bluuebunny/crossref_metadata_2025_split huggingface dataset:
Petrology and Nd–Sr isotopic composition of alkaline lamprophyres from the Early to Late Cretaceous Mundwara Alkaline Complex, NW India: evidence of crystal fractionation, accumulation and corrosion in a complex magma chamber plumbing system
Authors: Sharma Abhinay , Sahoo Samarendra , Rao N. V. Chalapathi , Belyatsky Boris , Dhote Prashant , Lehmann Bernd 
Published: January 2021

Abstract
The Early to Late Cretaceous Mundwara alkaline complex (comprising the Musala, Mer and Toa plugs) displays a broad spectrum of alkaline rocks closely associated in space and time with the Deccan large igneous province in NW India. Petrology and Nd–Sr isotopic data on the two youngest and altogether compositionally different lamprophyre dykes of the Mundwara alkaline complex are presented in this paper to understand their petrogenesis and also to constrain the magmatic processes responsible for generation of the rock spectrum in the complex (pyroxenite, picrite ankaramite, carbonatite, shonkinite, olivine gabbro, feldspathoidal and foid-free syenite). The two lamprophyre dykes occurring in the Mer and the Musala hills are referred to as basaltic camptonite I and camptonite II, respectively. The basaltic camptonite I is highly porphyritic and contains olivine, clinopyroxene and magnetite macrocrysts embedded within the groundmass of microphenocyrsts composed of clinopyroxene, phlogopite, magnetite and feldspar. Camptonite II, however, with a more or less similar texture, contains amphibole, biotite, magnetite and clinopyroxene within the microphenocrystic groundmass of amphibole, biotite, apatite and feldspar. Pyroxenes are chemically zoned and display corrosion of the cores, revealing that they are antecrysts developed during the early stages of magma evolution and later on inherited by more evolved magmas. The mineral chemistry and trace element composition of the lamprophyres reveal that fractional crystallization was a dominant process. Early segregation of olivine + Cr-rich clinopyroxene + Cr-spinel from a primary hydrous alkali basalt within a magmatic plumbing system is inferred, which led to the generation of basaltic camptonitic magma (M1) forming the Mer hill lamprophyre. Subsequently, progressive fractionation of pyroxene and Fe–Ti oxides from the basaltic camptonitic (M1) magma generated camptonitic (M2) magma forming the Musala hill lamprophyre. Both lamprophyre dykes on the Sr–Nd isotopic array reflect plume-type asthenospheric derivation, which largely corresponds to the Réunion plume and other alkaline rocks of the Deccan large igneous province. Our study brings out a complex sequence of processes such as crystal fractionation, accumulation and corrosion in the magmatic plumbing system involved in the generation of the Mundwara alkaline complex.
Osimertinib plus Ramucirumab: The Best of Both Worlds?
Authors: Garon Edward B. 
Published: January 2021

Abstract
Both osimertinib and the combination of erlotinib plus ramucirumab are approved for initial therapy of advanced EGFR mutation–positive non–small cell lung cancer. Osimertinib is also approved in previously treated T790M mutation–positive patients. The accompanying article reports on a study combining osimertinib with ramucirumab.
See related article by Yu et al., p. 992
Arginase Therapy Combines Effectively with Immune Checkpoint Blockade or Agonist Anti-OX40 Immunotherapy to Control Tumor Growth
Authors: Badeaux Mark D. , Rolig Annah S. , Agnello Giulia , Enzler Danlee , Kasiewicz Melissa J. , Priddy Leslie , Wiggins Jason F. , Muir Alexander , Sullivan Mark R. , Van Cleef Jessica , Daige Christopher , Vander Heiden Matthew G. , Rajamanickam Venkatesh , Wooldridge James E. , Redmond William L. , Rowlinson Scott W. 
Published: January 2021

