bluuebunny/crossref_metadata_2025_split huggingface dataset:
miR-18a Inhibits BMP4 and HIF-1α Normalizing Brain Arteriovenous Malformations
Authors: Marín-Ramos Nagore I. , Thein Thu Zan , Ghaghada Ketan B. , Chen Thomas C. , Giannotta Steven L. , Hofman Florence M. 
Published: August 2020

Rationale:
Brain arteriovenous malformations (AVMs) are abnormal tangles of vessels where arteries and veins directly connect without intervening capillary nets, increasing the risk of intracerebral hemorrhage and stroke. Current treatments are highly invasive and often not feasible. Thus, effective noninvasive treatments are needed. We previously showed that AVM-brain endothelial cells (BECs) secreted higher VEGF (vascular endothelial growth factor) and lower TSP-1 (thrombospondin-1) levels than control BEC; and that microRNA-18a (miR-18a) normalized AVM-BEC function and phenotype, although its mechanism remained unclear.

Objective:
To elucidate the mechanism of action and potential clinical application of miR-18a as an effective noninvasive treatment to selectively restore the phenotype and functionality of AVM vasculature.

Methods and Results:
The molecular pathways affected by miR-18a in patient-derived BECs and AVM-BECs were determined by Western blot, RT-qPCR (quantitative reverse transcription polymerase chain reaction), ELISA, co-IP, immunostaining, knockdown and overexpression studies, flow cytometry, and luciferase reporter assays. miR-18a was shown to increase TSP-1 and decrease VEGF by reducing PAI-1 (plasminogen activator inhibitor-1/SERPINE1) levels. Furthermore, miR-18a decreased the expression of BMP4 (bone morphogenetic protein 4) and HIF-1α (hypoxia-inducible factor 1α), blocking the BMP4/ALK (activin-like kinase) 2/ALK1/ALK5 and Notch signaling pathways. As determined by Boyden chamber assays, miR-18a also reduced the abnormal AVM-BEC invasiveness, which correlated with a decrease in MMP2 (matrix metalloproteinase 2), MMP9, and ADAM10 (ADAM metallopeptidase domain 10) levels.

In vivo pharmacokinetic studies showed that miR-18a reaches the brain following intravenous and intranasal administration. Intranasal co-delivery of miR-18a and NEO100, a good manufacturing practices-quality form of perillyl alcohol, improved the pharmacokinetic profile of miR-18a in the brain without affecting its pharmacological properties. Ultra-high-resolution computed tomography angiography and immunostaining studies in an Mgp
−
/−
AVM mouse model showed that miR-18a decreased abnormal cerebral vasculature and restored the functionality of the bone marrow, lungs, spleen, and liver.

Conclusions:
miR-18a may have significant clinical value in preventing, reducing, and potentially reversing AVM.
Characteristics and Outcomes of Patients With Takotsubo Syndrome: Incremental Prognostic Value of Baseline Left Ventricular Systolic Function
Authors: Alashi Alaa , Isaza Nicolas , Faulx Jackson , Popovic Zoran B. , Menon Venu , Ellis Stephen G. , Faulx Michael , Kapadia Samir R. , Griffin Brian P. , Desai Milind Y. 
Published: August 2020

Background
We sought to determine (1) long‐term outcomes in patients presenting with documented Takotsubo syndrome (TS), (2) whether left ventricular global longitudinal strain (LV‐GLS) provides incremental prognostic value, and (3) prognostic cutoffs of LV ejection fraction (LVEF) and LV‐GLS during an acute TS episode.

