characteristics, as well as device perception and knowledge, were assessed at baseline among ICD-eligible patients (EF ≤35% and New York Heart Association Class II-III). Patients were followed for the primary outcome of all-cause mortality. Among 3240 ICD-eligible patients (mean age 58.9±12.9 years, 79.1% men), 389 (12%) were ICD recipients. Utilization varied across Asia (from 1.5% in Indonesia to 52.5% in Japan) with a trend toward greater uptake in regions with government reimbursement for ICDs and lower out-of-pocket healthcare expenditure. ICD (versus non-ICD) recipients were more likely to be older (63±11 versus 58±13 year;
P
<0.001), have tertiary (versus ≤primary) education (34.9% versus 18.1%;
P
<0.001) and be residing in a high (versus low) income region (64.5% versus 36.5%;
P
<0.001). Among 2000 ICD nonrecipients surveyed, 55% were either unaware of the benefits of, or needed more information on, device therapy. ICD implantation reduced risks of all-cause mortality (hazard ratio, 0.71; 95% confidence interval, 0.52–0.97) and sudden cardiac deaths (hazard ratio, 0.33; 95% confidence interval, 0.14–0.79) over a median follow-up of 417 days.

Conclusions—

ICDs reduce mortality risk, yet utilization in Asia is low; with disparity across geographic regions and socioeconomic status. Better patient education and targeted healthcare reforms in extending ICD reimbursement may improve access.

Clinical Trial Registration—

URL:
https://clinicaltrials.gov/ct2/show/NCT01633398
. Unique identifier: NCT01633398.
Migration and Cardiovascular Disease Risk Among Ghanaian Populations in Europe:
Authors: Boateng Daniel , Agyemang Charles , Beune Erik , Meeks Karlijn , Smeeth Liam , Schulze Matthias , Addo Juliet , de-Graft Aikins Ama , Galbete Cecilia , Bahendeka Silver , Danquah Ina , Agyei-Baffour Peter , Owusu-Dabo Ellis , Mockenhaupt Frank P. , Spranger Joachim , Kengne Andre P. , Grobbee Diederick E. , Stronks Karien , Klipstein-Grobusch Kerstin
Published: November 2017

Background—

For migrant populations from sub-Saharan Africa, adverse cardiovascular disease (CVD) risk factors have been observed to be higher than found in their home country-based counterparts or among the host populations in high-income countries. Differences in absolute overall CVD risk, however, remain largely unexplained. We, therefore, predicted the differences in 10-year CVD risk among sub-Saharan African migrants (Ghanaians) living in 3 European cities and Ghana.

Methods and Results—

For 3864 subjects aged 40 to 70 years from the multicenter RODAM study (Research on Obesity and Diabetes Among African Migrants) conducted among Ghanaian adults residing in rural and urban Ghana and 3 European cities (Amsterdam, Berlin, and London), 10-year risk of CVD was estimated using the Pooled Cohort Equations with estimates ≥7.5% defining high CVD risk. Logistic regressions were used to determine the association of migration on CVD risk. The proportion with CVD risk ≥7.5% among Ghanaian men was 34.7% in rural Ghana, 45.4% in urban Ghana, 53.9% in Amsterdam, 61.0% in Berlin, and 52.2% in London. Compared with rural Ghana, CVD risk was significantly increased for Ghanaian men living in Berlin (adjusted odds ratio, 2.80; 95% confidence interval, 1.76–4.45) and Amsterdam (1.88; 1.25–2.84). Increased risk observed for men was largely not seen for women. CVD risk increased with longer stay in Europe.

Conclusions—

Knowledge about predictors of increased CVD risk among sub-Saharan African migrants in Europe and nonmigrants in urban centers will inform and support targeted health care and interventions to these populations.
Disparities in Management of Cardiovascular Disease in Rural South Africa
Authors: Jardim Thiago Veiga , Reiger Sheridan , Abrahams-Gessel Shafika , Crowther Nigel J. , Wade Alisha , Gómez-Olivé F. Xavier , Salomon Joshua , Tollman Stephen , Gaziano Thomas A.
Published: November 2017

Background—

Optimal secondary prevention is critical for the reduction of repeated cardiovascular events, and the control of cardiovascular risk factors in this context is essential. Data on secondary prevention of cardiovascular disease (CVD) in sub-Saharan Africa are needed to inform intervention strategies with a particular focus on local disparities. The aim of this study was to assess CVD management in a rural community in northeast South Africa.