Abstract
Metabolic dysregulation is a hallmark of cancer. Many tumors exhibit auxotrophy for various amino acids, such as arginine, because they are unable to meet the demand for these amino acids through endogenous production. This vulnerability can be exploited by employing therapeutic strategies that deplete systemic arginine in order to limit the growth and survival of arginine auxotrophic tumors. Pegzilarginase, a human arginase-1 enzyme engineered to have superior stability and enzymatic activity relative to the native human arginase-1 enzyme, depletes systemic arginine by converting it to ornithine and urea. Therapeutic administration of pegzilarginase in the setting of arginine auxotrophic tumors exerts direct antitumor activity by starving the tumor of exogenous arginine. We hypothesized that in addition to this direct effect, pegzilarginase treatment indirectly augments antitumor immunity through increased antigen presentation, thus making pegzilarginase a prime candidate for combination therapy with immuno-oncology (I-O) agents. Tumor-bearing mice (CT26, MC38, and MCA-205) receiving pegzilarginase in combination with anti–PD-L1 or agonist anti-OX40 experienced significantly increased survival relative to animals receiving I-O monotherapy. Combination pegzilarginase/immunotherapy induced robust antitumor immunity characterized by increased intratumoral effector CD8+ T cells and M1 polarization of tumor-associated macrophages. Our data suggest potential mechanisms of synergy between pegzilarginase and I-O agents that include increased intratumoral MHC expression on both antigen-presenting cells and tumor cells, and increased presence of M1-like antitumor macrophages. These data support the clinical evaluation of I-O agents in conjunction with pegzilarginase for the treatment of patients with cancer.
BH4 Increases nNOS Activity and Preserves Left Ventricular Function in Diabetes
Authors: Carnicer Ricardo , Duglan Drew , Ziberna Klemen , Recalde Alice , Reilly Svetlana , Simon Jillian N. , Mafrici Simona , Arya Ritu , Roselló-Lletí Esther , Chuaiphichai Surawee , Tyler Damian , Lygate Craig A. , Channon Keith M. , Casadei Barbara 
Published: January 2021

Rationale:
In diabetic patients, heart failure with predominant left ventricular (LV) diastolic dysfunction is a common complication for which there is no effective treatment. Oxidation of the NOS (nitric oxide synthase) cofactor tetrahydrobiopterin (BH4) and dysfunctional NOS activity have been implicated in the pathogenesis of the diabetic vascular and cardiomyopathic phenotype.

Objective:
Using mice models and human myocardial samples, we evaluated whether and by which mechanism increasing myocardial BH4 availability prevented or reversed LV dysfunction induced by diabetes.

Methods and Results:

In contrast to the vascular endothelium, BH4 levels, superoxide production, and NOS activity (by liquid chromatography) did not differ in the LV myocardium of diabetic mice or in atrial tissue from diabetic patients. Nevertheless, the impairment in both cardiomyocyte relaxation and [Ca
2+
]i (intracellular calcium) decay and in vivo LV function (echocardiography and tissue Doppler) that developed in wild-type mice 12 weeks post–diabetes induction (streptozotocin, 42–45 mg/kg) was prevented in mGCH1-Tg (mice with elevated myocardial BH4 content secondary to trangenic overexpression of GTP-cyclohydrolase 1) and reversed in wild-type mice receiving oral BH4 supplementation from the 12th to the 18th week after diabetes induction. The protective effect of BH4 was abolished by CRISPR/Cas9-mediated knockout of nNOS (the neuronal NOS isoform) in mGCH1-Tg. In HEK (human embryonic kidney) cells, S-nitrosoglutathione led to a PKG (protein kinase G)-dependent increase in plasmalemmal density of the insulin-independent glucose transporter GLUT-1 (glucose transporter-1). In cardiomyocytes, mGCH1 overexpression induced a NO/sGC (soluble guanylate cyclase)/PKG–dependent increase in glucose uptake via GLUT-1, which was instrumental in preserving mitochondrial creatine kinase activity, oxygen consumption rate, LV energetics (by
31
phosphorous magnetic resonance spectroscopy), and myocardial function.

Conclusions:
We uncovered a novel mechanism whereby myocardial BH4 prevents and reverses LV diastolic and systolic dysfunction associated with diabetes via an nNOS-mediated increase in insulin-independent myocardial glucose uptake and utilization. These findings highlight the potential of GCH1/BH4–based therapeutics in human diabetic cardiomyopathy.

Graphic Abstract:

A
graphic abstract
is available for this article.
Achieving Optimal Medical Therapy: Insights From the ORBITA Trial
Authors: Foley Michael , Rajkumar Christopher A. , Shun‐Shin Matthew , Ganesananthan Sashiananthan , Seligman Henry , Howard James , Nowbar Alexandra N. , Keeble Thomas R. , Davies John R. , Tang Kare H. , Gerber Robert , O’Kane Peter , Sharp Andrew S. P. , Petraco Ricardo , Malik Iqbal S. , Nijjer Sukhjinder , Sen Sayan , Francis Darrel P. , Al‐Lamee Rasha 
Published: January 2021

Background
In stable coronary artery disease, medications are used for 2 purposes: cardiovascular risk reduction and symptom improvement. In clinical trials and clinical practice, medication use is often not optimal. The ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina) trial was the first placebo‐controlled trial of percutaneous coronary intervention. A key component of the ORBITA trial design was the inclusion of a medical optimization phase, aimed at ensuring that all patients were treated with guideline‐directed truly optimal medical therapy. In this study, we report the medical therapy that was achieved.