Methods and Results

We studied 650 patients with TS (aged 66±14 years, 88% women) who were diagnosed clinically and angiographically between 2006 and 2018. Baseline LVEF and LV‐GLS (using velocity vector imaging) were recorded. The primary end point was all‐cause mortality. TS triggers were unknown (34%), emotional (16%), physical (41%), and neurologic (10%). Mean LVEF and LV‐GLS were 36±10% and −11.6±0.4%; in addition, 94% patients had LVEF <52%, and 80% had apical ballooning. No patient had obstructive coronary artery disease. At a median of 2.2 years (interquartile range, 0.7–4.4), 175 (27%) had died (9% in‐hospital deaths). Multivariate Cox survival analysis revealed that higher age (hazard ratio [HR], 1.35), male sex (HR, 1.75), lower baseline LVEF (HR, 1.02), worse LV‐GLS (HR, 1.04), neurologic trigger (HR, 2.66), and physical trigger (HR, 2.64) were associated with mortality, whereas aspirin (HR, 0.70) and β‐blockers (HR, 0.73) improved survival (all
P
<0.049). The addition of LVEF and LV‐GLS to clinical markers (age, sex, cardiogenic shock at presentation, and peak troponin I) significantly increased log‐likelihood ratios: clinical (−521.48), clinical plus LVEF (−511.32,
P
<0.001), and clinical plus LVEF and LV‐GLS (−500.68,
P
<0.001). On penalized spline analysis, LVEF of 38% and LV‐GLS of −10% were cutoffs below which survival was significantly worse.

Conclusions
Patients with TS with a neurologic or physical trigger had significantly worse survival than those without such a trigger, with baseline LVEF and LV‐GLS providing incremental prognostic value.
Degree of Blood Pressure Control and Incident Diabetes Mellitus in Chinese Adults With Hypertension
Authors: Zhang Yuanyuan , Nie Jing , Zhang Yan , Li Jianping , Liang Min , Wang Guobao , Tian Jianwei , Liu Chengzhang , Wang Binyan , Cui Yimin , Wang Xiaobin , Huo Yong , Xu Xiping , Hou Fan Fan , Qin Xianhui 
Published: August 2020

Background
The association between blood pressure (BP) control and incident diabetes mellitus remains unknown. We aim to investigate the association between degree of time‐averaged on‐treatment systolic blood pressure (SBP) control and incident diabetes mellitus in hypertensive adults.

Methods and Results
A total of 14 978 adults with hypertension without diabetes mellitus at baseline were included from the CSPPT (China Stroke Primary Prevention Trial). Participants were randomized double‐masked to daily enalapril 10 mg and folic acid 0.8 mg or enalapril 10 mg alone. BP measurements were taken every 3 months after randomization. The primary outcome was incident diabetes mellitus, defined as physician‐diagnosed diabetes mellitus, or use of glucose‐lowering drugs during follow‐up, or fasting glucose ≥126 mg/dL at the exit visit. Over a median of 4.5 years, a significantly higher risk of incident diabetes mellitus was found in participants with time‐averaged on‐treatment SBP 130 to <140 mm Hg (10.3% versus 7.4%; odds ratio [OR], 1.37; 95% CI, 1.15‒1.64), compared with those with SBP 120 to <130 mm Hg. Moreover, the risk of incident diabetes mellitus increased by 24% (OR, 1.24; 95% CI, 1.00‒1.53) and the incidence of regression to normal fasting glucose (<100 mg/dL) decreased by 29% (OR, 0.71; 95% CI, 0.57‒0.89) in participants with intermediate BP control (SBP/diastolic blood pressure, 130 to <140 and/or 80 to <90 mm Hg), compared with those with a tight BP control of <130/<80 mm Hg. Similar results were found when the time‐averaged BP were calculated using the BP measurements during the first 6‐ or 24‐month treatment period, or in the analysis using propensity scores.

Conclusions
In this non‐diabetic, hypertensive population, SBP control in the range of 120 to <130 mm Hg, compared with the 130 to <140 mm Hg, was associated with a lower risk of incident diabetes mellitus.
Cerebral Microbleeds and Leukoencephalopathy in Critically Ill Patients With COVID-19
Authors: Agarwal Shashank , Jain Rajan , Dogra Siddhant , Krieger Penina , Lewis Ariane , Nguyen Vinh , Melmed Kara , Galetta Steven 
Published: August 2020

Background and Purpose:
We conducted this study to investigate the prevalence and distribution of cerebral microbleeds and leukoencephalopathy in hospitalized patients with coronavirus disease 2019 (COVID-19) and correlate with clinical, laboratory, and functional outcomes.

Methods:
We performed a retrospective chart review of 4131 COVID-19 positive adult patients who were admitted to 3 tertiary care hospitals of an academic medical center at the epicenter of the COVID-19 pandemic in New York City from March 1, 2020, to May 10, 2020, to identify patients who had magnetic resonance imaging (MRI) of the brain. We evaluated the MRIs in detail, and identified a subset of patients with leukoencephalopathy and/or cerebral microbleeds. We compared clinical, laboratory, and functional outcomes for these patients to patients who had a brain MRI that did not show these findings.