Methods and Results—

We recruited adults aged ≥40 years residing in the Agincourt subdistrict of Mpumalanga province. Data collection included socioeconomic and clinical data, anthropometric measures, blood pressure, human immunodeficiency virus status, and point-of-care glucose and lipid levels. CVD was defined as self-report of myocardial infarction and stroke or angina diagnosed by Rose Criteria. A linear regression model was built to identify variables independently associated with the number of cardiovascular risk factors controlled. Of 5059 subjects, 592 (11.7%) met CVD diagnostic criteria. Angina was reported in 77.0% of these subjects, stroke in 25.2%, and myocardial infarction in 3.7%. Percent controlled of the 5 individual risk factors assessed were as follows: tobacco 92.9%; blood pressure 51.2%; body mass index 33.8%; low-density lipoprotein 31.4%; and waist-to-hip ratio 29.7%. Only 4.4% had all 5 risk factors controlled and 42.4% had ≥3 risk factors controlled. Male sex (β coefficient=0.44; 95% confidence interval, 0.25–0.63;
P
<0.001), absence of physical disability (β coefficient=0.40; 95% confidence interval, 0.16–0.65;
P
=0.001), and socioeconomic status (β coefficient=0.10; 95% confidence interval, 0.01–0.19;
P
=0.035) were directly associated with the number of risk factors controlled.

Conclusions—

Currently, CVD is not being optimally managed in this rural area of South Africa. There are significant disparities in control of CVD risk factors by sex, socioeconomic status, and level of disability. Efforts to improve secondary prevention in this population should be focused on females, subjects from lower socioeconomic status, and those with physical disabilities.
Availability, Sales, and Affordability of Tobacco Cessation Medicines in Kerala, India
Authors: Sarma Smitha , Harikrishnan Sivadasanpillai , Baldridge Abigail S. , Devarajan Raji , Mehta Aashna , Selvaraj Sakhtivel , Ali Mohammed K. , Mohanan Padinhare P. , Prabhakaran Dorairaj , Huffman Mark D.
Published: November 2017

Background—

India is the world’s second largest consumer of tobacco, but tobacco cessation remains uncommon due, at least in part, to underutilization of cessation pharmacotherapy. We evaluated the availability, sales, and affordability of nicotine replacement therapy, bupropion, and varenicline in the South Indian state of Kerala to understand potential reasons for underutilization.

Methods and Results—

From November 2016 to April 2017, we collected data on availability, inventory, and pricing of cessation medication through a cross-sectional survey of 199 public, semiprivate (Karunya), and private pharmacies across 5 districts in Kerala using World Health Organization/Health Action International methodology. Revenue and sales data were obtained from the latest Pharmatrac medication database. We assessed affordability using individual- and household-level income and expenditure data collected from November 2014 to November 2016 through the Acute Coronary Syndrome Quality Improvement in Kerala randomized trial. Cessation medications were not available in public hospitals (0%, n=58) nor in public specialty centers (0%, n=10) including those designated to provide cessation services. At least 1 cessation medicine was available at 63% of private pharmacies (n=109) and 27% of Karunya (semiprivate) pharmacies (n=22). Among the 75 pharmacies that stocked cessation medications, 96% had nicotine replacement therapy, 28% had bupropion, and 1% had varenicline. No outlets had sufficient inventory for a patient to purchase a 12-week treatment regimen. There were an estimated 253 270 treatment regimens sold throughout India and 14 092 in Kerala in 2013 to 2014. Treatment regimens cost 1.9 to 13.0× the median amount spent on smoked tobacco and between 8% and 52% of nonsubsistence income.

Conclusions—

Tobacco cessation medications are unavailable in the Kerala public sector and have limited availability in the private and semiprivate sectors. When available, medications are unaffordable for most patients. Addition of tobacco cessation medication onto national and state essential medicines lists may help increase access.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02256657.
Incremental Value of Repeated Risk Factor Measurements for Cardiovascular Disease Prediction in Middle-Aged Korean Adults
Authors: Cho In-Jeong , Sung Ji Min , Chang Hyuk-Jae , Chung Namsik , Kim Hyeon Chang
Published: November 2017

Background—

Increasing evidence suggests that repeatedly measured cardiovascular disease (CVD) risk factors may have an additive predictive value compared with single measured levels. Thus, we evaluated the incremental predictive value of incorporating periodic health screening data for CVD prediction in a large nationwide cohort with periodic health screening tests.