Methods and Results
After enrollment into the ORBITA trial, all 200 patients entered a 6‐week period of intensive medical therapy optimization, with initiation and uptitration of risk reduction and antianginal therapy. At the prerandomization stage, the median number of antianginals established was 3 (interquartile range, 2–4). A total of 195 patients (97.5%) reached the prespecified target of ≥2 antianginals; 136 (68.0%) did not stop any antianginals because of adverse effects, and the median number of antianginals stopped for adverse effects per patient was 0 (interquartile range, 0–1). Amlodipine and bisoprolol were well tolerated (stopped for adverse effects in 4/175 [2.3%] and 9/167 [5.4%], respectively). Ranolazine and ivabradine were also well tolerated (stopped for adverse effects in 1/20 [5.0%] and 1/18 [5.6%], respectively). Isosorbide mononitrate and nicorandil were stopped for adverse effects in 36 of 172 (20.9%) and 32 of 141 (22.7%) of patients, respectively. Statins were well tolerated and taken by 191 of 200 (95.5%) patients.

Conclusions
In the 12‐week ORBITA trial period, medical therapy was successfully optimized and well tolerated, with few drug adverse effects leading to therapy cessation. Truly optimal medical therapy can be achieved in clinical trials, and translating this into longer‐term clinical practice should be a focus of future study.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT02062593.
Endovascular Thrombectomy Versus Bridging Thrombolysis: Real‐World Efficacy and Safety Analysis Based on a Nationwide Registry Study
Authors: Geng Chang , Li Sheng‐De , Zhang Ding‐Ding , Ma Lin , Liu Guo‐Wei , Jiao Li‐Qun , Liu Jian‐Min , Chen Wen‐Huo , Zhu Wu‐Sheng , Wen Chang‐Ming , Peng Bin 
Published: January 2021

Background
It was uncertain if direct endovascular thrombectomy (ET) was superior to bridging thrombolysis (BT) for patients with acute ischemic stroke caused by large‐vessel occlusions. We aimed to examine real‐world clinical outcomes of ET using nationwide registry data in China and to compare the efficacy and safety between BT and direct ET.

Methods and Results

Patients treated with ET from a nationwide registry study in China were included. Rapid neurological improvement, intracranial hemorrhage, and in‐hospital mortality were compared between the 2 groups using multivariate logistic models and propensity‐score matching analyses. A total of 7674 patients from 592 stroke centers were included. The median onset‐to‐puncture time, onset‐to‐door time, and door to puncture time were 290, 170, and 99 minutes, respectively. A total of 2069 (27.0%) patients received BT treatment. Patients in the BT group had a significantly shorter onset‐to‐puncture time (235 versus 323 minutes;
P
<0.001) and onset‐to‐door time (90 versus 222 minutes;
P
<0.001) compared with the direct ET group. The prior use of intravenous thrombolysis was associated with a higher rate of rapid neurological improvement (adjusted odds ratio [OR], 0.83; 95% CI, 0.71–0.96) and higher risk of intracranial hemorrhage (adjusted OR, 1.46; 95% CI, 1.18–1.80) in multivariate analyses and propensity‐score matching analyses.

Conclusions
This study reflects the current application of ET in China. More patients received direct ET than BT. Our results suggested that favorable short‐term outcomes could be achieved with BT compared with direct ET. Higher risk of intracranial hemorrhage was observed in the BT group.
Papillary Muscles Abnormalities in Athletes With Otherwise Unexplained T‐Wave Inversion in the ECG Lateral Leads
Authors: De Lazzari Manuel , Zorzi Alessandro , Bettella Natascia , Cipriani Alberto , Pilichou Kalliopi , Cason Marco , Vessella Teresina , Sarto Patrizio , Gualea Maria Rita , Chianura Francesca , Tardini Lucia , Ricci Giuseppe , Mazzanti Ilaria , Ricci Fabrizio , Motta Raffaella , Perazzolo Marra Martina , Corrado Domenico 
Published: January 2021

Background
Papillary muscles (PMs) abnormalities may be associated with ECG repolarization abnormalities. We aimed to evaluate the relation between lateral T‐wave inversion (TWI) and PMs characteristics in a cohort of athletes with no clinically demonstrable cardiac disease.