Results:

Of 115 patients who had an MRI of the brain performed, 35 (30.4%) patients had leukoencephalopathy and/or cerebral microbleeds. Patients with leukoencephalopathy and/or cerebral microbleeds had neuroimaging performed later during the hospitalization course (27 versus 10.6 days;
P
<0.001), were clinically sicker at the time of brain MRI (median GCS 6 versus 14;
P
<0.001), and had higher peak D-dimer levels (8018±6677 versus 3183±3482;
P
<0.001), lower nadir platelet count (116.9±62.2 versus 158.3±76.2;
P
=0.03), higher peak international normalized ratio (2.2 versus 1.57;
P
<0.001) values when compared with patients who had a brain MRI that did not show these findings. They required longer ventilator support (34.6 versus 9.1 days;
P
<0.001) and were more likely to have moderate and severe acute respiratory distress syndrome score (88.6% versus 23.8%,
P
<0.001). These patients had longer hospitalizations (42.1 versus 20.9 days;
P
<0.001), overall worse functional status on discharge (mRS 5 versus 4;
P
=0.001), and higher mortality (20% versus 9%;
P
=0.144).

Conclusions:
The presence of leukoencephalopathy and/or cerebral microbleeds is associated with a critical illness, increased mortality, and worse functional outcome in patients with COVID-19.
Decadal to Multidecadal Variability of the Mixed Layer to the South of the Kuroshio Extension Region
Authors: Wu Baolan , Lin Xiaopei , Yu Lisan 
Published: August 2020

AbstractThe decadal to multidecadal mixed layer variability is investigated in a region south of the Kuroshio Extension (130°E–180°, 25°–35°N), an area where the North Pacific subtropical mode water forms, during 1948–2012. By analyzing the mixed layer heat budget with different observational and reanalysis data, here we show that the decadal to multidecadal variability of the mixed layer temperature and mixed layer depth is covaried with the Atlantic multidecadal oscillation (AMO), instead of the Pacific decadal oscillation (PDO). The mixed layer temperature has strong decadal to multidecadal variability, being warm before 1970 and after 1990 (AMO positive phase) and cold during 1970–90 (AMO negative phase), and so does the mixed layer depth. The dominant process for the mixed layer temperature decadal to multidecadal variability is the Ekman advection, which is controlled by the zonal wind changes related to the AMO. The net heat flux into the ocean surface Qnet acts as a damping term and it is mainly from the effect of latent heat flux and partially from sensible heat flux. While the wind as well as mixed layer temperature decadal changes related to the PDO are weak in the western Pacific Ocean. Our finding proposes the possible influence of the AMO on the northwestern Pacific Ocean mixed layer variability, and could be a potential predictor for the decadal to multidecadal climate variability in the western Pacific Ocean.
Entrenching Democracy: Education and Cultural Participation in the Spanish Republican Army, 1936–1939
Authors: Bjerström Carl-Henrik 
Published: August 2020

This article examines the mobilizing and legitimizing function of educational and cultural activities in the Spanish Republican Army during the Spanish Civil War, 1936–1939. Education and cultural participation played a crucial role in the Republican government’s attempts to co-opt left-wing revolutionary forces emboldened by the war and unite antagonistic constituencies in an inclusive, government-led war effort. Such attempts converged on the construction of a new conscript army, where investment in education was not solely a matter of military expediency but also a means to implement, in the crucible of war, important aspects of a reform programme initiated with the proclamation of the Spanish Second Republic in 1931. Consequently, the Republican Army did not only serve as the Republic’s armed defence force but also as a laboratory of political education in which both civil and military authorities could negotiate, articulate and disseminate new notions of Republican citizenship. Drawing primarily on army records and trench journals from the Army of the Centre, the article shows how Republican educators and cultural workers employed a diverse range of techniques to deliver a reform programme designed to profoundly change Spanish politics and society. It also examines largely neglected questions of reception. Where soldiers’ engagement was forthcoming, educational activities could equip individuals with experiences and skills that were – and were understood to be – empowering. Yet in quantitative terms, rank-and-file engagement with educational activities was uneven and often quite limited. Contextual factors on all levels – international, national and local – impacted in various ways on soldiers’ educational and cultural participation, but ultimately it was the impending defeat of the Republic that undermined most soldiers’ willingness to engage. As a positive progressive vision of a future Republic faded among the debris of destroyed buildings, enthusiasm for a Republican educational programme inevitably faded too.
Normoxic management of cardiopulmonary bypass reduces myocardial oxidative stress in adult patients undergoing coronary artery bypass graft surgery
Authors: Topcu Ahmet Can , Bolukcu Ahmet , Ozeren Kamile , Kavasoglu Tugba , Kayacioglu Ilyas 
Published: August 2020