Methods and Results—

A total of 467 708 persons aged 40 to 79 years and free from CVD were randomly divided into development (70%) and validation subcohorts (30%). We developed 3 different CVD prediction models: a single measure model using single time point screening data; a longitudinal average model using average risk factor values from periodic screening data; and a longitudinal summary model using average values and the variability of risk factors. The development subcohort included 327 396 persons who had 3.2 health screenings on average and 25 765 cases of CVD over 12 years. The C statistics (95% confidence interval [CI]) for the single measure, longitudinal average, and longitudinal summary models were 0.690 (95% CI, 0.682–0.698), 0.695 (95% CI, 0.687–0.703), and 0.752 (95% CI, 0.744–0.760) in men and 0.732 (95% CI, 0.722–0.742), 0.735 (95% CI, 0.725–0.745), and 0.790 (95% CI, 0.780–0.800) in women, respectively. The net reclassification index from the single measure model to the longitudinal average model was 1.78% in men and 1.33% in women, and the index from the longitudinal average model to the longitudinal summary model was 32.71% in men and 34.98% in women.

Conclusions—

Using averages of repeatedly measured risk factor values modestly improves CVD predictability compared with single measurement values. Incorporating the average and variability information of repeated measurements can lead to great improvements in disease prediction.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02931500.
Occurrence and Features of Childhood Myocarditis: A Nationwide Study in Finland
Authors: Arola Anita , Pikkarainen Essi , Sipilä Jussi OT , Pykäri Jouni , Rautava Päivi , Kytö Ville
Published: November 2017

Background

Epidemiology of myocarditis in childhood is largely unknown. Men are known to have a higher incidence of myocarditis than women in adults aged <50 years, but whether this is true by sex in pediatric age groups is unknown. We set out to study the occurrence and potential sex differences of myocarditis in a general pediatric population.

Methods and Results

Data of all hospital admissions with myocarditis in Finland occurring in patients aged ≤15 years from 2004 to 2014 were collected from a mandatory nationwide registry. All patients with myocarditis as a primary, secondary, or tertiary cause of admission were included. Total and age‐ and sex
‐
specific incidence rates were calculated using corresponding population data. There were 213 admissions with myocarditis in pediatric patients. Myocarditis was the primary cause of admission in 86%. The overall incidence rate of myocarditis was 1.95/100 000 person‐years. Of all patients, 77% were boys, but sex differences in incidence rates were age‐dependent. In children aged 0 to 5 years, there was no sex difference in the occurrence of myocarditis. Boys aged 6 to 10 years had a higher incidence rate compared with girls (72% boys; incidence rate ratio: 2.46; 95% confidence interval, 1.03–5.89;
P
=0.04). Sex difference further increased in children aged 11 to 15 years (80% boys; incidence rate ratio: 3.5; 95% confidence interval, 2.68–5.67;
P
<0.0001).

Conclusions

Myocarditis leading to hospital admission is relatively uncommon in children, but occurrence of myocarditis increases with age. There is no sex difference in the risk of myocarditis during the first 6 years of life, but boys have a significantly higher risk at ages 6 to 15 years.
Regional Validation and Recalibration of Clinical Predictive Models for Patients With Acute Heart Failure
Authors: Wessler Benjamin S. , Ruthazer Robin , Udelson James E. , Gheorghiade Mihai , Zannad Faiez , Maggioni Aldo , Konstam Marvin A. , Kent David M.
Published: November 2017

Background

Heart failure clinical practice guidelines recommend applying validated clinical predictive models (
CPM
s) to support decision making. While
CPM
s are now widely available, the generalizability of heart failure
CPM
s is largely unknown.

Methods and Results

We identified
CPM
s derived in North America that predict mortality for patients with acute heart failure and validated these models in different world regions to assess performance in a contemporary international clinical trial (N=4133) of patients with acute heart failure treated with guideline‐directed medical therapy. We performed independent external validations of 3
CPM
s predicting in‐hospital mortality, 60‐day mortality, and 1‐year mortality, respectively.
CPM
discrimination decreased in all regional validation cohorts. The median change in area under the receiver operating curve was −0.09 (range −0.05 to −0.23). Regional calibration was highly variable (90th percentile of absolute difference between smoothed observed and predicted values range <1% to >50%). Calibration remained poor after global recalibrations; however, region‐specific recalibration procedures significantly improved regional performance (recalibrated 90th percentile of absolute difference range <1% to 5% across all regions and all models).