Methods and Results

We included 53 athletes (median age, 20 years; 87% men) with lateral TWI and no evidence of heart disease on clinical and cardiac magnetic resonance evaluation. A group of healthy athletes with normal ECG served as controls. We evaluated the PMs dimensions, such as diameters, area, volume, mass, and ratio between PMs and left ventricular mass, and the prevalence of PMs apical displacement. Compared with controls, athletes with TWI showed PMs hypertrophy with significantly increased PMs diameters, area, volume, and mass. The ratio between PMs and left ventricular mass was 4.4% in athletes with TWI and 3.0% in controls (
P
<0.001). A PMs/left ventricular mass ratio >3.5% showed 85% sensitivity and 76% specificity for differentiating between athletes with TWI and controls. Apical displacement of PMs was found in 25 (47%) athletes with TWI versus 9 (17%) controls (
P
=0.001). At multivariable analysis, PMs/left ventricular mass ratio and apical displacement remained independent predictors of TWI. Clinical outcome of the athletes with TWI and PMs abnormalities was uneventful despite continuation of their sports activity.

Conclusions
PMs hypertrophy and apical displacement may underlie otherwise unexplained lateral TWI in the athlete. Lateral TWI associated with PMs abnormalities appears as a distinct anatomo‐clinical condition characterized by a favorable outcome.
Treatment and Outcome in Stroke Patients With Acute M2 Occlusion and Minor Neurological Deficits
Authors: Dobrocky Tomas , Piechowiak Eike I. , Volbers Bastian , Slavova Nedelina , Kaesmacher Johannes , Meinel Thomas R. , Arnold Marcel , Fischer Urs , Jung Simon , Gralla Jan , Mordasini Pasquale , Heldner Mirjam R. 
Published: January 2021

Background and Purpose:
Treatment in stroke patients with M2 segment occlusion of the middle cerebral artery presenting with mild neurological deficits is a matter of debate. The main purpose was to compare the outcome in patients with a minor stroke and a M2 occlusion.

Methods:
Consecutive intravenous thrombolysis (IVT) eligible patients admitted to the Bernese stroke center between January 2005 and January 2020 with acute occlusion of the M2 segment and National Institutes of Health Stroke Scale score ≤5 were included. Outcome was compared between IVT only versus endovascular therapy (EVT) including intra-arterial thrombolysis and mechanical thrombectomy (MT; ±IVT) and between IVT only versus MT only.

Results:

Among 169 patients (38.5% women, median age 70.2 years), 84 (49.7%) received IVT only and 85 (50.3%) EVT (±IVT), the latter including 39 (45.9%) treated with MT only. Groups were similar in sex, age, vascular risk factors, event cause, or preevent independency. Compared with IVT only, there was no difference in favorable outcome (modified Rankin Scale score, 0−2) for EVT (adjusted odds ratio, 0.96; adjusted
P
=0.935) or for MT only (adjusted odds ratio, 1.12; adjusted
P
=0.547) groups. Considering only patients treated after 2015, there was a significantly better 3-month modified Rankin Scale shift (adjusted
P
=0.032) in the EVT compared with the IVT only group.

Conclusions:
Our study demonstrates similar effectiveness of IVT only versus EVT (±IVT), and of IVT only versus MT only in patients with peripheral middle cerebral artery occlusions and minor neurological deficits and indicates a possible benefit of EVT considering only patients treated after 2015. There is an unmet need for randomized controlled trials in this stroke field, including imaging parameters, and more sophisticated evaluation of National Institutes of Health Stroke Scale score subitems, neurocognition, and quality of life neglected by the standard outcome scales such as modified Rankin Scale and National Institutes of Health Stroke Scale score.
The role of identity in chronic pain cognitions and pain-related disability within a clinical chronic pain population
Authors: Reed David E , Cobos Briana , Nagpal Ameet S , Eckmann Max , McGeary Donald D 
Published: January 2021