Introduction: We aimed to investigate whether normoxic cardiopulmonary bypass would limit myocardial oxidative stress in adults undergoing coronary artery bypass grafting. Methods: Patients scheduled to undergo elective isolated on-pump coronary artery bypass grafting were randomized to normoxia and hyperoxia groups. The normoxia group received 35% oxygen during anesthetic induction, 35% during hypothermic bypass, and 45% during rewarming. The hyperoxia group received 70%, 50%, and 70% oxygen, respectively. Coronary sinus blood samples were taken prior to initiation of cardiopulmonary bypass and after reperfusion for myocardial total oxidant and antioxidant status measurements. The primary endpoint was myocardial total oxidant status. Secondary endpoints were myocardial total antioxidant status and length of intensive care unit and hospital stay. Results: Forty-eight patients were included. Twenty-two received normoxic management. Mean ± standard deviation of age was 58 ± 9.07 years. Groups were balanced in terms of demographics, risk factors, and operative data. Myocardial total oxidant status was significantly lower in the normoxia group following reperfusion (p = 0.03). There was no statistically significant difference regarding myocardial total antioxidant status and length of intensive care unit and hospital stay (p = 0.08, p = 0.82, and p = 0.54, respectively). Conclusions: Normoxic cardiopulmonary bypass is associated with reduced myocardial oxidative stress compared to hyperoxic cardiopulmonary bypass in adult coronary artery bypass patients.
Maritime Theory Approach for Functional Effectiveness in the Indo-Pacific
Authors: Johnson Odakkal , Choudhury Priyanka 
Published: August 2020

The Indo-Pacific region is a centre of gravity for the world’s economic, political and strategic interests. It is a home of world’s most densely inhabited states, different forms of governance and includes over half of the world’s population. It is also a theatre of great power politics, competition and rivalry. Piracy in the vital choke points, dispute on the South China Sea and rising China factor in the Indian Ocean are some of the challenges faced in this region. As the maritime domain is unique, cooperation among nations is necessary to ensure peace in the region. Therefore, a maritime theory approach is needed to study good order at sea. Having laid down the emerging mandate of economic interaction across the global, regional and subregional canvas, there is a need for evolving functional mechanisms to ensure interoperability and progressing the overarching mandate. This will further ensure a cooperative solution in the maritime dimension. It also becomes a vital bridge between the apex policymaking and the basic execution of a decisive transaction. The Indo-Pacific region needs mutual cooperation for economic development and threat management. India is rightly positioned to be the facilitator through existing initiatives and harness potential opportunities. This article examines the aspect of functional mechanisms under the maritime theory approach in the Indo-Pacific. Nations can be encouraged to connect through efforts such as Indian Ocean Naval Symposium (IONS) and Project Mausam to collaborate and bring complementarity. With the region growing significant each day, the development of mutual partnership is of utmost importance. Keeping three principles of workable options, harmonising individual strength and taking all along, the Indo-Pacific nations can build lasting peace and stability in the region.
Dissecting the Cardiac Conduction System: Is It Worthwhile?
Authors: Tan Serena Y , Fritsch Michael K , White Steven , Arva Nicoleta C 
Published: August 2020