Conclusions

Acute heart failure
CPM
discrimination and calibration vary substantially across different world regions; region‐specific (as opposed to global) recalibration techniques are needed to improve
CPM
calibration.
Hypothermia Modulates Arrhythmia Substrates During Different Phases of Resuscitation From Ischemic Cardiac Arrest
Authors: Piktel Joseph S. , Cheng Aurelia , McCauley Matthew , Dale Zack , Nassal Michelle , Maleski Danielle , Pawlowski Gary , Laurita Kenneth R. , Wilson Lance D.
Published: November 2017

Background

We designed an innovative porcine model of ischemia‐induced arrest to determine dynamic arrhythmia substrates during focal infarct, global ischemia from ventricular tachycardia or fibrillation (VT/VF) and then reperfusion to determine the effect of therapeutic hypothermia (
TH
) on dynamic arrhythmia substrates and resuscitation outcomes.

Methods and Results

Anesthetized adult pigs underwent thoracotomy and regional plunge electrode placement in the left ventricle. Subjects were then maintained at either control (
CT
; 37°C, n=9) or
TH
(33°C, n=8). The left anterior descending artery (LAD) was occluded and ventricular fibrillation occurred spontaneously or was induced after 30 minutes. Advanced cardiac life support was started after 8 minutes, and
LAD
reperfusion occurred 60 minutes after occlusion. Incidences of
VF
/
VT
and survival were compared with ventricular ectopy, cardiac alternans, global dispersion of repolarization during
LAD
occlusion, and
LAD
reperfusion. There was no difference in incidence of
VT
/
VF
between groups during
LAD
occlusion (44% in
CT
versus 50% in
TH;
P
=1s). During
LAD
occlusion, ectopy was increased in
CT
and suppressed in
TH
(33±11 ventricular ectopic beats/min versus 4±6 ventricular ectopic beats/min;
P
=0.009). Global dispersion of repolarization and cardiac alternans were similar between groups. During
LAD
reperfusion,
TH
doubled the incidence of cardiac alternans compared with
CT
, with a marked increase in
VF
/
VT
(100% in
TH
versus 17% in
CT
;
P
=0.004). Ectopy and global dispersion of repolarization were similar between groups during
LAD
reperfusion.

Conclusions

TH
alters arrhythmia substrates in a porcine translational model of resuscitation from ischemic cardiac arrest during the complex phases of resuscitation.
TH
worsens cardiac alternans, which was associated with an increase in spontaneous
VT
/
VF
during reperfusion.
Elevated Baseline Serum Fibrinogen: Effect on 2‐Year Major Adverse Cardiovascular Events Following Percutaneous Coronary Intervention
Authors: Ang Lawrence , Behnamfar Omid , Palakodeti Samhita , Lin Felice , Pourdjabbar Ali , Patel Mitul P. , Reeves Ryan R. , Mahmud Ehtisham
Published: November 2017

Background

Elevated fibrinogen is associated with short‐term major adverse cardiovascular events (
MACE
) after percutaneous coronary intervention, but the relation with late
MACE
is unknown.

Methods and Results

Baseline demographics and 2‐year
MACE
were recorded among subjects undergoing nonemergent percutaneous coronary intervention. A total of 332 subjects (66.6±19.5 years, 69.9% male, 25.3% acute coronary syndrome) were enrolled. Two‐year
MACE
(periprocedural myocardial infarction 9.0%, rehospitalization 6.3%, revascularization 12.7%, non–periprocedural myocardial infarction 4.5%, stent thrombosis 0.9%, stroke 1.8%, and death 0.6%) were associated with higher fibrinogen (352.8±123.4 mg/dL versus 301.6±110.8 mg/dL;
P
<0.001), longer total stent length (40.1±25.3 mm versus 32.1±19.3 mm;
P
=0.004), acute coronary syndrome indication (38.7% versus 17.8%;
P
<0.001), number of bare‐metal stents (0.5±1.1 versus 0.2±0.5;
P
=0.002), and stent diameter ≤2.5 mm (55.8% versus 38.4%,
P
=0.003). No relation between platelet reactivity and 2‐year
MACE
was observed. Fibrinogen ≥280 mg/dL (odds ratio [
OR
] 3.0, confidence interval [
CI
], 1.6–5.4,
P
<0.001), total stent length ≥32 mm (
OR
2.2,
CI
, 1.3–3.8,
P
<0.001), acute coronary syndrome indication (
OR
4.1,
CI
, 2.3–7.5,
P
<0.001), any bare‐metal stents (
OR
3.2,
CI
, 1.6–6.1,
P
<0.001), and stent diameter ≤2.5 mm (
OR
2.0,
CI
, 1.2–3.5,
P
=0.010) were independently associated with 2‐year
MACE
. Following a landmark analysis excluding periprocedural myocardial infarction, fibrinogen ≥280 mg/dL remained strongly associated with 2‐year
MACE
(37.0% versus 17.4%, log‐rank
P
<0.001).