Objective Chronic pain has a significant impact on functioning and results in the disruption of one’s assumed life trajectory, potentially altering their self-perceived identity. The present research is designed to determine whether identity-related issues are associated with common chronic pain cognitions and pain-related disability, which may help inform understanding of clinical chronic pain populations. Method Ninety-eight adult chronic pain patients were assessed at a local pain clinic during a regularly scheduled appointment focusing on pain management. Multivariate hierarchal regression was used to determine whether issues related to identity and death anxiety were associated with pain catastrophizing, pain acceptance, and pain-related disability, above and beyond pain severity, fear-avoidance, and age. Results Self-concept clarity was significantly related to pain catastrophizing and pain acceptance, above and beyond death anxiety, pain severity, fear-avoidance, and age. Death anxiety was associated with pain catastrophizing, pain acceptance, and pain-related disability above and beyond pain severity, fear-avoidance, and age. Conclusions To the best of our knowledge, the present study is the first examination of self-concept clarity and death anxiety as they relate to pain catastrophizing, pain acceptance, and pain-related disability. These descriptive results support the inclusion of identity and death anxiety within the pain experience and could serve as a foundation for future directions relevant to clinical applications.
Impact of Treatment on Vestibular Schwannoma–Associated Symptoms: A Prospective Study Comparing Treatment Modalities
Authors: Barnes Jason H. , Patel Neil S. , Lohse Christine M. , Tombers Nicole M. , Link Michael J. , Carlson Matthew L. 
Published: January 2021

ObjectiveThe degree to which various treatment modalities modify vestibular schwannoma (VS)–associated symptoms has received limited attention. The purpose of this study was to determine how different treatment modalities affect subjective symptoms in those presenting with VS.Study DesignProspective survey.SettingTertiary neurotology referral center.MethodsPatients with sporadic VS who received treatment at our institution were prospectively surveyed with a VS symptom questionnaire. Those who completed a baseline survey prior to treatment and at least 1 posttreatment survey were included. The prospective survey evaluated the severity of self‐reported symptoms (Likert scale, 1‐10), including tinnitus, dizziness or imbalance, headaches, and hearing loss.ResultsA total of 244 patients were included (mean age, 57 years). The mean duration of follow‐up was 2.1 years, and the median number of surveys completed was 2 (interquartile range, 1‐3). Seventy‐eight (32%) cases were managed with observation, 118 (48%) with microsurgery, and 48 (20%) with radiosurgery. Multivariable analyses revealed no statistically significant difference in the change in tinnitus (P =. 15), dizziness or imbalance (P = 0.66), or headaches (P =. 24) among treatment groups. Evaluation of clinically important differences demonstrated that microsurgery leads to significant bidirectional changes in headaches.ConclusionsLimited prospective data exist regarding the progression or resolution of subjective symptoms in those presenting with VS. This study suggests that tinnitus, dizziness or imbalance, and headaches are unlikely to be significantly modified by treatment modality and generally should not be used to direct treatment choice.
Differential diagnosis of renal oncocytoma and chromophobe renal cell carcinoma using CT features: a central scar-matched retrospective study
Authors: Li Xiaoli , Nie Pei , Zhang Jing , Hou Feng , Ma Qianli , Cui Jiufa 
Published: January 2021

Background Renal oncocytoma (RO) and chromophobe renal cell carcinoma (chRCC) have a common cellular origin and different clinical management and prognosis. Purpose To explore the utility of computed tomography (CT) in the differentiation of RO and chRCC. Material and Methods Twenty-five patients with RO and 73 patients with chRCC presenting with the central scar were included retrospectively. Two experienced radiologists independently reviewed the CT imaging features, including location, tumor size, relative density ratio, segmental enhancement inversion (SEI), necrosis, and perirenal fascia thickening, among others. Interclass correlation coefficient (ICC, for continuous variables) or Kappa coefficient test (for categorical variables) was used to determine intra-observer and inter-observer bias between the two radiologists. Results The inter- and intra-reader reproducibility of the other CT imaging parameters were nearly perfect (>0.81) except for the measurements of fat (0.662). RO differed from chRCC in the cortical or medullary side ( P = 0.005), relative density ratio ( P = 0.020), SEI ( P < 0.001), and necrosis ( P = 0.045). The logistic regression model showed that location (right kidney), hypo-density on non-enhanced CT, SEI, and perirenal fascia thickening were highly predictive of RO. The combined indicators from logistic regression model were used for ROC analysis. The area under the ROC curve was 0.923 ( P < 0.001). The sensitivity and specificity of the four factors combined for diagnosing RO were 88% and 86.3%, respectively. The correlation coefficient between necrosis and tumor size in all tumors including both of RO and chRCC was 0.584, indicating a positive correlation ( P < 0.001). Conclusion The CT imaging features of location (right kidney), hypo-density on non-enhanced CT, SEI, and perirenal fascia thickening were valuable indicators in distinguishing RO from chRCC.