Background Pathologic examination of conduction system (CS) is not routinely performed, and histologic changes are mostly reported in forensic practice. Methods We studied the value of dissecting the CS in a cohort of pediatric patients with unexplained sudden death or severe, inexplicable arrhythmias. Histopathologic changes present in CS components were recorded and correlated with findings noted in other cardiac structures. Results Twenty-one subjects (11 unexplained sudden deaths and 10 life-threatening arrhythmias) were identified; 18 (86%) had CS pathologic abnormalities. In 13 patients (62%), the CS findings mirrored those found in other cardiac sections (inflammation, allograft vasculopathy, vascular fibromuscular dysplasia, cardiomyopathy-related changes, and tumor/tumor-like conditions). Five cases (24%) had abnormalities restricted to CS (bundle of His [BH] with fibrotic scar and patch material following ventricular septal defect repair, inflammation, BH with fibrosis and calcifications, and intimal fibroplasia of sinoatrial node artery). Conclusions Pathologic changes within the CS are present in a high number of pediatric patients presenting with unexplained sudden death or life-threatening arrhythmias. Frequently, the findings mirror those observed in other cardiac structures. However, in a significant number of cases (24%), the changes are restricted to CS and likely explain the patients’ symptoms or cause of death, suggesting that systematic dissection of CS unveils valuable information.
Through the Lens of Chronic Kidney Disease: A Qualitative Study of the Experiences of Young Women Living With CKD
Authors: Beanlands Heather , McCay Elizabeth , Pahati Sheryll , Hladunewich Michelle A. 
Published: August 2020

Background: Young women may be particularly vulnerable to the negative psychosocial consequences of living with chronic kidney disease (CKD). To date, little is known about how women themselves experience and manage their illness. Objectives: This study explored the experiences of young women living with CKD. Design: Qualitative descriptive study. Setting: Nephrology program in an urban setting in Ontario, Canada. Participants: Women with category G1-3 glomerular-based CKD between 18 and 40 years of age. Methods: Focus group discussions guided by semi-structured interview questions. Qualitative content analysis was used to analyze interview transcripts. Results: Eleven women participated in 3 separate focus group discussions. Participants described living life through the lens of CKD, which was the central theme unifying their experiences of encountering CKD, re-encountering CKD, and getting on with life. Life decisions significant to women like pursuing a career or motherhood were often colored by CKD, particularly by illness-related challenges, such as unsatisfactory health care support and the physical implications of chronic illness. The women used a variety of strategies including seeking information and relying on supportive people to mitigate these challenges. Although these strategies sometimes enabled them to balance the demands of illness with other life priorities, the lack of resources directed toward their unique needs as young women with CKD often caused them difficulties in managing their illness. Limitations: Participants were from one nephrology program in an urban setting and were well educated overall. Their experiences may not be reflective of young women in other settings or from diverse backgrounds. Conclusions: The women’s emotional well-being and life choices were considerably influenced by CKD. Although the women were often able to manage challenges associated with CKD, they acknowledged the need to seek additional professional resources to complement their own self-identified strategies. As the women sought out these supports, they identified gaps in resources specific to women with CKD. This article summarizes recommendations from their perspective. Trial Registration: Not applicable as this was a qualitative study.
The Spine Physical Examination Using Telemedicine: Strategies and Best Practices
Authors: Iyer Sravisht , Shafi Karim , Lovecchio Francis , Turner Robert , Albert Todd J. , Kim Han Jo , Press Joel , Katsuura Yoshihiro , Sandhu Harvinder , Schwab Frank , Qureshi Sheeraz 
Published: August 2020

Study Design: Technical note. Objectives: To provide spine surgeons new to telemedicine with a structured physical examination technique based on manual motor testing principles. Methods: Expert experience describing a series of specific maneuvers for upper and lower extremity strength testing that can be performed using a telemedicine platform. In addition, we offer instruction on “setting up” for these visits and highlight special tests that can be used to diagnose specific cervical and lumbar spine conditions. Results: From our experiences in conducting telemedicine visits, we provide a means of testing and scoring upper and lower extremity strength for interpretation of weakness in the context of traditional manual motor testing. Also, we acknowledge the limitations of a remote examination and discuss maneuvers that cannot be performed remotely. Conclusions: COVID-19 has drastically altered the delivery of care for patients with spine-related complaints. The need for social distancing has led to the widespread adoption of telemedicine. This technical note provides an urgently needed framework for the standardization of the remote physical exam. Validation of the exam as a diagnostic tool will be a crucial next step in studying the impact of telemedicine.