Conclusions

Elevated baseline fibrinogen level is associated with 2‐year
MACE
after percutaneous coronary intervention. Acute coronary syndrome indication for percutaneous coronary intervention, total stent length implanted, and use of bare‐metal stents or smaller‐diameter stents are also independently associated with 2‐year
MACE
, while measures of on‐thienopyridine platelet reactivity are not.
Induction of Dendritic Cell–Mediated Activation of T Cells From Atherosclerotic Plaques by Human Heat Shock Protein 60
Authors: Rahman Mizanur , Steuer Johnny , Gillgren Peter , Hayderi Assim , Liu Anquan , Frostegård Johan
Published: November 2017

Background

Atherosclerosis is characterized by the presence of activated immune‐competent cells including dendritic cells (
DC
s) and T cells, dead cells, and oxidized low‐density lipoprotein. HSP60 (Heat shock protein 60) has been implicated in atherosclerosis. A plasma protein, Annexin A5, has atheroprotective properties.

Methods and Results

Human
DC
s differentiated from peripheral blood monocytes were treated with human
HSP
60 or
HSP
90 and autologous T cells were cocultured with these pretreated
DC
s (
mDC
s).
HSP
60 induced
mDC
s and T‐cell activation as determined by
FACS
can (Fluorescence associated cell scan), gene‐activation, and cytokine production.
HSP
60‐induced T‐cell activation was partly major histocompatibility complex class
II
–dependent. T cells exposed to
HSP
60‐treated
mDC
s produced interferon‐γ, interleukin‐17, but not transforming growth factor‐β.
HSP
60 did not promote expression of Toll‐like receptors 2 or 4.
HSP
90 promoted
mDC
s maturation but had no effect on T‐cell activation. Annexin A5 inhibited
HSP
60‐proinflammatory Th1/Th17 effects on
mDC
s and T cells, and partly bound
HSP
60. Further, Annexin A5 inhibited
HSP
‐induced activation of
mDC
s and also oxidized low‐density lipoprotein–induced
HSP
‐production from
mDC
s. Experiments on
mDC
s and T cells derived from carotid atherosclerotic plaques from patients with symptomatic carotid disease gave similar results as from blood donors.

Conclusions

HSP
60 induces
mDC
s activation and partly major histocompatibility complex class
II
–dependent activation of blood‐ and plaque‐derived T cells, which is mostly of Th1/Th17 type.
HSP
60 could thus be an important T‐cell antigen in plaques, and also mediate oxidized low‐density lipoproteins immunogenic effects on
DC
‐T‐cell activation, promoting plaque rupture and clinical manifestations of cardiovascular disease. Annexin A5 inhibits both oxidized low‐density lipoprotein–induced
HSP
60, and
HSP
60‐mediated immune activation, which suggests a potential therapeutic role.
Efficacy and Safety of Adding Ezetimibe to Statin Therapy Among Women and Men: Insight From IMPROVE‐IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)
Authors: Kato Eri Toda , Cannon Christopher P. , Blazing Michael A. , Bohula Erin , Guneri Sema , White Jennifer A. , Murphy Sabina A. , Park Jeong‐Gun , Braunwald Eugene , Giugliano Robert P.
Published: November 2017

Background

IMPROVE
‐
IT
(Improved Reduction of Outcomes: Vytorin Efficacy International Trial) showed that adding the nonstatin ezetimibe to statin therapy further reduced cardiovascular events in patients after an acute coronary syndrome. In a prespecified analysis, we explore results stratified by sex.

Methods and Results

In
IMPROVE
‐
IT
, patients with acute coronary syndrome and low‐density lipoprotein cholesterol of 50 to 125 mg/dL were randomized to placebo/simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg. They were followed up for a median of 6 years for the primary composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, coronary revascularization ≥30 days, and stroke. Among 18 144 patients in
IMPROVE
‐
IT
, 4416 (24%) were women. At 12 months, the addition of ezetimibe to simvastatin significantly reduced low‐density lipoprotein cholesterol from baseline compared with simvastatin monotherapy in men and women equally (absolute reduction, 16.7 mg/dL in men and 16.4 mg/dL in women). Women receiving ezetimibe/simvastatin had a 12% risk reduction over those receiving placebo/simvastatin for the primary composite end point (hazard ratio, 0.88; 95% confidence interval, 0.79–0.99) compared with a 5% reduction for men (hazard ratio, 0.95; 95% confidence interval, 0.90–1.01;
P
=0.26 for interaction). When the total number of primary events was considered, women had an 18% reduction with the addition of ezetimibe (relative risk, 95% confidence interval, 0.81; 0.71–0.94) and men had a 6% reduction (relative risk, 0.94; 95% confidence interval, 0.87–1.02;
P
=0.08 for interaction). The addition of ezetimibe did not increase the rates of safety events in either women or men.

Conclusions

IMPROVE
‐
IT
demonstrated that the benefit of adding ezetimibe to statin is present in both women and men, with a good safety profile supporting the use of intensive, combination, lipid‐lowering therapy to optimize cardiovascular outcomes.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
00202878.
Hypertension in Obese Black Women is Not Caused by Increased Sympathetic Vascular Tone
Authors: Marinos Alejandro , Gamboa Alfredo , Celedonio Jorge E. , Preheim Brock A. , Okamoto Luis E. , Ramirez Claudia E. , Arnold Amy C. , Diedrich Andre , Biaggioni Italo , Shibao Cyndya A.
Published: November 2017

Background

Black women have one of the highest prevalence rates of hypertension and obesity in the United States. We previously reported that sympathetic activation induced by obesity is a significant contributor to hypertension in white patients. It is unknown whether sympathetic activity similarly contributes to hypertension in obese black women.

Methods and Results

We studied 42 obese women (16 white, body mass index 36±4 kg/m
2
, 44% with hypertension; 26 black, body mass index 35±4 kg/m
2
, 46% with hypertension). Antihypertensive medications were discontinued for 2 weeks before the day of the study. All patients underwent complete autonomic blockade with trimethaphan at a dosage of 4 mg/min. Resting sympathetic activity determined from muscle sympathetic nerve recordings was similar between obese black women with hypertension and those with normotension. In whites, sympathetic activity was elevated in obese patients with hypertension compared with normotension; the decrease in mean arterial blood pressure produced by trimethaphan was greater in obese white patients with hypertension compared with those with normotension (−26.8±9.7 mm Hg versus −14.8±7.9 mm Hg,
P
=0.02). In contrast, there was no difference in the depressor responses induced by trimethaphan between obese black women with hypertension and those with normotension (−15.5±10.5 mm Hg versus −12.3±10.2 mm Hg,
P
=0.45). Mean arterial blood pressure remained elevated in obese blacks with hypertension compared with those with normotension during trimethaphan infusion (83.7±15.0 mm Hg versus 71.7±9.8 mm Hg,
P
=0.02). Heart rate increased similarly with trimethaphan between white (
P
=0.11) and black (
P
=0.76) women with hypertension and normotension.

Conclusions

These findings suggest that sympathetic activity does not contribute to hypertension in obese black women and provide further evidence for racial differences in hypertension mechanisms.
Combination Therapy Is Superior to Sequential Monotherapy for the Initial Treatment of Hypertension: A Double‐Blind Randomized Controlled Trial
Authors: MacDonald Thomas M. , Williams Bryan , Webb David J. , Morant Steve , Caulfield Mark , Cruickshank J. Kennedy , Ford Ian , Sever Peter , Mackenzie Isla S. , Padmanabhan Sandosh , McCann Gerald P. , Salsbury Jackie , McInnes Gordon , Brown Morris J. ,   for The British Hypertension Society Programme of Prevention And Treatment of Hypertension With Algorithm‐based Therapy (PATHWAY)
Published: November 2017

Background

Guidelines for hypertension vary in their preference for initial combination therapy or initial monotherapy, stratified by patient profile; therefore, we compared the efficacy and tolerability of these approaches.

Methods and Results

We performed a 1‐year, double‐blind, randomized controlled trial in 605 untreated patients aged 18 to 79 years with systolic blood pressure (
BP
) ≥150 mm Hg or diastolic
BP
≥95 mm Hg. In phase 1 (weeks 0–16), patients were randomly assigned to initial monotherapy (losartan 50–100 mg or hydrochlorothiazide 12.5–25 mg crossing over at 8 weeks), or initial combination (losartan 50–100 mg plus hydrochlorothiazide 12.5–25 mg). In phase 2 (weeks 17–32), all patients received losartan 100 mg and hydrochlorothiazide 12.5 to 25 mg. In phase 3 (weeks 33–52), amlodipine with or without doxazosin could be added to achieve target
BP
. Hierarchical primary outcomes were the difference from baseline in home systolic
BP
, averaged over phases 1 and 2 and, if significant, at 32 weeks. Secondary outcomes included adverse events, and difference in home systolic BP responses between tertiles of plasma renin. Home systolic BP after initial monotherapy fell 4.9 mm Hg (range: 3.7–6.0 mm Hg) less over 32 weeks (
P
<0.001) than after initial combination but caught up at 32 weeks (difference 1.2 mm Hg [range: −0.4 to 2.8 mm Hg],
P
=0.13). In phase 1, home systolic BP response to each monotherapy differed substantially between renin tertiles, whereas response to combination therapy was uniform and at least 5 mm Hg more than to monotherapy. There were no differences in withdrawals due to adverse events.

Conclusions

Initial combination therapy can be recommended for patients with BP >150/95 mm Hg.

Clinical Trial Registration

URL
:
http://www.ClinicalTrials.gov
. Unique identifier:
NCT
00994617.
Predictors of Mortality in Patients With Severe Ischemic Cardiomyopathy Undergoing Surgical Mitral Valve Intervention
Authors: Kusunose Kenya , Obuchowski Nancy A. , Gillinov Marc , Popovic Zoran B. , Flamm Scott D. , Griffin Brian P. , Kwon Deborah H.
Published: November 2017

Background

Ischemic mitral regurgitation is associated with substantial risk of death. Although surgical mitral valve intervention (
MV
i) may improve symptoms, it has not been shown to improve survival. The aim of this study was to identify predictors of mortality in patients with ischemic mitral regurgitation and
MV
i.

Methods and Results

We evaluated 117 consecutive patients (age, 65±10 years) with advanced ischemic cardiomyopathy who underwent cardiac magnetic resonance and subsequent
MV
i between January 1, 2002 and January 1, 2012. Cardiac magnetic resonance was used to assess left ventricular remodeling and myocardial scarring. The effective regurgitant orifice area was calculated from the proximal isovelocity surface area by echocardiography. There were 43 deaths (37%) during follow‐up (median, 62 months). On multivariable analysis, age ≥70 years (
P
=0.013), diabetes mellitus (
P
=0.001), dyslipidemia (
P
=0.012), papillary muscle scar (
P
=0.010), incomplete revascularization (
P
=0.001), and total scar %×effective regurgitant orifice area ≥0.20 cm
2
(
P
=0.005) were each independently associated with all‐cause mortality. Although patients with effective regurgitant orifice area <0.2 cm
2
at baseline demonstrated an increased hazard ratio of 3.3 for every 10% increase in scar, the hazard ratio increased to 9 for every 10% increase in scar in those with baseline effective regurgitant orifice area ≥0.20 cm
2
. Mortality also was significantly higher in patients with incomplete revascularization compared with those with vascularized viable myocardium (61% versus 28%;
P
<0.001).

Conclusions

Increased total scar burden and the presence of incomplete revascularization are powerful predictors of mortality in patients with advanced ischemic cardiomyopathy undergoing
MV
i. Viability assessment with cardiac magnetic resonance imaging can identify which patients with ischemic mitral regurgitation are at highest risk for mortality after surgical
MV
i.
Very Late Pathological Responses to Cobalt–Chromium Everolimus‐Eluting, Stainless Steel Sirolimus‐Eluting, and Cobalt–Chromium Bare Metal Stents in Humans
Authors: Mori Hiroyoshi , Atmakuri Dheeraj R. , Torii Sho , Braumann Ryan , Smith Samantha , Jinnouchi Hiroyuki , Gupta Anuj , Harari Emanuel , Shkullaku Melsi , Kutys Robert , Fowler David , Romero Maria , Virmani Renu , Finn Aloke V.
Published: November 2017

Background

The “very late” clinical outcomes for durable polymer drug‐eluting stents and bare metal stents (
BMSs
) have been shown to be dissimilar in clinical studies. Conceptually, the long‐term vascular compatibility of
BMSs
is still regarded to be superior to drug‐eluting stents; however, no pathologic study to date has specifically addressed this issue. We evaluated the very late (≥1 year) pathologic responses to durable polymer drug‐eluting stents (cobalt–chromium [CoCr] everolimus‐eluting stents [
EESs
] and stainless steel sirolimus‐eluting stents [
SS
‐
SESs
]) versus
BMSs
(CoCr‐
BMSs
).

Methods and Results

From the
CVP
ath stent registry, we studied a total of 119 lesions (40 CoCr‐
EESs
, 44
SS
‐
SES
s, 35 CoCr‐
BMS
s) from 92 autopsy cases with a duration ranging from 1 to 5 years. Sections of stented coronary segments were pathologically analyzed. Inflammation score and the percentage of struts with giant cells were lowest in CoCr‐
EESs
(median inflammation score: 0.6; median percentage of struts with giant cells: 3.8%) followed by CoCr‐
BMSs
(median inflammation score: 1.3 [
P
<0.01]; median percentage of struts with giant cells: 8.9% [
P
=0.02]) and SS‐
SESs
(median inflammation score: 1.7 [
P
<0.01]; median percentage of struts with giant cells: 15.3% [
P
<0.01]). Polymer delamination was observed exclusively in
SS
‐
SESs
and was associated with increased inflammatory and giant cell reactions. The prevalence of neoatherosclerosis with CoCr‐
EESs
(50%) was significantly less than with
SS
‐
SESs
(77%,
P
=0.02) but significantly greater than with CoCr‐
BMSs
(20%,
P
<0.01).

Conclusions

CoCr‐
EESs
,
SS
‐
SESs
, and
BMSs
each demonstrated distinct vascular responses. CoCr‐
EESs
demonstrated the least inflammation, near‐equivalent healing to
BMSs
, and lower neointimal formation. These results challenge the belief that
BMSs
have superior biocompatibility compared with some polymeric coated drug‐eluting stents and may have implications for future stent design.
Association of procalcitonin values and bacterial infections in pediatric patients receiving extracorporeal membrane oxygenation
Authors: Tan Vi Ean , Moore Wayne S. , Chopra Arun , Cies Jeffrey J.
Published: November 2017

Objective:

There is increasing data in pediatrics demonstrating procalcitonin (PCT) is more sensitive and specific than other biomarkers in the setting of bacterial infections. However, the use of PCT in neonatal and pediatric extracorporeal membrane oxygenation (ECMO) is not well described. Therefore, the purpose of this study was to describe the clinical utility of PCT in determining the absence or presence of bacterial infections in neonatal and pediatric patients on ECMO.

Methods:

This was a retrospective electronic medical record (EMR) review of data between January 1, 2010 to June 30, 2016 at a single, free-standing, children ’s hospital. All patients on ECMO with ≥1 PCT level obtained while receiving ECMO support were eligible for inclusion. The EMR was searched for chest radiographs (CXR) and bacterial culture results (urine, blood, cerebrospinal fluid (CSF), bronchoalveolar lavage (BAL) and respiratory cultures). All bacterial and viral cultures obtained within 5 days of PCT levels being obtained were analyzed. PCT levels of 0.5, 0.9, 1.0, 1.4 and 2.0 were used as the initial cut-off values for the analysis. The sensitivity, specificity, positive predictive value (PPV), negative predictive values (NPV) and likelihood ratios were calculated for each of the PCT levels.

Results:

Twenty-seven patients met the inclusion criteria and contributed 193 PCT values for the analysis. The median age was 8 months (range 0 days to 18 years). Linear regression analysis demonstrated that a PCT cut-off of 0.5, 0.9 and 1.4 predicted the presence of a bacterial infection. The PCT value with the most utility was 0.5, with a sensitivity of 92%, a specificity of 43%, a positive predictive value of 60% and a negative predictive value (NPV) of 86%.

Conclusion:

This is the largest data set evaluating PCT in neonatal and pediatric patients on ECMO. A PCT value of 0.5 ng/mL had the most utility for determining the absence or presence of a bacterial infection in the setting of ECMO with a high sensitivity and NPV.